RESUMEN
Pneumococcal meningitis produces several inflammatory disorders in susceptible subjects. A worsening of meningitis can occur on the fourth day of evolution in relation with the withdrawal of steroids. Other complications include the development of inflammatory signs in the post-acute stage of infection associated with disseminated vasculitis of the cerebral blood vessels and, even later, an autoimmune chronic meningitis. All these inflammatory complications are well controlled with the use of steroids. We report a 53-year-old woman with pneumococcal meningitis that had a good response to treatment with antibiotics and steroids. On the four day, after the steroids were discontinued, she complained of headache, became confused, and had an abnormal cerebrospinal fluid (CSF), report CT angiography showed signs of arteritis. She improved when the steroids were re-started. She was discharged in good condition but after slow tapering of the steroids over a four-month period she had a relapse of all her symptoms and had a gait disturbance. On readmission, she had an inflammatory CSF, there were no signs of infection and the cerebral MRI showed meningeal thickening with ventricular space enlargement. She improved again with steroids and she is now well on high-dose steroids but deteriorates each time the steroids are stopped. She experienced both acute and sub-acute inflammatory responses and finally developed a chronic meningitis responsive, and is dependent on steroids.
Asunto(s)
Enfermedades Autoinmunes/microbiología , Meningitis Neumocócica/complicaciones , Antibacterianos/uso terapéutico , Enfermedades Autoinmunes/diagnóstico por imagen , Enfermedades Autoinmunes/tratamiento farmacológico , Líquido Cefalorraquídeo/microbiología , Enfermedad Crónica , Femenino , Humanos , Imagen por Resonancia Magnética , Meningitis Neumocócica/diagnóstico por imagen , Meningitis Neumocócica/tratamiento farmacológico , Persona de Mediana Edad , Esteroides/uso terapéutico , Tomografía Computarizada por Rayos X/métodos , Resultado del TratamientoRESUMEN
Pneumococcal meningitis produces several inflammatory disorders in susceptible subjects. A worsening of meningitis can occur on the fourth day of evolution in relation with the withdrawal of steroids. Other complications include the development of inflammatory signs in the post-acute stage of infection associated with disseminated vasculitis of the cerebral blood vessels and, even later, an autoimmune chronic meningitis. All these inflammatory complications are well controlled with the use of steroids. We report a 53-year-old woman with pneumococcal meningitis that had a good response to treatment with antibiotics and steroids. On the four day, after the steroids were discontinued, she complained of headache, became confused, and had an abnormal cerebrospinal fluid (CSF), report CT angiography showed signs of arteritis. She improved when the steroids were re-started. She was discharged in good condition but after slow tapering of the steroids over a four-month period she had a relapse of all her symptoms and had a gait disturbance. On readmission, she had an inflammatory CSF, there were no signs of infection and the cerebral MRI showed meningeal thickening with ventricular space enlargement. She improved again with steroids and she is now well on high-dose steroids but deteriorates each time the steroids are stopped. She experienced both acute and sub-acute inflammatory responses and finally developed a chronic meningitis responsive, and is dependent on steroids.
