Clasificación de los gliomas astrocíticos. Breves consideraciones / Classification of astrocyte gliomas. Brief considerations

Introducción. Los gliomas constituyen aproximadamente el 50 por ciento de los tumores cerebrales primarios del sistema nervioso central de los adultos. Dentro de ellos los tumores astrocíticos ocupan entre el 70 y 75 por ciento. Su gradación ha sido históricamente muy controvertida, a pesar de lo importante que resulta en el pronóstico y la planificación del tratamiento. Desarrollo. Hemos realizado una revisión de las propuestas existentes para clasificar las neoplasias astrogliales, desde los primeros trabajos hasta la última clasificación de la Organización Mundial de la Salud. Todas han perseguido el objetivo de conocer el grado histopatológico de la neoplasia, relacionarlo con la supervivencia y predecir pronóstico. Conclusión. La profundización en el conocimiento de estos tumores será la meta de los profesionales y estudiosos del tema, en el arduo camino de encontrar un mejor y eficiente tratamiento para estos enfermos (AU)

[Molecular studies in Cuban patients with progressive external ophthalmoplegia]. / Estudios moleculares en pacientes cubanos con oftalmoplejía externa progresiva.

INTRODUCTION: The mitochondria, subcellular organelles which possess their own DNA (mtDNA), produce most of the energy, in the form of ATP, which is necessary for life. This mtDNA may have diverse molecular defects which have been associated with a great variety of clinical syndromes. Deletions in mtDNA are one of the common mutations in patients with mitochondrial myopathies, which in the great majority present with the common symptom of progressive external ophthalmoplegia. In this study we report our findings in eight Cuban families with suspected mitochondrial disease. OBJECTIVES: To characterize these patients from the molecular point of view, which would allow a preliminary understanding of the behavior of these deletions in Cuban patients. PATIENTS AND METHODS: We studied nine patients from eight Cuban families in whom mitochondrial encephalomyopathy was suspected. We analyzed the presence of ragged red fibres, the enzymatic activity of the mitochondrial respiratory chain and detection of mtDNA mutations. We used the technique of restriction length polymorphism analysis for detection of deletions. RESULTS: Histochemical studies showed the presence of COX negative ragged red fibres in seven of the patients studied. The enzymatic activity of the mitochondrial respiratory chain was normal in all the patients. We detected four patients with single deletions of mtDNA, and one with multiple deletions and of the patients had the A3243G mutation. CONCLUSIONS: With the methods used we were able to determine the presence of a mitochondrial disorder in seven of the eight families studied and deletions of mtDNA were detected as the cause of the illness in five. The disorder was always associated with progressive external ophthalmoplegia and COX negative ragged red fibres.

Estudios moleculares en pacientes cubanos con oftalmoplejía externa progresiva / Molecular studies in cuban patients with progressive external ophthalmoplegia

Introducción. Las mitocondrias, organelas subcelulares que poseen su propio ADN (ADNmt), producen la mayor parte de la energía, en forma de ATP, necesaria para la vida. Ese ADNmt puede presentar diversos defectos moleculares que se han asociado a una gran variabilidad de síndromes clínicos. Las deleciones en el ADNmt es una de las mutaciones comunes en pacientes con miopatías mitocondriales, los cuales, en su gran mayoría, presentan como síntoma común la oftalmoplejía externa progresiva. En este trabajo estudiamos ocho familias cubanas, en las cuales se sospechó una enfermedad mitocondrial. Objetivos. Caracterizar desde el punto de vista molecular a estos pacientes, lo que permite conocer de manera preliminar el comportamiento de las deleciones en pacientes cubanos. Pacientes y métodos. Se estudiaron nueve pacientes correspondientes a ocho familias cubanas, en las cuales se sospechaba una encefalomiopatía mitocondrial. Se analizó la presencia de fibras rojas rasgadas, la actividad enzimática de la cadena respiratoria mitocondrial y la detección de mutaciones en el ADNmt. Se utilizó la técnica de polimorfismo en longitud de los fragmentos de restricción para la detección de deleciones. Resultados. Estudios histoquímicos mostraron la presencia de fibras rojo rasgadas COX negativas en siete de los pacientes analizados. La actividad enzimática de la cadena respiratoria mitocondrial fue normal en todos los pacientes. Detectamos cuatro pacientes con deleciones únicas del ADNmt y uno con deleciones múltiples. Ninguno de los pacientes presentó la mutación puntual A3243G. Conclusiones. Con los métodos utilizados se logró definir la presencia de una enfermedad mitocondrial en siete de las ocho familias estudiadas, de las cuales en cinco se detectó deleción en el ADNmt como causa de la enfermedad. La enfermedad estuvo siempre asociada a oftalmoplejía externa progresiva y fibras rojo rasgadas COX negativas (AU)

