bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of 5-Cyano-2,3-Ditolyl-Tetrazolium Chloride Staining as an Indicator of Biocidal Activity in a Rapid Assay for Anti-Acanthamoeba Agents
Authors: Kobayashi Takeshi , Mito Tsuyoshi , Watanabe Narumi , Suzuki Takashi , Shiraishi Atsushi , Ohashi Yuichi
Published: February 2012

The usefulness of 5-cyano-2,3-ditolyl-tetrazolium chloride (CTC) staining to determine the respiratory activity of
Acanthamoeba
was evaluated in this study.
Acanthamoeba
trophozoites and cysts have a red fluorescence after staining with CTC. To determine the effectiveness of CTC staining as a CTC biocidal assay for
Acanthamoeba
, the trophozoites and cysts of
Acanthamoeba castellanii
(ATCC 5037) were treated with serial concentrations of disinfectant solutions, namely, polyhexamethylene biguanide (PHMB) and commercial soft contact lens (SCL) disinfectant solutions. The treated
Acanthamoeba
organisms were stained with CTC, and their respiratory activity was determined by the intensity of fluorescence in a fluorescence microplate reader. The survival rates of the same samples were determined by a culture-dependent biocidal assay using the Spearman-Karber method. Our results showed that the respiratory activities determined by the CTC biocidal assay and the survival rates determined by the culture-dependent biocidal assay for
Acanthamoeba
trophozoites and cysts decreased in a dose-dependent way after PHMB treatments, and the results were significantly correlated (
r
= 0.83 and
P
< 0.01 for trophozoites;
r
= 0.60 and
P
< 0.01 for cysts; Spearman rank correlation test). The respiratory activities in the trophozoites and cysts treated with SCL disinfectant solutions were significantly correlated with the survival rate (
r
= 0.70 and
P
< 0.01 for trophozoites;
r
= 0.64 and
P
< 0.01 for cysts; Spearman rank correlation test). The significant correlation of the results indicated that the CTC biocidal assay can be used as an alternative method to a culture-dependent biocidal assay. The CTC biocidal assay is a rapid and simple method to test the effectiveness of disinfectant solutions against
Acanthamoeba
trophozoites and cysts.
Empyema Caused by Mycoplasma salivarium
Authors: Baracaldo Rafael , Foltzer Michael , Patel Robin , Bourbeau Paul
Published: February 2012

Mycoplasma salivarium
infections outside the oral cavity are rare. We describe a 49-year-old man with laryngeal cancer and right pleural space infection with
M. salivarium
. To our knowledge, this is the first report of empyema due to
Mycoplasma salivarium
.
The UL36 Tegument Protein of Herpes Simplex Virus 1 Has a Composite Binding Site at the Capsid Vertices
Authors: Cardone Giovanni , Newcomb William W. , Cheng Naiqian , Wingfield Paul T. , Trus Benes L. , Brown Jay C. , Steven Alasdair C.
Published: February 2012

Herpesviruses have an icosahedral nucleocapsid surrounded by an amorphous tegument and a lipoprotein envelope. The tegument comprises at least 20 proteins destined for delivery into the host cell. As the tegument does not have a regular structure, the question arises of how its proteins are recruited. The herpes simplex virus 1 (HSV-1) tegument is known to contact the capsid at its vertices, and two proteins, UL36 and UL37, have been identified as candidates for this interaction. We show that the interaction is mediated exclusively by UL36. HSV-1 nucleocapsids extracted from virions shed their UL37 upon incubation at 37°C. Cryo-electron microscopy (cryo-EM) analysis of capsids with and without UL37 reveals the same penton-capping density in both cases. As no other tegument proteins are retained in significant amounts, it follows that this density feature (∼100 kDa) represents the ordered portion of UL36 (336 kDa). It binds between neighboring UL19 protrusions and to an adjacent UL17 molecule. These observations support the hypothesis that UL36 plays a major role in the tegumentation of the virion, providing a flexible scaffold to which other tegument proteins, including UL37, bind. They also indicate how sequential conformational changes in the maturing nucleocapsid control the ordered binding, first of UL25/UL17 and then of UL36.
Paucity of HIV DNA Methylation in Latently Infected, Resting CD4
+
T Cells from Infected Individuals Receiving Antiretroviral Therapy
Authors: Blazkova Jana , Murray Danielle , Justement J. Shawn , Funk Emily K. , Nelson Amy K. , Moir Susan , Chun Tae-Wook , Fauci Anthony S.
Published: February 2012