Asunto(s)
Humanos , Femenino , Persona de Mediana Edad , Enfermedades Autoinmunes/microbiología , Meningitis Neumocócica/complicaciones , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/diagnóstico por imagen , Esteroides/uso terapéutico , Imagen por Resonancia Magnética , Tomografía Computarizada por Rayos X/métodos , Líquido Cefalorraquídeo/microbiología , Enfermedad Crónica , Resultado del Tratamiento , Meningitis Neumocócica/tratamiento farmacológico , Meningitis Neumocócica/diagnóstico por imagen , Antibacterianos/uso terapéuticoRESUMEN
BACKGROUND: Patients with Glioblastoma multiforme (GBM) have a five years survival of less than 5%, but the response to chemotherapy with alkylating agents can vary depending on the methylation status of O6-methylguanine-DNA-methyltransferase (MGMT). Genetic testing has limitations for routine use, while immunohistochemistry (IHC) offers a fast and affordable technique but with heterogeneous results in the literature. AIM: To evaluate MGMT expression by IHC in tumor tissue of Chilean patients with GBM. MATERIAL AND METHODS: Tumor samples of 29 patients with a pathological diagnosis of GBM were studied. We performed IHC staining and manual analysis of positive and negative cells for MGMT expression. A cut-off of at least 10% of cells expressing MGMT was used. Demographic and clinical features of patients were obtained from clinical records. RESULTS: The median number of cells counted per case was 692 (interquartile range [IQR] 492-928). Fifteen cases (52%) were positive for MGMT expression. Median overall survival was 5.3 months (IQR 3.4-12-8). The effect of MGMT expression on the therapeutic response was not studied since only 3 patients received chemotherapy. CONCLUSIONS: Our results are similar to international reports, but we were not able to determine the association between MGMT expression and therapeutic response.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/enzimología , Glioblastoma/enzimología , O(6)-Metilguanina-ADN Metiltransferasa/metabolismo , Adulto , Anciano , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Chile , Femenino , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , O(6)-Metilguanina-ADN Metiltransferasa/genética , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Background: Patients with Glioblastoma multiforme (GBM) have a five years survival of less than 5%, but the response to chemotherapy with alkylating agents can vary depending on the methylation status of O6-methylguanine-DNA-methyltransferase (MGMT). Genetic testing has limitations for routine use, while immunohistochemistry (IHC) offers a fast and affordable technique but with heterogeneous results in the literature. Aim: To evaluate MGMT expression by IHC in tumor tissue of Chilean patients with GBM. Material and Methods: Tumor samples of 29 patients with a pathological diagnosis of GBM were studied. We performed IHC staining and manual analysis of positive and negative cells for MGMT expression. A cut-off of at least 10% of cells expressing MGMT was used. Demographic and clinical features of patients were obtained from clinical records. Results: The median number of cells counted per case was 692 (interquartile range [IQR] 492-928). Fifteen cases (52%) were positive for MGMT expression. Median overall survival was 5.3 months (IQR 3.4-12-8). The effect of MGMT expression on the therapeutic response was not studied since only 3 patients received chemotherapy. Conclusions: Our results are similar to international reports, but we were not able to determine the association between MGMT expression and therapeutic response.
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Neoplasias Encefálicas/enzimología , Biomarcadores de Tumor/metabolismo , Glioblastoma/enzimología , O(6)-Metilguanina-ADN Metiltransferasa/metabolismo , Pronóstico , Neoplasias Encefálicas/genética , Inmunohistoquímica , Biomarcadores de Tumor , Regulación Neoplásica de la Expresión Génica , Chile , Tasa de Supervivencia , Estudios Retrospectivos , Glioblastoma/genética , O(6)-Metilguanina-ADN Metiltransferasa/genéticaRESUMEN
Posterior reversible encephalopathy (PRES) is a condition characterized by T2 and FLAIR hyperintensities in magnetic resonance imaging (MRI) studies, localized preferentially in the occipital-parietal white matter regions. Pathological MRI images located in midbrain, pons, medulla and spinal cord, that could be asymptomatic, were recently included in this entity. These images are interpreted as vasogenic edema, which is caused by arterial hypertension or eclampsia, neurotoxicity related to immunosuppressive agents or chemotherapy, among other causes. We report a 25 years old asymptomatic male with AIDS, with normal blood pressure who after initiating highly active antiretroviral therapy (HAART) reported vertigo. The MRI showed a central pontine T2 hyperintensity with diffusion restriction, which was interpreted as a central pontine myelinolysis (CPM), but the lack of motor symptoms made improbable a real demyelination of the pons. The follow-up MRI revealed complete regression of the images. To our knowledge, this case could be the second report of a reversible leucopathy of the pons in a patient with AIDS, were the MRI images also simulated a CPM. This report extends the knowledge around the variability of the pathogenic interpretation of CPM images and their association with HAART.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/complicaciones , Terapia Antirretroviral Altamente Activa/efectos adversos , Síndrome de Leucoencefalopatía Posterior/inducido químicamente , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Adulto , Humanos , Imagen por Resonancia Magnética , Masculino , Síndrome de Leucoencefalopatía Posterior/diagnóstico por imagenRESUMEN
Posterior reversible encephalopathy (PRES) is a condition characterized by T2 and FLAIR hyperintensities in magnetic resonance imaging (MRI) studies, localized preferentially in the occipital-parietal white matter regions. Pathological MRI images located in midbrain, pons, medulla and spinal cord, that could be asymptomatic, were recently included in this entity. These images are interpreted as vasogenic edema, which is caused by arterial hypertension or eclampsia, neurotoxicity related to immunosuppressive agents or chemotherapy, among other causes. We report a 25 years old asymptomatic male with AIDS, with normal blood pressure who after initiating highly active antiretroviral therapy (HAART) reported vertigo. The MRI showed a central pontine T2 hyperintensity with diffusion restriction, which was interpreted as a central pontine myelinolysis (CPM), but the lack of motor symptoms made improbable a real demyelination of the pons. The follow-up MRI revealed complete regression of the images. To our knowledge, this case could be the second report of a reversible leucopathy of the pons in a patient with AIDS, were the MRI images also simulated a CPM. This report extends the knowledge around the variability of the pathogenic interpretation of CPM images and their association with HAART.
