RESUMEN
Molecularly, the family Caryophylliidae is polyphyletic and different sets of genetic data converge towards a consensus that a taxonomic review of this family is necessary. Overall, the order of genes in the mitochondrial genome (mitogenome) together with DNA sequences have been used to successfully untangle evolutionary relationships in several groups of organisms. Published mitogenomes of two caryophylliid genera (Desmophyllum and Solenosmilia) present a transposition of the gene block containing cob, nad2, and nad6, which is located between nad5 5' exon and trnW, while that of Polycyathus chaishanensis presents the same gene order as the majority of scleractinian corals. In molecular-based evolutionary reconstructions, caryophylliids that have the mitochondrial gene rearrangement were recovered as a monophyletic lineage ("true" caryophylliids), while members of the genus Polycyathus were placed in a different position. In this study, additional mitogenomes of this family were assembled and included in evolutionary reconstructions of Scleractinia in order to improve our understanding on whether the mitogenome gene rearrangement is limited to and, therefore, could be a synapomorphy of the actual members of Caryophylliidae. Specimens of Caryophyllia scobinosa, Premocyathus sp., Heterocyathus sulcatus, and Trochocyathus caryophylloides, as well as Desmophyllum pertusum and Solenosmilia variabilis from the Southwest Atlantic were sequenced using Illumina platforms. Then, mitochondrial genomes were assembled and annotated, and nuclear datasets were recovered in-silico from assembled contigs using a previously published set of baits. Evolutionary reconstructions were performed using mitochondrial and nuclear datasets and based on Maximum Likelihood and Bayesian Inference. Obtained mitogenomes are circular and range between 15,816 and 18,225 bp in size and from 30.76% to 36.63% in GC content. The gene rearrangement is only seen in C. scobinosa, D. pertusum, Premocyathus sp., and S. variabilis, which were recovered as a monophyletic clade in both mitochondrial and nuclear phylogenies. On the other hand, the "caryophylliids" with the canonical mitogenome gene order were not recovered within this clade. Differences in features of the skeleton of "true" caryophylliids in comparison to traditional members of the family were observed and offer further support that the gene rearrangement might be seen as a synapomorphy of family Caryophylliidae.
Asunto(s)
Antozoos , Genoma Mitocondrial , Animales , Antozoos/genética , Teorema de Bayes , Orden Génico , Genes Mitocondriales , FilogeniaRESUMEN
BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Approximately 5%-10% of cases are familial (FALS) and the remaining are sporadic (SALS). To date FUS mutations are responsible for 4%-6% of familial cases as well as 0.7%-1.8% of sporadic cases. METHODS: The frequency of FUS mutations was investigated in an Italian cohort of 500 SALS and 40 FALS patients through direct sequencing of exons 5, 6, 13, 14 and 15. RESULTS: Eight FUS mutation carriers were identified in five SALS (1%) and three FALS (7.5%), five already known and three new mutations: a de novo mutation was identified in a sporadic subject as well as the co-presence of FUS/C9ORF72 mutations in a FALS subject. The molecular and clinical details of the three patients harbouring a novel mutation (G245V, G509D and R491C) are presented here. Moreover the co-presence of the R491C mutation and C9ORF72 pathological expansion was found according to the oligogenic disease model. CONCLUSIONS: In conclusion our results revealed a higher frequency of FUS mutation carriers (7.5%) in FALS compared to literature data together with a higher presence of female gender.
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Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/fisiopatología , Proteína FUS de Unión a ARN/genética , Adulto , Anciano , Estudios de Cohortes , Exones , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , Mutación , Factores SexualesRESUMEN
The integration of morphological and molecular lines of evidence has enabled the family Deltocyathidae to be erected to accommodate Deltocyathus species that were previously ascribed to the family Caryophylliidae. However, although displaying the same morphological characteristics as other species of Deltocyathus , molecular data suggested that D. magnificus was phylogenetically distant from Deltocyathidae, falling within the family Turbinoliidae instead. To elucidate the enigmatic evolutionary history of this species and skeletal microstructural features, the phylogenetic relationships of Deltocyathidae and Turbinoliidae were investigated using nuclear ultraconserved and exon loci and complete mitochondrial genomes. Both nuclear and mitochondrial phylogenomic reconstructions confirmed the position of D. magnificus within turbinolids. Furthermore, a novel mitochondrial gene order was uncovered for Deltocyathidae species. This gene order was not present in Turbinoliidae or in D. magnificus that both have the scleractinian canonical gene order, further indicating the taxonomic utility of mitochondrial gene order. D. magnificus is therefore formally moved to the family Turbinoliidae and accommodated in a new genus (Dennantotrochus Kitahara, Vaga & Stolarski, gen. nov.). Surprisingly, turbinolids and deltocyathids do not differ in microstructural organisation of the skeleton that consists of densely packed, individualised rapid accretion deposits and thickening deposits composed of fibres perpendicular to the skeleton surface. Therefore, although both families are clearly evolutionarily divergent, macromorphological features indicate a case of skeletal convergence while these may still share conservative biomineralisation mechanisms. ZooBank: urn:lsid:zoobank.org:pub:5F1C0E25-3CC6-4D1F-B1F0-CD9D0014678E.
