Methotrexate induced seizures associated with acute reversible magnetic resonance imaging (MRI) changes in a patient with acute lymphoblastic leukemia

A 27-year-old woman with acute lymphoblastic leukemia (ALL) had an episode of generalized tonic-clonic seizure after therapy with intrathecal and intravenous methotrexate (MTX). Magnetic resonance imaging (MRI) of her head showed meningeal, cortical and subcortical enhancement that was new when compared to a study done prior to therapy. Subsequent imaging 10 days later showed partial resolution of these findings. The association of seizures and MTX in ALL and the corresponding MRI changes are discussed.     

Safety of thrice-daily hyperfractionated radiation and BCNU for high-grade gliomas

PURPOSE: To investigate the safety of thrice-daily hyperfractionated radiotherapy (RT) given in conjunction with BCNU (carmustine) in high-grade gliomas. METHODS AND MATERIALS: Patients >18 years old with newly diagnosed high-grade gliomas were eligible. The dose of radiation was 5040 cGy, with a 1440-cGy boost in 180 cGy fractions delivered thrice daily in two 6-day periods with a 2-week interval. BCNU (200 mg/m(2)) was administered on the first day of radiation, then every 7 weeks for 1 year and every 10 weeks for another year. RESULTS: Eighteen patients were enrolled. The mean age was 49.6 years. Sixteen patients had astrocytomas (Grade 3 or 4 in 5 and 11 patients, respectively) and 2 had oligoastrocytomas (Grade 3 and 4 in 1 patient each). One underwent total resection, 9 subtotal resection, and 8 biopsy only. Thirteen patients had stable disease, 4 regression, and 1 progression. The median time to progression was 37.8 weeks. The median overall survival was 44.4 weeks. Nine patients had neurologic toxicities, including 2 deaths at 69 and 139 weeks. CONCLUSION: This regimen is unacceptably toxic. Factors that could have contributed to the toxicity may include the total radiation dose, thrice-daily hyperfractionation, and the concurrent use of i.v. BCNU.     

Neuropharmacological profile of Barleria lupulina Lindl. Extract in animal models

Barleria lupulina Lindl. is a popular medicinal plant distributed in mountains of southern and western India. In the present work, the effect of methanolic extract of aerial parts of B. lupulina on CNS activity has been evaluated. The CNS activity was tested in several experimental models, in mice and rats: general behavior, exploratory behavior, muscle relaxant activity, conditioned avoidance response and phenobarbitone sodium-induced sleeping time tests. The aerial parts of the plant B. lupulina was extracted with methanol and the solvent was removed by vacuum distillation. The methanol extract (100, 200 and 300 mg/kg) showed reduction in general behavioral pattern (spontaneous activity, alertness, awareness, pain response and touch response) in a dose dependent manner. The extract was found to produce a significant reduction of the exploratory behavioral profile (Y-maze test, head dip test) and conditioned avoidance response with all the tested doses. The methanolic extract showed significant motor incoordination and muscle relaxant activity. The extract also potentiated phenobarbitone sodium induced sleeping time. Preliminary investigation showed that the methanol extract of B. lupulina has significant psychopharmacological activity.     

Highly sensitive chemiluminescence immunoassay for benzo[a]pyrene-DNA adducts: validation by comparison with other methods,and use in human biomonitoring

A chemiluminescence immunoassay (CIA) utilizing antiserum elicited against DNA modified with (+/-)-7beta, 8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]- pyrene (BPDE) has been developed and validated to study the formation of polycyclic aromatic hydrocarbon (PAH)-DNA adducts in human tissues. Advantages include a low limit of detection for 10b-(deoxyguanosin-N(2)-yl)-7beta,8alpha,9alpha-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPdG, approximately 1.5 adducts/10(9) nucleotides using 20 micro g DNA) and a high signal-to-noise ratio (> or =100). The CIA BPDE-DNA standard curve gave 50% inhibition at 0.60 +/- 0.08 fmol BPdG (mean +/- SE, n = 30), which was a 10-fold increase in sensitivity compared with the dissociation-enhanced lanthanide fluoroimmunoassay (DELFIA). Calf thymus DNA modified with [1,3-(3)H]BPDE was assayed by radiolabeling, (32)P-postlabeling, DELFIA and CIA, and all assays gave similar values. Liver DNAs from mice exposed to 0.5 and 1.0 mg [7,8-(3)H]benzo[a]pyrene (BP) were assayed by the same four assays and a dose-response was obtained with all assays. The BPDE-DNA CIA was further validated in MCL-5 cells exposed to 4 micro M BP for 24 h, where nuclear and mitochondrial DNA adduct levels were associated with an increase in DNA tail length measured by the Comet assay. Human peripheral blood cell (buffy coat) DNA samples (n = 43) obtained from 25 individuals who were either colorectal adenocarcinoma patients or controls were assayed by BPDE-DNA CIA. Three samples (7%) were non-detectable, and the remaining 40 samples had values between 0.71 and 2.21 PAH-DNA adducts/10(8) nucleotides. The intra-assay coefficient of variation (CV), for four wells on the same microtiter plate, was 1.85%. Sufficient DNA for two assays, on separate plates, was available for 38 of the 43 samples, and the PAH-DNA adduct values obtained were highly correlated (r(2) = 0.95). Coded duplicate DNA samples from 15 individuals were assayed four times gave an inter-assay CV of 13.8%.     