[Classification of the astrocytic gliomas. Brief comments]. / Clasificación de los gliomas astrocíticos. Breves consideraciones.

INTRODUCTION: Gliomas make up approximately 50% of the primary brain tumors of the central nervous system in adults. Astrocytes from between 70 and 75% of these tumors. Historically grading these has been very controversial, in spite of its importance for prognosis and planning treatment. DEVELOPMENT: We have reviewed existing proposals for the classification of astroglial neoplasias, from the initial studies to the latest classification by the World Health Organization. All have pursued the objective of finding the histopathological grade of the neoplasm to relate it to survival and predict prognosis. CONCLUSION: Further knowledge of these tumors is the aim of professionals and others interested in the subject, in the difficult course of finding better and more efficient treatment for these patients.

Clasificación de los gliomas astrocíticos. Breves consideraciones / Classification of astrocyte gliomas. Brief considerations

Los gliomas constituyen aproximadamente el 50 por ciento de los tumores cerebrales primarios del sistema nervioso central de los adultos. Dentro de ellos los tumores astrocíticos ocupan entre el 70 y 75 por ciento. Su gradación ha sido históricamente muy controvertida, a pesar de lo importante que resulta en el pronóstico y la planificación del tratamiento. Hemos realizado una revisión de las propuestas existentes para clasificar las neoplasias astrogliales, desde los primeros trabajos hasta la última clasificación de la OMS. Todos han perseguido el objetivo de conocer el grado histopatológico de la neoplasia, relacionarlo con la supervivencia y predecir pronóstico. La profundización en el conocimiento de estos tumores será la meta de los profesionales y estudiosos del tema, en el arduo camino de encontrar un mejor y eficiente tratamiento p0ara estos enfermos

Neuropatía leprosa: caracterización de la casuística entre 1962 y 1995 / Neuropathy of leprosy: the characteristics of cases seen between 1962-1995

Se evaluaron 18 biopsias de nervio diagnosticadas como neuropatía por lepra y realizadas en el Instituto Nacional de Neurología y Neurocirugía de La Habana, Cuba, en el transcurso de toda su historia, y se revisaron las historias clínicas de todos los pacientes ingresados en el centro. La muestra se caracterizó por edad, sexo, cuadro clínico neurológico, nervios más comprometidos, lesiones de piel, estudios electrofisiológicos y descripción del estudio anatomopatológico. La mayoría de los pacientes eran del sexo masculino y sus edades en el 100/100 eran las reconocidas como laboralmente activas. El patron neuropático más frecuente fue el mononeuropático múltiple y la calidad, sensitiva pura o mixta, fue predominantemente sensitiva. Los nervios más afectados fueron el cubital en 10 pacientes y el mediano en 6. Las lesiones de piel más frecuentes fueron las máculas anestésicas. La anatomía patológica mostró infiltrado inflamatorio en todos los pacientes y el bacilo estuvo ausente sólo en uno

Spinocerebellar ataxia 2 (SCA2): morphometric analyses in 11 autopsies.

