Assessment of regional long-axis function during dobutamine echocardiography

Echocardiographic analysis of regional left ventricular function is based upon the assessment of radial motion. Long-axis motion is an important contributor to overall function. but has been difficult to evaluate clinically until the recent development of tissue Doppler techniques. We sought to compare the standard visual assessment of radial motion with quantitative tissue Doppler measurement of peak systolic velocity. timing and strain rate (SRI) in 104 patients with known or suspected coronary artery disease undergoing dobutamine stress echocardiography (DbE). A standard DbE protocol was used with colour tissue Doppler images acquired in digital cine-loop format. peak systolic velocity (PSV), time to peak velocity (TPV) and SRI were assessed off-line by an independent operator. Wall motion was assessed by an experienced reader. Mean PSV, TPV and SRI values were compared with wall motion and the presence of coronary artery disease by angiography. A further analysis included assessing the extent of jeopardized myocardium by comparing average values of PSV, TPV and SRI against the previously validated angiographic score. Segments identified as having normal and abnormal radial wall motion showed significant differences in mean PSV (7.9 +/- 3.8 and 5.9 +/- 3.3 cm/s respectively; P < 0.001), TPV (84 40 and 95 +/- 48 ms respectively; P = 0.005) and SRI (- 1.45 +/- 0.5 and - 1.1 +/- 0.9 s(-1) respectively; P < 0.001). The presence of a stenosed subtending coronary artery was also associated with significant differences from normally perfused segments for mean PSV (8.1 3.4 compared with 5.7 +/- 3.7 cm/s; P < 0.001), TPV (78 50 compared with 92 +/- 45 ms; P < 0.001) and SRI (- 1.35 0.5 compared with - 1.20 +/- 0.4 s(-1); P = 0.05). PSV, TPV and SRI also varied significantly according to the extent of jeopardized myocardium within a vascular territory. These results suggest that peak systolic velocity, timing of contraction and SRI reflect the underlying physiological characteristics of the regional myocardium during DbE, and may potentially allow objective analysis of wall motion.

A comparison of low-storage strategies for spectral analysis in dissipative systems: filter diagonalisation in the Lanczos representation and harmonic inversion of the Chebychev-order-domain autocorrelation function

We compare the performance of two different low-storage filter diagonalisation (LSFD) strategies in the calculation of complex resonance energies of the HO2, radical. The first is carried out within a complex-symmetric Lanczos subspace representation [H. Zhang, S.C. Smith, Phys. Chem. Chem. Phys. 3 (2001) 2281]. The second involves harmonic inversion of a real autocorrelation function obtained via a damped Chebychev recursion [V.A. Mandelshtam, H.S. Taylor, J. Chem. Phys. 107 (1997) 6756]. We find that while the Chebychev approach has the advantage of utilizing real algebra in the time-consuming process of generating the vector recursion, the Lanczos, method (using complex vectors) requires fewer iterations, especially for low-energy part of the spectrum. The overall efficiency in calculating resonances for these two methods is comparable for this challenging system. (C) 2001 Elsevier Science B.V. All rights reserved.

Genetics of brain function and cognition

There is overwhelming evidence for the existence of substantial genetic influences on individual differences in general and specific cognitive abilities, especially in adults. The actual localization and identification of genes underlying variation in cognitive abilities and intelligence has only just started, however. Successes are currently limited to neurological mutations with rather severe cognitive effects. The current approaches to trace genes responsible for variation in the normal ranges of cognitive ability consist of large scale linkage and association studies. These are hampered by the usual problems of low statistical power to detect quantitative trait loci (QTLs) of small effect. One strategy to boost the power of genomic searches is to employ endophenotypes of cognition derived from the booming field of cognitive neuroscience This special issue of Behavior Genetics reports on one of the first genome-wide association studies for general IQ. A second paper summarizes candidate genes for cognition, based on animal studies. A series of papers then introduces two additional levels of analysis in the ldquoblack boxrdquo between genes and cognitive ability: (1) behavioral measures of information-processing speed (inspection time, reaction time, rapid naming) and working memory capacity (performance on on single or dual tasks of verbal and spatio-visual working memory), and (2) electrophyiosological derived measures of brain function (e.g., event-related potentials). The obvious way to assess the reliability and validity of these endophenotypes and their usefulness in the search for cognitive ability genes is through the examination of their genetic architecture in twin family studies. Papers in this special issue show that much of the association between intelligence and speed-of-information processing/brain function is due to a common gene or set of genes, and thereby demonstrate the usefulness of considering these measures in gene-hunting studies for IQ.