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Antozoos , Filogenia , Animales , Antozoos/genética , Antozoos/clasificación , Genoma Mitocondrial/genética , Evolución BiológicaRESUMEN
Metachromatic leukodystrophy (MLD) is a lipidosis caused by deficiency of arylsulfatase A (ARSA). Although the genetics of MLD are known, its pathophysiology is not understood. The disease leads to progressive demyelination and early death and no effective treatment is available. We used lentiviral vectors to deliver a functional ARSA gene (human ARSA) into the brain of adult mice with germ-line inactivation of the mouse gene encoding ARSA, As2. We report sustained expression of active enzyme throughout a large portion of the brain, with long-term protection from development of neuropathology and hippocampal-related learning impairments. We show that selective degeneration of hippocampal neurons is a central step in disease pathogenesis, and provide evidence that in vivo transfer of ARSA by lentiviral vectors reverts the disease phenotype in all investigated areas. Therefore, in vivo gene therapy offers a unique option for MLD and other storage diseases affecting the central nervous system.
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Terapia Genética , Vectores Genéticos , Discapacidades para el Aprendizaje/prevención & control , Lentivirus/genética , Leucodistrofia Metacromática/terapia , Animales , Encéfalo/enzimología , Encéfalo/metabolismo , Encéfalo/patología , Cerebrósido Sulfatasa/genética , Cerebrósido Sulfatasa/metabolismo , Humanos , Discapacidades para el Aprendizaje/etiología , Leucodistrofia Metacromática/complicaciones , Leucodistrofia Metacromática/patología , Metabolismo de los Lípidos , RatonesRESUMEN
AIMS/HYPOTHESIS: Normal mitochondrial activity is a critical component of neuronal metabolism and function. Disruption of mitochondrial activity by altered mitochondrial fission and fusion is the root cause of both neurodegenerative disorders and Charcot-Marie-Tooth type 2A inherited neuropathy. This study addressed the role of mitochondrial fission in the pathogenesis of diabetic neuropathy. METHODS: Mitochondrial biogenesis and fission were assayed in both in vivo and in vitro models of diabetic neuropathy. Gene, protein, mitochondrial DNA and ultrastructural analyses were used to assess mitochondrial biogenesis and fission. RESULTS: There was greater mitochondrial biogenesis in dorsal root ganglion neurons from diabetic compared with non-diabetic mice. An essential step in mitochondrial biogenesis is mitochondrial fission, regulated by the mitochondrial fission protein dynamin-related protein 1 (DRP1). Evaluation of diabetic neurons in vivo indicated small, fragmented mitochondria, suggesting increased fission. In vitro studies revealed that short-term hyperglycaemic exposure increased levels of DRP1 protein. The influence of hyperglycaemia-mediated mitochondrial fission on cell viability was evaluated by knockdown of Drp1 (also known as Dnm1l). Knockdown of Drp1 resulted in decreased susceptibility to hyperglycaemic damage. CONCLUSIONS/INTERPRETATION: We propose that: (1) mitochondria undergo biogenesis in response to hyperglycaemia, but the increased biogenesis is insufficient to accommodate the metabolic load; (2) hyperglycaemia causes an excess of mitochondrial fission, creating small, damaged mitochondria; and (3) reduction of aberrant mitochondrial fission increases neuronal survival and indicates an important role for the fission-fusion equilibrium in the pathogenesis of diabetic neuropathy.
