bluuebunny/crossref_metadata_2025 huggingface dataset:
RecombinantMycobacterium bovisBCG Prime-Recombinant Adenovirus Boost Vaccination in Rhesus Monkeys Elicits Robust Polyfunctional Simian Immunodeficiency Virus-Specific T-Cell Responses
Authors: Cayabyab Mark J. , Korioth-Schmitz Birgit , Sun Yue , Carville Angela , Balachandran Harikrishnan , Miura Ayako , Carlson Kevin R. , Buzby Adam P. , Haynes Barton F. , Jacobs William R. , Letvin Norman L.
Published: March 2009

While mycobacteria have been proposed as vaccine vectors because of their persistence and safety, little has been done systematically to optimize their immunogenicity in nonhuman primates. We successfully generated recombinantMycobacterium bovisBCG (rBCG) expressing simian immunodeficiency virus (SIV) Gag and Pol as multigenic, nonintegrating vectors, but rBCG-expressing SIV Env was unstable. A dose and route determination study in rhesus monkeys revealed that intramuscular administration of rBCG was associated with local reactogenicity, whereas intravenous and intradermal administration of 106to 108CFU of rBCG was well tolerated. After single or repeat rBCG inoculations, monkeys developed high-frequency gamma interferon enzyme-linked immunospot responses against BCG purified protein derivative. However, the same animals developed only modest SIV-specific CD8+T-cell responses. Nevertheless, high-frequency SIV-specific cellular responses were observed in the rBCG-primed monkeys after boosting with recombinant adenovirus 5 (rAd5) expressing the SIV antigens. These cellular responses were of greater magnitude and more persistent than those generated after vaccination with rAd5 alone. The vaccine-elicited cellular responses were predominantly polyfunctional CD8+T cells. These findings support the further exploration of mycobacteria as priming vaccine vectors.
Varicella-Zoster Virus Infection Induces Autophagy in both Cultured Cells and Human Skin Vesicles
Authors: Takahashi Marie-Noëlle , Jackson Wallen , Laird Donna T. , Culp Timothy D. , Grose Charles , Haynes John I. , Benetti Luca
Published: March 2009

When grown in cultured cells, varicella-zoster virus (VZV) forms many aberrant light particles and produces low titers. Various studies have explored the reasons for such a phenotype and have pointed to impaired expression of specific late genes and at lysosomal targeting of egressing virions as possible causes. In the studies presented here, we report that the autophagic degradation pathway was induced at late time points after VZV infection of cultured cells, as documented by immunoblot analysis of the cellular proteins LC3B and p62/SQSTM1, along with electron microscopy analysis, which demonstrated the presence of both early autophagosomes and late autophagic compartments. Autophagy was induced in infected cells even in the presence of phosphonoacetic acid, an inhibitor of viral late gene expression, thus suggesting that accumulation of immediate-early and early viral gene products might be the major stimulus for its induction. We also showed that the autophagic response was not dependent on a specific cell substrate, virus strain, or type of inoculum. Finally, using immunofluorescence imaging, we demonstrated autophagosome-specific staining in human zoster vesicles but not in normal skin. Thus, our results document that this innate immune response pathway is a component of the VZV infectious cycle in both cultured cells and the human skin vesicle, the final site of virion formation in the infected human host.
Differential Effects of Hepatitis C Virus JFH1 on Human Myeloid and Plasmacytoid Dendritic Cells
Authors: Liang Hua , Russell Rodney S. , Yonkers Nicole L. , McDonald David , Rodriguez Benigno , Harding Clifford V. , Anthony Donald D.
Published: March 2009

Dendritic cells (DCs) are reported to be functionally deficient during chronic hepatitis C virus (HCV) infection. Differing results have been reported on direct effects of intact replicative-form HCV on DC function. To better understand the effect of HCV on DC function, we treated freshly purified human myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) with HCV JFH1. We found that HCV upregulated mDC maturation marker (CD83, CD86, and CD40) expression and did not inhibit Toll-like receptor 3 (TLR3) ligand [poly(I:C)]-induced mDC maturation, a finding consistent with the phenotype of DCs from HCV-infected subjects. At the same time, HCV JFH1 inhibited the ability of poly(I:C)-treated mDCs to activate naive CD4 T cells. In contrast, although there was no direct effect of virus on pDC maturation, HCV JFH1 inhibited TLR7 ligand (R848)-induced pDC CD40 expression, and this was associated with impaired ability to activate naive CD4 T cells. Parallel experiments with recombinant HCV proteins indicated HCV core protein may be responsible for a portion of the activity. Furthermore, HCV-mediated mDC maturation was dependent upon CD81-E2 interaction and, in part, TLR2. Using UV-treated HCV, we show that HCV-mediated mDC and pDC maturation is virus replication independent and, using strand specific PCR, we found no evidence for HCV replication within DCs. Because these effects of HCV on DC subset maturation and function in part recapitulate direct ex vivo analysis of DCs in chronic HCV infection, the mechanisms described here likely account for a portion of the DC subset defects observed in vivo.
Hip flexibility and strength measures: reliability and association with athletic groin pain
Authors: Malliaras P , Hogan A , Nawrocki A , Crossley K , Schache A
Published: March 2009

Objective:

Groin pain commonly affects football players and can be associated with prolonged recovery periods. Understanding the relationship between groin pain and reliable measures of hip flexibility and strength may facilitate the development of optimal rehabilitation and prevention strategies. In this study, the reliability and association with athletic groin pain of hip flexibility and strength measures were investigated.

