Metabolite mean transit times in the liver as predicted by various models of hepatic elimination

Predicted area under curve (AUC), mean transit time (MTT) and normalized variance (CV2) data have been compared for parent compound and generated metabolite following an impulse input into the liver, Models studied were the well-stirred (tank) model, tube model, a distributed tube model, dispersion model (Danckwerts and mixed boundary conditions) and tanks-in-series model. It is well known that discrimination between models for a parent solute is greatest when the parent solute is highly extracted by the liver. With the metabolite, greatest model differences for MTT and CV2 occur when parent solute is poorly extracted. In all cases the predictions of the distributed tube, dispersion, and tasks-in-series models are between the predictions of the rank and tube models. The dispersion model with mixed boundary conditions yields identical predictions to those for the distributed tube model (assuming an inverse gaussian distribution of tube transit times). The dispersion model with Danckwerts boundary conditions and the tanks-in series models give similar predictions to the dispersion (mixed boundary conditions) and the distributed tube. The normalized variance for parent compound is dependent upon hepatocyte permeability only within a distinct range of permeability values. This range is similar for each model but the order of magnitude predicted for normalized variance is model dependent. Only for a one-compartment system is the MIT for generated metabolite equal to the sum of MTTs for the parent compound and preformed metabolite administered as parent.

Structure and distribution of N-glycans on the S-7-allele stylar self-incompatibility ribonuclease of Nicotiana alata

S-RNases are the stylar products of the self-incompatibility (S)-locus in solanaceous plants (including Nicotiana alata), and as such, are involved in the prevention of self-pollination. All cDNA sequences of S-RNase products of functional S-alleles contain potential N-glycosylation sites, with one site being conserved in all cases, suggesting that N-glycosylation is important in self-incompatibility. In this study, we report on the structure and localization of the N-glycans on the S-7-allele RNase of N, alata, A total of nine N-glycans, belonging to the high-mannose- and xylosylated hybrid-classes, were identified and characterized by a combination of electrospray-ionization mass-spectrometry (ESI-MS), H-1-NMR spectroscopy, and methylation analyses. The glycosylation pattern of individual glycosylation sites was determined by ESI-MS of the glycans released from isolated chymotryptic glycopeptides, All three N-glycosylation sites showed microheterogeneity and each had a unique complement of N-glycans, The N-glycosylation pattern of the S-7-RNase is significantly different to those of the S-1- and S-2-RNases.

Effects of incubation temperature on the energetics of embryonic development and hatchling morphology in the Brisbane river turtle Emydura signata

Incubation temperature and the amount of water taken up by eggs from the substrate during incubation affects hatchling size and morphology in many oviparous reptiles. The Brisbane river turtle Emydura signata lays hard-shelled eggs and hatchling mass was unaffected by the amount of water gained or lost during incubation. Constant temperature incubation of eggs at 24 degrees C, 26 degrees C, 28 degrees C and 31 degrees C had no effect on hatchling mass, yolk-free hatchling mass, residual yolk mass, carapace length, carapace width, plastron length or plastron width. However, hatchlings incubated at 26 degrees C and 28 degrees C had wider heads than hatchlings incubated at 24 degrees C and 31 degrees C. Incubation period varied inversely with incubation temperature, while the rate of increase in oxygen consumption during the first part of incubation and the peak rate of oxygen consumption varied directly with incubation temperature. The total amount of oxygen consumed during development and hatchling production cost was significantly greater at 24 degrees C than at 26 degrees C, 28 degrees C and 31 degrees C. Hatchling mass and dimensions and total embryonic energy expenditure was directly proportional to initial egg mass.

Late Quaternary cycles of mangrove development and decline on the north Australian continental shelf

Mangrove communities in the Australian tropics presently occur as narrow belts of vegetation in estuaries and on sheltered, muddy coasts. Palynological data from continental shelf and deep-sea cores indicate a long-term cyclical component of mangrove development and decline at a regional scale, which can be linked to specific phases of late Quaternary sealevel change. Extensive mangrove development, relative to today, occurs during periods of marine transgression, whereas very diminished mangrove occurs during marine regressions and during rarer periods of relative sea-level stability. Episodes of flourishing mangrove cannot be linked to phases of humid climate, as has been suggested in studies elsewhere. Rather, the cycle of expansion and decline of mangrove communities on a grand scale is explained in terms of contrasting physiographic settings characteristic of continental-shelf coasts during transgressive and regressive phases, in particular by the existence, or lack, of well-developed tidal estuaries. Copyright (C) 1999 John Wiley & Sons, Ltd.