Asunto(s)
Humanos , Masculino , Adulto , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Terapia Antirretroviral Altamente Activa/efectos adversos , Síndrome de Leucoencefalopatía Posterior/inducido químicamente , Imagen por Resonancia Magnética , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Síndrome de Leucoencefalopatía Posterior/diagnóstico por imagenRESUMEN
Infection with human T-lymphotropic virus type 1/2 (HTLV-1/2) is a major health problem. HTLV-1/2 infection is endemic in Chile but representative donor prevalence data are lacking. Data on all blood donors in a large network of Chilean blood centers were examined during 2011-2013. Screening of HTLV-1/2 antibodies were measured by enzyme immunoassay (EIA) at all blood banks. Blood samples with anticoagulants from initially reactive blood donors were analyzed by serological confirmation tests (immunofluorescence or recombinant immunoblot) at the HTLV National Reference Laboratory of the Public Health Institute of Chile. Additionally, detection of HTLV-1 and HTLV-2 provirus in peripheral blood mononuclear cells (PBMCs) was performed in all blood donors as confirmatory test. Prevalence rates were calculated. Among 694,016 donors, 706 were seropositive for HTLV-1 (prevalence, 1.02 cases per 1,000; 95% confidence interval [CI], 0.94-1.09), and 97 were seropositive for HTLV-2 (prevalence, 0.14 cases per 1,000; 95%CI, 0.11-0.17). Prevalence of HTLV-1 differed considerably by region, from 0.51 to 1.69 per 1,000. Prevalence of HTLV-2 was similar across the country (0.12-0.16). HTLV-1 prevalence was associated with female sex, older age, and residence in the north of Chile. HTVL-2 prevalence was associated with older age. The HTLV-1 prevalence among Chilean blood donors was relatively high and could be reduced by improving donor recruitment and selection in high prevalence areas. Blood center data may contribute to surveillance for HTLV-1 and HTLV-2 infections.