Methods:

A cohort of 29 football players (15–21 years) participating in junior elite competitions (Australian Rules football and soccer) were recruited. The intra-rater reliability (n  =  13) and inter-rater reliability (n  =  12) of various hip flexibility (bent knee fall out test, hip internal rotation, hip external rotation) and strength (hip abduction, hip internal rotation, hip external rotation, hip adduction (squeeze test)) measures were investigated using intraclass correlation coefficients (ICC). Reliable hip flexibility and strength measures were compared between football players with (n  =  10) and without (n  =  19) groin pain.

Results:

The bent knee fall out test, hip internal rotation flexibility and the squeeze test demonstrated acceptable (ICC>0.75) intra-rater and inter-rater reliability, while hip external rotation flexibility and hip abduction strength demonstrated acceptable intra-rater but not inter-rater reliability. Hip internal and external rotation strength tests were not found to be reliable. Football players with groin pain had significantly reduced force production on the squeeze test (p>0.05).

Conclusion:

Several hip flexibility and strength measures were found to be reliable. Only the squeeze test discriminated between football players with and without groin pain.
HIGH-ORDER DESCRIPTION OF THE DYNAMICS IN FFAGs AND RELATED ACCELERATORS
Authors: MAKINO KYOKO , BERZ MARTIN , SNOPOK PAVEL , JOHNSTONE CAROL
Published: March 2009

In this paper, we describe newly developed tools for the study and analysis of the dynamics in FFAG accelerators based on transfer map methods unique to the code COSY INFINITY. With these new tools, closed orbits, transverse amplitude dependencies and dynamic aperture are determined inclusive of full nonlinear fields and kinematics to arbitrary order. The dynamics are studied at discrete energies, via a high-order energy-dependent transfer map.

The order-dependent convergence in the calculated maps allows precise determination of dynamic aperture and detailed particle dynamics. Using normal form methods, and minimal impact symplectic tracking, amplitude- and energy-dependent tune shifts and resonance strengths are extracted. Optimization by constrained global optimization methods further refine and promote robust machine attributes.

Various methods of describing the fields will be presented, including representation of fields in radius-dependent Fourier modes, which include complex magnet edge contours and superimposed fringe fields, as well as the capability to interject calculated or measured field data from a magnet design code or actual components, respectively.
CONCEPTUAL DESIGN OF A SUPERCONDUCTING QUADRUPOLE WITH ELLIPTICAL ACCEPTANCE AND TUNABLE HIGHER ORDER MULTIPOLES
Authors: MANIKONDA SHASHIKANT , NOLEN JERRY , BERZ MARTIN , MAKINO KYOKO
Published: March 2009

For charged particle beams that are wider in the dispersive plane compared to the transverse plane it is cost efficient to utilize magnets that accept beams with elliptic cross section. In this paper we presents the conceptual design of a quadrupole magnet with elliptic cross section and with tunable higher order multipoles. The design consists of 18 superconducting race-track coils placed on two hollow concentric rhombic prism support structures.

To compute the magnetic field for the proposed design a new method of calculating 2D and 3D fields for the air core magnets based on differential algebra (DA) techniques is developed. We will present the new method and discuss its implementation of new numerical tools based on this method in the code COSY Infinity.
ON THE BEAM DYNAMICS OPTIMIZATION PROBLEM
Authors: OVSYANNIKOV ALEXANDER D. , OVSYANNIKOV DMITRI A. , YU. BALABANOV MIKHAIL , CHUNG SHENG-LUEN
Published: March 2009

The problem of dynamics optimization for charged particle beams in RFQ accelerators is discussed in this article. The problems of the optimization of particle capture into the acceleration mode are analyzed. Accelerators with low injection energies are considered.
OPTIMIZATION OF A RADIAL MATCHING SECTION
Authors: OVSYANNIKOV ALEXANDER D. , OVSYANNIKOV DMITRI A. , CHUNG SHENG-LUEN
Published: March 2009

Optimization approach to define geometry (parameters) of the radial matching section in an RFQ accelerator is suggested. This approach gives wider opportunities for the design of the radial matching section because it does not have certain prescribed laws of variation of focusing strength along the section.
EFFECTS OF THE WIGGLER ON THE HEFEI LIGHT SOURCE STORAGE RING
Authors: ZHANG HE , BERZ MARTIN
Published: March 2009

The Hefei light source (HLS) is a second generation synchrotron radiation light source, in which a superconducting wiggler is installed and operating. The effects of the wiggler on the beam dynamics on the HLS storage ring are studied, in order to make sure the wiggler can operate properly when the ring is working in the high brilliance mode. We generate a model of the magnetic field in the midplane of the wiggler. The 3D magnetic field model is also builded up by COSY infinity 9.0. Both the linear and nonlinear effects of the wiggler are discussed. The vertical tune is changed from 2.535 to 2.567 and the vertical beta function is heavily distorted, while a symplectic tracking study shows the dynamic aperture is only slightly affected by the wiggler. And the wiggler should be able to run on the high brilliance mode after the linear effects get compensated.
CRYPTANALYSIS OF A NEW CHAOTIC CRYPTOSYSTEM BASED ON ERGODICITY
Authors: ARROYO DAVID , ALVAREZ GONZALO , LI SHUJUN , LI CHENGQING , FERNANDEZ VERONICA
Published: March 2009

