RESUMEN
3-O-sulfogalactosylceramide (sulfatide) constitutes a class of sphingolipids that comprise about 4% of myelin lipids in the central nervous system. Previously, our group characterized a mouse with sulfatide's synthesizing enzyme, cerebroside sulfotransferase (CST), constitutively disrupted. Using these mice, we demonstrated that sulfatide is required for establishment and maintenance of myelin, axoglial junctions, and axonal domains and that sulfatide depletion results in structural pathologies commonly observed in Multiple Sclerosis (MS). Interestingly, sulfatide is reduced in regions of normal appearing white matter (NAWM) of MS patients. Sulfatide reduction in NAWM suggests depletion occurs early in disease development and consistent with functioning as a driving force of disease progression. To closely model MS, an adult-onset disease, our lab generated a "floxed" CST mouse and mated it against the PLP-creERT mouse, resulting in a double transgenic mouse that provides temporal and cell-type specific ablation of the Cst gene (Gal3st1). Using this mouse, we demonstrate adult-onset sulfatide depletion has limited effects on myelin structure but results in the loss of axonal integrity including deterioration of domain organization accompanied by axonal degeneration. Moreover, structurally preserved myelinated axons progressively lose the ability to function as myelinated axons, indicated by the loss of the N1 peak. Together, our findings indicate that sulfatide depletion, which occurs in the early stages of MS progression, is sufficient to drive the loss of axonal function independent of demyelination and that axonal pathology, which is responsible for the irreversible loss of neuronal function that is prevalent in MS, may occur earlier than previously recognized.
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Vaina de Mielina , Sulfoglicoesfingolípidos , Ratones , Animales , Vaina de Mielina/patología , Ratones Noqueados , Axones/fisiología , Neuronas , Ratones TransgénicosRESUMEN
BACKGROUND: Head injuries are common injury in the fire service; however, very little data exist on the risks this may pose to the development of post-traumatic stress disorder (PTSD) and depression in this high-risk population. AIMS: Our study aimed to compare levels of PTSD and depression symptoms in firefighters with a line-of-duty head injury, non-line-of-duty head injury and no head injury. METHODS: In this cross-sectional study, we assessed current PTSD and depression symptoms as well as retrospective head injuries. RESULTS: Seventy-six per cent of the total sample reported at least one head injury in their lifetime. Depression symptoms were significantly more severe among firefighters with a line-of-duty head injury compared to those with no head injury, but not compared to those who sustained a non-line-of-duty head injury. Depression symptoms did not differ between firefighters with a non-line-of-duty head injury and those with no head injury. PTSD symptoms were significantly more severe among firefighters with a line-of-duty head injury compared to both firefighters with no head injury and those with a non-line-of-duty head injury. CONCLUSIONS: We found that firefighters who reported at least one line-of-duty head injury had significantly higher levels of PTSD and depression symptoms than firefighters who reported no head injuries. Our findings also suggest head injuries sustained outside of fire service could have less of an impact on the firefighter's PTSD symptom severity than head injuries that occur as a direct result of their job.
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Traumatismos Craneocerebrales , Bomberos , Distrés Psicológico , Trastornos por Estrés Postraumático , Traumatismos Craneocerebrales/complicaciones , Traumatismos Craneocerebrales/epidemiología , Estudios Transversales , Depresión/epidemiología , Depresión/etiología , Humanos , Estudios Retrospectivos , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/etiologíaRESUMEN
OBJECTIVE: To highlight the incidence of grade III PCL injuries with simultaneous PCL & popliteus injury. METHODS: Inclusion criteria: patients who underwent PCL reconstruction for grade III PCL tear & minimum of 1-year follow-up. Exclusion criteria: associated ACL injury & insufficient follow up. Patients seen postoperatively at 2 weeks, 6-8 weeks, 4-6 months, 6-9 months, 1 year, and 1 + years. RESULTS: 89.5% of patients in this study had an associated popliteus injury. CONCLUSIONS: Isolated grade III PCL injury may not frequently exist, rather undiagnosed & untreated concurrent popliteus injury can have less successful outcomes after isolated PCL reconstruction.