Asunto(s)
Anticuerpos Antivirales/sangre , Donantes de Sangre , Infecciones por HTLV-I/epidemiología , Infecciones por HTLV-II/epidemiología , Adolescente , Adulto , Chile/epidemiología , Femenino , Infecciones por HTLV-I/inmunología , Infecciones por HTLV-I/virología , Infecciones por HTLV-II/inmunología , Infecciones por HTLV-II/virología , Virus Linfotrópico T Tipo 1 Humano/inmunología , Virus Linfotrópico T Tipo 2 Humano/inmunología , Humanos , Técnicas para Inmunoenzimas , Leucocitos Mononucleares/virología , Masculino , Persona de Mediana Edad , Provirus , Estudios Seroepidemiológicos , Pruebas Serológicas , Adulto JovenRESUMEN
Human T-lymphotropic virus-type 1 (HTLV-1) is the etiologic agent of the neurologic disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Tax viral protein plays a critical role in viral pathogenesis. Previous studies suggested that extracellular Tax might involve cytokine-like extracellular effects. We evaluated Tax secretion in 18 h-ex vivo peripheral blood mononuclear cells (PBMCs) cultures from 15 HAM/TSP patients and 15 asymptomatic carriers. Futhermore, Tax plasma level was evaluated from other 12 HAM/TSP patients and 10 asymptomatic carriers. Proviral load and mRNA encoding Tax were quantified by PCR and real-time RT-PCR, respectively. Intracellular Tax in CD4(+)CD25(+) cells occurred in 100% and 86.7% of HAM/TSP patients and asymptomatic carriers, respectively. Percentage of CD4(+)CD25(+) Tax+, proviral load and mRNA encoding Tax were significantly higher in HAM/TSP patients. Western blot analyses showed higher secretion levels of ubiquitinated Tax in HAM/TSP patients than in asymptomatic carriers. In HTLV-1-infected subjects, Western blot of plasma Tax showed higher levels in HAM/TSP patients than in asymptomatic carriers, whereas no Tax was found in non-infected subjects. Immunoprecipitated plasma Tax resolved on SDS-PAGE gave two major bands of 57 and 48 kDa allowing identification of Tax and Ubiquitin peptides by mass spectrometry. Relative percentage of either CD4(+)CD25(+) Tax+ cells, or Tax protein released from PBMCs, or plasma Tax, correlates neither with tax mRNA nor with proviral load. This fact could be explained by a complex regulation of Tax expression. Tax secreted from PBMCs or present in plasma could potentially become a biomarker to distinguish between HAM/TSP patients and asymptomatic carriers.
Asunto(s)
Infecciones Asintomáticas , Productos del Gen tax/sangre , Virus Linfotrópico T Tipo 1 Humano/fisiología , Leucocitos Mononucleares/virología , Paraparesia Espástica Tropical/virología , Adulto , Anciano , Biomarcadores/sangre , Portador Sano/virología , Células Cultivadas , ADN Viral/análisis , Electroforesis en Gel de Poliacrilamida , Femenino , Virus Linfotrópico T Tipo 1 Humano/genética , Humanos , Masculino , Persona de Mediana Edad , Provirus/genética , ARN Mensajero , Ubiquitinación , Carga ViralRESUMEN
Human lymphotropic virus type 1 (HTLV-1) is a retrovirus causing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a neurodegenerative central nervous system (CNS) axonopathy. This virus mainly infects CD4(+) T lymphocytes without evidence of neuronal infection. Viral Tax, secreted from infected lymphocytes infiltrated in the CNS, is proposed to alter intracellular pathways related to axonal cytoskeleton dynamics, producing neurological damage. Previous reports showed a higher proteolytic release of soluble Semaphorin 4D (sSEMA-4D) from CD4(+) T cells infected with HTLV-1. Soluble SEMA-4D binds to its receptor Plexin-B1, activating axonal growth collapse pathways in the CNS. In the current study, an increase was found in both SEMA-4D in CD4(+) T cells and sSEMA-4D released to the culture medium of peripheral blood mononuclear cells (PBMCs) from HAM/TSP patients compared to asymptomatic carriers and healthy donors. After a 16-h culture, infected PBMCs showed significantly higher levels of CRMP-2 phosphorylated at Ser(522). The effect was blocked either with anti-Tax or anti-SEMA-4D antibodies. The interaction of Tax and sSEMA-4D was found in secreted medium of PBMCs in patients, which might be associated with a leading role of Tax with the SEMA-4D-Plexin-B1 signaling pathway. In infected PBMCs, the migratory response after transwell assay showed that sSEMA-4D responding cells were CD4(+)Tax(+) T cells with a high CRMP-2 pSer(522) content. In the present study, the participation of Tax-sSEMA-4D in the reduction in neurite growth in PC12 cells produced by MT2 (HTLV-1-infected cell line) culture medium was observed. These results lead to the participation of plexins in the reported effects of infected lymphocytes on neuronal cells.
