Abstract: Methotrexate (MTX) is an effective antimetabolite treatment for various oncological disorders including the central nervous system involvement (CNS) in widespread leukemia and CNS lymphoma. This form of treatment has a notable toxic effect on the nervous system, and the pediatric population seems to be more vulnerable to the neurologic toxicity of this drug. Though chronic leukoencephalopathy from an MTX regimen, especially when administered in conjunction with whole brain radiation, is well described, the acute manifestations are rare and not well understood. The diagnosis of acute focal symptoms from MTX treatment is especially difficult in patients who receive chemotherapy for neoplastic disorders and who may have many reasons for CNS involvement in general and parenchymal involvement in particular. We report the unusual clinical and neuro-imaging findings in a teenager with acute focal symptoms after MTX treatment for acute lymphoblastic leukemia.
Abstract: The prodromal period leading to schizophrenia has been the focus of significant interest in recent years. This is due not only to the possibility of identification of preschizophrenic states but also to the potential for improving prognosis as a result of early intervention. There are many approaches to the identification of the schizophrenia prodrome. Interventions in the prodromal period have met with various degrees of success. In this article, the authors present an overview of the literature reflecting the development of the prodromal concept and its implications for early identification. They also discuss various interventions proposed for this period and some ethical considerations related to these interventions. Despite the growing body of knowledge in this field, there is a need for more research data to support the establishment of treatment guidelines. Future directions of research are also discussed.
Abstract: Malignant gliomas represent the majority of primary brain tumors, and the prognosis of the patients afflicted with these tumors has been historically dismal, with almost uniform progressive neurologic impairment and rapid death. Even with multimodal treatment using surgery, focal radiation, and chemotherapy, no major strides were made until recently. The development of interstitial BCNU wafers (carmustine wafers, Gliadel((R))) has led to promising results in the treatment of a selected patients with malignant gliomas, as well as with other intracranial malignancies.BCNU is one of the first systemic chemotherapies which had obtained United States Food and Drug Administration (FDA) approval for the treatment of brain tumors. However, systemic use has been hampered by the modest prolongation of survival and by the prolonged myelosuppression and potentially fatal pulmonary toxicity. The development of interstitial therapies with BCNU represented a great step forward, allowing direct delivery to the tumor bed, with virtually no systemic toxicities. Clinical studies of BCNU wafers have showed good efficacy in both newly diagnosed and recurrent gliomas, as well as a possible therapeutic role in other primary or secondary intracranial malignancies. New studies are currently underway trying to improve the efficacy of the BCNU wafers (Gliadel((R))) by combining them with different systemic chemotherapies. An overview of the current knowledge ranging from the preclinical developments, to the efficacy and safety seen in the clinical trials and in clinical practice following the drug approval to the future avenues of research is therefore timely.
Abstract: INTRODUCTION: Schizophrenia is characterized by diminished insight, which fluctuates with disease progression. Insight deterioration in the prodrome of schizophrenia is poorly understood. Despite pharmacologic treatment, including early interventions, there is a high risk of relapse and need of acute care in schizophrenia patients. OBJECTIVE: To study if insight deterioration occurs during the prodrome and if insight preservation early in the illness might predict a better prognosis. METHODS: Data was collected retrospectively from the records of 24 patients initially diagnosed with schizophrenia during a 2-year period. Patients' progress was then tracked over a 3-year period. Insight was determined by a physician's subjective evaluation, patient interest and participation in treatment planning, and patient accuracy in reporting behaviors and symptoms when compared with reports from collaterals. RESULTS: Ten patients were determined to have insight regarding the developing illness at different presentations at the hospital. Insight preservation correlated with less need for emergency visits and fewer hospitalization days (P<.005). It was also associated with more depressive and anxious mood (P<.000). Patients and family members described early, ego-dystonic perceptual disturbances followed by diminished insight. Awareness into the illness, symptoms, and attribution of symptoms to the illness fluctuated at different presentations in the insight group. In the other group, insight was nil at each presentation after the psychotic debut. CONCLUSION: Most patients maintain insight during the perceptual disturbance phase. Insight diminishes as the early delusional phase sets in. Higher levels of preserved insight seem to correlate with less need for acute treatment. Further research in this area is warranted for determining if early insight oriented interventions in the prodromal phase can improve the prognosis of schizophrenia.