RESUMEN
BACKGROUND: Chronic microglia-mediated inflammation and oxidative stress are well-characterized underlying factors in neurodegenerative disease, whereby reactive inflammatory microglia enhance ROS production and impact neuronal integrity. Recently, it has been shown that during chronic inflammation, neuronal integrity is compromised through targeted disruption of the axon initial segment (AIS), the axonal domain critical for action potential initiation. AIS disruption was associated with contact by reactive inflammatory microglia which wrap around the AIS, increasing association with disease progression. While it is clear that chronic microglial inflammation and enhanced ROS production impact neuronal integrity, little is known about how acute microglial inflammation influences AIS stability. Here, we demonstrate that acute neuroinflammation induces AIS structural plasticity in a ROS-mediated and calpain-dependent manner. METHODS: C57BL/6J and NOX2-/- mice were given a single injection of lipopolysaccharide (LPS; 5 mg/kg) or vehicle (0.9% saline, 10 mL/kg) and analyzed at 6 h-2 weeks post-injection. Anti-inflammatory Didox (250 mg/kg) or vehicle (0.9% saline, 10 mL/kg) was administered beginning 24 h post-LPS injection and continued for 5 days; animals were analyzed 1 week post-injection. Microglial inflammation was assessed using immunohistochemistry (IHC) and RT-qPCR, and AIS integrity was quantitatively analyzed using ankyrinG immunolabeling. Data were statistically compared by one-way or two-way ANOVA where mean differences were significant as assessed using Tukey's post hoc analysis. RESULTS: LPS-induced neuroinflammation, characterized by enhanced microglial inflammation and increased expression of ROS-producing enzymes, altered AIS protein clustering. Importantly, inflammation-induced AIS changes were reversed following resolution of microglial inflammation. Modulation of the inflammatory response using anti-inflammatory Didox, even after significant AIS disruption occurred, increased the rate of AIS recovery. qPCR and IHC analysis revealed that expression of microglial NOX2, a ROS-producing enzyme, was significantly increased correlating with AIS disruption. Furthermore, ablation of NOX2 prevented inflammation-induced AIS plasticity, suggesting that ROS drive AIS structural plasticity. CONCLUSIONS: In the presence of acute microglial inflammation, the AIS undergoes an adaptive change that is capable of spontaneous recovery. Moreover, recovery can be therapeutically accelerated. Together, these findings underscore the dynamic capabilities of this domain in the presence of a pathological insult and provide evidence that the AIS is a viable therapeutic target.
Asunto(s)
Segmento Inicial del Axón/enzimología , Segmento Inicial del Axón/patología , Corteza Cerebral/enzimología , Corteza Cerebral/patología , NADPH Oxidasa 2/biosíntesis , Plasticidad Neuronal/fisiología , Animales , Segmento Inicial del Axón/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Femenino , Inflamación/inducido químicamente , Inflamación/enzimología , Inflamación/patología , Lipopolisacáridos/toxicidad , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/efectos de los fármacos , Microglía/enzimología , Microglía/patología , Plasticidad Neuronal/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoAsunto(s)
Azoospermia , Humanos , Masculino , Microdisección , Recuperación de la Esperma , Resultado del TratamientoRESUMEN
Mice incapable of synthesizing the myelin lipid sulfatide form paranodes that deteriorate with age. Similar instability also occurs in mice that lack contactin, contactin-associated protein or neurofascin155 (Nfasc155), the proteins that cluster in the paranode and form the junctional complex that mediates myelin-axon adhesion. In contrast to these proteins, sulfatide has not been shown to be enriched in the paranode nor has a sulfatide paranodal binding partner been identified; thus, it remains unclear how the absence of sulfatide results in compromised paranode integrity. Using an in situ extraction procedure, it has been reported that the absence of the myelin sphingolipids, galactocerebroside and sulfatide, increased the susceptibility of Nfasc155 to detergent extraction. Here, employing a similar approach, we demonstrate that in the presence of galactocerebroside but in the absence of sulfatide Nfasc155 is susceptible to detergent extraction. Furthermore, we use this in situ approach to show that stable association of myelin-associated glycoprotein (MAG) with the myelin membrane is sulfatide dependent while the membrane associations of myelin/oligodendrocyte glycoprotein, myelin basic protein and cyclic nucleotide phosphodiesterase are sulfatide independent. These findings indicate that myelin proteins maintain their membrane associations by different mechanisms. Moreover, the myelin proteins that cluster in the paranode and require sulfatide mediate myelin-axon adhesion. Additionally, the apparent dependency on sulfatide for maintaining Nfasc155 and MAG associations is intriguing since the fatty acid composition of sulfatide is altered and paranodal ultrastructure is compromised in multiple sclerosis. Thus, our findings present a potential link between sulfatide perturbation and myelin deterioration in multiple sclerosis.