Asunto(s)
Antígenos CD/genética , Productos del Gen tax/genética , Virus Linfotrópico T Tipo 1 Humano/metabolismo , Leucocitos Mononucleares/metabolismo , Neuritas/efectos de los fármacos , Paraparesia Espástica Tropical/metabolismo , Semaforinas/genética , Animales , Anticuerpos Neutralizantes/farmacología , Antígenos CD/metabolismo , Portador Sano , Estudios de Casos y Controles , Movimiento Celular/efectos de los fármacos , Medios de Cultivo Condicionados/farmacología , Regulación de la Expresión Génica , Productos del Gen tax/metabolismo , Virus Linfotrópico T Tipo 1 Humano/genética , Humanos , Células K562 , Leucocitos Mononucleares/patología , Leucocitos Mononucleares/virología , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuritas/metabolismo , Neuritas/ultraestructura , Células PC12 , Paraparesia Espástica Tropical/genética , Paraparesia Espástica Tropical/patología , Paraparesia Espástica Tropical/virología , Cultivo Primario de Células , Ratas , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Semaforinas/metabolismo , Transducción de SeñalRESUMEN
Although the accumulation of a misfolded and protease-resistant form of the prion protein (PrP) is a key event in prion pathogenesis, the cellular factors involved in its folding and quality control are poorly understood. PrP is a glycosylated and disulfide-bonded protein synthesized at the endoplasmic reticulum (ER). The ER foldase ERp57 (also known as Grp58) is highly expressed in the brain of sporadic and infectious forms of prion-related disorders. ERp57 is a disulfide isomerase involved in the folding of a subset of glycoproteins in the ER as part of the calnexin/calreticulin cycle. Here, we show that levels of ERp57 increase mainly in neurons of Creutzfeldt-Jacob patients. Using gain- and loss-of-function approaches in cell culture, we demonstrate that ERp57 expression controls the maturation and total levels of wild-type PrP and mutant forms associated with human disease. In addition, we found that PrP physically interacts with ERp57, and also with the closest family member PDIA1, but not ERp72. Furthermore, we generated a conditional knock-out mouse for ERp57 in the nervous system and detected a reduction in the steady-state levels of the mono- and nonglycosylated forms of PrP in the brain. In contrast, ERp57 transgenic mice showed increased levels of endogenous PrP. Unexpectedly, ERp57 expression did not affect the susceptibility of cells to ER stress in vitro and in vivo. This study identifies ERp57 as a new modulator of PrP levels and may help with understanding the consequences of ERp57 up-regulation observed in human disease.
Asunto(s)
Priones/metabolismo , Proteína Disulfuro Isomerasas/metabolismo , Animales , Línea Celular , Síndrome de Creutzfeldt-Jakob/metabolismo , Humanos , Ratones , Ratones Noqueados , Neuronas/metabolismo , Pliegue de ProteínaRESUMEN
The human retrovirus human T cell lymphotropic virus type-I (HTLV-1) is the etiologic agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Axonal degeneration in HAM/TSP patients occurs without neuron infection, with the secreted viral Tax protein proposed to be involved. We previously found that Tax secreted into the culture medium of MT-2 cells (HTLV-1-infected cell line) produced neurite retraction in neuroblastoma cells differentiated to neuronal type. To assess the relevance of Tax posttranslational modifications on this effect, we addressed the question of whether Tax secreted by MT-2 cells and peripheral blood mononuclear cells (PBMCs) of HTLV-1-infected subjects is modified. The interaction of Tax with calreticulin (CRT) that modulates intracellular Tax localization and secretion has been described. We studied Tax localization and modifications in MT-2 cells and its interaction with CRT. Intracellular Tax in MT-2 cells was assessed by flow cytometry, corresponding mainly to a 71-kDa protein followed by western blot. This protein reported as a chimera with gp21 viral protein-confirmed by mass spectrometry-showed no ubiquitination or SUMOylation. The Tax-CRT interaction was determined by confocal microscopy and coimmunoprecipitation. Extracellular Tax from HAM/TSP PBMCs is ubiquitinated according to western blot, and its interaction with CRT was shown by coimmunoprecipitation. A positive correlation between Tax and CRT secretion was observed in HAM/TSP PBMCs and asymptomatic carriers. For both proteins inhibitors and activators of secretion showed secretion through the endoplasmic reticulum-Golgi complex. Tax, present in PBMC culture medium, produced neurite retraction in differentiated neuroblastoma cells. These results suggest that Tax, whether ubiquitinated or not, is active for neurite retraction.