FAM deubiquitylating enzyme is essential for preimplantation mouse embryo development

FAM is a developmentally regulated substrate-specific deubiquitylating enzyme. It binds the cell adhesion and signalling molecules beta -catenin and A-F-6 in vitro, and stabilises both in mammalian cell culture. To determine if FAM is required at the earliest stages of mouse development we examined its expression and function in preimplantation mouse embryos. FAM is expressed at all stages of preimplantation development from ovulation to implantation. Exposure of two-cell embryos to FAM-specific antisense, but not sense, oligodeoxynucleotides resulted in depletion of the FAM protein and failure Of the embryos to develop to blastocysts. Loss of FAM had two physiological effects, namely, a decrease in cleavage rate and an inhibition of cell adhesive events. Depletion of FAM protein was mirrored by a loss of beta -catenin such that very little of either protein remained following 72 h culture. The residual beta -catenin was localised to sites of cell-cell contact suggesting that the cytoplasmic pool of beta -catenin is stabilised by FAM. Although AF-6 levels initially decreased they returned to normal. However, the nascent protein was mislocalised at the apical surface of blastomeres. Therefore FAM is required for preimplantation mouse embryo development and regulates beta -catenin and AF-6 in vivo. (C) 2001 Elsevier Science Ireland Lid. All rights reserved.

Dynamic assessment of tongue function in children with dysarthria associated with acquired brain injury using electromagnetic articulography

The study to be presented is the first to use a new physiological device, the electromagnetic articulograph, to assess articulatory dysfunction in children with acquired brain injury. Two children with dysarthria subsequent to acquired brain injury participated in the study. One child, a female aged 12 years 9 months exhibited a mild-moderate ataxic dysarthria following traumatic head injury while the other, a male aged 13 years 10 months, demonstrated a moderate-severe flaccid-ataxic dysarthria also following traumatic head injury. The speed and accuracy of their tongue movements was assessed using the Carstens AG100 electromagnetic articulograph. Movement trajectories together with a range of quantitative kinematic parameters were estimated during performance of ten repetitions of the lingual consonants /t, s, k/ and consonant cluster /kl/ in the word initial position of single syllable words. A group of ten non-neurologically impaired children served as controls. Examination of the kinematic parameters, including movement trajectories, velocity, acceleration, deceleration, distance travelled and duration of movement, revealed differences in the speed and accuracy of the tongue movements in both children with acquired brain injury compared to those produced by the non-neurologically impaired controls. The results are discussed in relation to contemporary theories of the effects of acquired brain injury on neuromuscular function. The implications of the findings for the treatment of articulatory dysfunction in children with motor speech disorders associated with acquired brain injury are highlighted.

Mass balance characterisation of Al-7Si-Mg alloy microstructures as a function of solution treatment time

Mass balance calculations were performed to model the effect of solution treatment time on A356 and A357 alloy microstructures. Image analysis and electron probe microanalysis were used to characterise microstructures and confirm model predictions. In as-cast microstructures, up to 8 times more Mg is tied up in the pi-phase than in Mg2Si. The dissolution of pi is accompanied by a corresponding increase in the amount of beta-phase. This causes the rate of pi dissolution to be limited by the rate of beta formation. It is predicted that solution treatments of the order of tens of minutes at 540degreesC produce near-maximum T6 yield strengths, and that Mg contents in excess of 0.52 wt% have no advantage.

