The influence of liver dysfunction on cyclosporine pharmacokinetics -A comparison between 70 per cent hepatectomy and complete bile duct ligation in dogs-

The influence of experimentally induced hepatic dysfunction on the pharmacokinetics of Cyclosporine A (CsA) was determined in dogs. The pharmacokinetics of oral (PO) and intravenous (IV) CsA were studied before and after 70 per cent hepatectomy or complete bile duct ligation (CBDL). Changes in liver function were monitored by serial measurements of serum bilirubin, and by the maximum removal rate (Rmax) and plasma disappearance rate (ICG-K) of indocyanine green (ICG). Concentrations of CsA in whole blood were measured by HPLC. Seventy per cent hepatectomy caused significant liver dysfunction: the ICG-Rmax decreased by 47.7±7.1 per cent (mean±SD) and the ICG-K decreased by 61.3±9.7 per cent during the first week after hepatectomy. At the same time, the systemic clearance (CLs) of IV-CsA decreased by 43.9±8.2 per cent, the area under the concentration curve (AUC) of IV-CsA increased by 35.4±20.8 per cent and the bioavailability of CsA decreased by 26.4±14.8 per cent. CBDL also induced significant liver dysfunction: the ICG-Rmax decreased by 39.1±12.8 per cent and the ICG-K decreased by 65.6±3.6 per cent in the second week after the operation. During the same period, the AUC of PO-CsA decreased by 69.9±10.7 per cent and the bioavailability of CsA also decreased markedly by 73.9±15.6 per cent. These data indicate that hepatic impairment significantly influences the pharmacokinetics of CsA, not only by the changes in intestinal absorption, but also by those in hepatic, metabolism. Dose adjustment is therefore necessary in the presence of hepatic dysfunction in order to maintain an adequate blood concentration of CsA without causing side effects. © 1989 The Japan Surgical Society

The differential contribution of maternal and paternal values to social competence of preschoolers

Multivariate analyses were conducted to clarify the nature of the influences of parental values on social behaviours of kindergarteners in the context of sociodemographic variables and sex of participants. This study included 217 mothers and 172 fathers from the same families, who completed a socio-demographic questionnaire and a new Q-sort that assesses parental values on Individualism (IND)/Collectivism (COL) and Horizontal (HOR)/Vertical (VER) continuums.To test the hypothesis of an association between parental values and children’s behaviours, teachers also provided information about each child’s social competence, anger-aggression, and anxiety-withdrawal in kindergarten using the Social Competence and Behavior Scale. Parents shared a greater proportion of IND/COL than VER values and mothers were more likely to emphasise IND and COL values than fathers. Mothers within IND and COL groups had more socially competent kindergartners as reported by teachers. Considering the mixed results found in the literature regarding sex differences in parenting and behaviours of children, the present results suggested that examining more closely the system of parental values might offer valuable avenues for uture research on early childhood socialisation

Spectral phase encoding for data storage and addressing

We propose to use a broad-bandwidth laser source for storing and retrieving multiple holograms in a photorefractive material. Each storage address is defined by a specific spectral encoding of the reference beam. The validity of the spectral encoding method is tested in a preliminary experiment

Inner-sphere oxidation of ternary iminodiacetatochromium(III) complexes involving DL-valine and L-arginine as secondary ligands. Isokinetic relationship for the oxidation of ternary iminodiacetato-chromium(III) complexes by periodate

