In vivo evidence that ethosuximide is a substrate for cytochrome P450IIIA.

The role of various subfamilies of rat hepatic cytochrome P450 in the oxidation of ethosuximide was evaluated by comparing ethosuximide clearance in control rats and those pretreated with relatively selective P450 inducers and/or inhibitors. Clotrimazole pretreatment increased ethosuximide clearance threefold (p less than 0.005). Dexamethasone increased ethosuximide clearance twofold (p less than 0.001), and the dexamethasone effect was completely abolished by a single dose of triacetyloleandomycin. These results suggest a prominent role for cytochrome P450IIIA in ethosuximide metabolism in the rat. Isoniazid increased ethosuximide clearance twofold (p less than 0.001), and this effect was abolished by a single dose of diallylsulfide, suggesting that ethosuximide is also processed by cytochrome P450IIE1 in rats. Phenobarbital pretreatment increased ethosuximide clearance 2-2.7 fold (p less than 0.001); an effect that was only partially reversed by orphenadrine, an inhibitor of cytochrome P450IIB/IIC enzymes. This suggests a quantitatively less important role for the IIB/IIC subfamilies in processing ethosuximide, since phenobarbital is an inducer of P450 subfamilies IIB, IIC, IIE, and IIIA. Neither the cytochrome P450IA inducer, beta-naphthoflavone, nor the inhibitor, alpha-naphthoflavone altered ethosuximide clearance. Ajmaline, an inhibitor of cytochrome P450IID, had no effect on ethosuximide clearance. Together, these findings suggest that ethosuximide is principally oxidized by cytochrome P450IIIA, and that cytochrome P450IIE may play an important role. Cytochromes P450IIB/C play less prominent roles in ethosuximide oxidation, and neither cytochrome P450IA nor cytochrome P450IID is involved.     

Integrating children's services in England: national evaluation of children's trusts

Background Poor co‐ordination of services can have severe consequences for disadvantaged children with complex needs. Since 2003 national and local governments in England embarked on sweeping reforms aimed at improving and integrating local health, education and social services for children. These were to be organized locally by children's trusts and piloted by 35 children's trust pathfinders. Methods This study described and compared the experience of integrating children's services in all 35 children's trust pathfinders, covering 20% of children in England. It had a prospective mixed‐methods design. Over 3 years we interviewed 147 managers and professionals working in the children's trusts, including 172 semi‐structured interviews, carried out two questionnaire surveys of the 35 children's trusts and analysed official documents. Results In most areas different agencies jointly commissioned children's services, especially for mental health, disabilities and multi‐purpose children's centres, and increasingly pooled finances. Provision of multi‐agency and multi‐professional services was increasing. Professionals generally supported these changes but found them stressful. All children's trusts appointed directors of children's services and established boards representing multiple agencies. Systems for sharing information about individual children were mostly in place but were still underused. Health services were generally less involved in joint work than were local authorities' education and social care services, with notable exceptions. Areas where local authorities and health authorities shared geographical boundaries made most progress. Some children's trusts made few changes beyond their statutory obligations. Conclusion Children's trusts enabled major changes to services in areas where local actors and organizations were motivated and empowered. In other areas the remit of children's trusts was often too broad and vague to overcome entrenched organizational and professional divisions and interests. Policymakers need to balance facilitation of change in areas with dynamic change agents with methods for ensuring that dormant areas and agencies are not left behind.     

Selective hepatic artery ligation for hepatic haemangioendothelioma: case report and review of the literature.

Although benign, hepatic haemangioendotheliomas (HHE) are rare vascular tumours of the infant which have a high mortality rate secondary to high output congestive heart failure. The management of these tumours is still controversial and none of the different medical or surgical options has been unanimously accepted. We report the case of a neonate with congestive heart failure (CHF) due to a localized HHE, treated successfully by selective ligation of the left hepatic artery branch irrigating the tumour, under perioperative ultrasound Doppler control. A review of the literature showed 35 cases of HHE treated by hepatic artery ligation (HAL) with a survival rate of 80 %.     

Electromyography of the internal anal sphincter performed under endosonographic guidance description of a new method

PURPOSE: The aim of our study was to investigate internal anal sphincter electromyographic signals. METHODS: Electromyography of the internal anal sphincter was performed with platinum wire electrodes in six healthy volunteers (three males and three females), inserted under endosonographic guidance. Platinum wire electrodes were also inserted into the external anal sphincter. Activity of both the internal and external anal sphincter in a 40-second period was measured. RESULTS: Internal anal sphincter median activity was 22.1 (range, 5.5–67.6) μ V. Slow-wave activity was 47 cycles/minute (range, 34–55 cycles/minute). After inflation of a rectal balloon with air until a constant relaxation of the anal canal was obtained, a decrease in internal anal sphincter activity to 15.9 (1.2–31.3) μV as well as a decrease in slow-wave activity to 34 cycles/minute (range, 27–40 cycles/minute) was found. The original internal anal sphincter EMG was resumed after deflation of the rectal balloon. External anal sphincter median activity was 31 (range, 0.77–18.6)μV. During inflation of the rectal balloon, a reflex increase in external sphincter EMG activity was found. With the rectal balloon fully inflated a part of this increase was still present, 11.0 (1.9–24.6)μV. In some of the subjects, this increased activity was superimposed on the internal anal sphincter recordings as well. During a voluntary squeeze it was not possible to identify internal anal sphincter activity due to activity of the external anal sphincter totally overriding the internal anal sphincter signal. CONCLUSION: Precise EMG recordings from the internal anal sphincter is possible with endosonographic guidance of the electrodes, except during voluntary squeezing of the external anal sphincter.     

