bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Selection of the K65R and M184V/I Mutations in Human Immunodeficiency Virus Type 1-Infected Patients Enrolled in a Trial of First-Line Triple-Nucleoside Analog Therapy (Tonus IMEA 021)
Authors: Delaunay Christophe , Brun-Vézinet Françoise , Landman Roland , Collin Gilles , Peytavin Gilles , Trylesinski Aldo , Flandre Philippe , Miller Michael , Descamps Diane
Published: July 2005

Tonus was a pilot study in which previously untreated human immunodeficiency virus type 1 (HIV-1)-infected patients received the combination of abacavir, lamivudine, and tenofovir once a day. There was a high rate of early virological failure, and the M184V and K65R mutations were frequently detected at week 12 (W12). The objective of this study was to examine the selection dynamics of the K65R and M184V/I mutations. Bulk sequencing of the reverse transcriptase (RT) gene was performed on plasma HIV-1 RNA at baseline, W4, and W12 for 21 patients with detectable viral loads. The RT genes from baseline, W4, and W12 plasma samples from five patients who developed both M184V and K65R but with different mutational patterns were also cloned and screened for the K65R mutation by selective real-time PCR. At baseline, bulk sequencing and clonal analysis showed only wild-type RT sequences. At W4, M184V/I was detected in 12/19 patients and K65K/R in 2 patients by bulk sequencing. At W12, M184V/I was found in 18/20 patient, together with the K65R in 13 patients. At W4, clonal analysis revealed the K65R mutation in 0.6 to 48% of clones in the five patients studied. At W12, the K65R mutation was found in 30 to 100% of clones. K65R and M184V/I seemed to arise in separate clones, followed by an enrichment of viruses containing both mutations. The clinical relevance of this independent evolution is unclear. M184V/I was selected more frequently than K65R at W4. However, K65R was also detected early using a clone-sensitive genotyping method. All three nucleoside analogs are known to select the K65R and/or M184V/I mutation. This convergent genetic pathway to resistance, associated with lower antiretroviral potency, may explain the high selection rate of these mutations in this trial.
Gene Expression and Antiviral Activity of Alpha/Beta Interferons and Interleukin-29 in Virus-Infected Human Myeloid Dendritic Cells
Authors: Österlund Pamela , Veckman Ville , Sirén Jukka , Klucher Kevin M. , Hiscott John , Matikainen Sampsa , Julkunen Ilkka
Published: July 2005

Dendritic cells (DCs) respond to microbial infections by undergoing phenotypic maturation and by producing multiple cytokines. In the present study, we analyzed the ability of influenza A and Sendai viruses to induce DC maturation and activate tumor necrosis factor alpha (TNF-α), alpha/beta interferon (IFN-α/β), and IFN-like interleukin-28A/B (IFN-λ2/3) and IL-29 (IFN-λ1) gene expression in human monocyte-derived myeloid DCs (mDC). The ability of influenza A virus to induce mDC maturation or enhance the expression of TNF-α, IFN-α/β, interleukin-28 (IL-28), and IL-29 genes was limited, whereas Sendai virus efficiently induced mDC maturation and enhanced cytokine gene expression. Influenza A virus-induced expression of TNF-α, IFN-α, IFN-β, IL-28, and IL-29 genes was, however, dramatically enhanced when cells were pretreated with IFN-α. IFN-α priming led to increased expression of Toll-like receptor 3 (TLR3), TLR7, TLR8, MyD88, TRIF, and IFN regulatory factor 7 (IRF7) genes and enhanced influenza-induced phosphorylation and DNA binding of IRF3. Influenza A virus also enhanced the binding of NF-κB to the respective NF-κB elements of the promoters of IFN-β and IL-29 genes. In mDC IL-29 induced MxA protein expression and possessed antiviral activity against influenza A virus, although this activity was lower than that of IFN-α or IFN-β. Our results show that in human mDCs viruses can readily induce the expression of IL-28 and IL-29 genes whose gene products are likely to contribute to the host antiviral response.
Marked Variation in Response of Consensus Binding Elements for the Rta Protein of Epstein-Barr Virus
Authors: Chen Lee-Wen , Chang Pey-Jium , Delecluse Henri-Jacques , Miller George
Published: July 2005

The R transactivator (Rta) protein activates Epstein-Barr virus (EBV) lytic-cycle genes by several distinct mechanisms that include direct binding to viral promoters, synergy with BamHI Z EBV replication activator (ZEBRA), and activation of cellular signaling pathways. In the direct and synergistic mechanisms of action, Rta binds to specific DNA sequences that are present in the promoters of responsive genes. It has been difficult to demonstrate the capacity of Rta expressed in mammalian cells to bind DNA in vitro in order to study the relative affinities of Rta binding elements. We discovered that a short C-terminal region of Rta inhibits the ability of Rta to bind DNA in vitro. C-terminally truncated versions of Rta bind DNA efficiently and thus facilitate a comparison of consensus Rta binding elements (CRBEs) found in promoters of five Rta-responsive genes: BMLF1, BHLF1, BMRF1, BaRF1, and BLRF2. All CRBEs in the promoters of the five genes conform to the proposed recognition sequence GNCCN9GGNG, where N is any nucleotide and N9 represents a sequence of nine nucleotides. Nonetheless, CRBEs varied markedly in their abilities to bind Rta in electrophoretic mobility shift assays. Not all CRBEs bound or responded to Rta. Binding affinities of the CRBEs and the capacity to be activated by Rta in reporter assays were strongly correlated. The CRBEs from the BMLF1 and BHLF1 promoters conferred the greatest response. The response of the BMRF1, BaRF1, and BLRF2 CRBEs was less robust. By creation of chimeras, inversions, and point mutations, differences in binding affinities and transcriptional activation levels could be attributed to N9 sequence variation. The length of N9 was also critical for a maximal response. In Raji and BZLF1-knockout cells, the mRNAs of the five Rta-responsive lytic-cycle genes differed dramatically in kinetics of expression, abundance, and synergistic responses to ZEBRA and Rta. Affinities of Rta response elements for Rta are likely to play an important role in temporal regulation and the level of lytic-cycle EBV gene expression.
Immunogenicity of Heterologous Prime-Boost Regimens Involving Recombinant Adenovirus Serotype 11 (Ad11) and Ad35 Vaccine Vectors in the Presence of Anti-Ad5 Immunity
Authors: Lemckert Angelique A. C. , Sumida Shawn M. , Holterman Lennart , Vogels Ronald , Truitt Diana M. , Lynch Diana M. , Nanda Anjali , Ewald Bonnie A. , Gorgone Darci A. , Lifton Michelle A. , Goudsmit Jaap , Havenga Menzo J. E. , Barouch Dan H.
Published: July 2005