Asunto(s)
Moléculas de Adhesión Celular/metabolismo , Detergentes/química , Vaina de Mielina/química , Glicoproteína Asociada a Mielina/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Animales , Western Blotting , Moléculas de Adhesión Celular/aislamiento & purificación , Ratones Noqueados , Glicoproteína Asociada a Mielina/aislamiento & purificación , Factores de Crecimiento Nervioso/aislamiento & purificación , Esfingolípidos/metabolismo , Sulfoglicoesfingolípidos/metabolismoRESUMEN
The galactolipids galactocerebroside and sulfatide have been implicated in oligodendrocyte (OL) development and myelin formation. Much of the early evidence for myelin galactolipid function has been derived from antibody and chemical perturbation of OLs in vitro. To determine the role of these lipids in vivo, we previously characterized mice lacking galactocerebroside and sulfatide and observed abundant, unstable myelin and an increased number of OLs. We have also reported that mice incapable of synthesizing sulfatide (CST-null) while maintaining normal levels of galactocerebroside generate relatively stable myelin with unstable paranodes. Additionally, Hirahara et al. (2004; Glia 45:269-277) reported that these CST-null mice also contain an increased number of OLs in the forebrain, medulla, and cerebellum at 7 days of age. Here, we further the findings of Hirahara et al. by demonstrating that the number of OLs in the CST-null mice is also increased in the spinal cord and that this elevated OL population is maintained through, at least, 7 months of age. Moreover, we show that the enhanced OL population is accompanied by increased proliferation and decreased apoptosis of oligodendrocytic-lineage cells. Finally, through ultrastructural analysis, we show that the CST-null OLs exhibit decreased morphological complexity, a feature that may result in decreased OL competition and increased OL survival.
Asunto(s)
Proliferación Celular , Vaina de Mielina/metabolismo , Fibras Nerviosas Mielínicas/metabolismo , Oligodendroglía/metabolismo , Sulfoglicoesfingolípidos/metabolismo , Sulfotransferasas/genética , Envejecimiento/genética , Envejecimiento/metabolismo , Animales , Apoptosis/genética , Recuento de Células , Diferenciación Celular/genética , Linaje de la Célula/genética , Supervivencia Celular/genética , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/metabolismo , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/fisiopatología , Ratones , Ratones Noqueados , Fibras Nerviosas Mielínicas/ultraestructura , Oligodendroglía/patología , Médula Espinal/metabolismo , Médula Espinal/patología , Médula Espinal/fisiopatología , Células Madre/metabolismo , Células Madre/patología , Regulación hacia Arriba/genéticaRESUMEN
Galactocerebroside (GalC) and sulfatide are abundant myelin lipids. In mice incapable of synthesizing these lipids, myelin is thin and regionally unstable and exhibits several subtle structural abnormalities. Although galactolipid-null mice have been beneficial in the analysis of galactolipid function, it has not been possible to differentiate between the functions of GalC and sulfatide with these mice alone. In the present work, we have analyzed a murine model that forms normal levels of GalC but is incapable of synthesizing sulfatide. By comparing a plethora of morphological features between the galactolipid-null and the sulfatide-null mice, we have begun to differentiate between the specific functions of these closely related lipids. The most striking difference between these two mutants is the reduction of myelin developmental abnormalities (e.g., redundant and uncompacted myelin sheaths) in young adult sulfatide-null mice as compared with the galactolipid-null animals. Although sulfatide appears to play a limited role in myelin development, this lipid is essential for myelin maintenance, as the prevalence of redundant, uncompacted, and degenerating myelin sheaths as well as deteriorating nodal/paranodal structure is increased significantly in aged sulfatide-null mice as compared with littermate wildtype mice. Finally, we show that the role played by sulfatide in CNS maintenance is not limited to the myelin sheath, as axonal caliber and circularity are normal in young adult mutant mice but are significantly altered in aged sulfatide-null animals.