Asunto(s)
Calreticulina/metabolismo , Productos del Gen tax/metabolismo , Interacciones Huésped-Patógeno , Virus Linfotrópico T Tipo 1 Humano/fisiología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/virología , Mapeo de Interacción de Proteínas , Western Blotting , Células Cultivadas , Citometría de Flujo , Infecciones por HTLV-I/inmunología , Infecciones por HTLV-I/virología , Humanos , Inmunoprecipitación , Microscopía Confocal , Procesamiento Proteico-PostraduccionalRESUMEN
The Meningitis-Retention Syndrome associates aseptic meningitis and neurogenic bladder, with a vesical dysfunction that outlasts meningitis widely. Urodynamic assessment shows a detrusor palsy with normal function of the external sphincter. We report a 24-year-old male admitted for headache, fever, myalgias and acute urinary retention, which was diagnosed as a urinary tract infection. Worsening of symptoms and slight meningeal signs prompted for a lumbar puncture that yielded a cerebrospinal fluid with 94 lymphocytes, in which etiological evaluation was inconclusive. Meningeal syndrome and myalgia subsided by the fifth day, while urinary retention persisted. A magnetic resonance imaging of the brain and spinal cord done at the fifth day, showed high intensity signals in basal ganglia and central spinal cord, not altered by contrast. These images disappeared in the imaging control performed two months later. Bladder dysfunction lasted at least until the second month of follow up.
Asunto(s)
Meningitis Aséptica/complicaciones , Retención Urinaria/etiología , Encéfalo/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Meningitis Aséptica/diagnóstico , Médula Espinal/patología , Síndrome , Vejiga Urinaria Neurogénica/etiología , Adulto JovenRESUMEN
The etiology of brain abscesses is mostly polymicrobial. Streptococci and anaerobic bacteria are the most commonly isolated pathogens. We report a previously healthy female without predisposing factors, presenting with a bifrontal cerebritis caused by a Streptococcus anginosus group infection. The patient developed a brain abscess and a subdural collection with severe intracranial hypertension of fatal evolution. The etiologic diagnosis was made culturing the material obtained from the subdural collection. It is presumed that, within the Streptococcus anginosus group, Streptococus intermedius could have been the causing bacteria, given its central nervous system tissue tropism and its predisposition to form brain abscesses.
Asunto(s)
Absceso Encefálico/microbiología , Encefalitis/complicaciones , Infecciones Estreptocócicas/microbiología , Streptococcus/clasificación , Resultado Fatal , Femenino , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Streptococcus/aislamiento & purificaciónRESUMEN
The etiology of brain abscesses is mostly polymicrobial. Streptococci and anaerobic bacteria are the most commonly isolated pathogens. We report a previously healthy female without predisposingfactors, presenting with a bifrontal cerebritis caused by a Streptococcus anginosus group infection. The patient developed a brain abscess and a subdural collection with severe intracranial hypertension offatal evolution. The etiologic diagnosis was made culturing the material obtained from the subdural collection. It is presumed that, within the Streptococcus anginosus group, Streptococus intermedius could have been the causing bacteria, given its central nervous system tissue tropism and its predisposition to form brain abscesses.
Asunto(s)
Femenino , Humanos , Persona de Mediana Edad , Absceso Encefálico/microbiología , Encefalitis/complicaciones , Infecciones Estreptocócicas/microbiología , Streptococcus/clasificación , Resultado Fatal , Imagen por Resonancia Magnética , Streptococcus/aislamiento & purificaciónRESUMEN
BACKGROUND: The identification of clinical and pathological forms of Creutzfeldt Jakob Disease (CJD) started with the first cases of the disease. Genetic and biomolecular prion status assessment are allowing now a better classification. AIM: To identify the clinical forms of the disease that exist in Chile, based on clinical and neuropathological data. PATIENTS AND METHODS: Review of records of 40 patients with CJD in whom a complete history, clinical details and neuropathological studies were available. Clinical aspects were grouped into five categories: behavioral and cognitive changes, sleep and alertness, visual impairment, motor disturbances, myoclonus and epilepsy. The neuropathological examination in each case allowed us to evaluate the damage of 13 areas of the central nervous system. RESULTS: Five forms of CJD were identified. The classic form was present in 28 patients (70%), the Heidenhain form was present in five (12.5%), the ataxic form in four (10%), the form with Kuru plaques in two (5%) and the Vacuolar was present in one patient (2.5%). CONCLUSIONS: The variety and forms of CJD in Chile do not differ substantially from those found abroad.