The high prevalence of preexisting immunity to adenovirus serotype 5 (Ad5) in human populations will likely limit the immunogenicity and clinical utility of recombinant Ad5 (rAd5) vector-based vaccines for human immunodeficiency virus type 1 and other pathogens. A potential solution to this problem is to utilize rAd vaccine vectors derived from rare Ad serotypes such as Ad35 and Ad11. We have previously reported that rAd35 vectors were immunogenic in the presence of anti-Ad5 immunity, but the immunogenicity of heterologous rAd prime-boost regimens and the extent that cross-reactive anti-vector immunity may limit this approach have not been fully explored. Here we assess the immunogenicity of heterologous vaccine regimens involving rAd5, rAd35, and novel rAd11 vectors expressing simian immunodeficiency virus Gag in mice both with and without anti-Ad5 immunity. Heterologous rAd prime-boost regimens proved significantly more immunogenic than homologous regimens, as expected. Importantly, all regimens that included rAd5 were markedly suppressed by anti-Ad5 immunity. In contrast, rAd35-rAd11 and rAd11-rAd35 regimens elicited high-frequency immune responses both in the presence and in the absence of anti-Ad5 immunity, although we also detected clear cross-reactive Ad35/Ad11-specific humoral and cellular immune responses. Nevertheless, these data suggest the potential utility of heterologous rAd prime-boost vaccine regimens using vectors derived from rare human Ad serotypes.
Hepatitis C Virus Stimulates the Expression of Cyclooxygenase-2 via Oxidative Stress: Role of Prostaglandin E2in RNA Replication
Authors: Waris Gulam , Siddiqui Aleem
Published: July 2005

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, which can lead to the development of liver cirrhosis and hepatocellular carcinoma. Recently, the activation of cyclooxygenase-2 (Cox-2) has been implicated in the HCV-associated hepatocellular carcinoma. In this study, we focus on the signaling pathway leading to Cox-2 activation induced by HCV gene expression. Here, we demonstrate that the HCV-induced reactive oxygen species and subsequent activation of NF-κB mediate the activation of Cox-2. The HCV-induced Cox-2 was sensitive to antioxidant (pyrrolidine dithiocarbamate), Ca2+chelator (BAPTA-AM), and calpain inhibitor (N-acetyl-Leu-Leu-Met-H). The levels of prostaglandin E2(PGE2), the product of Cox-2 activity, are increased in HCV-expressing cells. Furthermore, HCV-expressing cells treated with the inhibitors of Cox-2 (celecoxib and NS-398) showed significant reduction in PGE2levels. We also observed the enhanced phosphorylation of Akt and its downstream substrates glycogen synthase kinase-3β and proapoptotic Bad in the HCV replicon-expressing cells. These phosphorylation events were sensitive to inhibitors of Cox-2 (celecoxib and NS-398) and phosphatidylinositol 3-kinase (LY294002). Our results also suggest a potential role of Cox-2 and PGE2in HCV RNA replication. These studies provide insight into the mechanisms by which HCV induces intracellular events relevant to liver pathogenesis associated with viral infection.
Hepatitis B Virus DNA Replication Is Coordinated by Core Protein Serine Phosphorylation and HBx Expression
Authors: Melegari Margherita , Wolf Sarah K. , Schneider Robert J.
Published: July 2005

The hepatitis B virus (HBV) core protein forms the capsid of viral particles and is essential for viral genome DNA replication and maturation. The C terminus of core protein contains three serines at positions 155, 162, and 170, phosphorylation of which is important for viral DNA replication. We demonstrate that the phosphorylation of these serines is stimulated by the viral HBx protein, a regulatory protein that activates signal transduction pathways and viral replication. HBx is therefore shown to stimulate HBV replication by increasing core serine phosphorylation. Mutational, biochemical, and mixing studies of C-terminal core serine mutants demonstrate that multiple serine phosphorylations occur on the same core protein. Mutation of individual core protein serines is shown to inhibit HBV replication at distinct stages corresponding to encapsidation of viral pregenomic RNA, reverse transcription, and restriction to synthesis of specific DNA replicative intermediates. We therefore demonstrate that a primary target of HBV replication that is regulated by HBx protein corresponds to increased phosphorylation of the viral core protein. We also demonstrate that core phosphorylation mediated by HBx promotes sequential progression of viral replication through the assembly of capsids primed for different stages of DNA synthesis.
Induction of Neutralizing Antibodies and Th1-Polarized and CD4-Independent CD8+T-Cell Responses following Delivery of Human Immunodeficiency Virus Type 1 Tat Protein by Recombinant Adenylate Cyclase ofBordetella pertussis
Authors: Mascarell Laurent , Fayolle Catherine , Bauche Cécile , Ladant Daniel , Leclerc Claude
Published: July 2005

