Cerebrospinal fluid methotrexate level in children treated with medium-high and high doses of the drug]

Concentrations of MTX were determined in the cerebrospinal fluid (csf) and serum after intravenous infusion of MTX at intermediate dose (0.5-1.0 g/m2) and at high dose (5.0 g/m2) to 20 children (33 infusions) with ALL/NHL. The cytotoxic concentrations of MTX in csf (> 1.0 microM/l) were reached in half of the cases after the infusion of MTX at intermediate dose and in all patients after the infusion of 5.0 g/m2. Great inpatient and interpatient variations of MTX concentrations in csf were observed. No statistically significant difference was found between mean systemic clearance of MTX in patients with MTXcsf concentrations > 1.0 microM/l and < 1.0 microM/l after infusion of MTX at intermediate dose.     

Studies of methotrexate pharmacokinetics in children with neoplasms of the hematopoietic system after administration of different doses of the drug]

Concentration of MTX was determined in the serum after the infusion of MTX in a dose of 0.5 g/m2, 1.0 g/m2 and 5.0 g/m2 to 24 children with ALL/NHL. The mean value of steady-state concentrations of MTX was two-fold greater after the infusion of a dose of 1.0 g/m2 and ten-fold greater after the infusion of a dose 5.0 g/m2 than at dose 0.5 g/m2. Great inpatient and interpatient variations of serum MTX concentrations were observed. Pharmacokinetic analysis of the data revealed biphasic model of the elimination. Statistically significant differences were found between the half-life MTX values (ti/2 alpha) in the first postinfusion day: the higher the dose, the shorter ti/2 was observed. The ti/2 of MTX during the second postinfusion day was significantly longer than that of the first day after infusion, but values for the higher doses were not significantly shorter than those for 0.5 g/m2. Systemic clearance (Cl) of MTX showed inpatient and interpatient variations of the values. However, no statistically significant difference was found between Cl values at doses of 0.5 g/m2, 1.0 g/m2 and 5.0 g/m2.     

Developmental Instability and Working Memory Ability in Children: A Magnetic Resonance Spectroscopy Investigation

This study of children (ages 7 through 12) wishes to determine (a) whether variation in frontal lobe brain chemistry, determined from proton magnetic resonance spectroscopy (1H-MRS), is related to performance on a working memory task in children, and (b) whether developmental instability (DI; the imprecise expression of the genetic plan for development due to several known genetic and environmental effects) underlies phenotypic variation in brain chemistry. 1H-MRS assessed neurometabolites in a right frontal white matter voxel. The Visual Two-Back test assessed working memory. A composite measure of DI was created from measures of minor physical anomalies, fluctuating asymmetry of body characteristics, and fluctuating asymmetry of dermatoglyphic features. Greater DI strongly predicted lower concentrations of creatine-phosphocreatine (Cre) and choline-containing compounds, whereas Cre and N-acetyl-aspartate positively correlated with working memory skills. Working memory skills thus seem related to frontal lobe energy metabolism, which in turn is related to DI.     

Developmental instability and working memory ability in children: a magnetic resonance spectroscopy investigation

This study of children (ages 7 through 12) wishes to determine (a) whether variation in frontal lobe brain chemistry, determined from proton magnetic resonance spectroscopy (1H-MRS), is related to performance on a working memory task in children, and (b) whether developmental instability (DI; the imprecise expression of the genetic plan for development due to several known genetic and environmental effects) underlies phenotypic variation in brain chemistry. 1H-MRS assessed neurometabolites in a right frontal white matter voxel. The Visual Two-Back test assessed working memory. A composite measure of DI was created from measures of minor physical anomalies, fluctuating asymmetry of body characteristics, and fluctuating asymmetry of dermatoglyphic features. Greater DI strongly predicted lower concentrations of creatine-phosphocreatine (Cre) and choline-containing compounds, whereas Cre and N-acetyl-aspartate positively correlated with working memory skills. Working memory skills thus seem related to frontal lobe energy metabolism, which in turn is related to DI.     