Muscle strength and function before and after anterior cruciate ligament reconstruction using semitendonosus and gracilis

This study assessed the quadriceps and hamstring strength before and 6 months after anterior cruciate ligament (ACL) reconstructive surgery using the hamstrings and related the findings to functional performance. Six months after surgery is a critical time for assessment as this is when players are returning to sport. Maximum isokinetic strength of 31 patients with complete unilateral ACL ruptures was measured at speeds of 60 degrees and 120 degrees per second. Functional assessment included the single hop, the triple hop, the shuttle run, side-step and carioca tests. All patients underwent a controlled quadriceps emphasized home-based physiotherapy program both before and after surgery. Results show that before surgery there was a 7.3% quadriceps strength deficit at 60 degrees per second compared to the uninjured leg but no hamstring strength deficit. After surgery there was a statistically significant but relatively small loss of muscle strength. The quadriceps strength deficit had increased to 12% and there was a 10% hamstring deficit. Post-operatively there was an 11% and 6.3% improvement in the hop tests, a 9% (P < 0.01) improvement in the shuttle run, a 15% (P < 0.001) improvement in the side step and a 24% (P < 0.001) improvement in the carioca tests (P < 0.001) despite the loss of muscle strength. (C) 2001 Elsevier Science B.V. All rights reserved.

Vascular smooth muscle cell phenotypic modulation in culture is associated with reorganisation of contractile and cytoskeletal proteins

Smooth muscle cells (SMC) exhibit a functional plasticity, modulating from the mature phenotype in which the primary function is contraction, to a less differentiated state with increased capacities for motility, protein synthesis, and proliferation. The present study determined, using Western analysis, double-label immunofluorescence and confocal microscopy, whether changes in phenotypic expression of rabbit aortic SMC in culture could be correlated with alterations in expression and distribution of structural proteins. Contractile state SMC (days 1 and 3 of primary culture) showed distinct sorting of proteins into subcellular domains, consistent with the theory that the SMC structural machinery is compartmentalised within the cell. Proteins specialised for contraction (alpha -SM actin, SM-MHC, and calponin) were highly expressed in these cells and concentrated in the upper central region of the cell. Vimentin was confined to the body of the cell, providing support for the contractile apparatus but not co-localising with it. In line with its role in cell attachment and motility, beta -NM actin was localised to the cell periphery and basal cortex. The dense body protein alpha -actinin was concentrated at the cell periphery, possibly stabilising both contractile and motile apparatus. Vinculin-containing focal adhesions were well developed, indicating the cells' strong adhesion to substrate. In synthetic state SMC (passages 2-3 of culture), there was decreased expression of contractile and adhesion (vinculin) proteins with a concomitant increase in cytoskeletal proteins (beta -non-muscle [NM] actin and vimentin). These quantitative changes in structural proteins were associated with dramatic chan-es in their distribution. The distinct compartmentalisation of structural proteins observed in contractile state SMC was no longer obvious, with proteins more evenly distributed throughout die cytoplasm to accommodate altered cell function. Thus, SMC phenotypic modulation involves not only quantitative changes in contractile and cytoskeletal proteins, but also reorganisation of these proteins. Since the cytoskeleton acts as a spatial regulator of intracellular signalling, reorganisation of the cytoskeleton may lead to realignment of signalling molecules, which, in turn, may mediate the changes in function associated with SMC phenotypic modulation. (C) 2001 Wiley-Liss, Inc.