HIV-Tat, a conserved protein playing a key role in the early life cycle of the human immunodeficiency virus (HIV) has been proposed as a potential AIDS vaccine. An HIV-Tat-based vaccine should elicit a broad, long-lasting, and neutralizing immune response. We have previously demonstrated that the adenylate cyclase (CyaA) fromBordetella pertussistargets dendritic cells and delivers CD8+and CD4+T-cell epitopes into the major histocompatibility complex class I and class II presentation pathways. We have also showed that CyaA induced specific and protective cytotoxic T cell responses in vivo. Here, we designed a prototype vaccine based on the HIV type 1 Tat delivered by CyaA (CyaA-E5-Tat) and tested its capacity to induce HIV-Tat-specific cellular as well as antibody responses. We showed that immunization of mice by CyaA-E5-Tat in the absence of adjuvant elicited strong and long-lasting neutralizing anti-Tat antibody responses more efficient than those obtained after immunization with Tat toxoid in aluminum hydroxide adjuvant. Analyses of the anti-Tat immunoglobulin G isotypes and the cytokine pattern showed that CyaA-E5-Tat induced a Th1-polarized immune response in contrast to the Th2-polarized immune responses obtained with the Tat toxoid. In addition, our data demonstrated that HIV-Tat-specific gamma interferon-producing CD8+T cells were generated after vaccination with CyaA-E5-Tat in a CD4+T-cell-independent manner. Based on these findings, CyaA-E5-Tat represents an attractive vaccine candidate for both preventive and therapeutic vaccination involving CyaA as an efficient nonreplicative vector for protein delivery.
Kaposi's Sarcoma-Associated Herpesvirus K-bZIP Represses Gene Transcription via SUMO Modification
Authors: Izumiya Yoshihiro , Ellison Thomas J. , Yeh Edward T. H. , Jung Jae U. , Luciw Paul A. , Kung Hsing-Jien
Published: July 2005

Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus implicated in AIDS-related neoplasms. Previously, we demonstrated that the early lytic gene product K-bZIP is a transcriptional repressor that affects a subset of viral gene transcriptions mediated by the viral transactivator K-Rta (Y. Izumiya et al. J. Virol.
77:
1441-1451, 2003). Sumoylation has emerged as an important posttranslational modification that affects the location and function of cellular and viral proteins and also plays a significant role in transcriptional repression along with Ubc9, the E2 SUMO conjugation enzyme. Here, we provide evidence that K-bZIP is sumoylated at the lysine 158 residue and associates with Ubc9 both in a cell-free system and in virus-infected BCBL-1 cells. Reporter assays showed that the expression of SUMO-specific protease 1 attenuated the transcriptional repression activity of K-bZIP. The expression of a K-bZIPK158R mutant, which was no longer sumoylated, exhibited the reduced transcriptional repression activity. This indicates that sumoylation plays an important part in the transcriptional repression activity of K-bZIP. Finally, chromatin immunoprecipitation experiments demonstrated that K-bZIP interacts with and recruits Ubc9 to specific KSHV promoters. Thus, our data indicate that K-bZIP is a SUMO adaptor, which recruits Ubc9 to specific viral target promoters, thereby exerting its transcriptional repression activity.
WORMHOLES IN VACUUM BRANS–DICKE THEORY
Authors: BHADRA ARUNAVA , SARKAR KABITA
Published: July 2005

It is shown that among the different classes of claimed static wormhole solutions of the vacuum Brans–Dicke theory only Brans Class I solution with coupling constant ω less than -1.5 (excluding the point ω = 2) gives rise to physically viable traversable wormhole geometry. Usability of this wormhole geometry for interstellar travel has been examined.
CLAN STRUCTURE ANALYSIS AND QCD PARTON SHOWERS IN MULTIPARTICLE DYNAMICS: AN INTRIGUING DIALOG BETWEEN THEORY AND EXPERIMENT
Authors: GIOVANNINI A. , UGOCCIONI R.
Published: July 2005

This paper contains a review of the main results of a search of regularities in collective variables properties in multiparticle dynamics, regularities which can be considered as manifestations of the original simplicity suggested by QCD. The method is based on a continuous dialog between experiment and theory. The paper follows the development of this research line, from its beginnings in the 1970's to the current state of the art, discussing how it produced both sound interpretations of the most relevant experimental facts and intriguing perspectives for new physics signals in the TeV energy domain.
VITAMIN E, OXIDATIVE STRESS, AND INFLAMMATION
Authors: Singh U. , Devaraj S. , Jialal I.
Published: July 2005

