Outcome of Stem Cell Transplantation in HTLV-1-Associated North American Adult T-Cell Leukemia/Lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) remains challenging to treat and has dismal outcome. Allogeneic stem-cell transplantation (allo-SCT) has promising results, but data remain scarce. In this single-center retrospective analysis of 100 patients with ATLL from north America (67 acute, 22 lymphomatous), 17 underwent allo-SCT and 5 autologous SCT (ASCT), with a median follow-up of 65 months. Post-transplant 3-years relapse incidence (RI) and non-relapse mortality (NRM) were 51% and 37%, respectively, and 3-year progression-free survival (PFS) and overall survival (OS) were 31% and 35%, respectively. ASCT 1-year RI was 80% compared to 30% in allo-SCT (p = 0.03). After adjusting for immortal-time bias, allo-SCT had significantly improved OS (HR = 0.4, p = 0.01). In exploratory multivariate analysis, patients achieving first complete response and Karnofsky score ≥ 90 had significantly better outcomes, as did Black patients, compared to Hispanics, who had worse outcome. In transplanted patients, 14 died within 2 years, 4 of which ASCT recipients. Our data are the largest ATLL transplant cohort presented to date outside of Japan and Europe. We show that allo-SCT, but not ASCT, is a valid option in select ATLL patients, and can induce long term survival, with 40% of patients alive after more than 5 years.

Are astrocytes executive cells within the central nervous system?

Experimental evidence suggests that astrocytes play a crucial role in the physiology of the central nervous system (CNS) by modulating synaptic activity and plasticity. Based on what is currently known we postulate that astrocytes are fundamental, along with neurons, for the information processing that takes place within the CNS. On the other hand, experimental findings and human observations signal that some of the primary degenerative diseases of the CNS, like frontotemporal dementia, Parkinson's disease, Alzheimer's dementia, Huntington's dementia, primary cerebellar ataxias and amyotrophic lateral sclerosis, all of which affect the human species exclusively, may be due to astroglial dysfunction. This hypothesis is supported by observations that demonstrated that the killing of neurons by non-neural cells plays a major role in the pathogenesis of those diseases, at both their onset and their progression. Furthermore, recent findings suggest that astrocytes might be involved in the pathogenesis of some psychiatric disorders as well.

Are astrocytes executive cells within the central nervous system? / ¿Son los astrocitos células ejecutivas dentro del Sistema Nervioso Central?

ABSTRACT Experimental evidence suggests that astrocytes play a crucial role in the physiology of the central nervous system (CNS) by modulating synaptic activity and plasticity. Based on what is currently known we postulate that astrocytes are fundamental, along with neurons, for the information processing that takes place within the CNS. On the other hand, experimental findings and human observations signal that some of the primary degenerative diseases of the CNS, like frontotemporal dementia, Parkinson’s disease, Alzheimer’s dementia, Huntington’s dementia, primary cerebellar ataxias and amyotrophic lateral sclerosis, all of which affect the human species exclusively, may be due to astroglial dysfunction. This hypothesis is supported by observations that demonstrated that the killing of neurons by non-neural cells plays a major role in the pathogenesis of those diseases, at both their onset and their progression. Furthermore, recent findings suggest that astrocytes might be involved in the pathogenesis of some psychiatric disorders as well.

RESUMEN Evidencias experimentales sugieren que los astrocitos desempeñan un rol crucial en la fisiología del sistema nervioso central (SNC) modulando la actividad y plasticidad sináptica. En base a lo actualmente conocido creemos que los astrocitos participan, en pie de igualdad con las neuronas, en los procesos de información del SNC. Además, observaciones experimentales y humanas encontraron que algunas de las enfermedades degenerativas primarias del SNC: la demencia fronto-temporal; las enfermedades de Parkinson, de Alzheimer, y de Huntington, las ataxias cerebelosas primarias y la esclerosis lateral amiotrófica, que afectan solo a los humanos, pueden deberse a astroglíopatía. Esta hipótesis se sustenta en hallazgos que demostraron que la muerte neuronal que en ellas ocurre es debida al compromiso de células no-neuronales que juegan rol principal en su iniciación y desarrollo. Más aún, observaciones recientes señalan que los astrocitos podrían estar implicados en la patogenia de algunas enfermedades psiquiátricas.

