Cot mattresses and sudden infant death syndrome.
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Bedding and Linens↗
Biomedical subjects
M Cole
Publications and source records attributed to M Cole.
Cyclophosphamide metabolism in children.
The alkylating agent cyclophosphamide is a prodrug which is metabolized in vivo to produce both therapeutic and toxic effects. Cyclophosphamide metabolism was investigated in 36 children with various malignancies. Concentrations of cyclophosphamide and its principal metabolites were measured in plasma and urine using a quantitative high-performance TLC method. The results indicated a high degree of inter-patient variation in metabolism. In contrast to previous adult studies on urinary metabolites, plasma carboxyphosphamide concentrations did not support the existence of polymorphic metabolism. Plasma concentrations of dechlorethylcyclophosphamide and carboxyphosphamide were correlated in individual patients, suggesting that the activity of both aldehyde dehydrogenase and cytochrome P450 enzyme(s) determine carboxyphosphamide production in vivo. The presence of ketocyclophosphamide in plasma was strongly associated with dexamethasone pretreatment and was also accompanied by a high clearance of the parent drug. Interpatient differences in metabolism reflect individual levels of enzyme expression and may contribute to variation in clinical effect.
Adolescent↗
Screening for Wilms' tumour in patients with aniridia, Beckwith syndrome, or hemihypertrophy.
The role of screening for early detection of Wilms' tumour (WT) in patients with aniridia (A), Beckwith-Weidemann syndrome (BWS) and hemihypertrophy (HH) has been explored. Of the 1,622 Wilms' tumour patients registered with the National Childhood Cancer Registry from 1971 to 1991, 41 were recorded as having A, BWS or HH. Twenty-eight of these had their anomaly diagnosed before the WT and 13 had screening procedures carried out, mainly abdominal ultrasound. In 8 patients the screening procedure detected the WT. There was no significant difference in stage distribution or outcome for any of the three subgroups who were not screened, screen-positive or screen-negative. We conclude that regular screening with abdominal ultrasound is not of proven value. Parents should be taught abdominal palpation and advised to seek appropriate advice for untoward symptoms.
Aniridia↗
The kinetics of the auto-induction of ifosfamide metabolism during continuous infusion.
It has often been reported that the oxazaphosphorines ifosfamide and cyclophosphamide induce their own metabolism. This phenomenon was studied in 21 paediatric patients over 35 courses of therapy. All patients received 9 gm-2 of ifosfamide as a continuous infusion over 72 h. Plasma concentrations of parent drug and of the major metabolite in plasma, 3-dechloroethylifosfamide (3DC) were determined, using a quantitative thin-layer chromatography (TLC) technique. A one-compartment model was fitted simultaneously to both ifosfamide and 3DC data. The model included a time-dependent clearance term, increasing asymptotically from an initial value to a final induced clearance and characterised by a first-order rate constant. A time lag, before induction of clearance began, was determined empirically. Metabolite kinetics were characterised by an elimination rate constant for the metabolite and a composite parameter comprising a formation clearance, proportional to the time-dependent clearance of parent drug, divided by the volume of distribution of the metabolite. Thus, the parameters to estimate were the volume of distribution of parent drug (V), initial clearance (Cli), final clearance (Cls), the rate constant for changing clearance (Kc), the elimination rate constant for the metabolite (Km) and Vm/fm, the metabolite volume of distribution divided by the fractional clearance to 3DC. The model of drug and metabolite kinetics produced a good fit to the data in 22 of 31 courses. In a further 4 courses an auto-inductive model for parent drug alone could be used. In the remaining courses, auto-induction could be demonstrated, but there were insufficient data to fit the model. For some patients this was due to a long time lag (up to 54 h) relative to the infusion time. The time lag varied from 6 to 54 (median, 12)h and values for the other parameters were Cli, 3.27 +/- 2.52 lh-1 m-2, Cls, 7.50 +/- 3.03 lh-1 m-2, V, 22.0 +/- 11.0 1 m-2, Kc, 0.086 +/- 0.074 h-1; Km, 0.159 +/- 0.077 h-1 and Vm/fm, 104 +/- 82 1m-2. The values of Kc correspond to a half-life of change in clearance ranging from 2 to 157 h, although for the majority of the patients the half-life was less than 7 h and a new steady-state level was achieved during the 72 h infusion period. This model provides insight into the time course of enzyme induction during ifosfamide administration, which may continue for up to 10 days in some protocols.(ABSTRACT TRUNCATED AT 400 WORDS)
Adolescent↗
Comparison of methods for the estimation of carboplatin pharmacokinetics in paediatric cancer patients.