▪ Abstract  Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the Western world. Its incidence has also been increasing lately in developing countries. Several lines of evidence support a role for oxidative stress and inflammation in atherogenesis. Oxidation of lipoproteins is a hallmark in atherosclerosis. Oxidized low-density lipoprotein induces inflammation as it induces adhesion and influx of monocytes and influences cytokine release by monocytes. A number of proinflammatory cytokines such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) modulate monocyte adhesion to endothelium. C-reactive protein (CRP), a prototypic marker of inflammation, is a risk marker for CVD and it could contribute to atherosclerosis. Hence, dietary micronutrients having anti-inflammatory and antioxidant properties may have a potential beneficial effect with regard to cardiovascular disease. Vitamin E is a potent antioxidant with anti-inflammatory properties. Several lines of evidence suggest that among different forms of vitamin E, α-tocopherol (AT) has potential beneficial effects with regard to cardiovascular disease. AT supplementation in human subjects and animal models has been shown to decrease lipid peroxidation, superoxide (O2-) production by impairing the assembly of nicotinamide adenine dinucleotide phosphate (reduced form) oxidase as well as by decreasing the expression of scavenger receptors (SR-A and CD36), particularly important in the formation of foam cells. AT therapy, especially at high doses, has been shown to decrease the release of proinflammatory cytokines, the chemokine IL-8 and plasminogen activator inhibitor-1 (PAI-1) levels as well as decrease adhesion of monocytes to endothelium. In addition, AT has been shown to decrease CRP levels, in patients with CVD and in those with risk factors for CVD. The mechanisms that account for nonantioxidant effects of AT include the inhibition of protein kinase C, 5-lipoxygenase, tyrosine–kinase as well as cyclooxygenase-2. Based on its antioxidant and anti-inflammatory activities, AT (at the appropriate dose and form) could have beneficial effects on cardiovascular disease in a high-risk population.
PEDIATRIC OBESITY AND INSULIN RESISTANCE: Chronic Disease Risk and Implications for Treatment and Prevention Beyond Body Weight Modification
Authors: Cruz M.L. , Shaibi G.Q. , Weigensberg M.J. , Spruijt-Metz D. , Ball G.D.C. , Goran M.I.
Published: July 2005

▪ Abstract  The study of childhood obesity has continued to grow exponentially in the past decade. This has been driven in part by the increasing prevalence of this problem and the widespread potential effects of increased obesity in childhood on lifelong chronic disease risk. The focus of this review is on recent findings regarding the link between obesity and disease risk during childhood and adolescence. We describe recent reports relating to type 2 diabetes in youth ( 2 ), prediabetes ( 69 , 166 ), metabolic syndrome ( 33 , 35 ), polycystic ovarian syndrome ( 77 ), and nonalcoholic fatty liver disease ( 58 , 146 ), and the mediating role of insulin resistance in these conditions. In addition, we review the implications of this research for the design of more effective treatment and prevention strategies that focus more on the improvement of obesity-related metabolic abnormalities and chronic disease risk reduction than on the conventional energy balance approach that focuses on weight management.
THE COW AS A MODEL TO STUDY FOOD INTAKE REGULATION
Authors: Allen Michael S. , Bradford Barry J. , Harvatine Kevin J.
Published: July 2005

▪ Abstract  Animal models have been invaluable for studying aspects of food intake regulation that for various reasons cannot be observed in humans. The dairy cow is a unique animal model because of an unrivaled energy requirement; its great drive to eat results in feeding behavior responses to treatments within the physiological range. Cows' docile nature and large size make them ideal for measuring temporal treatment effects because digestion and absorption kinetics and responses in endocrine systems, gene expression, metabolite pools and fluxes, and feeding behavior can be measured simultaneously. Thus, cows are important models to investigate interactions of short-term signals regulating food intake. Furthermore, different physiological states throughout the lactation cycle provide powerful models to study how short- and long-term signals interact to affect long-term energy status. The use of the cow as a model can lead to breakthroughs in understanding the complex interactions of signals regulating food intake.
THE VITAMIN K–DEPENDENT CARBOXYLASE
Authors: Berkner Kathleen L.
Published: July 2005

▪ Abstract  The vitamin K–dependent (VKD) carboxylase uses the oxygenation of vitamin K to convert glutamyl residues (Glus) to carboxylated Glus (Glas) in VKD proteins, rendering them active in a broad range of physiologies that include hemostasis, apoptosis, bone development, arterial calcification, signal transduction, and growth control. The carboxylase has a high-affinity site that selectively binds VKD proteins, usually through their propeptide, and also has a second low-affinity site of VKD protein interaction. Propeptide binding increases carboxylase affinity for the Glu substrate, and the coordinated binding of the VKD propeptide and Glu substrate increases carboxylase affinity for vitamin K and activity, possibly through a mechanism of substrate-assisted catalysis. Tethering of VKD proteins to the carboxylase allows clusters of Glus to be modified to Glas by a processive mechanism that becomes disrupted during warfarin therapy. Warfarin inhibits a vitamin K oxidoreductase that generates the reduced vitamin K cofactor required for continuous carboxylation and causes decreased carboxylase catalysis and increased dissociation of partially carboxylated, inactive VKD proteins. The availability of reduced vitamin K may also control carboxylation in r-VKD protein-expressing cells, where the amounts of reduced vitamin K are sufficient for full carboxylation of low, but not high, expression levels of VKD proteins, and where carboxylation is not improved by overexpression of r-carboxylase. This review discusses these recent advances in understanding the mechanism of carboxylation. Also covered is the identification of functional carboxylase residues, a brief description of the role of VKD proteins in mammalian and lower organisms, and the potential impact of quality control components on carboxylation, which occurs in the endoplasmic reticulum during the secretion of VKD proteins.
Insulin sensitivity by oral glucose minimal models: validation against clamp
Authors: Dalla Man Chiara , Yarasheski Kevin E. , Caumo Andrea , Robertson Heather , Toffolo Gianna , Polonsky Kenneth S. , Cobelli Claudio
Published: July 2005