Maintenance of HIV latency
in vitro
has been linked to methylation of HIV DNA. However, examinations of the degree of methylation of HIV DNA in the latently infected, resting CD4
+
T cells of infected individuals receiving antiretroviral therapy have been limited. Here, we show that methylation of the HIV 5′ long terminal repeat (LTR) in the latent viral reservoir of HIV-infected aviremic individuals receiving therapy is rare, suggesting that other mechanisms are likely involved in the persistence of viral latency.
Live-Cell Imaging Reveals Multiple Interactions between Epstein-Barr Virus Nuclear Antigen 1 and Cellular Chromatin during Interphase and Mitosis
Authors: Jourdan Nathalie , Jobart-Malfait Aude , Dos Reis Gabriel , Quignon Frédérique , Piolot Tristan , Klein Christophe , Tramier Marc , Coppey-Moisan Maïté , Marechal Vincent
Published: February 2012

Epstein-Barr virus (EBV) establishes a life-long latent infection in humans. In proliferating latently infected cells, EBV genomes persist as multiple episomes that undergo one DNA replication event per cell cycle and remain attached to the mitotic chromosomes. EBV nuclear antigen 1 (EBNA-1) binding to the episome and cellular genome is essential to ensure proper episome replication and segregation. However, the nature and regulation of EBNA-1 interaction with chromatin has not been clearly elucidated. This activity has been suggested to involve EBNA-1 binding to DNA, duplex RNA, and/or proteins. EBNA-1 binding protein 2 (EBP2), a nucleolar protein, has been proposed to act as a docking protein for EBNA-1 on mitotic chromosomes. However, there is no direct evidence thus far for EBP2 being associated with EBNA-1 during mitosis. By combining video microscopy and Förster resonance energy transfer (FRET) microscopy, we demonstrate here for the first time that EBNA-1 and EBP2 interact in the nucleoplasm, as well as in the nucleoli during interphase. However, in strong contrast to the current proposed model, we were unable to observe any interaction between EBNA-1 and EBP2 on mitotic chromosomes. We also performed a yeast double-hybrid screening, followed by a FRET analysis, that led us to identify HMGB2 (high-mobility group box 2), a well-known chromatin component, as a new partner for EBNA-1 on chromatin during interphase and mitosis. Although the depletion of HMGB2 partly altered EBNA-1 association with chromatin in HeLa cells during interphase and mitosis, it did not significantly impact the maintenance of EBV episomes in Raji cells.
Hsp70 Protein Positively Regulates Rabies Virus Infection
Authors: Lahaye Xavier , Vidy Aurore , Fouquet Baptiste , Blondel Danielle
Published: February 2012

The Hsp70 chaperone plays a central role in multiple processes within cells, including protein translation, folding, intracellular trafficking, and degradation. This protein is implicated in the replication of numerous viruses. We have shown that rabies virus infection induced the cellular expression of Hsp70, which accumulated in Negri body-like structures, where viral transcription and replication take place. In addition, Hsp70 is present in both nucleocapsids purified from infected cells and in purified virions. Hsp70 has been shown to interact with the nucleoprotein N. The downregulation of Hsp70, using specific chaperone inhibitors, such as quercetin or RNA interference, resulted in a significant decrease of the amount of viral mRNAs, viral proteins, and virus particles. These results indicate that Hsp70 has a proviral function during rabies virus infection and suggest that Hsp70 is involved in at least one stage(s) of the viral life cycle, such as viral transcription, translation, and/or production. The mechanism by which Hsp70 controls viral infection will be discussed.
Anti-HIV-1 Activity of Elafin Is More Potent than Its Precursor's, Trappin-2, in Genital Epithelial Cells
Authors: Drannik Anna G. , Nag Kakon , Yao Xiao-Dan , Henrick Bethany M. , Jain Sumiti , Ball T. Blake , Plummer Francis A. , Wachihi Charles , Kimani Joshua , Rosenthal Kenneth L.
Published: February 2012