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ADN Mitocondrial/metabolismo , Diabetes Mellitus Experimental/metabolismo , Mitocondrias/ultraestructura , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Bromodesoxiuridina/metabolismo , Proteínas Quinasas Dependientes de Calcio-Calmodulina/genética , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Técnicas de Cultivo de Célula , Supervivencia Celular , ADN Mitocondrial/genética , Proteínas Quinasas Asociadas a Muerte Celular , Diabetes Mellitus Experimental/patología , GTP Fosfohidrolasas/genética , Ganglios Espinales/embriología , Ganglios Espinales/patología , Regulación de la Expresión Génica , Glutamina/farmacología , Hemoglobina Glucada/metabolismo , Ratones , MicroARNs/genética , Mitocondrias/metabolismo , Mitocondrias/patología , Neuronas/citología , Estrés OxidativoRESUMEN
OBJECTIVE: Serum IgG antibodies (Abs) to phosphorylated ribosomal (P ribosomal) proteins have been inconsistently associated with neuropsychiatric manifestations in systemic lupus erythematosus (SLE). Our aim was to assess whether serum IgG Abs to ribosomal P proteins are associated with neuropsychiatric SLE. PATIENTS AND METHODS: We examined an inception cohort of 219 SLE patients. Neuropsychiatric SLE manifestations were characterized using the American College of Rheumatology (ACR) definition. Serum Abs to P ribosomal proteins were searched for by immunoblotting. In a subgroup of patients, Abs were investigated also in cerebrospinal fluid (CSF). RESULTS: Abs to P ribosomal proteins were detected in 45 (21%) patients, 23 of whom (51%) with neuropsychiatric involvement. Abs to P ribosomal protein were present both in serum and CSF. Abs to P ribosomal proteins significantly correlated with psychosis (p=0.017), mononeuropathy multiplex (p=0.040), malar rash (p=0.004), serum anti-Sm Abs (p=0.042), and lupus anticoagulant (p=0.036). SLE onset age was significantly younger in patients with Abs to P ribosomal proteins. Logistic regression analysis confirmed the relationship between Abs to P ribosomal proteins and psychosis, malar rash, SLE onset age and lupus anticoagulant. CONCLUSIONS: Abs to ribosomal P proteins are associated with psychosis and might be associated with peripheral nervous system complications.
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Anticuerpos/inmunología , Vasculitis por Lupus del Sistema Nervioso Central/inmunología , Proteínas Ribosómicas/inmunología , Adolescente , Adulto , Anciano , Anticuerpos/sangre , Anticuerpos/líquido cefalorraquídeo , Niño , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Vasculitis por Lupus del Sistema Nervioso Central/líquido cefalorraquídeo , Vasculitis por Lupus del Sistema Nervioso Central/epidemiología , Masculino , Persona de Mediana EdadRESUMEN
In peripheral nerve myelin, the intraperiod line results from compaction of the extracellular space due to homophilic adhesion between extracellular domains (ECD) of the protein zero (P(0)) glycoprotein. Point mutations in this region of P(0) cause human hereditary demyelinating neuropathies such as Charcot-Marie-Tooth. We describe transgenic mice expressing a full-length P(0) modified in the ECD with a myc epitope tag. The presence of the myc sequence caused a dysmyelinating peripheral neuropathy similar to two distinct subtypes of Charcot-Marie-Tooth, with hypomyelination, altered intraperiod lines, and tomacula (thickened myelin). The tagged protein was incorporated into myelin and was associated with the morphological abnormalities. In vivo and in vitro experiments showed that P(0)myc retained partial adhesive function, and suggested that the transgene inhibits P(0)-mediated adhesion in a dominant-negative fashion. These mice suggest new mechanisms underlying both the pathogenesis of P(0) ECD mutants and the normal interactions of P(0) in the myelin sheath.
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Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/patología , Proteína P0 de la Mielina/genética , Vaina de Mielina/patología , Animales , Adhesión Celular , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/patología , Modelos Animales de Enfermedad , Epítopos/genética , Femenino , Expresión Génica/fisiología , Genes myc/genética , Técnicas In Vitro , Masculino , Ratones , Ratones Noqueados , Ratones Mutantes Neurológicos , Microscopía Electrónica , Mutagénesis/fisiología , Vaina de Mielina/ultraestructura , Fenotipo , Nervio Ciático/patologíaRESUMEN
We show that normal peripheral nerve myelination depends on strict dosage of the most abundantly expressed myelin gene, myelin protein zero (Mpz). Transgenic mice containing extra copies of Mpz manifested a dose-dependent, dysmyelinating neuropathy, ranging from transient perinatal hypomyelination to arrested myelination and impaired sorting of axons by Schwann cells. Myelination was restored by breeding the transgene into the Mpz-null background, demonstrating that dysmyelination does not result from a structural alteration or Schwann cell-extrinsic effect of the transgenic P(0) glycoprotein. Mpz mRNA overexpression ranged from 30-700%, whereas an increased level of P(0) protein was detected only in nerves of low copy-number animals. Breeding experiments placed the threshold for dysmyelination between 30 and 80% Mpz overexpression. These data reveal new points in nerve development at which Schwann cells are susceptible to increased gene dosage, and suggest a novel basis for hereditary neuropathy.