<p>Abstract</p> <p>Background</p> <p>In this paper, the kinetics of oxidation of [Cr^III(HIDA)(Val)(H₂O)₂]⁺and [Cr^III(HIDA)(Arg)(H₂O)₂]⁺(HIDA = iminodiacetic acid, Val = DL-valine and Arg = L-arginine) were studied. The choice of ternary complexes was attributed to two considerations. Firstly, in order to study the effect of the secondary ligands DL-valine and L-arginine on the stability of binary complex [Cr^III(HIDA)(IDA)(H₂O)] towards oxidation. Secondly, transition metal ternary complexes have received particular focus and have been employed in mapping protein surfaces as probes for biological redox centers and in protein capture for both purification and study.</p> <p>Results</p> <p>The results have shown that the reaction is first order with respect to both [IO₄^-] and the complex concentration, and the rate increases over the pH range 2.62 – 3.68 in both cases. The experimental rate law is consistent with a mechanism in which both the deprotonated forms of the complexes [Cr^III(IDA)(Val)(H₂O)₂] and [Cr^III(IDA)(Arg)(H₂O)₂] are significantly more reactive than the conjugate acids. The value of the intramolecular electron transfer rate constant for the oxidation of [Cr^III(HIDA)(Arg)(H₂O)₂]⁺, <it>k</it>₃(1.82 × 10^-3s^-1), is greater than the value of <it>k</it>₁(1.22 × 10^-3s^-1) for the oxidation of [Cr^III(HIDA)(Val)(H₂O)₂]⁺at 45.0°C and <it>I </it>= 0.20 mol dm^-3. It is proposed that electron transfer proceeds through an inner-sphere mechanism <it>via </it>coordination of IO₄^-to chromium(III).</p> <p>Conclusion</p> <p>The oxidation of [Cr^III(HIDA)(Val)(H₂O)₂]⁺and [Cr^III(HIDA)(Arg)(H₂O)₂]⁺by periodate may proceed through an inner-sphere mechanism via two electron transfer giving chromium(VI). The value of the intramolecular electron transfer rate constant for the oxidation of [Cr^III(HIDA)(Arg)(H₂O)₂]⁺, <it>k</it>₃, is greater than the value of <it>k</it>₁for the oxidation of [Cr^III(HIDA)(Val)(H₂O)₂]⁺. A common mechanism for the oxidation of ternary iminodiacetatochromium(III) complexes by periodate is proposed, and this is supported by an excellent isokinetic relationship between ΔH* and ΔS* values for these reactions.</p

Aggression in toddlerhood: the roles of parental beliefs, parenting behavior and precursors of theory of mind

Parental beliefs, parenting behavior, and precursors of theory of mind have been related uniquely to each other and to early aggression, but have not yet been studied simultaneously. The present study combined these risk factors in the prediction of aggression during toddlerhood using a sample of 152 mother–child dyads. At 20 months, mothers' parental beliefs (parental self‐efficacy and perceived parental impact) were examined with the Parental Cognitions and Conduct Toward the Infant Scale. Maternal parenting behavior (sensitivity, intrusiveness, and successful positive engagement) was observed during free play and teaching tasks, and children's precursors of theory of mind were assessed using a visual perspectives task and an imitation task. At 30 months, child aggression was examined using the Child Behavior Checklist. A regression analysis indicated that lower parental self‐efficacy and lower imitation skills predicted more aggressive behavior. When estimating the indirect effects using bootstrapping, a final model was found indicating that lower perceived parental impact was related to less successful positive engagement, which, in turn, was associated with children's poorer imitation abilities which predicted more aggressive behavior. It can be concluded that aggression during toddlerhood is predicted significantly by interrelated parental beliefs, parenting behavior, and children's early social cognitive abilities

Quantifying the efficiency of hydroxyapatite mineralising peptides

We present a non-destructive analytical calibration tool to allow quantitative assessment of individual calcium phosphates such as hydroxyapatite (HAP) from mixtures including brushite. Many experimental approaches are used to evaluate the mineralising capabilities of biomolecules including peptides. However, it is difficult to quantitatively compare the efficacy of peptides in the promotion of mineralisation when inseparable mixtures of different minerals are produced. To address this challenge, a series of hydroxyapatite and brushite mixtures were produced as a percent/weight (0–100%) from pure components and multiple (N=10) XRD patterns were collected for each mixture. A linear relationship between the ratio of selected peak heights and the molar ratio was found. Using this method, the mineralising capabilities of three known hydroxyapatite binding peptides, CaP(S) STLPIPHEFSRE, CaP(V) VTKHLNQISQSY and CaP(H) SVSVGMKPSPRP, was compared. All three directed mineralisation towards hydroxyapatite in a peptide concentration dependent manner. CaP(V) was most effective at inducing hydroxyapatite formation at higher reagent levels (Ca2+ = 200mM), as also seen with peptide-silk chimeric materials, whereas CaP(S) was most effective when lower concentrations of calcium (20mM) and phosphate were used. The approach can be extended to investigate HAP mineralisation in the presence of any number of mineralisation promoters or inhibitors