Expression of Human Recombination Activating Genes (RAG-1 and RAG-2) in Lymphoma

Two recently discovered genes, the recombination activating genes 1 and 2 (RAG-1 and RAG-2), are necessary to perform variable (V), diversity (D), and joining (J) recombination. They synergistically activate VDJ recombination to generate immunocompetent lymphocytes. Disruption of either gene results in a maturation arrest at a very early B and T cell progenitor stage. Expression and downregulation of RAG's are closely associated with interleukin 7, sIgM and TCR-CD3 complex, respectively. Assessment of RAG mRNA expression is a valuable marker in identifying the genotypic maturation status of leukemias and lymphomas. Persistent RAG expression in otherwise mature lymphoid proliferations may explain puzzling biological and clinical observations such as multiple rearrangements in lymphomas with a mature phenotype. Lack of RAG expression in Hodgkin's disease with abundant Reed-Stern-berg cells is consistent with a mature phenotype of the latter. Availability of a anti-RAG-1 monoclonal antibody in the near future will facilitate RAG analysis of lymphomas.     

Receptive field scatter,topography and map variability in different layers of the hindpaw representation of rat somatosensory cortex

We recorded neurons extracellularly in layers II/III, IV, and V of the hindpaw representation of primary somatosensory cortex in anesthetized rats and studied laminar features of receptive fields (RFs) and representational maps. On average, RFs were smallest in layer IV and largest in layer V; however, for individual penetrations we found substantial deviations from this rule. Within the hindpaw representation, a distinct rostrocaudal gradient of RF size was present in all layers. While layer V RFs were generally largest independent of this gradient, layer IV RFs recorded caudally representing the proximal portions of the paw were larger than layer II/III RFs recorded rostrally representing the digits. The individual scatter of the locations of RFs across laminar groups was in the range of several millimeters, corresponding to about 25% of the average RF diameter. The cutaneous representations of the hindpaw in extragranular layers were confined to the areal extent defined by responsive sites in layer IV. Comparison between RFs determined quantitatively and by handplotting showed a reliable correspondence. Repeated measurements of RFs revealed spontaneous fluctuations of RF size of no more than 5% of the initial condition over an observation period of several hours. The topography and variability of cortical maps of the hindpaw representation were studied with a quantitative interpolation method taking into account the geometric centers of RFs and the corresponding cortical recording sites. On average, the overall topography in terms of preservation of neighborhood relations was present in all layers, although some individual maps showed severe distortions of topography. Factors contributing to map variability were overall position of the representation on the cortical surface, internal topography and spatial extent. Interindividual variability of map layout was always highest in the digit representations. Local topographic orderliness was lowest in layer V, but comparable in layers II/III and IV. Within layer IV, the lowest orderliness was observed in the digit representations. Our data emphasize a substantial variability of RF size, overlap and position across layers and within layers. At the level of representational maps, we found a similar degree of variability that often co-varied across layers, with little evidence for significant layer specificity. Laminar differences are likely to arise from the specific input-output pattern, layer-specific cell types and the connectivity between different layers. Our findings emphasizing similarities in the variability across layers support the notion of tightly coupled columnar interactions between different layers.     

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Voronoi Polyhedra Analysis of Optimized Arterial Tree Models

Topological and metric properties of Voronoi polyhedra (VP) generated by the distal end points of terminal segments in arterial tree models grown by the method of constrained constructive optimization (CCO) are analyzed with the aim to characterize the spatial distribution of their supply sites relative to randomly distributed points as a reference model. The distributions of the number N _f of Voronoi cell faces, cell volume V, surface area S, area A of individual cell faces, and asphericity parameter of the CCO models are all significantly different from the ones of random points, whereas the distributions of V, S, and are also significantly different among CCO models optimized for minimum intravascular volume and minimum segment length (p < 0.0001). The distributions of N _f , V, and S of the CCO models are reasonably well approximated by two-parameter gamma distributions. We study scaling of intravascular blood volume and arterial cross-sectional area with the volume of supplied tissue, the latter being represented by the VP of the respective terminal segments. We observe scaling exponents from 1.20 ± 0.007 to 1.08 ± 0.005 for intravascular blood volume and 0.77 ± 0.01 for arterial cross-sectional area. Setting terminal flows proportional to the associated VP volumes during tree construction yields a relative dispersion of terminal flows of 37% and a coefficient of skewness of 1.12. © 2003 Biomedical Engineering Society. PAC2003: 8719Uv, 8710+e, 4720Ky, 0260Pn, 0230Oz     

Diuretic treatment and serum lipoproteins: Effects of tienilic acid and indapamide

Summary Treatment with the commonly used diuretic, chlorthalidone, has previously been found to increase the serum low-density-lipoprotein cholesterol (LDL-C) fraction. Therefore, the effects of two new agents, tienilic acid (a combined diuretic-uricosuric) and indapamide on serum lipid and lipoprotein levels were assessed. Six weeks of treatment with tienilic acid, 250 mg/day, markedly decreased serum uric acid and significantly increased LDL-C and triglycerides in 16 men. In contrast, indapamide 2.5 mg/day, had no apparent influence on serum lipids or lipoproteins in 18 men.Supported in part by the Swiss National Science Foundation