Astrocytes As the Main Players in Primary Degenerative Disorders of the Human Central Nervous System.

Along the last years it has been demonstrated that non-neural cells play a major role in the pathogenesis of the primary degenerative disorders (PDDs) of the human central nervous system. Among them, astrocytes coordinate and participate in many different and complex metabolic processes, in close interaction with neurons. Moreover, increasing experimental evidence hints an early astrocytic dysfunction in these diseases. In this mini review we summarize the astrocytic behavior in PDDs, with special consideration to the experimental observations where astrocytic pathology precedes the development of neuronal dysfunction. We also suggest a different approach that could be consider in human investigations in Alzheimer's and Parkinson's disease. We believe that the study of PDDs with human brain samples may hold the key of a paradigmatic physiopathological process in which astrocytes might be the main players.

[History of the Department of Neurology at the University of Buenos Aires (1887-2007)]. / Historia de la Cátedra de Neurología de la Universidad de Buenos Aires (1887-2007).

In 1887, only five years after Jean-Martin Charcot was awarded the Head of Neurology at "La Salpetrière" in Paris, José María Ramos Mejía became the first professor of Neurology in South America, at the School of Medicine of the University of Buenos Aires. Ramos Mejía convoked three assistants, the neuropathologist Christofredo Jakob, the clinician José A. Esteves and José Ingenieros. Hence it followed that Neurology in Argentina took a stand based on a clinical neurology-neuropathology approach (1941-1987) followed by a clinical-semiological attitude, finally inserting itself within the modern times (1987-present) by creating subspecialties. Throughout its history, Argentina has made remarkable contributions to Neurology, such as the diagnosis and pathogenesis of the nervous system involvement occurring in some regional endemic disorders -for instance, Chagas' disease-, the clinical approach to the diagnosis of dementias, and the pathogenesis of extrapyramidal illnesses and other primary degenerative diseases of the central nervous system, mainly amyotrophic lateral sclerosis. On the other hand, in recent years globalization allowed neurologists to participate in international cooperative projects, favoring a swifter development in the practice of this discipline.

Could astrocytes be the primary target of an offending agent causing the primary degenerative diseases of the human central nervous system? A hypothesis.

Most of the named primary degenerative diseases of the human central nervous system have been attributed to a direct, primary damage of some particular population of neurons. Within the spectrum of these illnesses there are disorders like amyotrophic lateral sclerosis, fronto-temporal dementia, Alzheimer's dementia, Parkinson's disease, Huntington's dementia and cerebellar ataxias affecting exclusively the human species. In the last years it has been shown that non-neural cells, mainly astrocytes, have a crucial role in the starting and development of these diseases. We suggest that the causative agent of these illnesses gets home first within the astrocytes, rather than the neurons, making them sick by modifying the structure of some proteins; from these cells the abnormal process would start a trip to other astrocytes having the same genetic, metabolic, structural and functional profiles that the originally affected astrocytes have, going through the gap junctions which connect that particular population devoted to a particular set of neurons. This appears to be a likely hypothesis because the astrocytes related to a defined population of neurons have their own, private properties and characteristics needed to support one particular set of neurons performing a defined function, making them a different and unique population, a fact which would limit the spreading of the disease to those astrocytes, sparing other astrocyte populations which do not share those characteristics. If this were the mechanism underlying these illnesses, the neurons, which their health depends on those astrocytes, would be deprived of their patronage and would start all the changes that characterizes a programmed cell death, and the clinical manifestations of a defined pathology would consequently appear.

[Amyotrophic lateral sclerosis: is the astrocyte the cell primarily involved?]. / Esclerosis lateral amiotrófica: ¿es el astrocito la célula primariamente dañada?