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Axones/fisiología , Sistema Nervioso Central/citología , Vaina de Mielina/fisiología , Sulfoglicoesfingolípidos/farmacología , Envejecimiento/fisiología , Algoritmos , Animales , Axones/ultraestructura , Sistema Nervioso Central/crecimiento & desarrollo , Sistema Nervioso Central/ultraestructura , Galactosilceramidas/genética , Galactosilceramidas/metabolismo , Inmunohistoquímica , Ratones , Ratones Noqueados , Microscopía Electrónica , Vaina de Mielina/ultraestructura , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sulfotransferasas/metabolismoRESUMEN
BACKGROUND: Term and preterm neonates experience quantitative and qualitative neutrophil deficiencies resulting in part from decreased production of granulocyte colony-stimulating factor (G-CSF). In adults, G-CSF improves neutrophil function by up-regulating adhesion molecules. PATIENTS AND METHODS: To evaluate the effects of G-CSF on neonatal neutrophil adhesive phenotypes, cord blood samples were incubated with G-CSF or phosphate-buffered saline and stimulated with N-formyl-methionyl-leucyl-phenylalanine (FMLP), and adhesion molecules were evaluated by flow cytometry. RESULTS: In term and preterm neutrophils, G-CSF incubation increased beta2-integrin expression significantly compared with baseline and to a greater extent than observed in adult neutrophils. With FMLP stimulation, beta2-integrin expression increased even more in the G-CSF group. L-selectin expression decreased after G-CSF incubation and decreased even more with FMLP stimulation in the G-CSF group compared with the phosphate-buffered saline group in term and preterm samples, but not in adult samples. CONCLUSIONS: The data show that G-CSF increases expression of beta2-integrin and decreases expression of L-selectin on unstimulated and stimulated term and preterm neonatal neutrophils in vitro. Further study is required to determine whether G-CSF improves neonatal neutrophil function.
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Antígenos CD18/metabolismo , Adhesión Celular/fisiología , Factor Estimulante de Colonias de Granulocitos/farmacología , Selectina L/metabolismo , Neutrófilos/efectos de los fármacos , Adulto , Femenino , Sangre Fetal/metabolismo , Citometría de Flujo , Humanos , Recién Nacido , Recien Nacido Prematuro/metabolismo , N-Formilmetionina Leucil-Fenilalanina/farmacología , Activación Neutrófila , Neutrófilos/metabolismoRESUMEN
The galactolipids galactocerebroside and sulfatide, which require the enzyme UDP-galactose:ceramide galactosyltransferase (CGT) for their synthesis, are among the most prevalent molecules in the myelin sheath. Numerous studies, mainly using antibody perturbation methods in vitro, have suggested that these molecules are crucial mediators of oligodendrocyte differentiation and myelin formation. Although we have previously demonstrated that myelin formation occurs in CGT null mutant mice, which are incapable of synthesizing the myelin galactolipids, here we show that there are developmental alterations in the CNS of these animals. There is a significant decrease in the number of myelinated axon segments in the mutant spinal cord despite normal levels of myelin gene-specific mRNAs and proteins. Also, there is an increased cellularity in the mature mutant spinal cord and the distinctive morphology of the additional cells suggests that they are actively myelinating oligodendrocytes. Using in situ hybridization techniques, we show that there is a 50% increase in the number of oligodendrocytes in the mutant spinal cord. The data suggest that galactolipids play an important developmental role in regulating the maturation program and final number of oligodendrocytes.
