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Background: Effective chemotherapy is lacking for most types of central nervous system (CNS) tumors in children. Temozolomide, an agent with activity against adult brain tumors, was investigated in children and adolescents with recurrent CNS tumors.Methods: Temozolomide was administered orally as monthly 5-day courses at doses of 200 mg/m(2)/d (patients with no prior craniospinal irradiation [CSI]) or 180 mg/m(2)/d (prior CSI). Patients with a complete (CR) or partial (PR) response or stable disease (SD) could continue temozolomide for up to 12 cycles.Results: The cohort comprised 122 patients, including 113 with CNS tumors. Median age was 11 years (range, 1-23 years). Among 104 evaluable patients with CNS tumors, 5 PRs and 1 CR were observed. PRs occurred in 1 of 23 evaluable patients with high-grade astrocytoma, 1 of 21 with low-grade astrocytoma, and 3 of 25 with medulloblastoma/primitive neuroectodermal tumor (PNET). The CR occurred in an additional patient with medulloblastoma/PNET. No responses were observed in patients with ependymoma, brain-stem glioma, or other CNS tumors. Notably, 41% of patients with low-grade astrocytoma had SD through 12 courses. The most frequent toxicities were grade 3 or 4 neutropenia (19%) and thrombocytopenia (25%); nonhematologic toxicity was infrequent.Conclusions: Although overall objective responses were limited, further exploration of temozolomide may be warranted in children with medulloblastoma and other PNETs, or in patients with low-grade astrocytoma, perhaps in a setting of less pretreatment than the patients in the current study, or in the context of multiagent therapy. [ABSTRACT FROM AUTHOR]

Torpor during hibernation defines the nadir of mammalian metabolism where whole animal rates of metabolism are decreased to as low as 2% of basal metabolic rate. This capacity to decrease profoundly the metabolic demand of organs and tissues has the potential to translate into novel therapies for the treatment of ischemia associated with stroke, cardiac arrest or trauma where delivery of oxygen and nutrients fails to meet demand. If metabolic demand could be arrested in a regulated way, cell and tissue injury could be attenuated. Metabolic suppression achieved during hibernation is regulated, in part, by the central nervous system through indirect and possibly direct means. In this study, we review recent evidence for mechanisms of central nervous system control of torpor in hibernating rodents including evidence of a permissive, hibernation protein complex, a role for A1 adenosine receptors, mu opiate receptors, glutamate and thyrotropin-releasing hormone. Central sites for regulation of torpor include the hippocampus, hypothalamus and nuclei of the autonomic nervous system. In addition, we discuss evidence that hibernation phenotypes can be translated to non-hibernating species by H2S and 3-iodothyronamine with the caveat that the hypothermia, bradycardia, and metabolic suppression induced by these compounds may or may not be identical to mechanisms employed in true hibernation. [ABSTRACT FROM AUTHOR]

Aim: Nitric oxide (NO) plays an important role in the transition from intrauterine to extrauterine life. If this transition fails, a condition called persistent pulmonary hypertension of the neonate (PPHN) may develop. The current treatment modalities for this disease include induction of alkalosis by hyperventilation or alkali infusion, inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation. There is evidence from animal studies that the elevated pH, not the low pCO2 is responsible for the resultant pulmonary vasodilatation. In this study, we examined the effect of pH on the activity and expression of endothelial nitric oxide synthase (eNOS) in cultured bovine aortic endothelial cells (BAEC) as a possible explanation for the pH dependent drop in pulmonary vascular resistance., Methods: BAEC were exposed to a pH gradient of 7.1-7.6 for 4 h (short-term) and 16 h (long-term). Standard Western blotting technique was used to detect expression of eNOS. Activity was measured by an indirect assay using bovine aortic smooth muscle cells (BASM) as reporter cells and measuring cGMP levels as a marker of NO production. The cells were exposed to the pH gradient for a total of 4 h and measurement were made at 30, 60 and 90 min, and 2, 3 and 4 hours., Results: eNOS activity and expression remained unchanged during the four and sixteen hours of exposure., Conclusion: In this in vitro experiment, we could not demonstrate an alkalosis-induced increase in eNOS activity and expression. The clinically observed pH dependent vasodilatation does not appear to be directly mediated through the induction of eNOS.