Asunto(s)
Síndrome de Creutzfeldt-Jakob/patología , Adulto , Anciano , Encéfalo/patología , Chile , Síndrome de Creutzfeldt-Jakob/clasificación , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Creutzfeldt-Jakob disease (CJD) is the most frequent human Prion-related disorder (PrD). The detection of 14-3-3 protein in the cerebrospinal fluid (CSF) is used as a molecular diagnostic criterion for patients clinically compatible with CJD. However, there is a pressing need for the identification of new reliable disease biomarkers. The pathological mechanisms leading to accumulation of 14-3-3 protein in CSF are not fully understood, however neuronal loss followed by cell lysis is assumed to cause the increase in 14-3-3 levels, which also occurs in conditions such as brain ischemia. Here we investigated the relation between the levels of 14-3-3 protein, Lactate dehydrogenase (LDH) activity and expression of the prion protein (PrP) in CSF of sporadic and familial CJD cases. Unexpectedly, we found normal levels of LDH activity in CJD cases with moderate levels of 14-3-3 protein. Increased LDH activity was only observed in a percentage of the CSF samples that also exhibited high 14-3-3 levels. Analysis of the PrP expression pattern in CSF revealed a reduction in PrP levels in all CJD cases, as well as marked changes in its glycosylation pattern. PrP present in CSF of CJD cases was sensitive to proteases. The alterations in PrP expression observed in CJD cases were not detected in other pathologies affecting the nervous system, including cases of dementia and tropical spastic paraparesis/HTLV-1 associated myelopathy (HAM/TSP). Time course analysis in several CJD patients revealed that 14-3-3 levels in CSF are dynamic and show a high degree of variability during the end stage of the disease. Post-mortem analysis of brain tissue also indicated that 14-3-3 protein is upregulated in neuronal cells, suggesting that its expression is modulated during the course of the disease. These results suggest that a combined analysis of 14-3-3 and PrP expression pattern in CSF is a reliable biomarker to confirm the clinical diagnosis of CJD patients and follow disease progression.
Asunto(s)
Síndrome de Creutzfeldt-Jakob/líquido cefalorraquídeo , Síndrome de Creutzfeldt-Jakob/metabolismo , Regulación de la Expresión Génica , Priones/líquido cefalorraquídeo , Proteínas 14-3-3/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/metabolismo , Encéfalo/metabolismo , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/enzimología , Progresión de la Enfermedad , Femenino , Glicosilación , Humanos , L-Lactato Deshidrogenasa/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Priones/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: Limbic encephalitis is a subacute syndrome characterized by memory impairment, confusion, seizures, hypothalamic dysfunction and psychiatric symptoms. It has been associated to tumors located outside of the central nervous system. In 2007, anti-N-methyl-D-aspartate receptors (NMDAr) antibodies were found in serum and CSF of patients with this particular type of encephalitis. We report a 25-year-old female who, following upper respiratory tract symptoms, developed serious behavioral and consciousness impairment that progressed to coma. Cerebrospinal fluid (CSF) analysis showed a lymphocyte pleocytosis, the electroencephalogram was altered with a slow encephalopathic rhythm and a brain magnetic resonance imaging was normal. Infectious etiologies were ruled out. CSF and serum anti NMDA receptors antibodies were positive.