Microtubule integrity is essential for apical polarization and epithelial morphogenesis in the thyroid

In this study, we examined the contribution of microtubules to epithelial morphogenesis in primary thyroid cell cultures. Thyroid follicles consist of a single layer of polarized epithelial cells surrounding a closed compartment, the follicular lumen. Freshly isolated porcine thyroid cells aggregate and reorganize to form follicles when grown in primary cultures. Follicular reorganization is principally a morphogenetic process that entails the assembly of biochemically distinct apical and basolateral membrane domains, delimited by tight junctions. The establishment of cell surface polarity during folliculogenesis coincided with the polarized redistribution of microtubules, predominantly in the developing apical poles of cells. Disruption of microtubule integrity using either colchicine or nocodazole caused loss of defined apical membrane domains, tight junctions and follicular lumina. Apical membrane and tight junction markers became randomly distributed at the outer surfaces of aggregates. In contrast, the basolateral surface markers, E-cadherin and Na+,K+-ATPase, remained correctly localized at sites of cell-cell contact and at the free surfaces of cell aggregates. These findings demonstrate that microtubules play a necessary role in thyroid epithelial morphogenesis. Specifically, microtubules are essential to preserve the correct localization of apical membrane components within enclosed cellular aggregates, a situation that is also likely to pertain where lumina must be formed from solid aggregates of epithelial precursors. (C) 2001 Wiley-Liss, Inc.

A soluble form of CD83 is released from activated dendritic cells and B lymphocytes, and is detectable in normal human sera

CD83 is an inducible glycoprotein expressed predominantly by dendritic cells (DC) and B lymphocytes. Expression of membrane CD83 (mCD83) is widely used as a marker of differentiated/ activated DC but its function and ligand(s) are presently unknown. We report the existence of a soluble form of CD83 (sCD83). Using both a sCD83-specific ELISA and Western blotting, we could demonstrate the release of sCD83 by mCD83(+) B cell and Hodgkin's disease-derived cell lines, but not mCD83(-) cells. Inhibition of de novo protein synthesis did not affect the release of sCD83 during short-term (2 h) culture of cell lines although mCD83 expression was significantly reduced, suggesting sCD83 is generated by the release of mCD83. Isolated tonsillar B lymphocytes and monocyte-derived DC, which are mCD83(low), released only low levels of sCD83 during culture. However, the differentiation/activation of these populations both up-regulated mCD83 and increased sCD83 release significantly. Analysis of sera from normal donors demonstrated the presence of low levels (121 +/- 3.6 pg/ml) of circulating sCD83. Further studies utilizing purified sCD83 and the analysis of sCD83 levels in disease may provide clues to the function and ligand(s) of CD83.

Effect of the toxic milk mutation (tx) on the function and intracellular localization of Wnd, the murine homologue of the Wilson copperATPase

Wilson disease is an autosomal recessive copper transport disorder resulting from defective biliary excretion of copper and subsequent hepatic copper accumulation and liver failure if not treated. The disease is caused by mutations in the ATP7B (WND) gene, which is expressed predominantly in the liver and encodes a copper-transporting P-type ATPase that is structurally and functionally similar to the Menkes protein (MNK), which is defective in the X-linked copper transport disorder Menkes disease. The toxic milk (tx) mouse has a clinical phenotype similar to Wilson disease patients and, recently, the tx mutation within the murine WND homologue (Wnd) of this mouse was identified, establishing it as an animal model for Wilson disease. In this study, cDNA constructs encoding the wild-type (Wnd-wt) and mutant (Wnd-tx) Wilson proteins (Wnd) were generated and expressed in Chinese hamster ovary (CHO) cells. The fx mutation disrupted the copper-induced relocalization of Wnd in CHO cells and abrogated Wnd-mediated copper resistance of transfected CHO cells. In addition, co-localization experiments demonstrated that while Wnd and MNK are located in the trans-Golgi network in basal copper conditions, with elevated copper, these proteins are sorted to different destinations within the same cell, Ultrastructural studies showed that with elevated copper levels, Wnd accumulated in large multivesicular structures resembling late endosomes that may represent a novel compartment for copper transport. The data presented provide further support for a relationship between copper transport activity and the copper-induced relocalization response of mammalian copper ATPases, and an explanation at a molecular level for the observed phenotype of fx mice.