Subgroup relations: A comparison of mutual intergroup differentiation and common ingroup identity models of prejudice reduction

Two studies examined relations between groups (humanities and math-science students) that implicitly or explicitly share a common superordinate category (university student). In Experiment 1, 178 participants performed a noninteractive decision-making task during which category salience was manipulated in a 2 (superordinate category salience) x 2 (subordinate category salience) between-groups design. Consistent with the mutual intergroup differentiation model, participants for whom both categories were salient exhibited the lowest levels of bias, whereas bias was strongest when the superordinate category alone was made salient. This pattern of results was replicated in Experiment 2 (N = 135). In addition, Experiment 2 demonstrated that members of subgroups that are nested within a superordinate category are more sensitive to how the superordinate category is represented than are members of subgroups that extend beyond the boundaries of the superordinate category.

Development and characterization of novel potent and stable inhibitors of endopeptidase EC 3.4.24.15

Solid-phase synthesis was used to prepare a series of modifications to the selective and potent inhibitor of endopeptidase EC 3.4.24.15 (EP24.15), N-[1(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP), which is degraded at the Ala-Tyr bond, thus severely limiting its utility in vivo. Reducing the amide bond between the Ala and Tyr decreased the potency of the inhibitor to 1/1000. However, the replacement of the second alanine residue immediately adjacent to the tyrosine with alpha-aminoisobutyric acid gave a compound (JA-2) that was equipotent with cFP, with a K-i of 23 nM. Like cFP, JA-2 inhibited the closely related endopeptidase EC 3.4.24.16 1/20 to 1/30 as potently as it did EP24.15, and did not inhibit the other thermolysin-like endopeptidases angiotensin-converting enzyme, endothelin-converting enzyme and neutral endopeptidase. The biological stability of JA-2 was investigated by incubation with a number of membrane and soluble sheep tissue extracts. In contrast with cFP, JA-2 remained intact after 48 h of incubation with all tissues examined. Further modifications to the JA-2 compound failed to improve the potency of this inhibitor. Hence JA-2 is a potent, EP24.15-preferential and biologically stable inhibitor, therefore providing a valuable tool for further assessing the biological functions of EP24.15.

Development and standardization of the Self-regulation Skills Interview (SRSI): A new clinical assessment tool for acquired brain injury

The Self-regulation Skills Interview (SRSI) is a clinical tool designed to measure a range of metacognitive skills essential for rehabilitation planning, monitoring an individual's progress, and evaluating the outcome of treatment interventions. The results of the present study indicated that the SRSI has sound interrater reliability and test-retest reliability. A principle components analysis revealed three SRSI factors: Awareness, Readiness to Change, and Strategy Behavior. A comparison between a group of 61 participants with acquired brain injury (ABI) and a group of 43 non-brain-injured participants indicated that the participants with ABI had significantly lower levels of Awareness and Strategy Behavior, but that level of Readiness to Change was not significantly different between the two groups. The significant relationship observed between the SRSI factors and measures of neuropsychological functioning confirmed the concurrent validity of the scale and supports the value of the SRSI for post-acute assessment.

The development and evaluation of an incontinence screening questionnaire for female primary care

Although there is a high prevalence of leaking urine among Australian women, there are currently no standardized procedures for screening patients for incontinence in the primary care setting (known in Australia as general practice). In response to this, an incontinence screening questionnaire (ISQ) was developed and evaluated for use in general practice. Eighty-nine women completed an original compilation of 33 items that asked about situations associated with leaking urine, avoidance of leakage, and concern about leakage. Each item was assessed according to its acceptability for the population of female general practice patients, discriminative value, and test-retest reliability. These patients also underwent an objective test of incontinence, the 48-hour pad test, so that the screening items could be validated against an objective classification of incontinence. The study included women who had bladder control problems and those who did not. Eight items on the ISQ were shown to be acceptable to patients, discriminative, reliable, and valid indicators of objective incontinence. Five items were capable of predicting almost 70% of patients who showed objective leakage of urine and misclassified fewer than 15% of these patients. Those five items were selected for inclusion in the (refined) ISQ. (C) 2000 Wiley-Liss, Inc.

Evolution of stress deficit and changing rates of seismicity in cellular automaton models of earthquake faults

We investigate the internal dynamics of two cellular automaton models with heterogeneous strength fields and differing nearest neighbour laws. One model is a crack-like automaton, transferring ail stress from a rupture zone to the surroundings. The other automaton is a partial stress drop automaton, transferring only a fraction of the stress within a rupture zone to the surroundings. To study evolution of stress, the mean spectral density. f(k(r)) of a stress deficit held is: examined prior to, and immediately following ruptures in both models. Both models display a power-law relationship between f(k(r)) and spatial wavenumber (k(r)) of the form f(k(r)) similar tok(r)(-beta). In the crack model, the evolution of stress deficit is consistent with cyclic approach to, and retreat from a critical state in which large events occur. The approach to criticality is driven by tectonic loading. Short-range stress transfer in the model does not affect the approach to criticality of broad regions in the model. The evolution of stress deficit in the partial stress drop model is consistent with small fluctuations about a mean state of high stress, behaviour indicative of a self-organised critical system. Despite statistics similar to natural earthquakes these simplified models lack a physical basis. physically motivated models of earthquakes also display dynamical complexity similar to that of a critical point system. Studies of dynamical complexity in physical models of earthquakes may lead to advancement towards a physical theory for earthquakes.