Cognitive and Academic Late Effects Among Children Previously Treated for Acute Lymphocytic Leukemia Receiving Chemotherapy as CNS Prophylaxis

Objective: Examine cognitive and academic late effects amongchildren and adolescents who had received central nervous system(CNS) prophylactic chemotherapy alone for acute lymphocyticleukemia (ALL); none had received whole brain radiation therapy(RT). Method: Subjects included 47 children and adolescents from 5to 22 years of age who were treated on the same protocol andhad been off treatment from 2 to 7 years at the time of assessment. Results: As a group the survivors displayed generally averageperformance on measures of cognitive and academic abilities,although they differed from normative means on tests of nonverbalskills. Girls performed more poorly than the normative sampleon nonverbal tasks, while no differences were found for boys.Age at diagnosis and time off treatment were not significantlyassociated with cognitive and academic functioning for survivorsof this particular chemotherapy-only protocol. Conclusions: Data were interpreted to support generally modestpotential late effects in specific areas for children and adolescentssurviving ALL. These findings suggest a need for monitoringnonverbal cognitive skills for childhood survivors of ALL, particularlyfor girls.     

In vivo methotrexate kinetics and metabolism in human hematopoietic cells. Clinical significance of methotrexate concentrations in erythrocytes

The author has performed in vivo investigations of the methotrexate (MTX) accumulation, kinetics and polyglutamate metabolism in erythrocytes, neutrophils and myeloid bone marrow cells during clinical MTX therapy of patients with acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma and psoriasis. On the basis of these studies the clinical applicability of monitoring erythrocyte MTX concentrations in children with ALL and adult psoriasis patients have been evaluated. To accomplish this task a set of methods has been developed: 1) An automated enzymatic assay adapted for a centrifugal analyzer was used to measure MTX concentrations between 10 and 60 nmol/l in erythrocytes and serum. 2) For the study of MTX kinetics in myeloid cells, age fractionated erythrocytes and HPLC fractionated methotrexate polyglutamates a sequential radioligand binding assay with a range of 1-8 (and 1-16) nmol/l was employed. 3) Discontinuous Percoll gradients of increasing densities were used to separate myeloid cells and erythrocytes of increasing mean cell age. Declining reticulocyte counts and erythrocyte-aspartate aminotransferase activity were taken as parameters of increasing mean erythrocyte age. 4) In order to study MTX polyglutamate metabolism a high performance liquid chromatography (HPLC) procedure was set up using tetrabutylammonium phosphate in acetonitrile in an automatically generated gradient buffer system. The MTX polyglutamates were separated, and the concentrations determined by the radioligand binding assay. The individual polyglutamates were identified by comparisons with the retention times of MTX polyglutamate standards (MTX-glu1+2+3+4+6+7) which were detected spectrophotometrically at 304 nm. During 24 hour infusions MTX was incorporated predominantly in the proliferating myeloid bone marrow cells before appearing in circulating neutrophils about seven days later. Evidence for MTX incorporation in the erythroid precursors of the bone marrow was provided by demonstrating high MTX content in density fractionated reticulocyte enriched erythrocyte populations. During weekly low dose MTX treatment the erythrocyte MTX concentration reached a constant level (steady state ery-MTX) after 4-6 weeks. MTX concentrations in age fractionated red blood cells and the terminal decline of the ery-MTX and its polyglutamate forms after cessation of MTX administration revealed that maintenance of the steady state ery-MTX depended on three conditions: 1) The amount of MTX added to the circulation via MTX containing reticulocytes. 2) The in vivo efflux of MTX from circulating erythrocytes, and 3) The loss of MTX with age dependent destruction of red blood cells. The in vivo efflux of MTX accounted for a loss of MTX which was 3-4 times greater than the amount that was lost with age dependent erythrocyte destruction.(ABSTRACT TRUNCATED AT 400 WORDS)     

Working memory is more sensitive than declarative memory to the acute effects of corticosteroids: a dose-response study in humans.

The effects of various doses (40 microg/kg/hr, 300 microg/kg/hr, 600 microg/kg/hr or placebo) of hydrocortisone on tasks assessing working and declarative memory function were measured in 4 groups of 10 young men. During the infusion, participants were given an item-recognition working memory task, a paired-associate declarative memory task, and a continuous performance task used to control possible concomitant effects of corticosteroids on vigilance. The results revealed significant acute effects of the highest dose of hydrocortisone on working memory function, without any significant effect on declarative memory function or arousal-vigilance performance. These results suggest that working memory is more sensitive than declarative memory to the acute elevations of corticosteroids, which could explain the detrimental effects of corticosteroids on acquisition and consolidation of information, as reported in the literature.     