RelB nuclear translocation mediated by C-terminal activator reigons of Epstein Barr virus-encoded latent membrane protein 1 and its effect on antigen-presenting function in B cells

Previous studies have shown that Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) is uniquely able to up-regulate the expression of the peptide transporters (referred to as TAP-1 and TAP-2) and major histocompatibility complex (MHC) class I in Burkitt's lymphoma (BL) cell lines. This up-regulation is often accompanied by a restoration of antigen-presenting function as measured by the ability of these cells to present endogenously expressed viral antigen to cytotoxic T lymphocytes. Here we show that the expression of LMP1 resulted in up-regulation and nuclear translocation of RelB that were coincident with increased expression of MHC class I in BL cells. Deletion of the C-terminal activator regions (CTARs) of LMP1 significantly impaired the abilities of LMP1 to translocate RelB into the nucleus and to up-regulate the expression of antigen-processing genes. Further analysis with single-point mutations within the CTARs confirmed that the residues critical for NF-kappaB activation directly contribute to antigen-processing function regulation in BL cells. This LMP1-mediated effect was blocked following expression of either dominant negative IkappaBalpha S32/36A, an NF-kappaB inhibitor, or antisense RelB. These observations indicate that upregulation of antigen-presenting function in B cells mediated by LMP1 is signaled through the NF-kappaB subunit RelB. The data provide a mechanism by which LMP1 modulates immunogenicity of Epstein-Barr virus-infected normal and malignant cells.

Human immunodeficiency virus type 1 reverse transcription is stimulated by Tat from other lentiviruses

The tat gene is required by HIV-1 for efficient reverse transcription and this function of Tat can be distinguished from its role in transcription by RNA polymerase II using tat point mutations that abrogate each function independently The mechanism of Tat's role in reverse transcription, however, is not known, nor is it known whether this role is conserved among trans-activating factors in other retroviruses. Here we examine the abilities of heterologous viral trans-activating proteins from jembrana disease virus (jTat), HIV-2 (Tat2), and equine infectious anemia virus (eTat) to substitute for HIV-1 Tat (Tat1) and restore reverse transcription in HIV-1 carrying an inactivated tat gene. Natural endogenous reverse transcription assays showed that trans-activators from some retroviruses (Tat2 and jTat, but not eTat) could substitute for Tat1 in complementation of HIV-1 reverse transcription. Finally, we show that Y47 is critical for Tat1 to function in reverse transcription, but not HIV-1 gene expression. We mutated the homologous position in jTat to H62Y and found it did not improve its ability to stimulate reverse transcription, but an H62A mutation did inhibit jTat complementation. These data highlight the finding that the role of Tat in reverse transcription is not related to trans-activation and demonstrate that other tat genes conserve this function. (C) 2002 Elsevier Science (USA).

Existence of a semicontinuous or continuous utility function: a unified approach and an elementary proof

In this paper, we present a new unified approach and an elementary proof of a very general theorem on the existence of a semicontinuous or continuous utility function representing a preference relation. A simple and interesting new proof of the famous Debreu Gap Lemma is given. In addition, we prove a new Gap Lemma for the rational numbers and derive some consequences. We also prove a theorem which characterizes the existence of upper semicontinuous utility functions on a preordered topological space which need not be second countable. This is a generalization of the classical theorem of Rader which only gives sufficient conditions for the existence of an upper semicontinuous utility function for second countable topological spaces. (C) 2002 Elsevier Science B.V. All rights reserved.

The non-existence of a utility function and the structure of non-representable preference relations

In this paper we investigate the structure of non-representable preference relations. While there is a vast literature on different kinds of preference relations that can be represented by a real-valued utility function, very little is known or understood about preference relations that cannot be represented by a real-valued utility function. There has been no systematic analysis of the non-representation problem. In this paper we give a complete description of non-representable preference relations which are total preorders or chains. We introduce and study the properties of four classes of non-representable chains: long chains, planar chains, Aronszajn-like chains and Souslin chains. In the main theorem of the paper we prove that a chain is non-representable if and only it is a long chain, a planar chain, an Aronszajn-like chain or a Souslin chain. (C) 2002 Published by Elsevier Science B.V.