Measuring insulin sensitivity in the presence of physiological changes in glucose and insulin concentrations, e.g., during a meal or OGTT, is important to better understand insulin resistance in a variety of metabolic conditions. Recently, two oral minimal models have been proposed to measure overall insulin sensitivity (SI) and its selective effect on glucose disposal (SI*) from oral tests. SI and SI* have been successfully validated against multiple tracer meal estimates, but validation against euglycemic hyperinsulinemic clamp estimates is lacking. Here, we do so in 21 subjects who underwent both a multiple-tracer OGTT and a labeled euglycemic hyperinsulinemic clamp. Correlation between minimal-model SI, SI and corresponding clamp estimates SI*clamp, SI*clamp was satisfactory, respectively r = 0.81, P < 0.001, and r = 0.71, P < 0.001. SI was significantly lower than SIclamp (8.08 ± 0.89 vs. 13.66 ± 1.69 10−4 dl·kg−1·min−1 per μU/ml, P = 0.0002), whereas SI and SI*clamp were very similar (8.17 ± 1.59 vs. 8.84 ± 1.39 10−4 dl·kg−1·min−1 per μU/ml, P = 0.52). These results add credibility to the oral minimal-model method as a simple and reliable physiological tool to estimate SI and SI*, also in large-scale clinical trials.
Fetal and neonatal exposure to AZT and low-protein diet affects glucose homeostasis: a model with implications for AIDS prevention
Authors: Morten K. , Field P. , Ashley N. , Williams K. A. , Harris D. , Hartley M. , Clark A. , Poulton J.
Published: July 2005

Zidovudine (AZT) lowers the perinatal transmission of HIV but can impair mitochondrial function by depleting mitochondrial DNA (mtDNA). AZT therapy and perinatal nutritional deprivation affect the body fat distribution, which influences glucose tolerance. We sought to model intrauterine exposure to AZT in humans to determine whether it interacts with low-protein diet (LPD) to impact on birth weight and glucose homeostasis in the offspring. Pregnant dams and their offspring were given AZT, an LPD, or AZT and an LPD (LPD + AZT). AZT reduced mtDNA copy number in liver and birth weight in the offspring and increased their fasting glucose and insulin ( P = 0.021, 0.03, 0.001, and 0.011 respectively) at 6–8 wk of age. LPD decreased litter size and birth weight ( P = 0.01 and 0.012). In the LPD + AZT group, birth weight and litter size were reduced compared with untreated controls, and fasting blood glucose and insulin were raised. There was a significant interaction between LPD and AZT on fasting insulin levels ( P = 0.025). Islet size was not significantly affected, but the mean β-cell area/islet was reduced in the LPD + AZT group compared with controls ( P < 0.05). Early exposure to AZT interacts with LPD to impair fetal development in this model. This combination appeared to impair the supply of insulin and, hence, glucose homeostasis, perhaps as a result of impaired mitochondrial function. Although it is not certain that this can be extrapolated to humans, maternal nutritional deprivation combined with AIDS therapy could influence both birth weight and onset of diabetes.
A role for T lymphocytes in mediating cardiac diastolic function
Authors: Yu Qianli , Watson Ronald R. , Marchalonis John J. , Larson Douglas F.
Published: July 2005

The induction of T helper (TH) lymphocytes by distinct TH ligands results in a differentiation to TH1/TH2 subsets based on their unique pattern of cytokine secretion and effector functions. We hypothesized that the relative proportion of TH1/TH2 directly relates to cardiac fibroblast (CF) function and thereby cardiac extracellular matrix (ECM) composition and cardiac diastolic function in the absence of injury or altered wall stress. We compared the effect of selective TH1 with TH2 inducers on cardiac gene expression, ECM composition, and diastolic function in C57BL/J mice. Twelve weeks after immune modulation, the left ventricular stiffness (β) was significantly increased in the TH1 group and decreased in the TH2 group ( P < 0.01). The TH2 group also demonstrated significantly increased end-diastolic and end-systolic volumes ( P < 0.01). Cardiac gene expression patterns for pro-matrix metalloproteinase (MMP)-9 and -13 were increased by greater than fivefold in the TH2 group and significantly decreased in the TH1 group ( P < 0.05). The total cardiac collagen and cross-linked collagen were significantly increased in the TH1 group and decreased in the TH2 group ( P < 0.01). Coculturing lymphocytes harvested from the treated mice with naive primary CF demonstrated a direct control of the lymphocytes on CF pro-collagen, pro-MMP gene expression, and MMP activity. These results suggest that the TH phenotype differentially affects diastolic function through modulating CF pro-collagen and pro-MMP gene expression, MMP activity, and cardiac collagen cross-linking, resulting in altered ECM composition. Thus modulation of TH lymphocyte function could promote adaptive remodeling in heart failure and postmyocardial infarction.
SGK1 as a determinant of kidney function and salt intake in response to mineralocorticoid excess
Authors: Vallon Volker , Huang Dan Yang , Grahammer Florian , Wyatt Amanda W. , Osswald Hartmut , Wulff Peer , Kuhl Dietmar , Lang Florian
Published: July 2005