Cervicovaginal lavage fluid (CVL) is a natural source of anti-HIV-1 factors; however, molecular characterization of the anti-HIV-1 activity of CVL remains elusive. In this study, we confirmed that CVLs from HIV-1-resistant (HIV-R) compared to HIV-1-susceptible (HIV-S) commercial sex workers (CSWs) contain significantly larger amounts of serine antiprotease trappin-2 (Tr) and its processed form, elafin (E). We assessed anti-HIV-1 activity of CVLs of CSWs and recombinant E and Tr on genital epithelial cells (ECs) that possess (TZM-bl) or lack (HEC-1A) canonical HIV-1 receptors. Our results showed that immunodepletion of 30% of Tr/E from CVL accounted for up to 60% of total anti-HIV-1 activity of CVL. Knockdown of endogenous Tr/E in HEC-1A cells resulted in significantly increased shedding of infectious R5 and X4 HIV-1. Pretreatment of R5, but not X4 HIV-1, with either Tr or E led to inhibition of HIV-1 infection of TZM-bl cells. Interestingly, when either HIV-1 or cells lacking canonical HIV-1 receptors were pretreated with Tr or E, HIV-1 attachment and transcytosis were significantly reduced, and decreased attachment was not associated with altered expression of syndecan-1 or CXCR4. Determination of 50% inhibitory concentrations (IC
50
) of Tr and E anti-HIV-1 activity indicated that E is ∼130 times more potent than its precursor, Tr, despite their equipotent antiprotease activities. This study provides the first experimental evidence that (i) Tr and E are among the principal anti-HIV-1 molecules of CVL; (ii) Tr and E affect cell attachment and transcytosis of HIV-1; (iii) E is more efficient than Tr regarding anti-HIV-1 activity; and (iv) the anti-HIV-1 effect of Tr and E is contextual.
The Lipid Raft-Associated Protein CD98 Is Required for Vaccinia Virus Endocytosis
Authors: Schroeder Nina , Chung Che-Sheng , Chen Chein-Hung , Liao Chung-Lin , Chang Wen
Published: February 2012

Mature vaccinia virus (vaccinia MV) infects a broad range of animalsin vivoand cell culturesin vitro; however, the cellular receptors that determine vaccinia MV tropism and entry pathways are poorly characterized. Here, we performed quantitative proteomic analyses of lipid raft-associated proteins upon vaccinia MV entry into HeLa cells. We found that a type II membrane glycoprotein, CD98, is enriched in lipid rafts upon vaccinia MV infection compared to mock-infected HeLa cells. The knockdown of CD98 expression in HeLa cells significantly reduced vaccinia MV entry. Furthermore, CD98 knockout (KO) mouse embryonic fibroblasts (MEFs) also exhibited reduced vaccinia MV infectivity without affecting MV attachment to cells, suggesting a role for CD98 in the postbinding step of virus entry. Further characterization with inhibitors and dominant negative proteins that block different endocytic pathways revealed that vaccinia MV entry into MEFs occurs through a clathrin-independent, caveolin-independent, dynamin-dependent, fluid-phase endocytic pathway, implying that CD98 plays a specific role in the vaccinia MV endocytic pathway. Infections of wild-type and CD98 KO MEF cells with different strains of vaccinia MV provided further evidence that CD98 plays a specific role in MV endocytosis but not in plasma membrane fusion. Finally, different CD98-C69 chimeric proteins were expressed in CD98 KO MEFs, but none were able to reconstitute MV infectivity, suggesting that the overall structure of the CD98 protein is required for vaccinia MV endocytosis.
Strain-Specific Contribution of NS1-Activated Phosphoinositide 3-Kinase Signaling to Influenza A Virus Replication and Virulence
Authors: Ayllon Juan , Hale Benjamin G. , García-Sastre Adolfo
Published: February 2012