Eleven autopsies of patients from the large founder-population with dominantly inherited spinocerebellar ataxia 2 (SCA2) in Holguín, Cuba, were analyzed by the same observers, including quantitative microscopic evaluation. As expected in this disease with highly unstable polyglutamine expansions, considerable variability was observed, which correlated to age at onset and to progression of clinical symptoms. The degeneration of the olivopontocerebellar regions as in classical olivopontocerebellar atrophy occurred early and severely in SCA2. The neuropathological progression soon included neuronal loss in the substantia nigra, striatum, pallidum and later even the neocortex, while the dentate nucleus was consistently spared. This widespread degeneration pattern goes clearly beyond purely cerebellar degenerations such as SCA5 and 6 and beyond spinocerebellar degenerations such as SCA1, 3, 7, also involves regions known to degenerate in Huntington's disease, and is quite similar to the degeneration pattern in sporadic patients with multi-system atrophy.

[Neuropathy of leprosy: characteristics of cases in 1962-1995]. / Neuropatía leprosa: caracterización de la casuística entre 1962 y 1995.

INTRODUCTION: Neuropathy due to leprosy is the most frequent cause of peripheral nervous system disorders due to an infective agent, one of the commonest aetiologies of peripheral neuropathy, and also one of the few peripheral neuropathies which is curable. Hansen's disease, initially and predominantly involves the skin, so it is not usually seen by a neurologist; a neurologist sees cases which are difficult to diagnose and often after the condition has been ruled out by other doctors from other medical specialties. PATIENTS AND METHODS: In the National Institute of Neurology and Neurosurgery of La Habana, Cuba, 18 nerve biopsies were studied (during its history), that had been diagnosed as leprous neuropathy. We reviewed the clinical histories of all the patients admitted to this centre. The sample was characterized by: age, sex, neurological clinical picture, nerves most affected, skin lesions, electrophysiological studies and a description of the anatomopathological findings. RESULTS AND DISCUSSION: Most patients were male and all (100%) were adults of 'working age' (19-65 years). The most frequent neuropathic pattern was multiple mono-neuropathy (78%) and the quality, purely sensitive or mixed was predominantly sensitive (100%). The nerves most affected were the ulnar (10 patients) and median (6 patients). The most frequent skin lesions were anesthetic maculae. Anatomo-pathological study showed inflammatory infiltration in all patients and the bacillus was absent in only one case.

Neuropatía leprosa: caracterización de la casuística entre 1962 y 1965 / Neuropathy of leprosy : the characteristics of cases seen between 1962 and 1995

Introducción. La neuropatía por lepra constituye la causa más frecuente de afectación del sistema nervioso periférico por un agente infeccioso y una de las etiologías más comunes de la neuropatía periférica; además, es una de las pocas neuropatías curables. La enfermedad de Hansen, al provocar afectación inicial y predominante de la piel, no es abordada en general porel neurólogo a quien llegan casos de difícil diagnóstico, muchas veces después de ser descartada la enfermedad por otras especialidades. Pacientes y métodos. Se evaluaron 18 biopsias de nervio diagnosticadas como neuropatía por lepra y realizadas en el Instituto Nacional de Neurología y Neurocirugía de La Habana, Cuba, en el transcurso de toda su historia, y revisamos las historias clínicas de todos los pacientes ingresados en el centro. La muesra se caracteriza por: edad, sexo, cuadro clínico neurológico, nervios más comprometidos, lesiones de piel, estudios electrofisiológicos y descripción del estudio anatomopatológico. Resultados y discusión. La mayoría de los pacientes eran del sexo masculino y sus edades en el 100 por ciento eran las reconocidas como laboralmente activas (19-65 años). El patrón neuropático más frecuente fue el mononeuropático múltiple (78 por ciento) y la calidad, sensitiva pura o mixta, fue predominantemente sensitiva (100 por ciento). Los nervios más afectados fueron el cubital (10 pacientes) y el mediano (6 pacientes). Las lesiones de piel más frecuentes fueron las máculas anestésicas. La anatomía patológica mostró infiltrado inflamatorio en todos los pacientes y el bacilo estuvo ausente sólo en uno(AU)

En-bloc resection of the distal fibula for aneurysmal bone cyst.