Asunto(s)
Regulación del Desarrollo de la Expresión Génica/fisiología , Glucolípidos/deficiencia , Vaina de Mielina/genética , Vaina de Mielina/metabolismo , Oligodendroglía/metabolismo , Animales , Axones/metabolismo , Axones/patología , Axones/ultraestructura , Recuento de Células , Diferenciación Celular/genética , Galactolípidos , Galactosiltransferasas/deficiencia , Galactosiltransferasas/genética , Balactosiltransferasa de Gangliósidos , Glucolípidos/genética , Ratones , Ratones Mutantes Neurológicos , Proteínas de la Mielina/análisis , Proteínas de la Mielina/genética , Oligodendroglía/citología , ARN/análisis , Médula Espinal/metabolismo , Médula Espinal/patología , Médula Espinal/ultraestructuraRESUMEN
Mice incapable of synthesizing the abundant galactolipids of myelin exhibit disrupted paranodal axo-glial interactions in the central and peripheral nervous systems. Using these mutants, we have analyzed the role that axo-glial interactions play in the establishment of axonal protein distribution in the region of the node of Ranvier. Whereas the clustering of the nodal proteins, sodium channels, ankyrin(G), and neurofascin was only slightly affected, the distribution of potassium channels and paranodin, proteins that are normally concentrated in the regions juxtaposed to the node, was dramatically altered. The potassium channels, which are normally concentrated in the paranode/juxtaparanode, were not restricted to this region but were detected throughout the internode in the galactolipid-defi- cient mice. Paranodin/contactin-associated protein (Caspr), a paranodal protein that is a potential neuronal mediator of axon-myelin binding, was not concentrated in the paranodal regions but was diffusely distributed along the internodal regions. Collectively, these findings suggest that the myelin galactolipids are essential for the proper formation of axo-glial interactions and demonstrate that a disruption in these interactions results in profound abnormalities in the molecular organization of the paranodal axolemma.
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Axones/metabolismo , Comunicación Celular/fisiología , Neuroglía/metabolismo , Nódulos de Ranvier/química , Animales , Ancirinas/análisis , Axones/química , Moléculas de Adhesión Celular/análisis , Galactolípidos , Galactosiltransferasas/deficiencia , Galactosiltransferasas/genética , Balactosiltransferasa de Gangliósidos , Eliminación de Gen , Glucolípidos/biosíntesis , Glucolípidos/deficiencia , Glucolípidos/genética , Glicoproteínas de Membrana/análisis , Ratones , Ratones Noqueados , Vaina de Mielina/metabolismo , Factores de Crecimiento Nervioso/análisis , Neuroglía/citología , Neuropéptidos/análisis , Canales de Potasio/análisis , Nervio Ciático/química , Nervio Ciático/citología , Canales de Sodio/análisis , Médula Espinal/química , Médula Espinal/citologíaRESUMEN
Acetylcholinesterase (AChE) is the enzyme that hydrolyzes the neurotransmitter acetylcholine at cholinergic synapses and neuromuscular junctions. However, results from our laboratory and others indicate that AChE has an extrasynaptic, noncholinergic role during neural development. This article is a review of our findings demonstrating the morphogenic role of AChE, using a neuronal cell culture model. We also discuss how these data suggest that AChE has a cell adhesive function during neural development. These results could have additional significance as AChE is the target enzyme of agricultural organophosphate and carbamate pesticides as well as the commonly used household organophosphate chlorpyrifos (Dursban). Prenatal exposure to these agents could have adverse effects on neural development by interfering with the morphogenic function of AChE.