So far, amyotrophic lateral sclerosis (ALS) is thought as due to a primary insult of the motor neurons. None of its pathogenic processes proved to be the cause of the illness, nor can be blamed environmental agents. Motor neurons die by apoptosis, leaving the possibility that their death might be due to an unfriendly environment, unable to sustain their health, rather than being directly targeted themselves. These reasons justify an examination of the astrocytes, because they have the most important role controlling the neurons' environment. It is known that astrocytes are plastic, enslaving their functions to the requirements of the neurons to which they are related. Each population of astrocytes is unique, and if it were affected the consequences would reach the neurons that it normally sustains. In regard to the motor neurons, this situation would lead to a disturbed production and release of astrocytic neurotransmitters and transporters, impairing nutritional and trophic support as well. For explaining the spreading of muscle symptoms in ALS, correlated with the type of spreading observed at the cortical and spinal motor neurons pools, the present hypotheses suggests that the illness-causing process is spreading among astrocytes, through their gap junctions, depriving the motor neurons of their support. Also it is postulated that a normal astrocytic protein becomes misfolded and infectious, inducing the misfolding of its wild type, travelling from one protoplasmatic astrocyte to another and to the fibrous astrocytes encircling the pyramidal pathway which joints the upper and lower motoneurones.

Esclerosis lateral amiotrófica: ¿es el astrocito la célula primariamente dañada? / [Amyotrophic lateral sclerosis: is the astrocyte the cell primarily involved?].

So far, amyotrophic lateral sclerosis (ALS) is thought as due to a primary insult of the motor neurons. None of its pathogenic processes proved to be the cause of the illness, nor can be blamed environmental agents. Motor neurons die by apoptosis, leaving the possibility that their death might be due to an unfriendly environment, unable to sustain their health, rather than being directly targeted themselves. These reasons justify an examination of the astrocytes, because they have the most important role controlling the neurons’ environment. It is known that astrocytes are plastic, enslaving their functions to the requirements of the neurons to which they are related. Each population of astrocytes is unique, and if it were affected the consequences would reach the neurons that it normally sustains. In regard to the motor neurons, this situation would lead to a disturbed production and release of astrocytic neurotransmitters and transporters, impairing nutritional and trophic support as well. For explaining the spreading of muscle symptoms in ALS, correlated with the type of spreading observed at the cortical and spinal motor neurons pools, the present hypotheses suggests that the illness-causing process is spreading among astrocytes, through their gap junctions, depriving the motor neurons of their support. Also it is postulated that a normal astrocytic protein becomes misfolded and infectious, inducing the misfolding of its wild type, travelling from one protoplasmatic astrocyte to another and to the fibrous astrocytes encircling the pyramidal pathway which joints the upper and lower motoneurones.

Esclerosis lateral amiotrófica: ¿es el astrocito la célula primariamente dañada? / [Amyotrophic lateral sclerosis: is the astrocyte the cell primarily involved?].

So far, amyotrophic lateral sclerosis (ALS) is thought as due to a primary insult of the motor neurons. None of its pathogenic processes proved to be the cause of the illness, nor can be blamed environmental agents. Motor neurons die by apoptosis, leaving the possibility that their death might be due to an unfriendly environment, unable to sustain their health, rather than being directly targeted themselves. These reasons justify an examination of the astrocytes, because they have the most important role controlling the neurons environment. It is known that astrocytes are plastic, enslaving their functions to the requirements of the neurons to which they are related. Each population of astrocytes is unique, and if it were affected the consequences would reach the neurons that it normally sustains. In regard to the motor neurons, this situation would lead to a disturbed production and release of astrocytic neurotransmitters and transporters, impairing nutritional and trophic support as well. For explaining the spreading of muscle symptoms in ALS, correlated with the type of spreading observed at the cortical and spinal motor neurons pools, the present hypotheses suggests that the illness-causing process is spreading among astrocytes, through their gap junctions, depriving the motor neurons of their support. Also it is postulated that a normal astrocytic protein becomes misfolded and infectious, inducing the misfolding of its wild type, travelling from one protoplasmatic astrocyte to another and to the fibrous astrocytes encircling the pyramidal pathway which joints the upper and lower motoneurones.

Is amyotrophic lateral sclerosis a primary astrocytic disease?