A 21-year-old woman who presented with a voluminous aneurysmal bone cyst in the distal left fibula was treated with en-bloc resection. After 30 months of follow-up, the stability and range of motion of the left ankle were similar to that of the contralateral ankle.

Dominantly inherited olivopontocerebellar atrophy from eastern Cuba. Clinical, neuropathological, and biochemical findings.

A form of dominantly inherited olivopontocerebellar atrophy (OPCA) occurs commonly in persons of Spanish ancestry in northeastern Cuba. Its prevalence in the Province of Holguin is 41 per 100,000, a figure much higher than that found in western Cuba or in other parts of the world. The high prevalence is probably the result of a founder effect, but might be due to an interaction between a mutant gene and an unidentified environmental neurotoxin. We describe the clinical features of this disorder, and the neuropathological abnormalities in 7 autopsied patients. In addition, we report biochemical findings in plasma, cerebrospinal fluid (CSF) and urine obtained from 10 living OPCA patients. Quantitation of amino acids in fasting plasma showed a number of differences between the Cuban patients and healthy Canadian controls, but these are likely to have been caused by dietary differences. Amino acid concentrations in the CSF of the Cuban OPCA patients were similar to those of healthy Cuban controls, except for a decreased concentration of ethanolamine. Mean concentrations of dopamine metabolites were significantly low in the CSF of the OPCA patients, corresponding to neuronal depletion observed in the substantia nigra of autopsied cases. Examination of the patients' urines provided no evidence that either cyanide or 3-acetylpyridine is involved in causing this form of OPCA.

Regulation of the pentose phosphate pathway in human astrocytes and gliomas.

Several aspects of the regulation of the pentose phosphate pathway were examined in cultured normal human cortical astrocytes and gliomas of pathological grades I-IV. The generation of radiolabeled CO2 from [1-14C]glucose by the oxidative arm of the pentose phosphate pathway is a saturable process and has a maximum flux rate of 8-9 nmol/hr/mg cell protein. The flux can be blocked by the glycolytic inhibitor iodoacetamide but is unaffected by agents which inhibit oxidative phosphorylation. The magnitude of the pentose phosphate flux is directly related to the glioma grade. Grade IV gliomas (glioblastoma) show a pentose phosphate flux rate of approximately 4% of the total glucose flux. The flux rate can be increased by pharmacological agents which decrease the NADPH/NADP+ ratio. Both the activity and the regulation of glioma glucose-6-phosphate dehydrogenase (G6PDH) are altered in high-grade gliomas. While the affinity constants for cofactors in whole homogenates were not significantly different in glioma or normal astrocyte homogenates, normal astrocytes have a lower Km for glucose-6-phosphate and a G6PDH activity which is 10-fold greater than that of gliomas. NADPH is a powerful regulator of G6PDH activity in the normal astrocytes and in gliomas. At a NADPH/NADP+ ratio of 7:1 the normal astrocyte G6PDH is entirely inhibited, while the glioma enzyme is only 70% inhibited even at a ratio of 20:1. Increased metabolic flux through the oxidative arm of the pentose phosphate pathway is apparently due to an altered form of G6PDH.

Enzymes of glucose metabolism in cultured human gliomas: neoplasia is accompanied by altered hexokinase, phosphofructokinase, and glucose-6-phosphate dehydrogenase levels.