Visuomotor Function in Children Treated for Acute Lymphoblastic Leukaemia With Chemotherapy Only

This study aimed to evaluate visuomotor function in children treated for acute lymphoblastic leukaemia (ALL). The performance of 64 children, 1–7 years post-chemotherapy for ALL, was compared to that of their healthy peers (n?=?56) on visuomotor integration (VMI) and motor coordination (MC) tasks. Children posttreatment for ALL displayed significantly reduced VMI, but not MC, performances as compared to controls. Children treated on chemotherapy-only ALL regimes are at heightened risk for visuomotor integration deficits. Monitoring of visuomotor skills and implementation of appropriate interventions targeting higher level visuomotor integration skills should form an important component of any ALL long-term effects program.     

Assessment of neuropsychological function through use of the Cambridge Neuropsychological Testing Automated Battery: performance in 4- to 12-year-old children

In this article, children's performance on subtasks from the Cambridge Neuropsychological Testing Automated Battery (CANTAB) is described. Two samples were recruited, one of which included children who spoke English as a second language. Children in this group also completed subtests from the Wechsler Intelligence Scale for Children-Third Revision (WISC-III). Despite the fact that ESL children scored over 1 SD below the norm on the WISC-III Vocabulary subtest, there were no CANTAB performance distinctions between primary versus secondary English-language speakers. In addition, several aspects of CANTAB performance were significantly correlated with verbal and nonverbal IQ. When developmental trends were examined, findings indicated that several aspects of frontal lobe function (memory span, working memory, and planning skills) are not functionally mature by the age of 12 years. Implications for use of the CANTAB in clinical studies are discussed.     

The subacute effects of CNS prophylaxis for acute lymphoblastic leukemia on neuropsychological performance: a comparison of four protocols.

We report an assessment of the intellectual functioning after one year of therapy of 117 children treated for acute lymphoblastic leukemia (ALL) who were assigned to one of four protocols for central nervous systems (CNS) prophylaxis. These protocols were (a) 2400 rad cranial irradiation plus concurrent intrathecal methotrexate (i.t. MTX), (b)i.t. MTX alone, (c) 1800 rad cranial irradiation plus concurrent i.t. MTX, and (d) a protocol for high-risk patients that included intensive systemic chemotherapy plus 2400 rad delayed irradiation. Neuropsychological evaluation consisted of the Wechsler intelligence scales, the Wide Range Achievement Test, and selected tests from the Halstead-Reitan Neuropsychological Battery administered one year after diagnosis. All patients performed in the average range on measures, although the high-risk patients performed marginally worse than did the others. In general, our results do not support previous reports that cranial irradiation results in early adverse neuropsychological sequelae.     

Assessment of Neuropsychological Function Through Use of the Cambridge Neuropsychological Testing Automated Battery: Performance in 4- to 12-Year-Old Children

In this article, children's performance on subtasks from the Cambridge Neuropsychological Testing Automated Battery (CANTAB) is described. Two samples were recruited, one of which included children who spoke English as a second language. Children in this group also completed subtests from the Wechsler Intelligence Scale for Children-Third Revision (WISC-III). Despite the fact that ESL children scored over 1 SD below the norm on the WISC-III Vocabulary subtest, there were no CANTAB performance distinctions between primary versus secondary English-language speakers. In addition, several aspects of CANTAB performance were significantly correlated with verbal and nonverbal IQ. When developmental trends were examined, findings indicated that several aspects of frontal lobe function (memory span, working memory, and planning skills) are not functionally mature by the age of 12 years. Implications for use of the CANTAB in clinical studies are discussed.     

Processing speed, working memory, and IQ: a developmental model of cognitive deficits following cranial radiation therapy

IQ decrements following cranial radiation therapy (CRT) for acute lymphoblastic leukemia (ALL) are most apparent years after treatment. The authors examined a developmental model for delayed deficits by evaluating the relationship between processing speed, working memory, and IQ in long-term survivors of childhood ALL (n = 27) compared with demographically matched controls (n = 27). The ALL group treated with CRT showed deficits in IQ, working memory, and processing speed relative to controls. Differences in IQ between the CRT group and controls were mediated by differences in working memory. Processing speed did not fully account for the working memory deficit in the CRT group. Participants with ALL treated only with chemotherapy showed similar working memory and processing speed as matched controls. Data suggest that deficits in processing speed and working memory following CRT may underlie declines in IQ.     

Neuropsychological correlates of ADHD symptoms in preschoolers

The authors examined the neuropsychological status of 22 preschoolers at risk for attention-deficit/hyperactivity disorder (ADHD) and 50 matched control children, using measures of nonverbal working memory, perceptual and motor inhibition, and memory for relative time. All tasks included paired control conditions, which allowed for the isolation of discrete executive function constructs. Group differences were evident on several measures of neuropsychological functioning; however, after accounting for nonexecutive abilities, no deficits could be attributed to specific functions targeted by the tasks. Performance on executive measures was not related to objective indices of activity level or ratings of ADHD symptoms. Yet, the fact that at-risk preschoolers were highly symptomatic casts doubt on whether executive function deficits and/or frontostriatal networks contribute etiologically to early behavioral manifestations of ADHD.     