Abstract: Lon now emerges as a major regulator of multiple mitochondrial functions in human beings. Lon catalyzes the degradation of oxidatively modified matrix proteins, chaperones the assembly of inner membrane complexes, and participates in the regulation of mitochondrial gene expression and genome integrity. An early result of Lon downregulation in WI-38 VA-13 human lung fibroblasts is massive caspase 3 activation and extensive (although not universal) apoptotic death. At a later stage, the surviving cells fail to divide, display highly abnormal mitochondrial function and morphology, and rely almost exclusively on anaerobic metabolism. In a selected subpopulation of cells, the mitochondrial mass decreases probably as a result of mitochondrial inability to divide. At this final point the Lon-deficient cells are not engaged anymore in apoptosis, and are lost by necrosis or "mitoptosis." Our results indicate that mitochondrial Lon is required for normal survival and proliferation; a clear impetus for Lon's evolutionary conservation.
Abstract: Mitochondrial aconitase is sensitive to oxidative inactivation and can aggregate and accumulate in many age-related disorders. Here we report that Lon protease, an ATP-stimulated mitochondrial matrix protein, selectively recognizes and degrades the oxidized, hydrophobic form of aconitase after mild oxidative modification, but that severe oxidation results in aconitase aggregation, which makes it a poor substrate for Lon. Similarly, a morpholino oligodeoxynucleotide directed against the lon gene markedly decreases the amount of Lon protein, Lon activity and aconitase degradation in WI-38 VA-13 human lung fibroblasts and causes accumulation of oxidatively modified aconitase. The ATP-stimulated Lon protease may be an essential defence against the stress of life in an oxygen environment. By recognizing minor oxidative changes to protein structure and rapidly degrading the mildly modified protein, Lon protease may prevent extensive oxidation, aggregation and accumulation of aconitase, which could otherwise compromise mitochondrial function and cellular viability. Aconitase is probably only one of many mitochondrial matrix proteins that are preferentially degraded by Lon protease after oxidative modification.
Abstract: We compared Lon protease expression in murine skeletal muscle of young and old, wild-type and Sod2(-/+) heterozygous mice, and studied Lon involvement in the accumulation of damaged (oxidized) proteins. Lon protease protein levels were lower in old and oxidatively challenged animals, and this Lon deficiency was associated with increased levels of carbonylated proteins. We identified one of these proteins as aconitase, and another as an aconitase fragmentation product, which we can also generate in vitro by treating purified aconitase with H(2)O(2). These results imply that aging and oxidative stress down-regulate Lon protease expression which, in turn, may be responsible for the accumulation of damaged proteins, such as aconitase, within mitochondria.
Abstract: The mitochondrial genome encodes just a small number of subunits of the respiratory chain. All the other mitochondrial proteins are encoded in the nucleus and produced in the cytosol. Various enzymes participate in the activation and intramitochondrial transport of imported proteins. To finally take their place in the various mitochondrial compartments, the targeting signals of imported proteins have to be cleaved by mitochondrial processing peptidases. Mitochondria must also be able to eliminate peptides that are internally synthesized in excess, as well as those that are improperly assembled, and those with abnormal conformation caused by mutation or oxidative damage. Damaged mitochondrial proteins can be removed in two ways: either through lysosomal autophagy, that can account for at most 25-30% of the biochemically estimated rates of average mitochondrial catabolism; or through an intramitochondrial proteinolytic pathway. Mitochondrial proteases have been extensively studied in yeast, but evidence in recent years has demonstrated the existence of similar systems in mammalian cells, and has pointed to the possible importance of mitochondrial proteolytic enzymes in human diseases and ageing. A number of mitochondrial diseases have been identified whose mechanisms involve proteolytic dysfunction. Similar mechanisms probably play a role in diminished resistance to oxidative stress, and in the aging process. In this paper we review current knowledge of mammalian mitochondrial proteolysis, under normal conditions and in several disease states, and we propose an etiological classification of human diseases characterized by a decline or loss of function of mitochondrial proteolytic enzymes.