The enzymes of glycolysis and selected enzymes of the pentose phosphate pathways were measured by fluorometric methods in extracts prepared from cultures of normal cortical human astrocytes and from cultures derived from low-grade (II) or high-grade (IV) gliomas. The hexokinase and phosphofructokinase levels of the low-grade glioma-derived line were not significantly different from those of the normal astrocyte cultures. However, the activities of hexokinase and phosphofructokinase were consistently and significantly increased in the high-grade glioma-derived lines. The activity of glucose-6-phosphate dehydrogenase was significantly decreased in all glioma-derived lines and by more than 90% in the high-grade-derived lines. Other enzymes of the glycolytic pathway were not significantly different from those of normal astrocytes, or they showed a variation inconsistently related to the neoplastic state. Glucose flux is not apparently regulated to a significant degree of hexokinase in glioma-derived lines, since the measured Vmax values are in substantial excess over the measured flux rates. Reversible binding of hexokinase to the particulate fraction was observed in both the normal astrocytes cultures and the high-grade glioma-derived lines. A twofold displacement of particulate hexokinase by ATP, ADP, 1-O-methylglucose, sorbitol-6-phosphate, and dibutyryl cyclic AMP was observed in the high-grade glioma-derived lines. The degree of displacement by various agents and the basal ratio of free/bound was not significantly different between the transformers and the nontransformants. The hexokinase from both the gliomas and the normal astrocytes was noncompetitively inhibited by the glucose analogue 2-deoxy-d-glucose. Phosphofructokinase activity is close to the observed glucose flux rates in both the normal astrocyte and the glioma-derived cultures. The phosphofructokinase activity of normal astrocytes is activated twofold or more by ADP, AMP, fructose-2,6-diphosphate, and Pi. However, these same ligands activate phosphofructokinase by less than twofold in a typical high-grade glioma-derived line. ATP, dibutyryl cyclic AMP, and citrate inhibit glioma and normal astrocytic phosphofructokinase, but the magnitude of the inhibition is much less than in the glioma-derived lines.

Glucose metabolism in human gliomas: correspondence of in situ and in vitro metabolic rates and altered energy metabolism.

The rates of disappearance of glucose from the medium of 13 human glioma-derived cell lines and one cultured of normal human cortical astrocytes were determined by fluorometric techniques. High-grade glioma-derived cultures showed a range of glucose consumption between 1 and 5 nmol/min/mg protein. Normal astrocyte cultures and cultures derived from grades I-III gliomas had a glucose consumption rate of 2-3 nmol/min/mg protein. Seven high-grade glioma lines were derived from surgical samples taken from patients who had been scanned by 18F-2-deoxy-d-glucose positron computed tomography. The rate of glucose consumption in these high-grade glioma-derived lines was close to the maximum local cerebral metabolic rate for glucose (LCMRglc) measured in situ in the tumors from which the cultures were derived. In cultured glioma-derived lines, approximately one-half of the glucose consumed was recovered as lactate and pyruvate, suggesting a reliance of glioma cells on aerobic glycolysis. ATP and phosphocreatine (PCr) levels were variable in the glioma-derived lines, and ATP was lower in the glioma-derived lines than in the normal astrocytes. Levels and regulation of glycogen differed significantly among the various glioma-derived cell lines. Glycogen content did not diminish as glucose was consumed, suggesting that glycogen utilization is not tightly regulated by the glucose metabolic rate. These results suggest that human glioma-derived cell cultures (1) adequately reflect the metabolic capacity of gliomas in situ and (2) are significantly altered in several aspects of their glycolytic metabolism.

Mouse mammary tumour virus and polyoma virus information in mammary tumours of athymic mice inoculated with polyoma virus.

Polyoma virus inoculation of athymic mice results in the development of mammary tumours with a much higher incidence than the development of salivary gland tumours, the latter being the most common for immunocompetent normal mice. The possibility existed that polyoma virus might act as a co-carcinogen in activating the expression of mouse mammary tumour virus (MMTV). Molecular hybridization studies, however, showed that the mammary tumour development was accompanied by neither the amplification of MMTV genomic sequences nor by their more extensive transcription. In contrast, tumour tissue contained about 60 to 100 copies of polyoma virus genome equivalents per cell and some of these sequences were apparently transcribed into RNA. While these results do not rule out the transient involvement of MMTV expression in mammary tumour development, it appeared that the mammary gland cells were directly transformed by polyoma virus. Apparently, polyoma virus displayed a tropism in athymic mice that was different from that in normal mice.