Asunto(s)
Enfermedades Desmielinizantes/congénito , Dosificación de Gen , Proteína P0 de la Mielina/biosíntesis , Proteína P0 de la Mielina/genética , Enfermedades del Sistema Nervioso Periférico/congénito , Animales , Western Blotting , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/patología , Regulación de la Expresión Génica , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Proteína Básica de Mielina/biosíntesis , Proteína Básica de Mielina/genética , Proteínas de la Mielina/biosíntesis , Proteínas de la Mielina/genética , Especificidad de Órganos , Enfermedades del Sistema Nervioso Periférico/genética , Enfermedades del Sistema Nervioso Periférico/metabolismo , Enfermedades del Sistema Nervioso Periférico/patología , Isoformas de Proteínas/biosíntesis , Isoformas de Proteínas/genética , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células de Schwann/metabolismo , Células de Schwann/ultraestructura , Nervio Ciático/metabolismo , Nervio Ciático/ultraestructuraRESUMEN
Some inflammatory mediators play an important role not only in the pathogenesis of the inflammatory pain, but also in that of neuropathic and visceral pain. We previously showed the antihyperalgesic effect of oATP, the inhibitor of the P2X7 receptors for the pro-nociceptive ATP, in experimental inflammation. Here we show the antihyperalgesic effect of oATP in mouse models of neuropathic and visceral pain, other than in a model of arthritic pain mimicking rheumatoid arthritis in humans. We also show that mice lacking P2X7 receptors (KO) are resistant to hyperalgesic thermal stimuli following the induction of arthritic, neuropathic and visceral pain. Local (injection into the right hind paw) pre-treatment with oATP is able to prevent the successive induction of ATP-dependent hyperalgesia in wild type mice. In addition, KO mice are not insensitive to intraplantar treatment with ATP. Our data suggest that, even if oATP is able to inhibit purinoceptors different from P2X7, the latter are the more important involved in pain transmission.
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Adenosina Trifosfato/análogos & derivados , Hiperalgesia/tratamiento farmacológico , Receptores Purinérgicos P2/fisiología , Adenosina Trifosfato/farmacología , Adenosina Trifosfato/uso terapéutico , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Neuralgia/tratamiento farmacológico , Umbral del Dolor/efectos de los fármacos , Antagonistas del Receptor Purinérgico P2 , Receptores Purinérgicos P2X7RESUMEN
The aim of this work was to investigate the structural features of type I collagen isoforms and collagen-based films at atomic and molecular scales, in order to evaluate whether and to what extent different protocols of slurry synthesis may change the protein structure and the final properties of the developed scaffolds. Wide Angle X-ray Scattering data on raw materials demonstrated the preferential orientation of collagen molecules in equine tendon-derived collagens, while randomly oriented molecules were found in bovine skin collagens, together with a lower crystalline degree, analyzed by the assessment of FWHM (Full Width at Half Maximum), and a certain degree of salt contamination. WAXS and FT-IR (Fourier Transform Infrared) analyses on bovine collagen-based films, showed that mechanical homogenization of slurry in acidic solution was the treatment ensuring a high content of super-organization of collagen into triple helices and a high crystalline domain into the material. In vitro tests on rat Schwannoma cells showed that Schwann cell differentiation into myelinating cells was dependent on the specific collagen film being used, and was found to be stimulated in case of homogenization-treated samples. Finally DHT/EDC crosslinking treatment was shown to affect mechanical stiffness of films depending on collagen source and processing conditions.