The antitumour and toxic effects of platinum drugs, in particular carboplatin, have been related to their plasma concentration and this has led to the concept of a target area under the plasma concentration-time curve (AUC) for carboplatin dosing. A formula based on renal function has been successfully applied to carboplatin dosing in adults and modified versions have also been proposed for paediatric patients. In order to monitor carboplatin AUC with maximum efficiency and minimum patient inconvenience, limited sampling strategies are desirable. A population method with Bayesian estimation is described, based on one or two samples taken following a dose of carboplatin. Population data were obtained from 22 paediatric patients treated with 200-1000 mg/m2 carboplatin as a 60-90 min infusion. Ultrafilterable carboplatin was determined by atomic absorption spectrophotometry. A two compartment model was fitted to each data set using the Maximum Likelihood estimator of the ADAPT programme. These parameter estimates provided the prior means and covariance matrix for the Bayesian estimator using a lognormal distribution. The test data sets consisted of ultrafilterable carboplatin concentrations in 23 patients (aged 1 month-18 years) who received similar treatment. The two compartment model was fitted to data sets containing one or two points, using the Bayesian maximum a posteriori (MAP) estimator and an error model derived from the population error model parameters. Results from the Bayesian analysis and other methods for the estimation of AUC, including relating clearance to surface area or to renal function, were evaluated by comparing the AUC estimate with the AUC determined by model-independent analysis. Overall, the optimal sampling strategy performed better than estimates based on renal function, which had a median bias of 5% and precision of 22%. With one data point at 60 min postinfusion, the median bias and precision were 3 and 6%, respectively. Addition of a second data point at 30 min during the infusion improved the estimate slightly (median bias -2%, precision 3%). Bayesian estimation produced more reliable estimates of AUC compared to values based on renal function, which in turn was slightly better than using surface area. A technique, developed in adult patients, for estimating AUC from a measurement of 24 h total plasma platinum was comparable to estimates based on renal function, but was less reliable. The estimation of carboplatin AUC can be performed using only one or two plasma samples and Bayesian analysis. This approach is less biased and more precise than methods based on surface area, renal function or total platinum at 24 h postdose, but is probably best used in combination with dosing based on renal function.
Adolescent↗
Exposure of neonatal rats to alcohol by vapor inhalation demonstrates specificity of microcephaly and Purkinje cell loss but not astrogliosis.
The artificial rearing model (AR) of fetal alcohol syndrome (FAS) has been shown to induce several major pathologies in the early postnatal rat brain development: microcephaly, selective neuronal cell loss, and activation of astroglia in the neocortex. The purpose of this study was to determine whether these pathologies were specific to the action of alcohol or, in contrast, could result from confounds attributed to this model of FAS. For this purpose, the pathological effects of AR were compared with those of a vapor inhalation (VI) model of FAS. Our studies showed that the microcephaly that developed after exposure to periodic blood alcohol levels (BALs) of 300-350 mg% during postnatal days 4-9 could be achieved by both AR and IV models of FAS, and thus is independent of the method of alcohol administration. In contrast, the gliosis measured by glial fibrillary acidic protein (GFAP) mRNA levels in cortex, as well as by immunohistochemical staining for GFAP, was found only in the AR-FAS model, but not in the VI model. However, the lack of gliosis in VI was apparently not due to a less intrusive intervention of alcohol, because VI exposure resulted in a reduction in Purkinje cell number comparable with that found after AR or intragastric intubation of alcohol. Based on these observations, we conclude that the activation of gliosis observed after AR is not a specific effect of alcohol, but rather is caused by an interaction of alcohol with as yet unidentified factors present in AR.