Slow GABAA mediated synaptic transmission in rat visual cortex

<p>Abstract</p> <p>Background</p> <p>Previous reports of inhibition in the neocortex suggest that inhibition is mediated predominantly through GABA_Areceptors exhibiting fast kinetics. Within the hippocampus, it has been shown that GABA_Aresponses can take the form of either fast or slow response kinetics. Our findings indicate, for the first time, that the neocortex displays synaptic responses with slow GABA_Areceptor mediated inhibitory postsynaptic currents (IPSCs). These IPSCs are kinetically and pharmacologically similar to responses found in the hippocampus, although the anatomical specificity of evoked responses is unique from hippocampus. Spontaneous slow GABA_AIPSCs were recorded from both pyramidal and inhibitory neurons in rat visual cortex.</p> <p>Results</p> <p>GABA_Aslow IPSCs were significantly different from fast responses with respect to rise times and decay time constants, but not amplitudes. Spontaneously occurring GABA_Aslow IPSCs were nearly 100 times less frequent than fast sIPSCs and both were completely abolished by the chloride channel blocker, picrotoxin. The GABA_Asubunit-specific antagonist, furosemide, depressed spontaneous and evoked GABA_Afast IPSCs, but not slow GABA_A-mediated IPSCs. Anatomical specificity was evident using minimal stimulation: IPSCs with slow kinetics were evoked predominantly through stimulation of layer 1/2 apical dendritic zones of layer 4 pyramidal neurons and across their basal dendrites, while GABA_Afast IPSCs were evoked through stimulation throughout the dendritic arborization. Many evoked IPSCs were also composed of a combination of fast and slow IPSC components.</p> <p>Conclusion</p> <p>GABA_Aslow IPSCs displayed durations that were approximately 4 fold longer than typical GABA_Afast IPSCs, but shorter than GABA_B-mediated inhibition. The anatomical and pharmacological specificity of evoked slow IPSCs suggests a unique origin of synaptic input. Incorporating GABA_Aslow IPSCs into computational models of cortical function will help improve our understanding of cortical information processing.</p

A Unified Model of the GABA(A) Receptor Comprising Agonist and Benzodiazepine Binding Sites

We present a full-length α(1)β(2)γ(2) GABA receptor model optimized for agonists and benzodiazepine (BZD) allosteric modulators. We propose binding hypotheses for the agonists GABA, muscimol and THIP and for the allosteric modulator diazepam (DZP). The receptor model is primarily based on the glutamate-gated chloride channel (GluCl) from C. elegans and includes additional structural information from the prokaryotic ligand-gated ion channel ELIC in a few regions. Available mutational data of the binding sites are well explained by the model and the proposed ligand binding poses. We suggest a GABA binding mode similar to the binding mode of glutamate in the GluCl X-ray structure. Key interactions are predicted with residues α(1)R66, β(2)T202, α(1)T129, β(2)E155, β(2)Y205 and the backbone of β(2)S156. Muscimol is predicted to bind similarly, however, with minor differences rationalized with quantum mechanical energy calculations. Muscimol key interactions are predicted to be α(1)R66, β(2)T202, α(1)T129, β(2)E155, β(2)Y205 and β(2)F200. Furthermore, we argue that a water molecule could mediate further interactions between muscimol and the backbone of β(2)S156 and β(2)Y157. DZP is predicted to bind with interactions comparable to those of the agonists in the orthosteric site. The carbonyl group of DZP is predicted to interact with two threonines α(1)T206 and γ(2)T142, similar to the acidic moiety of GABA. The chlorine atom of DZP is placed near the important α(1)H101 and the N-methyl group near α(1)Y159, α(1)T206, and α(1)Y209. We present a binding mode of DZP in which the pending phenyl moiety of DZP is buried in the binding pocket and thus shielded from solvent exposure. Our full length GABA(A) receptor is made available as Model S1

Perceptions and Practices of Stimulating Children’s Cognitive Development Among Moroccan Immigrant Mothers

We explored the perceptions of children’s cognitive development among Moroccan Arabic and Berber immigrant mothers who cannot read, who are less educated, middle educated or highly educated in the Netherlands. A series of in-depth interviews was conducted with 22 mothers with young children (mean age = 5 years and 6 months). Qualitative data analyses revealed five major themes that are of significant importance to these mothers: moral attitudes, social values and religiousness; conversation, reading and playing as stimulating activities; importance attached to education; parental expectations; attributions of school success. The parental perceptions about the cognitive development of young children differed according to their own educational level. Mothers who cannot read and mothers with less education emphasized the development of moral, social and religious values for strengthening the cultural identity of their children. This sense of identity would enable them to function within their own cultural group and help them to perform well at school. School success was attributed in large part to a combination of the efforts of the child and the school. Middle and highly educated mothers, on the other hand, valued scholastic development and attributed school success to their own efforts and to the kind of support the child received. The ethnic background of the parents, whether Arabic or Berber, did not make a difference in the perceptions