This paper analyzes the security of a recent cryptosystem based on the ergodicity property of chaotic maps. It is shown how to obtain the secret key using a chosen-ciphertext attack. Some other design weaknesses are also shown.
STOCHASTIC SPIKING COHERENCE IN COUPLED SUBTHRESHOLD MORRIS-LECAR NEURONS
Authors: LIM WOOCHANG , KIM SANG-YOON
Published: March 2009

We consider a large population of globally coupled subthreshold Morris-Lecar neurons. By varying the noise intensity D, we numerically investigate stochastic spiking coherence (i.e., collective coherence between noise-induced neural spikings). As D passes a lower threshold, a transition from an incoherent to a coherent state occurs because of a constructive role of noise to stimulate coherence between noise-induced spikings. However, when passing a higher threshold of D, another transition from a coherent to an incoherent state takes place due to a destructive role of noise to spoil the spiking coherence. Such an incoherence-coherence-incoherence transition is well-described in terms of the order parameter which is just the mean square deviation of the global potential. In the coherent regime, we also characterize the degree of stochastic spiking coherence by using a coherence measure which reflects the degree of "resemblance" of the global potential to the local potential. Thus, stochastic spiking coherence with large coherence measure is found to occur over a large range of intermediate noise intensity.
THE STUDY OF GAY–BERNE FLUID: INTEGRAL EQUATIONS METHOD
Authors: KHORDAD REZA , MOHEBBI MEHRAN , KESHAVARZI ABOLLA , POOSTFORUSH AHMAD , GHAJARI HAGHIGHI FARNAZ
Published: March 2009

We study a classical fluid of nonspherical molecules. The components of the fluid are the ellipsoidal molecules interacting through the Gay–Berne potential model. A method is described, which allows the Percus–Yevick (PY) and hypernetted-chain (HNC) integral equation theories to be solved numerically for this fluid. Explicit results are given and comparisons are made with recent Monte Carlo (MC) simulations. It is found that, at lower cutoff lmax, the HNC and the PY closures give significantly different results. The HNC and PY (approximately) theories, at higher cutoff lmax, are superior in predicting the existence of the phase transition in a qualitative agreement with computer simulation.
ABSORPTION CROSS SECTION OF A RN BLACK HOLE
Authors: SINI R. , KURIAKOSE V. C.
Published: March 2009

The behavior of a charged scalar field in the RN black hole space–time is studied using the WKB approximation. In the present work, it is assumed that matter waves can be reflected from the event horizon. Using this effect, the Hawking temperature and the absorption cross section for an RN black hole placed in a charged scalar field are calculated. The absorption cross section σabs is found to be inversely proportional to the square of the Hawking temperature of the black hole.
VELOCITY DOMINATED SINGULARITIES IN THE CHEESE SLICE UNIVERSE
Authors: GIANG DAN , DYER CHARLES C.
Published: March 2009

We investigate the properties of space–times resulting from matching together exact solutions using the Darmois matching conditions. In particular, we focus on the asymptotically velocity-term dominated property (AVTD). We propose a criterion that can be used to test if a space–time constructed from a matching can be considered AVTD. Using the "cheese slice" universe as an example, we show that a space–time constructed from a such a matching can inherit the AVTD property from the original space–times. Furthermore the singularity resulting from this particular matching is an AVTD singularity.
THERMODYNAMICAL PROPERTIES OF TOPOLOGICAL BORN–INFELD-DILATON BLACK HOLES
Authors: SHEYKHI AHMAD
Published: March 2009

We examine the (n + 1)-dimensional (n ≥ 3) action in which gravity is coupled to the Born–Infeld nonlinear electrodynamic and a dilaton field. We construct a new (n + 1)-dimensional analytic solution of this theory in the presence of Liouville-type dilaton potentials. These solutions, which describe charged topological dilaton black holes with nonlinear electrodynamics, have unusual asymptotics. They are neither asymptotically flat nor (anti)-de Sitter. The event horizons of these black holes can be an (n - 1)-dimensional positive, zero or negative constant curvature hypersurface. We also analyze the thermodynamics and stability of these solutions and disclose the effect of the dilaton and Born–Infeld fields on the thermal stability in the canonical ensemble.
STATEFINDER DIAGNOSTIC FOR QUINTESSENCE WITH OR WITHOUT THERMAL INTERACTION
Authors: LIU WEI-ZHONG , LIU DAO-JUN
Published: March 2009

The cosmological dynamics of a minimally coupled scalar field that couples to the background matter with thermal interactions is investigated using statefinder diagnostics. The time evolution of the statefinder pairs {r, s} and {r, q} are obtained under the circumstance that different values of model parameters are chosen. We show that the thermal coupling term does not affect the location of the late-time attractor, but exerts an influence on the evolution of the statefinder parameters. The most notable feature of the r–s plane for the thermal coupling model, which is distinguished from the other dark energy models, is that some part of the curve with thermal coupling can form a closed loop in the second quadrant (r > 1, s < 0).
VACUUM POLARIZATION BY A MAGNETIC FLUX TUBE AT FINITE TEMPERATURE IN THE COSMIC STRING SPACE–TIME
Authors: SPINELLY J. , BEZERRA DE MELLO E. R.
Published: March 2009