Stable expression of the alkaline phosphatase marker gene by neural cells in culture and after transplantation into the CNS using cells derived from a transgenic rat

Multipotent stem cells and more developmentally restricted precursors have previously been isolated from the developing nervous system and their properties analyzed by culture assays in vitro and by transplantation in vivo. However, the variety of labeling techniques that have been used to identify grafted cells in vivo have been unsatisfactory. In this article we describe the characteristics of cells isolated from a transgenic rat in which the marker gene human placental alkaline phosphatase (hPAP) is linked to the ubiquitously active R26 gene promoter. We show that hPAP is readily detected in embryonic neuroepithelial stem cells, neuronal-restricted precursor cells, and glial-restricted precursor cells. Transgene expression is robust and can be detected by both immunocytochemistry and histochemistry. Furthermore, the levels of hPAP on the cell surface are sufficient for live cell labeling and fluorescence-activated cell sorting. Expression of hPAP is stable in isolated cells in culture and in cells transplanted into the spinal cord for at least 1 month. We submit that cells isolated from this transgenic rat will be valuable for studies of neural development and regeneration.     

Watching where you look: modulation of visual processing of foveal stimuli by spatial attention

Two experiments investigated the effect of sustained selective spatial attention upon the perceptual analysis of stimuli within the center of gaze. Spatial attention has typically been studied in relation to peripheral stimuli, and its relevance to the processing of central stimuli has remained relatively ignored. Here, behavioral measures in normal human volunteer participants showed that focused spatial attention can also influence responses to central stimuli, over and beyond the advantage conferred by their foveation. Event-related potentials (ERPs) showed that the action of attention upon foveal stimuli included the modulation of perceptual processing in extrastriate visual areas. Surprisingly, the visual modulation revealed an intriguing and consistent pattern of hemispheric asymmetry, in both experiments. These findings show that in addition to the established right hemisphere dominance of the brain areas that direct attention, the consequences of directed attention may also be asymmetrical.     

Heart rate time series: decreased chaos after intravenous lactate and increased non-linearity after isoproterenol in normal subjects

In this study, we reanalyzed our previous heart rate time series data on the effects of intravenous sodium lactate (n=9) and intravenous isoproterenol (n=11) using non-linear techniques. Our prior findings of significantly higher baseline non-linear scores (NL: S(netGS)) and significantly lower largest Lyapunov exponents in supine posture in patients with panic disorder compared to control subjects prompted this study. We obtained the largest Lyapunov exponent (LLE), and a measure of non-linearity (NL: S(netGS)) of heart rate time series. LLE quantifies predictability and NL quantifies the deviation from linear processes. There was a significant increase in NL score, (S(netGS)) after isoproterenol infusions and a significant decrease in LLE (an increase in predictability indicating decreased chaos), after intravenous lactate in supine posture in normal control subjects. Increased NL scores in supine posture after intravenous isoproterenol may be due to a relative increase in cardiac sympathetic activity or a decrease in vagal activity at least in certain circumstances, and an overall decrease in LLE may indicate an impaired cardiac autonomic flexibility after intravenous sodium lactate, as LLE is diminished by autonomic blockade by atropine. Band analysis of LLE (LF/HF) (LF: 0.04-0.15 Hz and HF: 0.15-0.5 Hz) showed an increase of these ratios during either condition with a higher sympathovagal interaction after the drug administration. These findings may throw new light on the association of anxiety and significant cardiovascular events.     

Is heart failure with preserved systolic function an overlooked enigma?

Heart failure with preserved systolic function, or diastolic heart failure, represents the neglected other half of the pandemic of heart failure. Unlike previously held beliefs, diastolic heart failure carries with it the same connotation of morbidity and mortality as systolic heart failure, particularly in the elderly. Due to lack of standards in application of the diagnosis of diastolic heart failure, studies are difficult to interpret due to heterogeneity in the clinical criteria applied to the patient enrollment. It is imperative that preventive efforts be implemented in high-risk groups, and screening measures with newer biomarkers be considered for identifying underlying structural heart disease in order to employ preventive therapy early in the course of illness. No evidence-based therapeutic strategy to reduce morbidity and mortality has been established, even after the diagnosis of diastolic heart failure is manifest. Current therapy targets lusitropic abnormalities in the realm of impaired relaxation, abnormal diastolic compliance, avoidance of tachycardia, and restoration of atrial booster pump function. Outcomes-based placebocontrolled clinical trials are currently underway to define appropriate therapeutic strategies in diastolic heart failure.