Development and subunit composition of synaptic NMDA receptors in the amygdala: NR2B Synapses in the adult central amygdala

NMDA receptors are well known to play an important role in synaptic development and plasticity. Functional NMDA receptors are heteromultimers thought to contain two NR1 subunits and two or three NR2 subunits. In central neurons, NMDA receptors at immature glutamatergic synapses contain NR2B subunits and are largely replaced by NR2A subunits with development. At mature synapses, NMDA receptors are thought to be multimers that contain either NR1/NR2A or NR1/NR2A/NR2B subunits, whereas receptors that contain only NR1/NR2B subunits are extrasynaptic. Here, we have studied the properties of NMDA receptors at glutamatergic synapses in the lateral and central amygdala. We find that NMDA receptor-mediated synaptic currents in the central amygdala in both immature and mature synapses have slow kinetics and are substantially blocked by the NR2B-selective antagonists (1S, 2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propano and ifenprodil, indicating that there is no developmental change in subunit composition. In contrast, at synapses on pyramidal neurons in the lateral amygdala, whereas NMDA EPSCs at immature synapses are slow and blocked by NR2B-selective antagonists, at mature synapses their kinetics are faster and markedly less sensitive to NR2B-selective antagonists, consistent with a change from NR2B to NR2A subunits. Using real-time PCR and Western blotting, we show that in adults the ratio of levels of NR2B to NR2A subunits is greater in the central amygdala than in the lateral amygdala. These results show that the subunit composition synaptic NMDA receptors in the lateral and central amygdala undergo distinct developmental changes.

Development Resource Planning: Complexity of Product Development and the Capacity to Launch New Products

Overcommitment of development capacity or development resource deficiencies are important problems in new product development (NPD). Existing approaches to development resource planning have largely neglected the issue of resource magnitude required for NPD. This research aims to fill the void by developing a simple higher-level aggregate model based on an intuitive idea: The number of new product families that a firm can effectively undertake is bound by the complexity of its products or systems and the total amount of resources allocated to NPD. This study examines three manufacturing companies to verify the proposed model. The empirical results confirm the study`s initial hypothesis: The more complex the product family, the smaller the number of product families that are launched per unit of revenue. Several suggestions and implications for managing NPD resources are discussed, such as how this study`s model can establish an upper limit for the capacity to develop and launch new product families.

A prospective comparison of two models of cannabis use and psychotic relapse in early psychosis

No abstract

Homicide mortality, socioeconomic development, and police violence in the city of Sao Paulo, Brazil

Objective. To analyze the association between police violence and homicide mortality rates taking into consideration the effect of contextual variables. Methods. This was an environmental, cross-sectional study that included the 96 census districts in the City of Sao Paulo. The association between the variables was analyzed using Spearman`s rank correlation and simple and multiple regression analysis. Results. Univariate analysis revealed a strong and significant association between homicide mortality coefficients and all the indicators of socioeconomic development and police violence. After controlling for potential confounding factors, the association between police violence and homicide mortality coefficients remained strong and significant. This significance was lost only after control for the size of the resident population. Conclusion. The results indicate that police action that violates basic human rights is not the right answer to urban violence. The combination of homicides from interpersonal violence and deaths from police violence results in negative socialization and promotes further violence.

Soil mineral genesis and distribution in a saline lake landscape of the Pantanal Wetland, Brazil

The origin of the saline lakes in the Pantanal wetland has been classically attributed to processes occurring in past periods. However, recent studies have suggested that saline water is currently forming from evaporative concentration of fresh water, which is provided annually by seasonal floods. Major elements (Ca, Mg, K) and alkalinity appear to be geochemically controlled during the concentration of waters and may be involved in the formation of carbonates and clay minerals around the saline lakes. The mineralogy of soils associated with a representative saline lake was investigated using XRD, TEM-EDS, and ICP-MS in order to identify the composition and genesis of the secondary minerals suspected to be involved in the control of major elements. The results showed that Ca, Mg, and K effectively undergo oversaturation and precipitation as the waters become more saline. These elements are incorporated in the authigenically formed carbonates, smectites, and micas surrounding the saline lake. The control of Ca occurs by precipitation of calcite and dolomite in nodules while Mg and K are mainly involved in the neoformation of Mg-smectites (stevensitic and saponitic minerals) and, probably, iron-enriched micas (ferric-illite) in surface and subsurface horizons. Therefore, our study confirms that the salinity of Pantanal, historically attributed to inheritance from former regimes, has a contribution of current processes. (C) 2009 Elsevier B.V. All rights reserved.