Administration, Inhalation↗
Patients who have been advised to have immediate or urgent discectomies because of low back pain.
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Bed Rest↗
Recognising and treating thyroid-associated ophthalmopathy.
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Eye Diseases↗
Primary angiitis and angiopathy of the central nervous system and their relationship to systemic giant cell arteritis.
Three cases of primary angiitis of the central nervous system were compared with previously published cases. Most cases occurred in older adults, were diagnosed histologically, and had a male-female ratio of 2:1. Angiographically identified cases, demonstrating angiopathy but not necessarily vasculitis as might be seen in histologically identified cases, were found in younger adults and showed a male-female ratio of 1:2. The autopsy cases had some similarities to systemic giant cell arteritis, including many cases with vasculitis in large branches of the circle of Willis and foci of systemic vasculitis. Vasculitides in arteries of different sizes may result from different responses to a variety of antigens or immune complexes rather than represent different disease processes. If causative immune mechanisms can be identified, primary angiitis of the central nervous system may become classified immunologically rather than histopathologically.
Adult↗
Alcohol selectively attenuates stress-induced c-fos expression in rat hippocampus.
The ability of ethyl alcohol to modify responses to stress has been well documented (cf. Pohorecky, 1990). However, the structural substrate mediating these effects of alcohol remains undefined. Using immediate early gene (IEG) expression in the brain as a marker of altered neuronal response, we investigated the effect of acute alcohol exposure on the activity of brain regions of rats exposed to 15 min of restraint stress. Immunocytochemical localization c-Fos protein demonstrated that restraint stress led to an induction of c-Fos expression in several brain structures including cingulate and piriform cortex, cortico-amygdaloid and hippocampo-amygdaloid transition zones, hippocampus, hypothalamus, supramammillary nucleus, and centromedial nucleus of thalamus. An intraperitoneal injection of 2 g/kg alcohol prior to stress decreased c-Fos expression in several but not all of these structures. In particular, alcohol strongly attenuated the stress-induced expression of c-Fos in hippocampus and cingulate cortex. Using slot-blot hybridization, significant induction of c-fos mRNA after restraint stress was demonstrated both in hippocampus and cortex, but prior alcohol exposure specifically attenuated c-fos induction only in the hippocampus. The response of c-fos mRNA expression to stress and alcohol differed from the effects on jun-B, c-jun and jun-D mRNA levels. Perhaps surprisingly, acute exposure to alcohol in otherwise unstressed rats did not induce significant changes in expression of IEGs in comparison to control (saline-injected) animals even with doses sufficient to elevate plasma corticosterone. In summary, these studies demonstrate a selective sensitivity of stress-induced activity of neurons of hippocampus and cingulate cortex to acute alcohol exposure.
Animals↗
Expression of mu class glutathione S-transferase correlates with event-free survival in childhood acute lymphoblastic leukemia.
Expression of the main classes (pi, mu, and alpha) of glutathione S-transferase (GST) was assessed in the blasts of children presenting with acute lymphoblastic leukemia using an immunohistochemical technique. Bone marrow trephine biopsies obtained at presentation from 71 cases were studied (42 boys, 29 girls; age range, 6 months-14 years; median age, 4 years) and expression was correlated with event-free survival. The period of follow-up was 12-108 months, during which time 21 patients (30%) relapsed. All the samples examined were negative for alpha class GST. Samples from 8 patients, all of whom remained in remission at the time of analysis, were found to be negative for pi class GST at presentation. Samples from 44 (patients were negative for mu class GST (62%); of these, 36 patients (82%) remained in remission. In comparison, of the 27 patients who were positive for mu class GST, only 14 (52%) remained in remission. Analysis of event-free survival demonstrated that expression of mu class GST predicts a 3-fold increased risk of relapse (95% confidence interval, 1.25-7.26). This risk factor appears to be independent of other recognized prognostic factors.
Adolescent↗
A humanized antibody specific for the platelet integrin gpIIb/IIIa.