Mineralocorticoids modify salt balance by both stimulating salt intake and inhibiting salt loss. Renal salt retention is accomplished by upregulation of reabsorption, an effect partially mediated by serum- and glucocorticoid-inducible kinase 1 (SGK1). The present study explored the contribution of SGK1 to the regulation of renal function, salt intake, and blood pressure during mineralocorticoid excess. DOCA/1% NaCl treatment increased blood pressure and creatinine clearance to a similar extent in SGK1-deficient sgk1−/−and wild-type sgk1+/+mice but led to more pronounced increase of proteinuria in sgk1+/+mice (by 474 ± 89%) than in sgk1−/−mice (by 154 ± 31%). DOCA/1% NaCl treatment led to significant increase of kidney weight (by 24%) and to hypokalemia (from 3.9 ± 0.1 to 2.7 ± 0.1 mmol/l) only in sgk1+/+mice. The treatment enhanced renal Na+excretion significantly more in sgk1+/+mice (from 3 ± 1 to 134 ± 32 μmol·24 h−1·g body wt−1) than in sgk1−/−mice (from 4 ± 1 to 49 ± 8 μmol·24 h−1·g body wt−1), pointing to SGK1-dependent stimulation of salt intake. With access to two drinking bottles containing 1% NaCl or water, DOCA treatment did not significantly affect water intake in either genotype but increased 1% NaCl intake in sgk1+/+mice (within 9 days from 3.5 ± 0.9 to 16.5 ± 2.4 ml/day) consistent with DOCA-induced salt appetite. This response was significantly attenuated in sgk1−/−mice (from 2.6 ± 0.6 to 5.9 ± 0.9 ml/day). Thus SGK1 contributes to the stimulation of salt intake, kidney growth, proteinuria, and renal K+excretion during mineralocorticoid excess.
Dietary fish oil positively regulates plasma leptin and adiponectin levels in sucrose-fed, insulin-resistant rats
Authors: Rossi Andrea S. , Lombardo Yolanda B. , Lacorte Jean-Marc , Chicco Adriana G. , Rouault Christine , Slama Gérard , Rizkalla Salwa W.
Published: July 2005

Insulin resistance and adiposity induced by a long-term sucrose-rich diet (SRD) in rats could be reversed by fish oil (FO). Regulation of plasma leptin and adiponectin levels, as well as their gene expression, by FO might be implicated in these findings. This study was designed to evaluate the long-term regulation of leptin and adiponectin by dietary FO in a dietary model of insulin resistance induced by long-term SRD in rats and to determine their impact on adiposity and insulin sensitivity. Rats were randomized to consume a control diet (CD; n = 25) or an SRD ( n = 50) for 7 mo. Subsequently, the SRD-fed rats were randomized to consume SRD+FO or to continue on SRD for an additional 2 mo. Long-term SRD induced overweight and decreased both plasma leptin and adiponectin levels without change in gene expression. Dyslipidemia, adiposity, and insulin resistance accompanied these modifications. Shifting the source of fat to FO for 2 mo increased plasma levels of both adipokines, reversed insulin resistance and dyslipidemia, and improved adiposity. These results were not associated with modifications in gene expression. These results suggest that increasing both adipokines by dietary FO might play an essential role in the normalization of insulin resistance and adiposity in dietary-induced, insulin-resistant models.
Imitating Unfamiliar Sequences of Connected Linear Motions
Authors: Agam Yigal , Bullock Daniel , Sekuler Robert
Published: July 2005

A fundamental challenge in neuroscience is to understand the mechanisms by which multicomponent actions are represented and sequenced for production. We addressed this challenge with a movement-imitation task in which subjects viewed the quasi-random, two-dimensional movements of a disc and then used a stylus to reproduce the remembered trajectory. The stimulus disc moved along straight segments, which differed sufficiently from one another that it was possible to trace individual segments' fate in the resulting movement imitation. A biologically based segmentation algorithm decomposed each imitation into segments whose directions could be compared with those of homologous segments in the model. As the number of linked segments in a stimulus model grew from three to seven, imitation became less accurate, with segments more likely to be deleted, particularly from a model's final stages. When fidelity of imitation was assessed segment by segment, the resulting serial position curves showed a strong primacy effect and a moderate recency effect. Analysis of pairwise transposition errors revealed a striking preponderance of exchanges between adjacent segments that, along with the serial position effects, supports a competitive queuing model of sequencing. In analogy to results with verbal serial recall, repetition of one directed segment in the model reduced imitation quality. Results with longer stimulus models suggest that the segment-by-segment imitation generator may be supplemented in the final stages of imitation by an error-signal driven overlay that produces a late-course, real-time correction. Results are related to neural mechanisms that are known to support sequential motor behavior and working memory.
Variation in gene expression profiles of peripheral blood mononuclear cells from healthy volunteers
Authors: Eady John J. , Wortley Gary M. , Wormstone Yvette M. , Hughes Jackie C. , Astley Siân B. , Foxall Robert J. , Doleman Joanne F. , Elliott Ruan M.
Published: July 2005

The normal degree of intra- and interindividual variation in gene transcription profiles of healthy human tissues has not been extensively investigated. In the study described here, microarrays were employed to analyze gene transcription in peripheral blood mononuclear cells prepared from serial blood samples that had been obtained, at weekly intervals, from apparently healthy human volunteers. Transcript levels for the majority of genes examined were found to be remarkably consistent within samples from a single donor. Conversely, marked differences were observed in samples obtained from different donors. Genes that exhibited differential expression dependent on sex, age, body mass index, and the presence of varying proportions of different leukocyte subsets were identified. These results emphasize the important contributions of genetic and environmental factors, as well as varying representation of different cell types, in determining the overall gene transcriptional profiles of human tissues. However, the study also provides evidence that, within an individual, the gene transcription profiles of sampled tissues can be comparatively stable over time.
The complete product of annihilatingly unique digraphs
Authors: GAN C. S.
Published: July 2005

Let G be a digraph with n vertices and let A(G) be its
adjacency matrix. A monic polynomial f(x) of degree at most n is called an annihilating polynomial of G if f(A(G)) = 0. G is said to be annihilatingly unique if it possesses a unique
annihilating polynomial. Difans and diwheels are two classes of
annihilatingly unique digraphs. In this paper, it is shown that
the complete product of difan and diwheel is annihilatingly unique.
Character theory of infinite wreath products
Authors: Boyer Robert
Published: July 2005