Motor and perceptual timing deficits among survivors of childhood leukemia

OBJECTIVE: There is growing evidence of cerebellar-frontal system change in children treated for leukemia with chemotherapy alone (Lesnik et al., 1998). METHODS: We compared 22 long-term survivors of acute lymphoblastic leukemia (ALL), aged 8-18, to 22 age- and gender-matched controls on tasks emphasizing cerebellar-frontal functioning including judgment of time duration and motor timing. Groups were also compared on a judgment of pitch task, used as a control measure. Children with ALL were at least 5 years from diagnosis, treated with intrathecal chemotherapy (methotrexate in all, hydrocortisone and cytarabine in 20/22), but not radiation therapy, and free from recurrence of disease. RESULTS: After controlling for IQ, the ALL group had poorer performance than controls on judgment of long duration and motor timing, but not judgment of pitch. CONCLUSIONS: Treatment with intrathecal and infusional chemotherapy for childhood ALL may be associated with skill deficits comparable to those seen in individuals with cerebellar-frontal abnormalities.     

Verbal vs. visual categories on the Wechsler memory scale - revised: How meaningful a distinction?

This study investigated whether the a priori classification of Wechsler Memory Scale-Revised (WMS-R) subtests into separate Verbal and Visual categories is warranted. Correlational and hierarchial clustering analyses found that (a) memory test performance correlated significantly with performance on subtests of Form II of the Luria-Nebraska Neuropsychological Battery (LNNB-II) that measure substrates of particular memory processes; and (b) subtests that appeared a priori to involve verbal skills clustered separately from those that appeared to involve nonverbal (visual) skills. However, the WMS-R Visual Paired Associates subtest did not cluster with the nonverbal scales as expected, and the LNNB-II Memory Scale appeared to be predominantly a test of verbal memory. Practical consequences of these findings were discussed.     

The impact of specific language impairment on working memory in children with ADHD combined subtype.

The objective of this study was to examine the impact of comorbid specific language impairment (SLI) on verbal and spatial working memory in children with DSM-IV combined subtype Attention Deficit Hyperactivity Disorder (ADHD-C). Participants were a clinical sample of 812- to 1212-year-old children diagnosed with ADHD-C. A group of ADHD-C with SLI was compared to a group of ADHD-C without SLI, and a group of normal children, matched on age and nonverbal intelligence. The results show that ADHD-C children with SLI scored significantly lower than those without SLI and normal children, on verbal working memory measures only. Both ADHD groups performed normally on spatial working memory measures. It is concluded that working memory deficits are not a specific characteristic of ADHD but are associated with language impairments. The importance of screening for language disorders in studies of neuropsychological functioning in children with ADHD is emphasized.     

N-acetyl cysteine supplementation prevents impairment of spatial working memory functions in rats following exposure to hypobaric hypoxia

Exposure to high altitude (HA), especially extreme altitude, is associated with impairment of cognitive functions including memory and increased oxidative stress. However, the underlying mechanisms involved are not well understood. It is hypothesized that HA induced oxidative stress may be one of the factors underlying hypoxia induced memory impairment. The aim of the present study was to investigate the effect of hypobaric hypoxia (HH) on spatial working and reference memory functions, oxidative stress markers in rats and effect of supplementation of N-acetyl cysteine (NAC). The rats were divided into four groups. Group I served as normoxic (n=6), Group II served as hypoxic (n=6), Group III as hypoxia group treated with NAC (n=6) and Group IV served as normoxic group treated with NAC (n=6). Group II & III were exposed to HH for 3 days equivalent to 6100 m and received oral NAC supplementation (750 mg/kg) daily. Rats from all the groups were trained in Morris Water Maze (MWM) task for 8 consecutive days. Spatial working and reference memory were tested immediately after the termination of HH and then the rats were sacrificed for estimation of oxidative stress markers in hippocampus. Rats displayed significant deficits in spatial working memory, and increased oxidative stress along with decrease in antioxidant status on hypoxic exposure. Supplementation with NAC in hypoxia-exposed group improved spatial memory performance, and decreased oxidative stress. These findings indicate that hypoxic exposure is associated with increased oxidative stress, which may have caused memory deficit in rats exposed to simulated HA.     