C4G1, a murine mAb reactive with the platelet gpIIb/IIIa integrin, was humanized for potential treatment of thrombosis-related disorders. The variable regions of light- and heavy-chain cDNAs from the C4G1 hybridoma were first cloned and sequenced. Humanized C4G1 Ab of the IgG1 isotype was constructed by combining the complementarity-determining regions of C4G1 with human framework and constant regions. The human framework was chosen to maximize homology with the C4G1 variable region sequence, and a computer model of C4G1 was used to aid design of the final framework sequence. Genetic constructs were also developed to produce Fab and F(ab')2 fragments of the humanized C4G1 Ab. The humanized IgG1 Ab as well as the Fab and F(ab')2 fragments showed equivalent binding affinities to their murine counterparts, indicating no loss in binding affinity during the humanization process. The humanized Ab and its fragments were also shown to inhibit platelet aggregation and to inhibit binding of fibrinogen to gpIIb/IIIa in vitro.
Amino Acid Sequence↗
False positive results in a neuroblastoma screening programme.
Twenty thousand, eight hundred and twenty-nine babies were screened for neuroblastoma at 6 months of age by measuring homovanillic (HVA) and vanillylmandelic (VMA) acid in urine and rationing these to creatinine. Using a "cut off" of the mean + 3 SD, 10 were found to be positive. Two were found on evaluation to have neuroblastoma and in the remaining 8 the raised levels of HVA and/or VMA returned to normal. Only one of the 8 false positive babies was absolutely normal, most having a chronic disorder or illness. Utilising new centiles which relate HVA and VMA to creatinine, only 3 of the 8 would have remained positive, a false positive rate of 0.01%. The false negative rate would have remained unchanged.
Creatinine↗
Loss of red blood cell viability associated with limited thermal inactivation of extracellular HIV-1.
The effects of incubation at mildly elevated temperatures on HIV-1 inactivation and in vitro red blood cell properties were investigated. Red cells (55% Hct) were leukodepleted (3 log10) by filtration, maintained at 45 or 47 degrees C for 4 or 8 h, and then stored at 4 degrees C. Hemolysis was twice that of controls after 42-day storage for samples treated for 4 h at 45 degrees C, and five times larger for samples heated at 47 degrees C. There was also a significant increase in the rate of potassium loss, an early decrease in ATP levels, and an initial drop in pH for samples treated at either temperature. Larger differences were observed for samples exposed to these elevated temperatures for 8 h. Osmotic deformability curves obtained by ektacytometry showed dramatic decreases in red cell deformability at both temperatures and for both time periods. HIV-1 inactivation in red cells treated at 45 degrees C (approximately 0.25 log10/h) was considerably less than that obtained in tissue culture medium (1-2 log10/h). Since the decrease in red cell deformability is likely to indicate reduced red cell function and survival, and the rate of HIV-1 inactivation is low, mild heat treatment is not an adequate process for viral inactivation of red cell products.
Blood↗
Inaccuracy of glomerular filtration rate estimation from height/plasma creatinine ratio.
Use of a height/plasma creatinine formula to estimate glomerular filtration rate (GFR) is simpler and less invasive than renal or plasma clearance methods. The aim of this study was to determine whether these formulas enabled accurate prediction of GFR measured from the plasma clearance of 51Cr labelled ethylenediaminetetra-acetic acid (51Cr-EDTA). Thirty nine patients underwent GFR measurement at least six months after potentially nephrotoxic chemotherapy. Altman-Bland analysis was performed on the measured GFR and that estimated simultaneously using the original and a modified Counahan-Barratt formula and the Schwartz formula. The limits of agreement of the estimated GFR with the measured GFR were unacceptably wide in each case, despite highly significant correlation coefficients. The bias was smallest for the modified Counahan-Barratt formula. Use of these formulas to estimate GFR in children is insufficiently accurate for research purposes and has limitations in clinical practice. Furthermore, use of correlation coefficients to evaluate different methods of measuring GFR is inappropriate.
Adolescent↗
The foreign policy of the cerebellum.
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Aged↗