Amyotrophic lateral sclerosis (ALS) is thought to be due to primary involvement of motor neurons. Pathogenic mechanisms underlying its appearance are relatively well known and include inflammation, excitotoxicity, oxidative stress, endoplasmic reticulum stress, protein damage, genetic abnormalities and type of neuronal death. Although these processes have been investigated in detail in the past two decades none of them appear to be the cause of the illness. In addition several possible environmental agents have been investigated but the results, in every case, were conflicting and therefore inconclusive. However, since the motor neurons display the features of apoptosis in this illness, the possibility remains that the motor neurons die because of a hostile environment, one that is unable to sustain their health, rather than being directly targeted themselves. The above considerations lead to an examination of astrocytes, for these cells play a key role in controlling the environment of neurons. It is known that astrocytes are exquisitely plastic, adapting their metabolism and behaviour to the needs of the neurons they contact. Each population of astrocytes is therefore unique and, were one to be adversely affected at the start of a disease process, the consequences would extend to the neurons that it normally chaperoned. The disturbed relationship might involve inappropriate production and secretion of astrocytic neurotransmitters, defective transport of glutamate and impaired trophic and metabolic support of the motor neurons. In order to explain the spread of weakness and pyramidal signs in ALS patients, which is very often from one group of muscles to a neighbouring one, it is postulated that, within the spinal cord, the brainstem and the motor cortex, the disease-causing process is also spreading-in this case, from one group of astrocytes to its neighbours. A misfolded protein, possibly a prion-like protein, would be a candidate for this type of transmission.

Morphological abnormalities in mitochondria of the skin of patients with sporadic amyotrophic lateral sclerosis.

OBJECTIVES: Mitochondrial dysfunction has been reported in the central nervous system, hepatocytes and peripheral blood lymphocytes from patients with sporadic amyotrophic lateral sclerosis (SALS). However, the status of skin mitochondria has not been reported, in spite of the fact that SALS patients present skin abnormalities. The objective of the present study was to compare mitochondrial ultrastructural parameters in keratinocytes from patients with SALS and healthy controls. METHODS: Our study was based on the analysis of 112 skin mitochondria from 5 SALS patients and 99 organelles from 4 control subjects by electron microscopy. RESULTS: Computerized image analysis showed that mitochondrial major axis length, area and perimeter of the organelle were significantly smaller in SALS respect of healthy control subjects. Morphologically, SALS mitochondria presented cristolysis and breakage of the outer membrane. CONCLUSIONS: Mitochondrial dysfunction in the skin may possibly reflect changes occurring in mitochondria of the central nervous system. The analysis of mitochondrial morphology in this tissue may be of value to follow disease progression and, eventually, the effectiveness of current therapies for SALS.

Morphological abnormalities in mitochondria of the skin of patients with sporadic amyotrophic lateral sclerosis / Alteraciones morfológicas en las mitocondrias en la piel de enfermos con esclerosis lateral amiotrófica esporádica

OBJECTIVES: Mitochondrial dysfunction has been reported in the central nervous system, hepatocytes and peripheral blood lymphocytes from patients with sporadic amyotrophic lateral sclerosis (SALS). However, the status of skin mitochondria has not been reported, in spite of the fact that SALS patients present skin abnormalities. The objective of the present study was to compare mitochondrial ultrastructural parameters in keratinocytes from patients with SALS and healthy controls. METHODS: Our study was based on the analysis of 112 skin mitochondria from 5 SALS patients and 99 organelles from 4 control subjects by electron microscopy. RESULTS: Computerized image analysis showed that mitochondrial major axis length, area and perimeter of the organelle were significantly smaller in SALS respect of healthy control subjects. Morphologically, SALS mitochondria presented cristolysis and breakage of the outer membrane. CONCLUSIONS: Mitochondrial dysfunction in the skin may possibly reflect changes occurring in mitochondria of the central nervous system. The analysis of mitochondrial morphology in this tissue may be of value to follow disease progression and, eventually, the effectiveness of current therapies for SALS.