In this paper, we analyze the effect produced by the temperature in the vacuum polarization associated with a charged massless scalar field in the presence of a magnetic flux tube in the cosmic string space–time. Three different configurations of magnetic fields are taken into account: (i) a homogeneous field inside the tube, (ii) a field proportional to 1/r, and (iii) a cylindrical shell with δ-function. In these three cases, the axis of the infinitely long tube of radius R coincides with the cosmic string. Because of the complexity of this analysis in the region inside the tube, we consider the thermal effect in the region outside. In order to develop this analysis, we construct the thermal Green function associated with this system for the three above-mentioned situations considering points in the region outside the tube. We explicitly calculate, in the high-temperature limit, the thermal average of the field square and the energy–momentum tensor.
CAUSAL LOOP QUANTUM COSMOLOGY IN MOMENTUM SPACE
Authors: SHOJAI ALI , SHOJAI FATIMAH
Published: March 2009

We shall show that it is possible to make a causal interpretation of loop quantum cosmology using the momentum as the dynamical variable. We shall show that one can derive Bohmian trajectories. For a sample cosmological solution with cosmological constant, the trajectory is plotted.
Atherosclerotic plaque disruption induced by stress and lipopolysaccharide in apolipoprotein E knockout mice
Authors: Ni Mei , Wang Yan , Zhang Mei , Zhang Peng Fei , Ding Shi Fang , Liu Chun Xi , Liu Xiao Ling , Zhao Yu Xia , Zhang Yun
Published: March 2009

To establish an animal model with disruptions of atherosclerotic plaques, 96 male apolipoprotein E knockout (apoE−/−) mice were randomly divided into stress, lipopolysaccharide (LPS), stress+LPS, and control groups ( n = 24 each). All mice were fed a high-fat diet throughout the experiment, and carotid atherosclerotic lesions were induced by placement of a constrictive perivascular collar. Four weeks after surgery, mice in the LPS and stress+LPS groups were intraperitoneally injected with LPS (1 mg/kg twice per week for 8 wk). Eight weeks after surgery, mice in the stress and stress+LPS groups were treated with intermittent physical stress (electric foot shock and noise stimulation) for 4 wk. Morphological analysis revealed a plaque disruption rate of 16.7% in control, 34.8% in LPS, 54.2% in stress, and 60.9% in stress+LPS groups. The disruption rates in stress and stress+LPS groups were both significantly higher than those of controls ( P = 0.007 and P = 0.002, respectively). Luminal thrombosis secondary to plaque disruption was observed only in the stress+LPS group. Both stress and LPS stimulation significantly decreased fibrous cap thickness and increased macrophage and lipid contents in plaques. Moreover, the combination of stress and LPS stimulation further lowered cap thickness and enhanced accumulation of macrophages and expression of inflammatory cytokines and matrix metalloproteinases. Stress activated the sympathetic nervous system, as manifested by increased blood pressure and flow velocity. Plasma fibrinogen levels were remarkably elevated in the stress and stress+LPS groups. In conclusion, stress- and LPS-costimulated apoE−/− mice provide a useful model for studies of plaque vulnerability and interventions.
Increased O2 cost of basal metabolism and excitation-contraction coupling in hearts from type 2 diabetic mice
Authors: Boardman Neoma , Hafstad Anne D. , Larsen Terje S. , Severson David L. , Aasum Ellen
Published: March 2009

We have reported previously that hearts from type 2 diabetic ( db/ db) mice show decreased cardiac efficiency due to increased work-independent myocardial O2 consumption (unloaded MV̇o2), indicating higher O2 use for nonmechanical processes such as basal metabolism (MV̇o2BM) and excitation-contraction coupling (MV̇o2ECC). Although alterations in cardiac metabolism and/or Ca2+ handling may contribute to increased energy expenditure in diabetic hearts, direct measurements of the O2 cost for these individual processes have not been determined. In this study, we 1) validate a procedure for measuring unloaded MV̇o2 directly (MV̇o2unloaded) and for determining MV̇o2BM and MV̇o2ECC separately in isolated perfused mouse hearts and 2) determine O2 cost for these processes in hearts from db/ db mice. Unloaded MV̇o2, extrapolated from the relationship between cardiac work (measured as pressure-volume area, PVA) and MV̇o2, was found to correspond with MV̇o2 measured directly in unloaded retrograde perfused hearts (MV̇o2unloaded). MV̇o2 in K+-arrested hearts was defined as MV̇o2BM; the difference between MV̇o2unloaded and MV̇o2BM represented MV̇o2ECC. This procedure was validated by demonstrating that elevations in perfusate fatty acid (FA) and/or Ca2+ concentrations resulted in changes in either MV̇o2BM and/or MV̇o2ECC. The higher MV̇o2unloaded in db/ db mice was due to both a higher MV̇o2BM and MV̇o2ECC. Elevation of glucose and insulin decreased FA oxidation and reduced both MV̇o2unloaded and MV̇o2BM. In conclusion, this study provides direct evidence that MV̇o2BM and MV̇o2ECC are elevated in diabetes and that acute metabolic interventions can have a therapeutic benefit in diabetic hearts due to a MV̇o2-lowering effect.
Artificial gravity as a countermeasure to microgravity: a pilot study examining the effects on knee extensor and plantar flexor muscle groups
Authors: Caiozzo V. J. , Haddad F. , Lee S. , Baker M. , Paloski William , Baldwin K. M.
Published: March 2009