We generated influenza A viruses expressing mutant NS1 proteins unable to activate phosphoinositide 3-kinase (PI3K) in two mouse-lethal strains. The recombinant A/Puerto Rico/8/34 (rPR8) mutant virus strain was attenuated and caused reduced morbidity/mortality. For the recombinant A/WSN/33 (rWSN) virus strain, the inability to stimulate PI3K had minimal impact on replication or morbidity/mortality. Cell-based assays revealed subtly distinct intracellular sites of NS1 localization and PI3K activation between the strains. We hypothesize that specific spatially regulated NS1-activated PI3K signaling, rather than simply the total level of active PI3K, is important for virus replication and virulence.
Temperature-Sensitive Mutants and Revertants in the Coronavirus Nonstructural Protein 5 Protease (3CLpro) Define Residues Involved in Long-Distance Communication and Regulation of Protease Activity
Authors: Stobart Christopher C. , Lee Alice S. , Lu Xiaotao , Denison Mark R.
Published: February 2012

Positive-strand RNA virus genomes are translated into polyproteins that are processed by viral proteases to yield functional intermediate and mature proteins. Coronaviruses (CoVs) carry genes that encode an nsp5 protease (also known as 3CLpro or Mpro) responsible for 11 maturation cleavages. The nsp5 structure contains two chymotrypsin-like domains (D1 and D2) and a unique domain (D3), and forms functional dimers. However, little is known of interactions or communication across the structure of the protease during nsp5 activity. Using reverse genetic mutagenesis of the CoV murine hepatitis virus (MHV) nsp5, we identified a new temperature-sensitive (
ts
) mutation in D2 of nsp5 (Ser133Ala) and confirmed a
ts
residue in D3 (Phe219Leu). Both D2
-ts
S133A and D3-
ts
F219L were impaired for viral replication and nsp5-mediated polyprotein processing at the nonpermissive temperature. Passage of
ts
S133A and
ts
F219L at the nonpermissive temperature resulted in emergence of multiple second-site suppressor mutations, singly and in combinations. Among the second-site mutations, a D2 His134Tyr change suppressed the
ts
phenotype of D2-
ts
S133A and D3-
ts
F219L, as well as the previously reported D2-
ts
V148A. Analysis of multiple CoV nsp5 structures, and alignment of nonredundant nsp5 primary sequences, demonstrated that
ts
and suppressor residues are not conserved across CoVs and are physically distant (>10 Å) from each other, from catalytic and substrate-binding residues, and from the nsp5 dimer interface. These findings demonstrate that long-distance communication pathways between multiple residues and domains of nsp5 play a significant role in nsp5 activity and viral replication, suggesting possible novel targets for non-active site inhibitors of nsp5.
Latency Type-Dependent Modulation of Epstein-Barr Virus-Encoded Latent Membrane Protein 1 Expression by Type I Interferons in B Cells
Authors: Salamon Daniel , Adori Monika , Ujvari Dorina , Wu Liang , Kis Lorand L. , Madapura Harsha S. , Nagy Noemi , Klein George , Klein Eva
Published: February 2012

We report that type I interferons (IFNs) upregulate latent membrane protein 1 (LMP-1) expression by direct activation of the ED-L1 promoter in several Epstein-Barr virus (EBV)-carrying Burkitt's lymphoma lines. In EBV-infected primary B cells, IFN-α transiently upregulates LMP-1 mRNA, but not protein levels, followed by downregulation of both, suggesting a novel antiproliferative mechanism of type I IFNs. Furthermore, our results may explain the expression of LMP-1 in memory B cells of systemic lupus erythematosus patients.
Efficient Nef-Mediated Downmodulation of TCR-CD3 and CD28 Is Associated with High CD4
+
T Cell Counts in Viremic HIV-2 Infection
Authors: Khalid Mohammad , Yu Hangxing , Sauter Daniel , Usmani Shariq M. , Schmokel Jan , Feldman Jerome , Gruters Rob A. , van der Ende Marchina E. , Geyer Matthias , Rowland-Jones Sarah , Osterhaus Albert D. , Kirchhoff Frank
Published: February 2012