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Colágeno Tipo I/química , Células de Schwann/citología , Piel/citología , Tendones/citología , Andamios del Tejido/química , Animales , Bovinos , Células Cultivadas , Caballos , Humanos , Ensayo de Materiales , Ratas , Medicina Regenerativa , Dispersión de Radiación , Células de Schwann/química , Piel/química , Tendones/química , Resistencia a la Tracción , Ingeniería de Tejidos/métodosRESUMEN
Successful gene therapy approaches for metachromatic leukodystrophy (MLD), based either on hematopoietic stem/progenitor cells (HSPCs) or direct central nervous system (CNS) gene transfer, highlighted a requirement for high levels of arylsulfatase A (ARSA) expression to achieve correction of disease manifestations in the mouse model. Full assessment of the safety of ARSA expression above physiological levels thus represents a prerequisite for clinical translation of these approaches. Here, using lentiviral vectors (LVs), we generated two relevant models for the stringent evaluation of the consequences of ARSA overexpression in transduced cells. We first demonstrated that ARSA overexpression in human HSPCs does not affect their clonogenic and multilineage differentiation capacities in clonogenic assays and in a neonatal hematochimeric mouse model. Further, we studied ARSA overexpression in all body tissues by generating transgenic mice overexpressing the ARSA enzyme by LV up to 15-fold above the normal range and carrying multiple copies of LV in their genome. Characterization of these mice demonstrated the safety of ARSA overexpression in two main gene therapy targets, HSPCs and neurons, with maintenance of the complex functions of the hematopoietic and nervous system in the presence of supraphysiological enzyme levels. The activity of other sulfatases dependent on the same common activator, sulfatase-modifying factor-1 (SUMF1), was tested in ARSA-overexpressing HSPCs and in transgenic mice, excluding the occurrence of saturation phenomena. Overall, these data indicate that from the perspective of clinical translation, therapeutic levels of ARSA overexpression can be safely achieved. Further, they demonstrate an experimental platform for the preclinical assessment of the safety of new gene therapy approaches.
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Cerebrósido Sulfatasa/metabolismo , Terapia Genética , Leucodistrofia Metacromática/genética , Leucodistrofia Metacromática/terapia , Animales , Animales Recién Nacidos , Antígenos CD34/inmunología , Antígenos CD34/metabolismo , Southern Blotting , Diferenciación Celular , Linaje de la Célula , Proliferación Celular , Cerebrósido Sulfatasa/efectos adversos , Cerebrósido Sulfatasa/análisis , Ensayo de Unidades Formadoras de Colonias , Estudios de Factibilidad , Vectores Genéticos , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Humanos , Lentivirus/genética , Leucodistrofia Metacromática/metabolismo , Leucodistrofia Metacromática/patología , Ratones , Ratones Transgénicos , Modelos Animales , Neuronas/citología , Neuronas/metabolismo , Reacción en Cadena de la Polimerasa , Bazo/citología , Transducción GenéticaRESUMEN
Clusterin is a protein involved in multiple biological events, including neuronal cytoprotection, membrane recycling and regulation of complement-mediated membrane attack after injury. We investigated the effect of recombinant human clusterin in preclinical models of peripheral neuropathies. Daily treatment with clusterin accelerated the recovery of nerve motor evoked potential parameters after sciatic nerve injury. Prophylactic or therapeutic treatment of experimental autoimmune neuritis rats with clusterin also accelerated the rate of recovery from the disease, associated with remyelination of demyelinated nerve fibers. These data demonstrate that clusterin is capable of ameliorating clinical, neurophysiological and pathological signs in models of peripheral neuropathies.
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Clusterina/farmacología , Factores de Crecimiento Nervioso/farmacología , Regeneración Nerviosa/efectos de los fármacos , Nervios Periféricos/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Animales , Clusterina/inmunología , Clusterina/uso terapéutico , Citocinas/efectos de los fármacos , Citocinas/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/fisiopatología , Femenino , Hipocampo/inmunología , Hipocampo/metabolismo , Hipocampo/patología , Ratones , Ratones Endogámicos C57BL , Proteína Básica de Mielina/efectos de los fármacos , Proteína Básica de Mielina/inmunología , Proteína Básica de Mielina/metabolismo , Vaina de Mielina/efectos de los fármacos , Vaina de Mielina/inmunología , Vaina de Mielina/patología , Factores de Crecimiento Nervioso/inmunología , Factores de Crecimiento Nervioso/uso terapéutico , Regeneración Nerviosa/inmunología , Neuronas/efectos de los fármacos , Neuronas/inmunología , Neuronas/patología , Técnicas de Cultivo de Órganos , Nervios Periféricos/inmunología , Nervios Periféricos/fisiopatología , Enfermedades del Sistema Nervioso Periférico/inmunología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Neuropatía Ciática/tratamiento farmacológico , Neuropatía Ciática/inmunología , Neuropatía Ciática/fisiopatología , Resultado del TratamientoRESUMEN
Integrins, a subgroup of adhesion receptors, are transmembrane glycoproteins that mediate interactions between cytoplasm and the extracellular environment. These interactions influence, among others, events such as cell migration, proliferation, and differentiation. Differential expression of integrins is developmentally regulated in the peripheral nervous system (PNS) and is associated with crucial events in both physiological and pathological processes. Preliminary studies suggest that integrin expression influences neural crest cell migration, axonal outgrowth, and Schwann cell differentiation. Similarly, the abnormal expression of integrins or their ligands, is associated with degenerative, inflammatory, and malignant disorders of the PNS. Finally, integrins participate in the complex interactions that promote repair of the PNS. A better comprehension of the role of integrins in the PNS, their protein interactions and transducing signals is being achieved by selected biochemical and genetic experiments. Here we review a large bias of evidence suggesting the key functions for integrins in the PNS.