Asunto(s)
Anticuerpos/líquido cefalorraquídeo , Encefalitis Límbica/diagnóstico , N-Metilaspartato/inmunología , Receptores de N-Metil-D-Aspartato/inmunología , Adulto , Femenino , Humanos , Encefalitis Límbica/fisiopatologíaRESUMEN
There is no effective therapy for human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Glucocorticoids are effective to reduce the motor disability in these patients, but its role as anti-spastic drugs is unknown. Here it is reported the use of corticosteroids in HAM/TSP. The goal was to find reliable molecular markers linked to treatment effectiveness. The clinical efficacy of corticosteroids was studied in 22 HAM/TSP. The treatment was a single dose of 7.0 mg of systemic betamethasone. Pre-treatment samples were obtained immediately before steroid administration and post-treatment samples were collected after 5 days. Neurological disability was evaluated by the Osame's Motor Disability Scales. Relative levels of Tax, Foxp3, IL-10, TGF-ß, CTLA-4, and GITR mRNA were measured and the percentage of CD4(+) Foxp3(+) and CD4(+) Tax(+) populations was quantified in PBMCs by real-time PCR and flow cytometry, respectively. The same parameters were studied in eight untreated carriers. Betamethasone treatment showed neurological improvement in 21 HAM/TSP patients, with one patient without response to treatment. This therapy was associated with a decrease in Tax mRNA load and CD4(+) Tax(+) T cells in HAM/TSP. Simultaneously, an increase in Foxp3 mRNA and CD4(+) Foxp3(+) T cell was detected in these patients. The other markers studied had no significant changes after treatment. Clinical improvement in betamethasone-treated HAM/TSP was associated with an inverse relationship between a decrease in Tax and an increase in Foxp3 at the mRNA and protein levels. These results suggest that both Tax and Foxp3 may represent potential biomarkers for drug treatment assessments in HAM/TSP.
Asunto(s)
Betametasona/uso terapéutico , Factores de Transcripción Forkhead/sangre , Productos del Gen tax/sangre , Virus Linfotrópico T Tipo 1 Humano , Paraparesia Espástica Tropical/tratamiento farmacológico , Adulto , Anciano , Antígenos CD/sangre , Betametasona/administración & dosificación , Biomarcadores/sangre , Linfocitos T CD4-Positivos/virología , Citocinas/sangre , Femenino , Citometría de Flujo , Productos del Gen tax/genética , Virus Linfotrópico T Tipo 1 Humano/efectos de los fármacos , Virus Linfotrópico T Tipo 1 Humano/genética , Virus Linfotrópico T Tipo 1 Humano/fisiología , Humanos , Leucocitos Mononucleares , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Paraparesia Espástica Tropical/virología , Reacción en Cadena de la Polimerasa , ARN Mensajero , Carga ViralRESUMEN
Human T-cell leukemia virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease characterized by selective loss of axons and myelin in the corticospinal tracts. This central axonopathy may originate from the impairment of anterograde axoplasmic transport. Previous work showed tau hyperphosphorylation at T(181) in cerebrospinal fluid of HAM/TSP patients. Similar hyperphosphorylation occurs in SH-SY5Y cells incubated with supernatant from MT-2 cells (HTLV-I-infected lymphocytes secreting viral proteins, including Tax) that produce neurite shortening. Tau phosphorylation at T(181) is attributable to glycogen synthase kinase 3-ß (GSK3-ß) and cyclin-dependent kinase 5 (CDK5) activation. Here we investigate whether neurite retraction in the SH-SY5Y model associates with concurrent changes in other tau hyperphosphorylable residues. Threonine 181 turned out to be the only tau hyperphosphorylated residue. We also evaluate the role of GSK3-ß and CDK5 in this process by using specific kinase inhibitors (LiCl, TDZD-8, and roscovitine). Changes in both GSK3-ß active and inactive forms were followed by measuring the regulatory phosphorylable sites (S(9) and Y(216) , inactivating and activating phosphorylation, respectively) together with changes in ß-catenin protein levels. Our results showed that LiCl and TDZD-8 were unable to prevent MT-2 supernatant-mediated neurite retraction and also that neither Y(216) nor S(9) phosphorylations were changed in GSK3-ß. Thus, GSK3-ß seems not to play a role in T(181) hyperphosphorylation. On the other hand, the CDK5 involvement in tau phosphorylation was confirmed by both the increase in its enzymatic activity and the absence of MT-2 neurite retraction in the presence of roscovitine or CDK5 siRNA transfection.