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Acetilcolinesterasa/fisiología , Axones/fisiología , Ganglios Espinales/embriología , Animales , Anticuerpos Monoclonales/inmunología , Bencenamina, 4,4'-(3-oxo-1,5-pentanodiil)bis(N,N-dimetil-N-2-propenil-), Dibromuro/farmacología , Adhesión Celular , Células Cultivadas , Inhibidores de la Colinesterasa/toxicidad , Citoesqueleto/efectos de los fármacos , Matriz Extracelular/fisiología , Femenino , Morfogénesis , Neuritas/fisiología , Embarazo , RatasRESUMEN
The roles that the myelin galactolipids galactocerebroside (GalC) and sulfatide play in cellular differentiation, myelin formation and maintenance have been investigated for nearly 3 decades. During that time the primary approach has been to perturb lipid activity using antibodies and chemical agents in artificial systems. Recently, the isolation of the gene that encodes UDP-galactose:ceramide galactosyltransferase (CGT), the enzyme that catalyzes an essential step in the synthetic pathway of GalC and sulfatide, has enabled the generation of mice that lack myelin galactolipids. These mice display a severe tremor, hindlimb paralysis and electrophysiological defects. In addition, the CGT null mutants exhibit: 1) impaired oligodendrocyte differentiation, 2) myelin sheaths that are thin, incompletely compacted and unstable, and 3) structural abnormalities in the nodal and paranodal regions including disrupted axo-glial junctions. Collectively, these findings suggest that GalC and sulfatide are essential in myelin formation and maintenance, possibly by mediating intra- and intercellular interactions.
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Galactosilceramidas/genética , Galactosilceramidas/metabolismo , Vaina de Mielina/fisiología , Sulfoglicoesfingolípidos/metabolismo , Animales , Colesterol/análogos & derivados , Ratones , Ratones Noqueados , Vaina de Mielina/químicaRESUMEN
The CGT enzyme is responsible for catalyzing the final step in GalC synthesis. The isolation of the CGT cDNA has allowed for the genetic analysis of galactolipid function by providing the opportunity to generate null mutants deficient in CGT enzymatic activity. The detailed analyses of CGT mutant mice demonstrate that the galactolipids are essential for the formation and maintenance of normal CNS myelin, but neither GalC or sulfatide appear to be required for the development of structurally normal PNS myelin. These studies also show that the differentiation of myelinating cells is not dependent on galactolipid function, in contrast to the conclusions drawn from prior antibody perturbation studies. The abnormal node of Ranvier formations present in the CNS likely explain the disrupted electrophysiological properties displayed by mutant spinal cord axons and the tremoring phenotype of these mice. The abnormal myelin structures present in the mutant animals are consistent with the possibility that the galactolipids play a role in regulating or mediating proper axo-glial interactions. The further detailed analysis of these animals should help refine our understanding of galactolipid function in the myelination process.
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Galactosiltransferasas/genética , Nódulos de Ranvier/patología , Animales , Galactosiltransferasas/deficiencia , Galactosiltransferasas/metabolismo , Balactosiltransferasa de Gangliósidos , Ratones , Ratones Noqueados , Vaina de Mielina/patología , Vaina de Mielina/fisiologíaRESUMEN
Vertebrate myelin is enriched in the lipid galactocerebroside (GalC) and its sulfated derivated sulfatide. To understand the in vivo function of these lipids, we analyzed myelination in mice that contain a null mutation in the gene encoding UDP-galactose:ceramide galactosyltransferase, the enzyme responsible for catalyzing the final step in GalC synthesis. Galactolipid-deficient myelin is regionally unstable and progressively degenerates. At postnatal day 30, demyelination is restricted to the midbrain and hindbrain, but by postnatal day 90, it spreads throughout the central nervous system. Activated microglial cells and reactive astrocytes appear with the loss of myelin in older animals. Nonetheless, major myelin protein gene mRNA levels are normal throughout the life of these animals, suggesting that widespread oligodendrocyte death is not the primary cause of demyelination. The developmental switch in myelin-associated glycoprotein isoform expression, however, does not occur normally in these mice, suggesting an alteration in oligodendrocyte maturation. Taken together, these findings indicate that GalC and sulfatide are required for the long-term maintenance of myelin and that their absence may have subtle effects on the development of oligodendrocytes.