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Integrinas/fisiología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Sistema Nervioso Periférico/fisiopatología , Animales , Diferenciación Celular/fisiología , Humanos , Regeneración Nerviosa/fisiologíaRESUMEN
Laminin may alter the biological behavior of gliomas. Therefore, we investigated the expression of two laminin receptors, alpha6 beta1 and alpha6 beta4 integrins in normal brain, astrogliotic brain, and astrocytomas as compared to other central nervous system (CNS) tumors. In most CNS tumors, the expression of these integrins was unchanged in neoplastic as compared to normal counterpart cells. In contrast, increased numbers of reactive and neoplastic astrocytes expressed beta4 integrin as compared to normal astrocytes, whereas alpha6 and beta1 integrin expression did not change. Conversely, lower numbers of astrocytoma blood vessels expressed beta4, whereas all blood vessels in normal brain expressed beta4. These data suggest that the profile of laminin receptors changes in neoplastic astrocytes and in astrocytoma blood vessels; this change may play an important role in astrocytoma pathogenesis.
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Astrocitoma/metabolismo , Neoplasias Encefálicas/metabolismo , Integrinas/metabolismo , Astrocitoma/patología , Biopsia , Vasos Sanguíneos/metabolismo , Neoplasias Encefálicas/patología , Humanos , InmunohistoquímicaRESUMEN
Anti-GM1 antibodies in patients with motor neuropathy or motor neuron disease frequently recognize the Gal(beta 1-3)GalNAc epitope, which is shared by several glycoproteins in peripheral nerve. In this study, cholera toxin (CT), which is specific for GM1, and the lectin peanut agglutinin (PNA), which binds to Gal(beta 1-3)GalNAc-bearing glycoproteins, were used in tissue section and intraneural injection studies to examine the distribution of GM1 and Gal(beta 1-3)GalNAc epitopes in human and rat peripheral nerve by epifluorescence and confocal microscopy. In tissue sections, CT stained the compact myelin in both human and rat nerves, whereas PNA was localized at the outer edge of the myelin sheath or Schwann cell membrane. Following intraneural injection into rat sciatic nerves, both CT and PNA bound to the nodes of Ranvier, although CT was concentrated in the paranodal myelin region whereas PNA was concentrated at the nodal gap. These structures may be targets for anti-GM1 antibodies in peripheral nerve.
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Antígenos de Carbohidratos Asociados a Tumores/inmunología , Epítopos/análisis , Gangliósido G(M1)/inmunología , Nervios Periféricos/química , Animales , Arachis , Toxina del Cólera/farmacocinética , Humanos , Lectinas/farmacocinética , Microscopía Fluorescente , Aglutinina de Mani , Lectinas de Plantas , Ratas , Valores de Referencia , Nervio Ciático/química , Coloración y Etiquetado , Nervio Sural/químicaRESUMEN
We report a 57-year-old man with progressive symmetric weakness and fasciculation affecting the legs. Electromyography revealed fibrillations and neurogenic motor unit potentials in the leg muscles. Biopsy of a motor branch of the obturator nerve revealed axonal degeneration, loss of myelinated nerve fibers, and amyloidosis with deposits of lambda light chains. At 6-month follow-up, the patient manifested sensory and autonomic symptoms, and lambda light chains were first detected in the serum. In this case, diagnosis of amyloidosis remained elusive until motor nerve biopsy.