OBJETIVOS: Existen alteraciones en la función mitocondrial en el sistema nervioso central, en hepatocitos y en linfocitos de sangre periférica en SALS. Aunque, no se ha estudiado si existen cambios estructurales en las mitocondrias de la piel. Nuestro objetivo fue comparar la ultraestructura de mitocondrias en queratinocitos de enfermos con SALS con la de controles sanos. MÉTODO: Fueron analizadas en el microscopio electrónico 112 mitocondrias dérmicas de 5 pacientes y 99 provenientes de 4 controles. RESULTADOS: EL análisis computarizado mostró que el eje mayor mitocondrial, el área y el perímetro de las organelas fueran significativamente menor que en controles. Morfológicamente, las mitocondrias de SALS presentaron cristólisis y ruptura de la membrana externa. CONCLUSIÓN: La alteración mitocondrial en la piel posiblemente refleje cambios que también ocurran en las mitocondrias neuronales. Este análisis morfológico de las mitocondrias podría tener valor en el seguimiento de la enfermedad y eventualmente en la evaluación de la efectividad de futuras terapias.

Epidemiology of amyotrophic lateral sclerosis patients in a centre in Buenos Aires / Epidemiología de los pacientes con esclerosis lateral amiotrófica en el centro de Buenos Aires

Sporadic amyotrophic lateral sclerosis (sALS) is considered a multifactorial disease with genetic and environmental factors causing motor neuron degeneration. OBJECTIVE: To describe the epidemiological and occupational characteristics of patients with sALS who attended the Ramos Mejía Hospital at Buenos Aires, Argentina. METHOD: We analyzed the medical records of sALS patients diagnosed between 2001 and 2008. All occupations were coded according to the International Standard Classification of Occupation (ISCO). RESULTS: 187 patients were assessed, 38.5 percent were women and 61.5 percent men. Mean age at diagnosis was 55 years. 16 percent of them came from rural areas; 68 percent of the studied population had no health insurance. 40 percent were employed in elementary occupations, 19 were technicians and 8 handicraftsmen. CONCLUSION: The most represented profession was elementary occupation. A large proportion of patients came from rural areas, which might suggest an increased risk of environmental exposure to an unknown agent in those regions.

La esclerosis lateral amiotrófica esporádica (ELAe) es considerada una enfermedad multifactorial. OBJETIVO: Describir las características epidemiológicas y laborales de un grupo de pacientes con ELAe que fueron evaluados en el Hospital Ramos Mejía de Buenos Aires, Argentina. MÉTODO: Se analizaron los registros médicos de pacientes con ELAe diagnosticados entre 2001 y 2008. Las ocupaciones fueron codificadas de acuerdo a la Clasificación Internacional de Ocupaciones (ISCO). RESULTADOS: 187 pacientes fueron evaluados, 38,5 por ciento mujeres y 61,5 por ciento hombres. Edad media al diagnóstico 55 años. 16 por ciento procedían de zonas rurales, 68 por ciento no tenía seguro de salud. 40 por ciento se encontraba empleado en ocupaciones elementales, 19 por ciento eran técnicos , 8 por ciento artesanos y 7 por ciento operadores de maquinas. CONCLUSIÓN: La profesión más representada fue la de ocupación elemental. Una gran proporción de los pacientes provenían de zonas rurales, lo que podría sugerir un mayor riesgo de exposición ambiental a un agente desconocido en esas regiones.

Sporadic amyotrophic lateral sclerosis: new hypothesis regarding its etiology and pathogenesis suggests that astrocytes might be the primary target hosting a still unknown external agent.

This article briefly describes the already known clinical features and pathogenic mechanisms underlying sporadic amyotrophic lateral sclerosis, namely excitoxicity, oxidative stress, protein damage, inflammation, genetic abnormalities and neuronal death. Thereafter, it puts forward the hypothesis that astrocytes may be the cells which serve as targets for the harmful action of a still unknown environmental agent, while neuronal death may be a secondary event following the initial insult to glial cells. The article also suggests that an emergent virus or a misfolded infectious protein might be potential candidates to accomplish this task.