The goal of this project was to examine the effects of artificial gravity (AG) on skeletal muscle strength and key anabolic/catabolic markers known to regulate muscle mass. Two groups of subjects were selected for study: 1) a 21 day-bed rest (BR) group ( n = 7) and 2) an AG group ( n = 8), which was subjected to 21 days of 6° head-down tilt bed rest plus daily 1-h exposures to AG (2.5 G at the feet). Centrifugation was produced using a short-arm centrifuge with the foot plate ∼220 cm from the center of rotation. The torque-velocity relationships of the knee extensors and plantar flexors of the ankle were determined pre- and posttreatment. Muscle biopsy samples obtained from the vastus lateralis and soleus muscles were used for a series of gene expression analyses (mRNA abundance) of key factors implicated in the anabolic vs. catabolic state of the muscle. Post/pre torque-velocity determinations revealed greater decrements in knee extensor performance in the BR vs. AG group ( P < 0.04). The plantar flexors of the AG subjects actually demonstrated a net gain in the torque-velocity relationship, whereas in the BR group, the responses declined (AG vs. BR, P < 0.001). Muscle fiber cross-sectional area decreased by ∼20% in the BR group, whereas no losses were evident in the AG group. RT-PCR analyses of muscle biopsy specimens demonstrated that markers of growth and cytoskeletal integrity were higher in the AG group, whereas catabolic markers were elevated in the BR group. Importantly, these patterns were seen in both muscles. We conclude that paradigms of AG have the potential to maintain the functional, biochemical, and structural homeostasis of skeletal muscle in the face of chronic unloading.
Anatomic capillarization is elevated in the medial gastrocnemius muscle of mighty mini mice
Authors: Wong Lisa E. , Garland Theodore , Rowan Sharon L. , Hepple Russell T.
Published: March 2009

House mice selectively bred for high voluntary wheel running display a mini-muscle (MM) phenotype wherein mass-specific mitochondrial enzyme activities are double that of normal, but muscle mass is reduced by half. In addition, mini-muscles are characterized by small muscle fibers in the superficial region of the plantaris and medial gastrocnemius muscles. To determine the structural alterations facilitating aerobic metabolism in these mini-muscles, cross-sections of the medial gastrocnemius muscle of normal (N; n = 6) and mini-muscle (MM; n = 6) mice were histo- and immunochemically labeled and analyzed for fiber size, capillarization, and fiber type. On the basis of the higher mitochondrial enzyme activities in muscles of MM mice, we hypothesized that they would have greater fiber capillarization in the medial gastrocnemius than N mice. Furthermore, we hypothesized that augmented capillarization in MM would principally be a function of the smaller fibers in the superficial aspect of this muscle. On average, MM had higher capillary-to-fiber ratio and higher capillary density. Binning fibers according to size revealed that it was primarily the normal-sized fibers of the MM that had higher capillarity. The small fibers seen in the superficial region of MM were distinct from N mice in that they had heterogeneous myofibrillar ATPase staining and patchy succinate dehydrogenase staining in the interior of the fibers. These results support the hypothesis that the MM have higher indexes of capillarity, caused primarily by greater capillary number around normally sized fibers. These alterations are consistent with the superior mass-specific aerobic function of these muscles.
Copy variations in schizophrenia and bipolar disorder
Authors: Lachman H.M.
Published: March 2009

The analysis of copy number variations (CNVs) is an emerging tool for identifying genetic factors underlying complex traits. In this chapter I will review studies that have been carried out showing that CNVs play a role in the development of two such complex traits; schizophrenia (SZ) and bipolar disorder (BD). There are two aspects to consider regarding the role of copy variations in these conditions. One is gene discovery in which DNA from patients is analyzed for the purpose of identifying rare, patient-specific CNVs that may be informative to a larger population of affected individuals. The model for this concept is based on the emergence of DISC1 as a SZ candidate gene, which was discovered in a single informative family with a rare chromosomal translocation. Another aspect revolves around the idea that polymorphic CNVs found in the general population, many of which appear to disrupt previously identified SZ and BD candidate genes, contribute to disease pathogenesis. Here, gene-disrupting CNVs are viewed in the same manner as functional SNPs and analyzed for involvement in disease susceptibility using genetic association. Although the analysis of CNVs in patients with psychiatric disorders is in its infancy, informative new findings have already been made, suggesting that this is a very promising line of research.
The role of rare structural variants in the genetics of autism spectrum disorders
Authors: Kusenda M. , Sebat J.
Published: March 2009

Autism is a neurodevelopmental disorder characterized by impaired social interaction and communication and restricted interests and behaviors. Despite high estimates of heritability, genetic causes of ASD have long been elusive, due in part to a high degree of genetic and phenotypic heterogeneity (Bailey et al., 1995). Recently, important advances have been made in the genetics of ASD with the use of new technologies for the direct detection of copy number variation (CNV) in the human genome. CNV studies have revealed that de novo deletions and duplications, typically less than 1 Mb in size, are strongly associated with ASD, suggesting that spontaneous structural mutations play a more important role in the etiology of disease than was previously recognized. Rare mutations have been identified at many different locations in the genome, and multiple ‘hot spots’ have been identified where identical rearrangements recur with high frequency. These findings are consistent with the hypothesis that autism, like mental retardation, is caused by a large number of individually rare mutations. These studies serve as a model for how other emerging technologies for mutation detection (e.g. next generation sequencing platforms) could be used to further elucidate the role of rare sequence changes in ASD.
Copy number variants in genetic susceptibility and severity of systemic lupus erythematosus
Authors: Ptacek T. , Li X. , Kelley J.M. , Edberg J.C.
Published: March 2009

Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder characterized by the presence of auto-antibodies to nuclear antigens, immune complex deposition, and subsequent tissue destruction. Early studies in twins suggested that SLE has, at least in part, a genetic basis, and a role for class II alleles in the major histocompatibility complex has been known for over 30 years. Through both linkage studies and candidate gene studies, numerous additional genetic risk factors have been identified. The recent publication of two SNP-based genome-wide association studies (GWAS) has resulted in the confirmation of a number of previously identified genetic risk loci and has identified new previously unappreciated loci conferring risk for development of SLE. A role for gene copy number variation (CNV) in SLE has also been appreciated through studies of the complement component 4 (C4) loci and more recent work in the IgG Fc receptor loci. The availability of large SNP-based GWAS datasets will undoubtedly lead to the genome-wide analysis and identification of copy number variants related to genetic susceptibility for development of SLE. We review current studies of CNV in SLE susceptibility that include reports of association between SLE and CNV in C4, IgG Fc receptors, TLR7, and CCL3L1.
Copy number alterations and copy number variation in cancer: close encounters of the bad kind
Authors: Speleman F. , Kumps C. , Buysse K. , Poppe B. , Menten B. , De Preter K.
Published: March 2009

Recent studies have unveiled copy number variants (CNVs) as an important source of genetic variation. Many of these CNVs contain coding sequences, which have been shown to be dosage sensitive. Evidence is accumulating that certain CNVs have impact on susceptibility to human diseases such as HIV infection and autoimmune diseases, as well as on adaptability to environmental conditions or nutrition. The possible role and impact of CNVs on cancer development and progression is only now emerging. In this review we look into the role of CNVs and their associated genomic structural features in relation to the formation of chromosome alterations in cancer cells and evolutionary genomic plasticity, as well as the de novo occurrence of known or putative CNVs as somatic events during oncogenesis. The role of germline CNVs in cancer predisposition is still largely unexplored. A number of observations seem to warrant the importance of further studies to elucidate the impact of these variants in the early steps of carcinogenesis.
CNVs of human genes and their implication in pharmacogenetics
Authors: Johansson I. , Ingelman-Sundberg M.
Published: March 2009

Pharmacogenetics encompasses genetic variation with importance for drug response and adverse drug reactions with emphasis on drug transporters, drug metabolizing enzymes, and drug receptors. The highest penetrance with respect to drug action is generally observed for variability in genes encoding drug metabolizing enzymes, and gene copy number variations play a very important role in this respect. Alleles containing 0–13 active gene copies have been described, and this variation affects the clinical outcome of treatment for about 20–30% of all drugs. Gene copy number variation has also an influence on nicotine metabolism and detoxification by glutathione transferases and sulfotransferases. In the current overview we provide an update of the situation with emphasis on clinically important examples.
Human copy number polymorphic genes
Authors: Bailey J.A. , Kidd J.M. , Eichler E.E.
Published: March 2009

Recent large-scale genomic studies within human populations have identified numerous genomic regions as copy number variant (CNV). As these CNV regions often overlap coding regions of the genome, large lists of potentially copy number polymorphic genes have been produced that are candidates for disease association. Most of the current data regarding normal genic variation, however, has been generated using BAC or SNP microarrays, which lack precision especially with respect to exons. To address this, we assessed 2,790 candidate CNV genes defined from available studies in nine well-characterized HapMap individuals by designing a customized oligonucleotide microarray targeted specifically to exons. Using exon array comparative genomic hybridization (aCGH), we detected 255 (9%) of the candidates as true CNVs including 134 with evidence of variation over the entire gene. Individuals differed in copy number from the control by an average of 100 gene loci. Both partial- and whole-gene CNVs were strongly associated with segmental duplications (55 and 71%, respectively) as well as regions of positive selection. We confirmed 37% of the whole-gene CNVs using the fosmid end sequence pair (ESP) structural variation map for these same individuals. If we modify the end sequence pair mapping strategy to include low-sequence identity ESPs (98–99.5%) and ESPs with an everted orientation, we can capture 82% of the missed genes leading to more complete ascertainment of structural variation within duplicated genes. Our results indicate that segmental duplications are the source of the majority of full-length copy number polymorphic genes, most of the variant genes are organized as tandem duplications, and a significant fraction of these genes will represent paralogs with levels of sequence diversity beyond thresholds of allelic variation. In addition, these data provide a targeted set of CNV genes enriched for regions likely to be associated with human phenotypic differences due to copy number changes and present a source of copy number responsive oligonucleotide probes for future association studies.
Copy number variation on the human Y chromosome
Authors: Jobling M.A.
Published: March 2009

The Y chromosome is unusual in being constitutively haploid and escaping recombination for most of its length. This has led to a correspondingly unusual genomic landscape, rich in segmental duplications, which provide a potent environment for the generation of copy number variation (CNV). Interest in the chromosome comes from diverse fields, including infertility research, population genetics, forensics, and genealogy. Together with inclusion in more systematic surveys, this has led to the ascertainment of a variety of CNVs. Assessment in the context of the well-resolved Y phylogeny allows their mutational history to be deciphered and an estimation of mutation rate. The functional consequences of variants are moderated by the specialization of the chromosome and the presence of functionally equivalent X-chromosomal homologues for some genes. However, deletions of the AZFa, b, and c regions cause impaired spermatogenesis, while partial deletions and duplications within these regions, and deletions and duplications elsewhere, may be selectively neutral or have subtle phenotypes.
Successful Outcome after Prenatal Treatment of a Cardiac Diverticulum with Massive Pericardial Effusion
Authors: Abi-Nader Khalil , David Anna L. , Yates Robert , Pandya Pranav
Published: March 2009