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Neuropatías Amiloides/diagnóstico , Enfermedad de la Neurona Motora/diagnóstico , Neuropatías Amiloides/fisiopatología , Biopsia , Diagnóstico Diferencial , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de la Neurona Motora/fisiopatología , Conducción Nerviosa/fisiologíaRESUMEN
The role of the corpus callosum in the inter-hemispheric integration of the visuo-spatial attention system, was investigated in patients with a total callosotomy or with an anterior callosal section. Subjects produced simple reaction times (RTs) to visual targets shown to the left or right visual hemifield. Preceding the target by an interval of 500 ms, arrow cues predicting the target location were shown left and right of the point of ocular fixation. For a majority of total and anterior callosotomy patients, results with valid focused cues (both arrows pointing to the target location) and with divided-attention cues (arrows pointing away from fixation) did not differ and both conditions produced shorter RTs than with neutral cues (equal signs). In contrast, neurologically intact subjects showed equal RTs with divided-attention and neutral cues, whereas valid focused cues produced reduced RTs relative to neutral cues. These results indicate that most split-brains, in contrast to normal observers, are capable of directing their attention to left and right visual field locations simultaneously, and therefore that each cerebral hemisphere controls its own visuo-spatial attention mechanism.
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Atención/fisiología , Cuerpo Calloso/fisiología , Lateralidad Funcional/fisiología , Percepción Espacial/fisiología , Percepción Visual/fisiología , Adulto , Cuerpo Calloso/cirugía , Señales (Psicología) , Epilepsia/cirugía , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Lóbulo Parietal/fisiología , Estimulación Luminosa , Tiempo de Reacción/fisiologíaRESUMEN
We describe three patients with a sensorimotor axonal polyneuropathy and an IgG M-protein that binds to a 68 kDa axonal protein identified as the low molecular weight neurofilament protein (NF-L). The immunological studies revealed that the M-proteins have different target epitopes: one is phosphorylated and the other two are nonphosphorylated. One of the nonphosphorylated epitopes is common to other intermediate filaments, such as desmin and vimentin.
Asunto(s)
Axones/inmunología , Proteínas Sanguíneas/inmunología , Epítopos/inmunología , Inmunoglobulina G/inmunología , Inmunoglobulinas , Proteínas de Neurofilamentos/inmunología , Enfermedades del Sistema Nervioso Periférico/inmunología , Humanos , Inmunoglobulina G/análisis , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso Periférico/patología , FosforilaciónRESUMEN
We report a patient with a progressive, predominantly sensory neuropathy and a IgM kappa M-protein that binds to Schmidt-Lantermann incisures. A sural nerve biopsy showed primary axonal damage and IgM deposits at Schmidt-Lantermann incisures were seen by direct immunoperoxidase. Serum from the patient injected into rat sciatic nerve reacts with the incisures as with those in the patient's nerve. The IgM kappa M-protein reacts with chondroitin sulfate C and binds to a broad nerve protein band with a mobility of between 170 and 118 kDa. Peripheral neuropathy may be related to the M-protein, which had immunocytochemical reactivity not previously described for patients with polyneuropathy and IgM monoclonal gammopathy.
Asunto(s)
Axones/patología , Proteínas Sanguíneas/inmunología , Inmunoglobulina M/análisis , Cadenas kappa de Inmunoglobulina/análisis , Inmunoglobulinas , Fibras Nerviosas Mielínicas/inmunología , Enfermedades del Sistema Nervioso Periférico/inmunología , Sulfatos de Condroitina/análisis , Humanos , Immunoblotting , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso Periférico/patología , Nervio Sural/patologíaRESUMEN
Sera from eight of 25 patients with chronic sensory neuropathy had high titers of antibodies to sulfatide and chondroitin sulfate C or both. Preclearing of patients' sera with either sulfatide or chondroitin sulfate C revealed that in four patients the antisulfatide antibodies crossreacted with chondroitin sulfate C. By indirect immunohistochemistry sera reactive to sulfatide only had a different staining pattern from those reactive to both sulfatide and chondroitin sulfate C. By direct immunohistochemistry we found immunoglobulins bound to nerve fibers only in patients with serum antibodies against both sulfatide and chondroitin sulfate C. Our study provides evidence that antibodies to sulfatide and to chondroitin sulfate C differ in their fine specificity and are present in 30% of patients with chronic sensory neuropathy.