The representation theory of infinite wreath product
groups is developed by means of the relationship
between their group algebras and conjugacy classes
with those of the infinite symmetric group.
Further, since these groups are inductive limits of
finite groups, their finite characters can be
classified as limits of normalized irreducible
characters of prelimit finite groups. This
identification is called the “asymptotic character
formula.” The K0‐invariant of the group
C∗‐algebra is also determined.
On solvability of general nonlinear variational‐like inequalities in reflexive Banach spaces
Authors: Liu Zeqing , Sun Juhe , Shim Soo Hak , Kang Shin Min
Published: July 2005

We introduce and study a new class of general nonlinear variational‐like inequalities in reflexive Banach spaces. By applying a minimax inequality, we establish two existence and uniqueness theorems of solutions for the general nonlinear variational‐like inequality.
A noncommutative generalization of Auslander′s last theorem
Authors: Enochs Edgar E. , Jenda Overtoun M. G. , López-Ramos J. A.
Published: July 2005

We show that every finitely generated left R‐module in the
Auslander class over an n‐perfect ring R having a dualizing
module and admitting a Matlis dualizing module has a Gorenstein
projective cover.
Boundary value problems with regular singularities and singular boundary conditions
Authors: Freiling G. , Yurko V.
Published: July 2005

Singular boundary conditions are formulated for
nonselfadjoint Sturm‐Liouville operators with singularities and
turning points. For boundary value problems with singular
boundary conditions, properties of the spectrum are studied and
the completeness of the system of root functions is proved.
Cortisol, Testosterone, and Coronary Heart Disease
Authors: Smith George Davey , Ben-Shlomo Yoav , Beswick Andrew , Yarnell John , Lightman Stafford , Elwood Peter
Published: July 2005

Background—

There is a popular belief that chronic stress causes heart disease through psychoneuroendocrine mechanisms. We have examined whether an elevated circulating cortisol-to-testosterone ratio increases the risk of ischemic heart disease.

Methods and Results—

We undertook a prospective cohort study of 2512 men aged 45 to 59 years between 1979 and 1983 from Caerphilly, South Wales, with a mean follow-up of 16.5 years. Subjects underwent a clinical examination, and morning fasting blood samples were taken for analysis of cortisol levels, testosterone levels, and other cardiovascular risk factors. The ratio of cortisol to testosterone showed weak associations with potential confounding factors but strong positive associations with components of the insulin resistance syndrome (
P
<0.001). A positive linear trend was seen across quintiles of cortisol:testosterone ratio for incident ischemic heart disease (age-adjusted OR per
z
score change in ratio 1.22, 95% CI 1.07 to 1.38,
P
=0.003). This was markedly attenuated after adjustment for components of the insulin resistance syndrome (age-adjusted OR per
z
score change in ratio 1.10, 95% CI 0.96 to 1.25,
P
=0.18). There was no association between the cortisol:testosterone ratio and other causes of death (age-adjusted hazard ratio 0.99, 95% CI 0.88 to 1.11,
P
=0.81).

Conclusions—

This is the first population-based prospective study that has found a specific association between cortisol:testosterone ratio and incident ischemic heart disease, apparently mediated through the insulin resistance syndrome. Whether this reflects the effects of chronic stress, behavioral factors, or genetic influences remains to be determined.
Cardiorespiratory Fitness Is Inversely Associated With the Incidence of Metabolic Syndrome
Authors: LaMonte Michael J. , Barlow Carolyn E. , Jurca Radim , Kampert James B. , Church Timothy S. , Blair Steven N.
Published: July 2005

Background—

Few studies have reported the relationship between cardiorespiratory fitness and metabolic syndrome incidence, particularly in women.

Methods and Results—

We prospectively studied 9007 men (mean±SD age, 44±9 years; body mass index, 25±3 kg/m
2
) and 1491 women (age, 44±9 years; body mass index, 22±2 kg/m
2
) who were free of metabolic syndrome and for whom measures of waist girth, resting blood pressure, fasting lipids, and glucose were taken during baseline and follow-up examinations. Baseline cardiorespiratory fitness was quantified as duration of a maximal treadmill test. Metabolic syndrome was defined with NCEP ATP-III criteria. During a mean follow-up of 5.7 years, 1346 men and 56 women developed metabolic syndrome. Age-adjusted incidence rates were significantly lower (linear trend,
P
<0.001) across incremental thirds of fitness in men and women. After further adjustment for potential confounders, multivariable hazard ratios for incident metabolic syndrome among men in the low, middle, and upper thirds of fitness, were 1.0 (referent), 0.74 (95% CI, 0.65 to 0.84), and 0.47 (95% CI, 0.40 to 0.54) (linear trend
P
<0.001); in women, they were 1.0 (referent), 0.80 (95% CI, 0.44 to 1.46), and 0.37 (95% CI, 0.18 to 0.80) (linear trend
P
=0.01), respectively. Similar patterns of significant inverse associations between fitness and metabolic syndrome incidence were seen when men were stratified on categories of body mass index, age, and number of baseline metabolic risk factors, but patterns were variable in women.

Conclusions—

Low cardiorespiratory fitness is a strong and independent predictor of incident metabolic syndrome in women and men. Clinicians should consider the potential benefits of greater cardiorespiratory fitness in the primary prevention of metabolic syndrome, particularly among patients who have already begun to cluster metabolic syndrome components.
Eight-Year Follow-Up of Patients With Permanent Vena Cava Filters in the Prevention of Pulmonary Embolism
Authors:   The PREPIC Study Group
Published: July 2005

Background—

In a randomized trial in patients with proximal deep-vein thrombosis, permanent vena cava filters reduced the incidence of pulmonary embolism but increased that of deep-vein thrombosis at 2 years. An 8-year follow-up was performed to assess their very long-term effect.