The role of the multifunctional accessory Nef protein in the immunopathogenesis of HIV-2 infection is currently poorly understood. Here, we performed comprehensive functional analyses of 50
nef
genes from 21 viremic (plasma viral load, >500 copies/ml) and 16 nonviremic (<500) HIV-2-infected individuals. On average,
nef
alleles from both groups were equally active in modulating CD4, TCR-CD3, CD28, MHC-I, and Ii cell surface expression and in enhancing virion infectivity. Thus, many HIV-2-infected individuals efficiently control the virus in spite of efficient Nef function. However, the potency of
nef
alleles in downmodulating TCR-CD3 and CD28 to suppress the activation and apoptosis of T cells correlated with high numbers of CD4
+
T cells in viremic patients. No such correlations were observed in HIV-2-infected individuals with undetectable viral load. Further functional analyses showed that the Nef-mediated downmodulation of TCR-CD3 suppressed the induction of Fas, Fas-L, PD-1, and CTLA-4 cell surface expression as well as the secretion of gamma interferon (IFN-γ) by primary CD4
+
T cells. Moreover, we identified a single naturally occurring amino acid variation (I132T) in the core domain of HIV-2 Nef that selectively disrupts its ability to downmodulate TCR-CD3 and results in functional properties highly reminiscent of HIV-1 Nef proteins. Taken together, our data suggest that the efficient Nef-mediated downmodulation of TCR-CD3 and CD28 help viremic HIV-2-infected individuals to maintain normal CD4
+
T cell homeostasis by preventing T cell activation and by suppressing the induction of death receptors that may affect the functionality and survival of both virally infected and uninfected bystander cells.
PGV04, an HIV-1 gp120 CD4 Binding Site Antibody, Is Broad and Potent in Neutralization but Does Not Induce Conformational Changes Characteristic of CD4
Authors: Falkowska Emilia , Ramos Alejandra , Feng Yu , Zhou Tongqing , Moquin Stephanie , Walker Laura M. , Wu Xueling , Seaman Michael S. , Wrin Terri , Kwong Peter D. , Wyatt Richard T. , Mascola John R. , Poignard Pascal , Burton Dennis R.
Published: February 2012

Recently, several broadly neutralizing monoclonal antibodies (bnMAbs) directed to the CD4-binding site (CD4bs) of gp120 have been isolated from HIV-1-positive donors. These include VRC01, 3BNC117, and NIH45-46, all of which are capable of neutralizing about 90% of circulating HIV-1 isolates and all of which induce conformational changes in the HIV-1 gp120 monomer similar to those induced by the CD4 receptor. In this study, we characterize PGV04 (also known as VRC-PG04), a MAb with potency and breadth that rivals those of the prototypic VRC01 and 3BNC117. When screened on a large panel of viruses, the neutralizing profile of PGV04 was distinct from those of CD4, b12, and VRC01. Furthermore, the ability of PGV04 to neutralize pseudovirus containing single alanine substitutions exhibited a pattern distinct from those of the other CD4bs MAbs. In particular, substitutions D279A, I420A, and I423A were found to abrogate PGV04 neutralization. In contrast to VRC01, PGV04 did not enhance the binding of 17b or X5 to their epitopes (the CD4-induced [CD4i] site) in the coreceptor region on the gp120 monomer. Furthermore, in contrast to CD4, none of the anti-CD4bs MAbs induced the expression of the 17b epitope on cell surface-expressed cleaved Env trimers. We conclude that potent CD4bs bnMAbs can display differences in the way they recognize and access the CD4bs and that mimicry of CD4, as assessed by inducing conformational changes in monomeric gp120 that lead to enhanced exposure of the CD4i site, is not uniquely correlated with effective neutralization at the site of CD4 binding on HIV-1.
Hepatitis C Virus Nonstructural Protein 5B Is Involved in Virus Morphogenesis
Authors: Gouklani Hamed , Bull Rowena A. , Beyer Claudia , Coulibaly Fasséli , Gowans Eric J. , Drummer Heidi E. , Netter Hans J. , White Peter A. , Haqshenas Gholamreza
Published: February 2012