Congenital ventricular cardiac diverticula are rare. They may occur prenatally in association with a pericardial effusion which, if large enough, can compromise fetal circulatory and lung development. Parental counseling is difficult because some cases resolve in the second trimester and others progress to worsening hydrops and intrauterine death. We present a case associated with a massive pericardial effusion that had a good outcome after successful pericardiocentesis relatively late in gestation considering the time of critical pulmonary development. We also review similar cases presented in the literature and discuss management options.
Vocal Symptoms in Telemarketers: A Random and Controlled Field Trial
Authors: Oliveira A.G.A. , Behlau M. , Gouveia N.
Published: March 2009

The present study was carried out to evaluate the effectiveness of a specific program regarding the occurrence of vocal attrition symptoms in telemarketers. A total of 71 subjects participated in this study: 28 completed the Vocal Symptoms questionnaire to test its reliability, and 43 were randomly assigned to two groups: an 8-week vocal training group (n = 14) and a no-training control group (n = 29), to evaluate the effectiveness of the training program with this tool. The voice training group also filled in the posttraining questionnaire ‘Benefits Obtained with Voice Training’ (BVT). The vocal training program was not considered effective with regard to the occurrence of vocal symptoms. However, due to a probable increase in symptoms in untrained telemarketers, it can work as a protective factor. According to BVT answers, the vocal training contributed to an improvement in vocal use as a communication tool for telemarketers.
Tripterygium wilfordii Hook F Treatment for Idiopathic Refractory Nephrotic Syndrome in Adults: A Meta-Analysis
Authors: Xu Gaosi , Tu Weiping , Jiang Dongfeng , Xu Chengyun
Published: March 2009

Tripterygium wilfordii Hook F (TwHF) is a Chinese herbal medicine with immunosuppressive effects and an established history of use in the treatment of inflammatory and autoimmune diseases. We have carried out a meta-analysis of randomized controlled trials (RCTs) and quasi-RCTs which assessed the effectiveness of TwHF in the treatment for idiopathic refractory nephrotic syndrome (IRNS). After reading the full text, only three RCTs or quasi-RCTs meeting our inclusion criteria were selected. Our meta-analysis indicated that TwHF has beneficial effects on the remission of IRNS. There was no significant publication bias in the meta-analysis studies. However, studies with a larger sample size and including patients with both a mild and severe histopathological change involvement separately are needed to assess the effects of TwHF in IRNS patients before exact conclusions can be drawn.
Can Pulsatile Cardiopulmonary Bypass Prevent Perioperative Renal Dysfunction during Myocardial Revascularization in Elderly Patients?
Authors: Presta Pierangela , Onorati Francesco , Fuiano Laura , Mastroroberto Pasquale , Santarpino Giuseppe , Tozzo Carmela , Andreucci Michele , Renzulli Attilio , Fuiano Giorgio
Published: March 2009

Backgrounds/Aims: We recently demonstrated that pulsatile cardiopulmonary bypass (CPB) versus standard linear CPB is associated with better perioperative renal function. Since older subjects have a higher risk of acute renal failure, we have extended our study to evaluate the specific impact of pulsatile CPB on the perioperative renal function in elderly patients. Methods: We enrolled 50 patients with normal preoperative renal function: they were stratified by age (65–75 vs. 50–64 years) and randomized to nonpulsatile (group A) or pulsatile CPB (group B). Twenty-seven patients aged ≥50 years and <65 years were randomized to group A (n = 12) or to group B (n = 15) and 23, aged ≥65 years and ≤75 years, to group A (n = 13) or to group B (n = 10). Glomerular filtrate rate (GFR), daily diuresis, lactatemia and other parameters were measured during the pre- and perioperative period. Results: The percent perioperative decrease in GFR was lower in group A than in group B (p < 0.001), without differences between older and younger patients. By contrast, perioperative plasma lactate levels were higher in group A than in group B (p < 0.001), both in older and younger patients. No difference was observed for 24 h urine output and blood urea nitrogen. Conclusions: Pulsatile CPB preserves renal function better than standard CPB even in patients older than 65. CPB could be adopted as the procedure of choice in this subgroup of patients.
TIP47, a Lipid Cargo Protein Involved in Macrophage Triglyceride Metabolism
Authors: Buers Insa , Robenek Horst , Lorkowski Stefan , Nitschke Yvonne , Severs Nicholas J. , Hofnagel Oliver
Published: March 2009

Objective—

Uptake of lipids by macrophages (MΦ) leads to lipid droplet accumulation and foam cell formation. The PAT family proteins are implicated in lipid droplet formation, but the precise function of the 47-kDa tail interacting protein (TIP47), a member of this family, is poorly defined. The present study was performed to determine the function of TIP47 in MΦ lipid metabolism.

Methods and Results—

Freeze-fracture cytochemistry demonstrates that TIP47 is present in the plasma membrane of MΦ and is aggregated into clusters when the cells are incubated with oleate. Suppression of adipophilin levels using siRNA knockdown leads to migration of TIP47 from a cytoplasmic pool to the lipid droplet. Further, reduction of TIP47 decreases triglyceride levels, whereas raising TIP47 levels by expression of EGFP-TIP47 shows the opposite effect.