Sporadic amyotrophic lateral sclerosis: new hypothesis regarding its etiology and pathogenesis suggests that astrocytes might be the primary target hosting a still unknown external agent / Esclerosis lateral amiotrófica esporádica: nueva hipótesis relacionada con su etiología y patogenia que sugiere que los astrocitos podrían ser el blanco primario alojando un agente nocivo aun desconocido

This article briefly describes the already known clinical features and pathogenic mechanisms underlying sporadic amyotrophic lateral sclerosis, namely excitoxicity, oxidative stress, protein damage, inflammation, genetic abnormalities and neuronal death. Thereafter, it puts forward the hypothesis that astrocytes may be the cells which serve as targets for the harmful action of a still unknown environmental agent, while neuronal death may be a secondary event following the initial insult to glial cells. The article also suggests that an emergent virus or a misfolded infectious protein might be potential candidates to accomplish this task.

El artículo presente describe, brevemente, las características clínicas y los mecanismos patogénicos de la esclerosis lateral amiotrófica esporádica, tales como la excitotoxicidad, el stress oxidativo, el daño proteico, la inflamación, las anormalidades genéticas y la muerte neuronal. Luego de ello, sugiere la posibilidad hipotética de que los astrocitos podrían ser el blanco primario de la acción de una agente ambiental, externo, aún desconocido, y que la muerte neuronal aconteciera secundariamente a ese daño astrocitario inicial. El artículo concluye discutiendo la posibilidad de que un virus ambiental o endógeno o una proteína mal plegada, que adquiriera características de infectividad, puedan ser la causa de la enfermedad.

Epidemiology of amyotrophic lateral sclerosis patients in a centre in Buenos Aires.

UNLABELLED: Sporadic amyotrophic lateral sclerosis (sALS) is considered a multifactorial disease with genetic and environmental factors causing motor neuron degeneration. OBJECTIVE: To describe the epidemiological and occupational characteristics of patients with sALS who attended the Ramos Mejía Hospital at Buenos Aires, Argentina. METHOD: We analyzed the medical records of sALS patients diagnosed between 2001 and 2008. All occupations were coded according to the International Standard Classification of Occupation (ISCO). RESULTS: 187 patients were assessed, 38.5% were women and 61.5% men. Mean age at diagnosis was 55 years. 16% of them came from rural areas; 68% of the studied population had no health insurance. 40% were employed in elementary occupations, 19 were technicians and 8 handicraftsmen. CONCLUSION: The most represented profession was elementary occupation. A large proportion of patients came from rural areas, which might suggest an increased risk of environmental exposure to an unknown agent in those regions.

Progesterone and cortisol levels in sporadic amyotrophic lateral sclerosis (sALS): correlation with prognostic factors.

UNLABELLED: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder. Worse prognostic factors in ALS are: (a) advanced age, (b) bulbar onset, and (c) short time between onset and diagnosis. Progesterone (PROG) has been associated with neuroprotective and promyelinating activities in injury, ischemia and degeneration of the central and peripheral nervous system. Cortisol is connected to the response to stress situations and could contribute to neuronal damage. The goals of this study were: (i) to investigate whether PROG levels are modified by ALS prognostic factors and (ii) to determine whether cortisol follows the same pattern. We determined serum steroid levels in 27 patients with sporadic ALS (sALS) and 21 controls. Both steroid hormones showed significantly increased levels in ALS patients versus controls (mean±SEM: PROG ALS vs. CONTROL: 0.54±0.05 vs. 0.39±0.04 ng/mL, p<0.05; cortisol ALS vs. CONTROL: 17.02±1.60 vs. 11.83±1.38 µg/dL, p<0.05).1 A trend towards higher levels of PROG were demonstrated in spinal onset patients compared with bulbar onset (p=0.07), positive correlation with survival time (RRho=0.43, p=0.04) and a trend towards significance with time to diagnosis (RRho=0.36, p=0.06). These correlations have not been demonstrated for cortisol. Elevated serum steroid levels in sALS were probably due to hyperfunction of the hypothalamic-pituitary-adrenal axis. However, only PROG correlated with better prognostic factors. Future studies will determine if the different behavior of PROG and cortisol relate to any particular role they might play during the course of this motor neuron degenerative disease.