The p7 protein of hepatitis C virus (HCV) is a viroporin that is dispensable for viral genome replication but plays a critical role in virus morphogenesis. In this study, we generated a JFH1-based intergenotypic chimeric genome that encoded a heterologous genotype 1b (GT1b) p7. The parental intergenotypic chimeric genome was nonviable in human hepatoma cells, and infectious chimeric virions were produced only when cells transfected with the chimeric genomes were passaged several times. Sequence analysis of the entire polyprotein-coding region of the recovered chimeric virus revealed one predominant amino acid substitution in nonstructural protein 2 (NS2), T23N, and one in NS5B, K151R. Forward genetic analysis demonstrated that each of these mutations
per se
restored the infectivity of the parental chimeric genome, suggesting that interactions between p7, NS2, and NS5B were required for virion assembly/maturation. p7 and NS5B colocalized in cellular compartments, and the NS5B mutation did not affect the colocalization pattern. The NS5B K151R mutation neither increased viral RNA replication in human hepatoma cells nor altered the polymerase activity of NS5B in an
in vitro
assay. In conclusion, this study suggests that HCV NS5B is involved in virus morphogenesis.
Budding of Retroviruses Utilizing Divergent L Domains Requires Nucleocapsid
Authors: Bello Nana F. , Dussupt Vincent , Sette Paola , Rudd Victoria , Nagashima Kunio , Bibollet-Ruche Frederic , Chen Chaoping , Montelaro Ronald C. , Hahn Beatrice H. , Bouamr Fadila
Published: February 2012

We recently reported that human immunodeficiency virus type 1 (HIV-1) carrying PTAP and LYPX
n
L L domains ceased budding when the nucleocapsid (NC) domain was mutated, suggesting a role for NC in HIV-1 release. Here we investigated whether NC involvement in virus release is a property specific to HIV-1 or a general requirement of retroviruses. Specifically, we examined a possible role for NC in the budding of retroviruses relying on divergent L domains and structurally homologous NC domains that harbor diverse protein sequences. We found that NC is critical for the release of viruses utilizing the PTAP motif whether it functions within its native Gag in simian immunodeficiency virus cpzGAB2 (SIVcpzGAB2) or SIVsmmE543 or when it is transplanted into the heterologous Gag protein of equine infectious anemia virus (EIAV). In both cases, virus release was severely diminished even though NC mutant Gag proteins retained the ability to assemble spherical particles. Moreover, budding-defective NC mutants, which displayed particles tethered to the plasma membrane, were triggered to release virus when access to the cell endocytic sorting complex required for transport pathway was restored (i.e., in
trans
expression of Nedd4.2s). We also examined the role of NC in the budding of EIAV, a retrovirus relying exclusively on the (L)YPX
n
L-type L domain. We found that EIAV late budding defects were rescued by overexpression of the isolated Alix Bro1 domain (Bro1). Bro1-mediated rescue of EIAV release required the wild-type NC. EIAV NC mutants lost interactions with Bro1 and failed to produce viruses despite retaining the ability to self-assemble. Together, our studies establish a role for NC in the budding of retroviruses harboring divergent L domains and evolutionarily diverse NC sequences, suggesting the utilization of a common conserved mechanism and/or cellular factor rather than a specific motif.
Portal-Large Terminase Interactions of the Bacteriophage T4 DNA Packaging Machine Implicate a Molecular Lever Mechanism for Coupling ATPase to DNA Translocation
Authors: Hegde Shylaja , Padilla-Sanchez Victor , Draper Bonnie , Rao Venigalla B.
Published: February 2012

DNA packaging by double-stranded DNA bacteriophages and herpesviruses is driven by a powerful molecular machine assembled at the portal vertex of the empty prohead. The phage T4 packaging machine consists of three components: dodecameric portal (gp20), pentameric large terminase motor (gp17), and 11- or 12-meric small terminase (gp16). These components dynamically interact and orchestrate a complex series of reactions to produce a DNA-filled head containing one viral genome per head. Here, we analyzed the interactions between the portal and motor proteins using a direct binding assay, mutagenesis, and structural analyses. Our results show that a portal binding site is located in the ATP hydrolysis-controlling subdomain II of gp17. Mutations at key residues of this site lead to temperature-sensitive or null phenotypes. A conserved helix-turn-helix (HLH) that is part of this site interacts with the portal. A recombinant HLH peptide competes with gp17 for portal binding and blocks DNA translocation. The helices apparently provide specificity to capture the cognate prohead, whereas the loop residues communicate the portal interaction to the ATPase center. These observations lead to a hypothesis in which a unique HLH-portal interaction in the symmetrically mismatched complex acts as a lever to position the arginine finger and trigger ATP hydrolysis. Transiently connecting the critical parts of the motor; subdomain I (ATP binding), subdomain II (controlling ATP hydrolysis), and C-domain (DNA movement), the portal-motor interactions might ensure tight coupling between ATP hydrolysis and DNA translocation.
Gout and the risk for incident heart failure and systolic dysfunction
Authors: Krishnan Eswar
Published: February 2012