MTX单次与多次给药方式保守治疗异位妊娠比较

目的比较不同的氨甲喋呤(MTX)给药方式治疗异位妊娠的疗效及副反应。方法回顾性分析我院2007年1月-2009年9月MTX药物保守治疗异位妊娠患者。其中A组(86例)采用MTX50mg/m2,单次肌注,最多不超过3个疗程。B组(74例)采用MTX-CF(甲酰四氢叶酸)方案:MTX1mg/kg隔日肌注,第1,3,5,7天,CF0.1mg/kg,第2,4,6,8天。两组患者均定期复查血β-HCG、阴超、血常规及肝肾功能,并每日严密观察生命体征、腹痛及阴道流血情况。结果单次给药与多次给药成功率无明显差异,但从两者用药后患者副反应表现来看,单次给药副反应要少。结论单次给药用量少,副反应小,易被患者接受。     

Perception of effort at low and moderate intensity exercise in survivors of childhood acute lymphoblastic leukaemia

OBJECTIVE: The study examined the degree to which male and female survivors of acute lymphoblastic leukaemia (ALL) perceive effort at low and moderate intensity exercise in association with related physiological variables. MATERIALS AND METHODS: Participants were 67 children. Thirty-five (14 boys and 21 girls) were long-time survivors of ALL and 32 (18 boys and 14 girls) were control subjects. The Children's Effort Rating Table (CERT) was used to measure whole-body perceived exertion at low and moderate intensity exercise. Peak oxygen uptake was measured using a motorized treadmill. CERT and physiological data were analysed using 2 x 2 mixed analyses of variance, appropriate t-tests and coefficients of correlation. RESULTS: In absolute terms, boys treated for ALL found perception of effort to be more strenuous at both low (3.9 vs. 3.5 units) and moderate (6.1 vs. 5.3 units) intensity exercise than control subjects, although differences were not significant (p > 0.05); girls treated for ALL found perception of effort to be the same as controls at low intensity exercise (3.1 vs. 3.1 units) but slightly higher than controls at moderate intensity exercise (5.6 vs. 5.2 units); neither of these differences were significant (p > 0.05). When CERT values were adjusted for (.-)VO(2) peak (%) and heart rate (HR) peak (%) differences remained non-significant. There were no significant interactions (Intensity x Group) in males, but the interaction for (.-)VO(2) peak (%) was significant in females (p < 0.05). The main effect for Intensity (low and moderate) was significant for all variables in boys and girls (p < 0.0001). The main effect for Group (ALL and controls) identified significantly greater absolute (b.p.m.) and relative (%) HR values in ALL boys at low and moderate intensity exercise. In female ALL and control subjects the interaction (Intensity x Group) distinguished between (.-)VO(2) peak (%) at moderate intensity exercise and HR peak (%) at low and moderate intensity exercise. Coefficients of correlation between perceived effort and (.-)VO(2) peak (%) in boys and girls were low to high (0.28-0.76), and between absolute and relative HR were also low to high (0.33-0.73). There were low correlations between time 'off therapy' and perceived effort, (.-)VO(2) peak (%) and HR peak (%) (-0.003 to -0.49). CONCLUSION: It was concluded that perception of effort in survivors of ALL at low and moderate intensity exercise was the same as that of control subjects. Correlations between perceived effort and physiological variables at moderate exercise were low to high, while those between perceived effort and time from treatment were generally weak.     

Short-term memory, working memory, and executive functioning in preschoolers: longitudinal predictors of mathematical achievement at age 7 years

This study examined whether measures of short-term memory, working memory, and executive functioning in preschool children predict later proficiency in academic achievement at 7 years of age (third year of primary school). Children were tested in preschool (M age = 4 years, 6 months) on a battery of cognitive measures, and mathematics and reading outcomes (from standardized, norm-referenced school-based assessments) were taken on entry to primary school, and at the end of the first and third year of primary school. Growth curve analyses examined predictors of math and reading achievement across the duration of the study and revealed that better digit span and executive function skills provided children with an immediate head start in math and reading that they maintained throughout the first three years of primary school. Visual-spatial short-term memory span was found to be a predictor specifically of math ability. Correlational and regression analyses revealed that visual short-term and working memory were found to specifically predict math achievement at each time point, while executive function skills predicted learning in general rather than learning in one specific domain. The implications of the findings are discussed in relation to further understanding the role of cognitive skills in different mathematical tasks, and in relation to the impact of limited cognitive skills in the classroom environment.