Methods and Results—

Four hundred patients with proximal deep-vein thrombosis with or without pulmonary embolism were randomized either to receive or not receive a filter in addition to standard anticoagulant treatment for at least 3 months. Data on vital status, venous thromboembolism, and postthrombotic syndrome were obtained once a year for up to 8 years. All documented events were reviewed blindly by an independent committee. Outcome data were available in 396 patients (99%). Symptomatic pulmonary embolism occurred in 9 patients in the filter group (cumulative rate 6.2%) and 24 patients (15.1%) in the no-filter group (
P
=0.008). Deep-vein thrombosis occurred in 57 patients (35.7%) in the filter group and 41 (27.5%) in the no-filter group (
P
=0.042). Postthrombotic syndrome was observed in 109 (70.3%) and 107 (69.7%) patients in the filter and no-filter groups, respectively. At 8 years, 201 (50.3%) patients had died (103 and 98 patients in the filter and no-filter groups, respectively).

Conclusions

At 8 years, vena cava filters reduced the risk of pulmonary embolism but increased that of deep-vein thrombosis and had no effect on survival. Although their use may be beneficial in patients at high risk of pulmonary embolism, systematic use in the general population with venous thromboembolism is not recommended.
Perception of Atrial Fibrillation Before and After Radiofrequency Catheter Ablation
Authors: Hindricks Gerhard , Piorkowski Christopher , Tanner Hildegard , Kobza Richard , Gerds-Li Jin-Hong , Carbucicchio Corrado , Kottkamp Hans
Published: July 2005

Background—

The objective of this study was to assess the incidence and impact of asymptomatic arrhythmia in patients with highly symptomatic atrial fibrillation (AF) who qualified for radiofrequency (RF) catheter ablation.

Methods and Results—

In this prospective study, 114 patients with at least 3 documented AF episodes together with corresponding symptoms and an ineffective trial of at least 1 antiarrhythmic drug were selected for RF ablation. With the use of CARTO, circumferential lesions around the pulmonary veins and linear lesions at the roof of the left atrium and along the left atrial isthmus were placed. A continuous, 7-day, Holter session was recorded before ablation, right after ablation, and after 3, 6, and 12 months of follow-up. During each 7-day Holter monitoring, the patients recorded quality and duration of any complaints by using a detailed symptom log. More than 70 000 hours of ECG recording were analyzed. In the 7-day Holter records before ablation, 92 of 114 patients (81%) had documented AF episodes. All episodes were symptomatic in 35 patients (38%). In 52 patients (57%), both symptomatic and asymptomatic episodes were recorded, whereas in 5 patients (5%), all documented AF episodes were asymptomatic. After ablation, the percentage of patients with only asymptomatic AF recurrences increased to 37% (
P
<0.05) at the 6-month follow-up. An analysis of patient characteristics and arrhythmia patterns failed to identify a specific subset who were at high risk for the development of asymptomatic AF.

Conclusions—

Even in patients presenting with highly symptomatic AF, asymptomatic episodes may occur and significantly increase after catheter ablation. A symptom-only–based follow-up would substantially overestimate the success rate. Objective measures such as long-term Holter monitoring are needed to identify asymptomatic AF recurrences after ablation.
Downregulation of Peroxisome Proliferator–Activated Receptor-α Gene Expression in a Mouse Model of Ischemic Cardiomyopathy Is Dependent on Reactive Oxygen Species and Prevents Lipotoxicity
Authors: Dewald Oliver , Sharma Saumya , Adrogue Julia , Salazar Rebecca , Duerr Georg D. , Crapo James D. , Entman Mark L. , Taegtmeyer Heinrich
Published: July 2005

Background—

The peroxisome proliferators–activated receptor-α (PPARα), a transcription factor that modulates fatty acid metabolism, regulates substrate preference in the heart. Although in acute ischemia there is a switch in substrate preference from fatty acids to glucose, metabolic gene expression in repetitive ischemia is not well described. In a mouse model of ischemic cardiomyopathy induced by repetitive ischemia/reperfusion (I/R), we postulated that downregulation of PPARα is regulated by reactive oxygen species and is necessary for maintaining contractile function in the heart.

Methods and Results—

Repetitive closed-chest I/R (15 minutes) was performed daily in C57/BL6 mice, mice overexpressing extracellular superoxide dismutase, and mice treated with the PPARα agonist-WY-14,643. Echocardiography, histology, and candidate gene expression were measured at 3, 5, 7, and 28 days of repetitive I/R and 15 and 30 days after discontinuation of I/R. Repetitive I/R was associated with a downregulation of PPARα-regulated genes and both myosin heavy chain isoform transcript levels, which was reversible on discontinuation of I/R. Overexpression of EC-SOD prevented the downregulation of PPARα-regulated genes and myosin iso-genes by repetitive I/R. Furthermore, reactivation of PPARα in mice exposed to repetitive I/R worsened contractile function, induced microinfarctions, and increased intramyocardial triglyceride deposition, features suggestive of cardiac lipotoxicity.

Conclusions—

Metabolic and myosin isoform gene expression in repetitive I/R is mediated by reactive oxygen species. Furthermore, we suggest that downregulation of PPARα in repetitive I/R is an adaptive mechanism that is able to prevent lipotoxicity in the ischemic myocardium.