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Enfermedades Desmielinizantes/genética , Galactosilceramidas/fisiología , Regulación del Desarrollo de la Expresión Génica , Vaina de Mielina/metabolismo , Glicoproteína Asociada a Mielina/biosíntesis , Proteínas del Tejido Nervioso/biosíntesis , Isoformas de Proteínas/biosíntesis , Sulfoglicoesfingolípidos/metabolismo , Animales , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Encéfalo/patología , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/patología , Galactosilceramidas/deficiencia , Galactosiltransferasas/deficiencia , Galactosiltransferasas/genética , Balactosiltransferasa de Gangliósidos , Ratones , Ratones Noqueados , Ratones Mutantes Neurológicos , Proteínas de la Mielina/biosíntesis , Proteínas de la Mielina/genética , Vaina de Mielina/patología , Glicoproteína Asociada a Mielina/genética , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Oligodendroglía/patología , Isoformas de Proteínas/genética , ARN Mensajero/biosíntesisRESUMEN
Web creep is a common complication following surgical release of syndactyly. Currently, normal web height has not been objectively determined, which prevents accurate analysis of the degree of web creep after surgery. The purpose of this study was to design a technique to reproducibly measure web height and to define the standard web height in a control population. Four hundred thirty-seven standard left posteroanterior hand x-rays of children without any upper extremity pathology were evaluated. Web height was measured as a relative ratio to digital length using standard landmarks. All measurements were tabulated according to gender, age, and web space. Statistical analysis was performed to determine the reliability of this technique and to delineate any differences between web space, gender, and age. There was no significant intraobserver or interobserver difference and web height was similar in males and females. There was a significant difference between web height with respect to web location and age. Normal ranges of web height with regard to age and web position were determined and plotted as graphs. Using this measurement method, web creep can be evaluated and comparison studies of different surgical techniques performed.
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Complicaciones Posoperatorias/diagnóstico por imagen , Sindactilia/diagnóstico por imagen , Sindactilia/cirugía , Adolescente , Análisis de Varianza , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Variaciones Dependientes del Observador , Radiografía , Recurrencia , Valores de Referencia , ReoperaciónRESUMEN
Cystic fibrosis (CF) is an autosomal recessive disorder affecting exocrine gland function. Although CF was formerly a deadly disease of infants and children, recent improvements in antibiotics, nutritional therapy, and supportive care have extended the median survival to adulthood. Patients with CF often present with sinusitis and nasal polyposis in addition to recurrent pulmonary infections. Although the effectiveness of endoscopic sinus surgery in children with CF has been documented, the treatment guidelines and efficacy in the adult CF patient are unknown. We present a series of 16 adult patients with CF and chronic sinusitis. The majority of patients presented with nasal polyposis and concomitant pulmonary complications. Endoscopic findings are reviewed, with an emphasis on improving pulmonary function following endoscopic sinus surgery. Preliminary findings suggest that endoscopic sinus surgery improves symptoms of sinusitis and exercise tolerance and may delay the progressive respiratory failure that often affects the adult CF patient.
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Fibrosis Quística/complicaciones , Sinusitis/etiología , Sinusitis/cirugía , Adulto , Enfermedad Crónica , Endoscopía , Femenino , Humanos , Masculino , Sinusitis/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
Among the most abundant components of myelin are the galactolipids galactocerebroside (GalC) and sulfatide. In spite of this abundance, the roles that these molecules play in the myelin sheath are not well understood. Until recently, our concept of GalC and sulfatide functions had been principally defined by immunological and chemical perturbation studies that implicate these lipids in oligodendrocyte differentiation, myelin formation, and myelin stability. Recently, however, genetic studies have allowed us to re-analyze the functions of these lipids. Two laboratories have independently generated mice that are incapable of synthesizing either GalC or sulfatide by inactivating the gene encoding the enzyme UDP-galactose:ceramide galactosyltransferase (CGT), which is required for myelin galactolipid synthesis. These galactolipid-deficient animals exhibit a severe tremor, hindlimb paralysis, and display electrophysiological deficits in both the central and peripheral nervous systems. In addition, ultrastructural studies have revealed hypomyelinated white matter tracts with unstable myelin sheaths and a variety of myelin abnormalities including altered node length, reversed lateral loops, and compromised axo-oligodendrocytic junctions. Collectively, these observations indicate that cell-cell interactions, which are essential in the formation and maintenance of a properly functioning myelin sheath, are compromised in these galactolipid-deficient mice.
