The development and validation of a health-related quality of life questionnaire for pre-school children with a chronic heart disease.

PURPOSE: Heart diseases are often associated with residual injuries, persisting functional restrictions, and long-term sequelae for psychosocial development. Currently, there are no disease-specific instruments to assess the health-related quality of life (HrQoL) of pre-school children. The aims of this study were to develop a parent proxy instrument to measure the HrQoL of children aged 3-7 years with a heart disease and to confirm its validity and reliability. METHODS: Items from the Preschool Pediatric Cardiac Quality of Life Inventory (P-PCQLI) were generated through focus groups of caregivers. In a pilot study, comprehensibility and feasibility were tested. Five subdimensions were defined theoretically. Psychometric properties were analysed within a multicentre study with 167 parental caregivers. RESULTS: The final 52-item instrument contains a total score covering five moderately inter-correlated dimensions. The total score of the questionnaire showed a very high internal consistency (Cronbachs' α = 0.95). Test-retest correlation was at r tt = 0.96. External validity was indicated by higher correlations (r = 0.24-0.68) with a generic paediatric quality of life questionnaire (KINDL) compared to the Strengths and Difficulties Questionnaire (r = 0.17 to 0.59). Low P-PCQLI total scores were significantly associated with inpatient as opposed to outpatient treatment (t = 6.04, p < .001), with at least moderate disease severity ((t = 5.05, p < .001) NYHA classification) and with poorer prognosis (t = 5.53, p < .001) as estimated by the physician. CONCLUSIONS: The P-PCQLI is reliable and valid for pre-school children with a heart disease. It could be used as a screening instrument in routine care, and for evaluation of HrQoL outcomes in clinical trials and intervention research.

Diagnostic assessment of brain tumours and non-neoplastic brain disorders in vivo using proton nuclear magnetic resonance spectroscopy and artificial neural networks.

PURPOSE: Experiments were carried out to assess the potential of artificial neural network (ANN) analysis in the differential diagnosis of brain tumours (low- and high-grade gliomas) from non-neoplastic focal brain lesions (tuberculomas and abscesses), using proton magnetic resonance spectroscopy (1H MRS) as input data. METHODS: Single-voxel stimulated echo acquisition mode (STEAM) (echo time of 20 ms) spectra were acquired from 138 subjects including 15 with low-grade gliomas, 47 with high-grade gliomas, 18 with tuberculomas, 18 with abscesses and 40 healthy controls. Two neural networks were constructed using the spectral points from 0.6 to 3.4 parts per million. In the first network construction, the ANN had to differentiate between tumours from infections, while the second network had to differentiate between all five histological classes. RESULTS: ANN analysis gave a histologically correct diagnosis for low- and high-grade gliomas with an accuracy of 73% and 98% respectively. None of the 62 tumours was diagnosed as an infectious lesion. Among the non-neoplastic lesions, ANN classification was correct in 89% of tuberculomas and in 83% of brain abscesses. The specificity of ANN diagnosis was 98%, 92%, 99%, and 100% for low-grade gliomas, high-grade gliomas, tuberculomas and abscesses respectively. CONCLUSION: The present data show the clinical utility of non-invasive 1H MRS by automated ANN analysis in the diagnosis of tumour and non-tumour cerebral disorders.

Metabolism of the dimethyl ester of [2,3-(13)C]succinic acid in rat hepatocytes.

Hepatocytes prepared from overnight fasted rats were incubated for 120 min in the presence of the dimethyl ester of [2,3-(13)C]succinic acid (10 mM). The identification and quantification of 13C-enriched metabolites in the incubation medium were performed by a novel computational strategy for the deconvolution of NMR spectra with multiplet structures and constraints. The generation of 13C-labelled metabolites, including succinate, fumarate, malate, lactate, alanine, aspartate and glucose accounted for about half of the initial amount of the ester present in the incubation medium. A fair correlation was observed between the experimental abundance of each 13C-labelled glucose isotopomer and the corresponding values derived from a model for the metabolism of [2,3-(13)C]succinate. Newly formed glucose was more efficiently labelled in the carbon C5 than C2, as well as the carbon C6 than C1, supporting the concept that D-glyceraldehyde-3-phosphate may undergo enzyme-to-enzyme channelling between glyceraldehyde-3-phosphate dehydrogenase and phosphofructoaldolase.

A computational strategy for the deconvolution of NMR spectra with multiplet structures and constraints: analysis of overlapping 13C-2H multiplets of 13C enriched metabolites from cell suspensions incubated in deuterated media.

A computational strategy for the deconvolution of complex spectra involving scalar multiplet patterns is presented. This approach fits spectra that can be composed of single resonances as well as scalar coupling multiplets for which resonance frequencies, intensities, and lineshape parameters can be optimized. For multiplets, the coupling constant also is optimized. Any external information about the optimizable parameters can be taken into account as external constraints. A lineshape described by absorptive and dispersive Lorentzian and Gaussian contributions and the baseline with up to 40 Fourier and polynomial terms can likewise be optimized. The effectiveness of the procedure is assessed on the basis of computer simulated deconvolutions of a composite of 1J(13C-2H) multiplets arising from a mixture of all possible 13C-2H isotopomers of deuterated L-[3-13C]lactate generated from cell preparations incubated with D-[1-13C]glucose in D2O, which was analyzed previously with a manual deconvolution procedure (R. Willem, M. Biesemans, F. Kayser, W. J. Malaisse, Magn, Reson. Med. 31, 259-267 (1994)). The use of constraints is shown to lead to an improvement in the results. The fitting strategies and the importance of the baseline as an origin of bias are discussed.

Cocaine N-demethylation and the metabolism-related hepatotoxicity can be prevented by cytochrome P450 3A inhibitors.

Cocaine is eliminated and detoxified principally through the metabolism of nonspecific plasma and tissue esterases. Microsomal oxidative metabolism is of importance in cocaine N-demethylation, this being a principal pathway of cocaine bioactivation and hepatotoxicity. The contribution of different cytochrome P450 (CYP) enzymes to cocaine N-demethylase activity was studied in vitro with DBA/2 mouse and human liver microsomes, and cocaine hepatotoxicity was examined in vivo in DBA/2 male mice. Species dependent enzyme kinetics was observed. Cocaine N-demethylase displayed two Km values in murine liver (40-60 microM and 2-3 mM), whereas only one Km value was observed in human liver microsomes (2.3-2.7 mM). We suggest that CYP3A plays a prominent role in the N-demethylation of cocaine for the following reasons: (i) pregnenolone-16 alpha-carbonitrile, an inducer of CYP3As increases cocaine N-demethylase in parallel with testosterone 6 beta-hydroxylase activity and immunoreactive 3A protein in mouse liver; (ii) human and mouse cocaine N-demethylase and testosterone 6 beta-hydroxylase activities can be inhibited by triacetyloleandomycin, cannabidiol, or gestodene, all selective inhibitors of CYP3A P450s; (iii) antibodies directed against P450s within subfamilies 1A, 2A, 2B, 2C, or 2E inhibited cocaine N-demethylase activity only marginally, and finally, (iv) treatment of mice with triacetyloleandomycin or cannabidiol in vivo significantly attenuated the cocaine-elicited hepatotoxicity as assessed by the serum alanine aminotransferase activity and liver histology in parallel with decreased cocaine N-demethylase activity.(ABSTRACT TRUNCATED AT 250 WORDS)