Conclusion—

Our results show that the TIP47 protein levels directly correlate with triglyceride levels. We propose that TIP47 may act as a carrier protein for free fatty acids and in this way participates in conversion of MΦ into foam cells.
Protective Role of SIRT1 in Diabetic Vascular Dysfunction
Authors: Orimo Masayuki , Minamino Tohru , Miyauchi Hideyuki , Tateno Kaoru , Okada Sho , Moriya Junji , Komuro Issei
Published: March 2009

Objective—

Calorie restriction (CR) prolongs the lifespan of various species, ranging from yeasts to mice. In yeast, CR extends the lifespan by increasing the activity of silencing information regulator 2 (Sir2), an NAD
+
-dependent deacetylase. SIRT1, a mammalian homolog of Sir2, has been reported to downregulate p53 activity and thereby prolong the lifespan of cells. Although recent evidence suggests a link between SIRT1 activity and metabolic homeostasis during CR, its pathological role in human disease is not yet fully understood.

Methods and Results—

Treatment of human endothelial cells with high glucose decreases SIRT1 expression and thus activates p53 by increasing its acetylation. This in turn accelerates endothelial senescence and induces functional abnormalities. Introduction of SIRT1 or disruption of p53 inhibits high glucose–induced endothelial senescence and dysfunction. Likewise, activation of Sirt1 prevents the hyperglycemia-induced vascular cell senescence and thereby protects against vascular dysfunction in mice with diabetes.

Conclusions—

These findings represent a novel mechanism of vascular cell senescence induced by hyperglycemia and suggest a protective role of SIRT1 in the pathogenesis of diabetic vasculopathy.
Long-Term Recurrent Subarachnoid Hemorrhage After Adequate Coiling Versus Clipping of Ruptured Intracranial Aneurysms
Authors: Schaafsma Joanna D. , Sprengers Marieke E. , van Rooij Willem Jan , Sluzewski Menno , Majoie Charles B.L.M. , Wermer Marieke J.H. , Rinkel Gabriel J.E.
Published: March 2009

Background and Purpose—

Coiling is increasingly used as treatment for intracranial aneurysms. Despite its favorable short-term outcome, concerns exist about long-term reopening and inherent risk of recurrent subarachnoid hemorrhage (SAH). We hypothesized a higher risk for recurrent SAH after adequate coiling compared with clipping.

Methods—

Patients with ruptured intracranial aneurysms coiled between 1994 and 2002 with adequate (>90%) aneurysm occlusion at 6-month follow-up angiograms were included. We interviewed these patients about new episodes of SAH. By survival analysis, we assessed the cumulative incidence of recurrent SAH after coiling and compared it with the incidence of recurrent SAH in a cohort of 748 patients with clipped aneurysms by calculating age and sex-adjusted hazard ratios.

Results—

Of 283 coiled patients with a total follow-up of 1778 patient-years (mean, 6.3 years), one patient had a recurrent SAH (0.4%) and 2 patients had a possible recurrent SAH. For recurrent SAH within the first 8 years after treatment, the cumulative incidence was 0.4% (95% CI, −0.4 to 1.2) after coiling versus 2.6% (95% CI, 1.2 to 4.0) after clipping (hazard ratio, 0.2; 95% CI, 0.03 to 1.6). For possible and confirmed recurrent SAH combined, the cumulative incidence was 0.7% (95% CI, 0.3 to 1.7) after coiling versus 3.0% (95% CI, 1.3 to 4.6) after clipping (hazard ratio, 0.7; 95% CI, 0.2 to 2.3).

Conclusion—

Patients with adequately occluded aneurysms by coiling at short-term follow-up are at low risk for recurrent SAH in the long term. Within the first 8 years after treatment, the risk of recurrent SAH is not higher after adequate coiling than after clipping.
Blood Markers for the Prognosis of Ischemic Stroke
Authors: Whiteley William , Chong Wei Li , Sengupta Anshuman , Sandercock Peter
Published: March 2009

Background and Purpose—

The performance of validated prognostic clinical models in acute ischemic stroke might be improved by addition of data on blood biomarkers.

Methods—

We searched Medline and EMBASE from 1966 to January 2007 for studies of blood markers in patients with ischemic stroke and an assessment of outcome (death, disability, or handicap). We adopted several strategies to reduce bias.

Results—

Studies were generally small (median number of subjects, 85; interquartile range, 49 to 184). Few had evidence of a sample size calculation (7 of 82 [9%]) or reported blinding to whether patients had stroke (21 of 82 [26%]). Of the 66 studies reporting a measure of association, 10 did not adjust for age or stroke severity, 14 adjusted for age, 7 adjusted for severity, and 35 adjusted for both; 30% (20 of 66) used a data-dependent threshold to predict good or bad outcome. There was evidence of within-study reporting bias and publication bias. Cardiac markers showed the most consistent association with poor outcome.

Conclusions—

Blood biomarkers might provide useful information to improve the prediction of outcome after acute ischemic stroke. However, this review showed that many studies were subject to bias. Although some markers had some predictive ability, none of the studies was able to demonstrate that the biomarker added predictive power to a validated clinical model. The clinical usefulness of blood biomarkers for predicting prognosis in the setting of ischemic stroke has yet to be established.