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Glucolípidos/fisiología , Vaina de Mielina/fisiología , Animales , Axones/ultraestructura , Diferenciación Celular , Galactolípidos , Galactosilceramidas/fisiología , Ratones , Ratones Noqueados , Microscopía Electrónica , Vaina de Mielina/ultraestructura , Oligodendroglía/citología , Sulfoglicoesfingolípidos/metabolismoRESUMEN
The myelin-associated glycoprotein (MAG) is a member of the immunoglobulin gene superfamily and is thought to play a critical role in the interaction of myelinating glial cells with the axon. Myelin from mutant mice incapable of expressing MAG displays various subtle abnormalities in the CNS and degenerates with age in the peripheral nervous system (PNS). Two distinct isoforms, large MAG (L-MAG) and small MAG (S-MAG), are produced through the alternative splicing of the primary MAG transcript. The cytoplasmic domain of L-MAG contains a unique phosphorylation site and has been shown to associate with the fyn tyrosine kinase. Moreover, L-MAG is expressed abundantly early in the myelination process, possibly indicating an important role in the initial stages of myelination. We have adapted the gene-targeting approach in embryonic stem cells to generate mutant mice that express a truncated form of the L-MAG isoform, eliminating the unique portion of its cytoplasmic domain, but that continue to express S-MAG. Similar to the total MAG knockouts, these animals do not express an overt clinical phenotype. CNS myelin of the L-MAG mutant mice displays most of the pathological abnormalities reported for the total MAG knockouts. In contrast to the null MAG mutants, however, PNS axons and myelin of older L-MAG mutant animals do not degenerate, indicating that S-MAG is sufficient to maintain PNS integrity. These observations demonstrate a differential role of the L-MAG isoform in CNS and PNS myelin.
Asunto(s)
Sistema Nervioso Central/fisiología , Citoplasma/fisiología , Vaina de Mielina/fisiología , Glicoproteína Asociada a Mielina/genética , Nervios Periféricos/fisiología , Alelos , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Sistema Nervioso Central/patología , Marcación de Gen , Heterocigoto , Isomerismo , Ratones/genética , Datos de Secuencia Molecular , Mutación , Vaina de Mielina/ultraestructura , Glicoproteína Asociada a Mielina/metabolismo , Nervios Periféricos/ultraestructura , Valores de ReferenciaRESUMEN
The vertebrate myelin sheath is greatly enriched in the galactolipids galactocerebroside (GalC) and sulfatide. Mice with a disruption in the gene that encodes the biosynthetic enzyme UDP-galactose:ceramide galactosyl transferase (CGT) are incapable of synthesizing these lipids yet form myelin sheaths that exhibit major and minor dense lines with spacing comparable to controls. These CGT mutant mice exhibit a severe tremor that is accompanied by hindlimb paralysis. Furthermore, electrophysiological studies reveal nerve conduction deficits in the spinal cord of these mutants. Here, using electron microscopic techniques, we demonstrate ultrastructural myelin abnormalities in the CNS that are consistent with the electrophysiological deficits. These abnormalities include altered nodal lengths, an abundance of heminodes, an absence of transverse bands, and the presence of reversed lateral loops. In contrast to the CNS, no ultrastructural abnormalities and only modest electrophysiological deficits were observed in the peripheral nervous system. Taken together, the data presented here indicate that GalC and sulfatide are essential in proper CNS node and paranode formation and that these lipids are important in ensuring proper axo-oligodendrocyte interactions.