Objective

To test the hypothesis that gouty arthritis (gout) is a risk factor for incidence of heart failure and for echocardiographic measures signifying subclinical heart failure.

Design

Post-hoc, longitudinal and cross-sectional analyses of a prospective cohort study where data were collected in 4-year intervals since 1971.

Settings

The population-based Framingham Offspring Study.

Participants

4989 adults (mean age 36 years, 52% women) free of clinical heart failure at baseline.

Outcome measures

Incident heart failure, echocardiographic measures of left ventricular systolic dysfunction, dilatation and hypertrophy.

Results

Participants with gout (n=228) had two to three times higher incidence of clinical heart failure and echocardiographic measures of systolic dysfunction compared with those without. In Cox regression analyses, gout was associated with an adjusted HR of 1.74 (95% CI 1.03 to 2.93) for incident heart failure and RRs of 3.70 (95% CI 1.68 to 8.16) for abnormally low left ventricular ejection fraction and of 3.60 (95% CI 1.80 to 7.72) for global left ventricle systolic dysfunction. These risk relationships were consistently observed in all clinical subgroups. Overall, participants with gout had greater mortality than those without (adjusted HR 1.58, 95% CI 1.40 to 1.78). Mortality was elevated in subgroup of patients with gout and heart failure (adjusted HR 1.50, 95% CI 1.30 to 1.73) compared to those with heart failure but without gout.

Conclusion

Gout is associated with increased risk for clinical heart failure, subclinical measures of systolic dysfunction and mortality.
Disparities in mortality among doctors in Taiwan: a 17-year follow-up study of 37 545 doctors
Authors: Shang Tung-Fu , Chen Pau-Chung , Wang Jung-Der
Published: February 2012

Objectives

The authors used cohort data from the registry of all doctors in Taiwan to determine if the effect of health disparities exists after control of potential confounding by different occupational exposures in different specialties.

Design

Retrospective cohort study, 1990–2006.

Settings

The Taiwan Medical Association.

Participants

A total of 37 545 doctors from the registry of the doctor file maintained by the Taiwan Medical Association. The registry has been required by the governmental regulation for verification of credentials of all practicing doctors.

Main outcome measures

Cause-specific standardised mortality ratios for surgeons and anaesthesiologists were compared with those of the internists. The Cox proportional hazard model was constructed to explore multiple risk factors for mortality, including specialties, age, gender, geographic region of practices, regional health resources, ages of beginning practices and years of beginning practice.

Results

The all-cause-specific standardised mortality ratios for surgeons and anaesthesiologists were marginally elevated at 1.15 (95% CI 0.98 to 1.34) and 1.62 (95% CI 0.93 to 2.64), respectively. The Cox regression model showed that the anaesthesiologists had the highest HR of 1.97, seconded by surgeons at 1.23. Localities with the doctor-to-population ratio lower than 1:500 were associated with an increased HR of doctor mortality.

Conclusions

The doctor-to-population ratio and the region of practice may influence doctor's mortality. Increasing number of doctors and/or improving the practice environment may be helpful in reducing the health disparities in regions with poor resources.
Self-rated health and mortality in individuals with diabetes mellitus: prospective cohort study
Authors: Wennberg Patrik , Rolandsson Olov , Jerdén Lars , Boeing Heiner , Sluik Diewertje , Kaaks Rudolf , Teucher Birgit , Spijkerman Annemieke , de Mesquita Bas Bueno , Dethlefsen Claus , Nilsson Peter , Nöthlings Ute
Published: February 2012

Objectives

To investigate whether low self-rated health (SRH) is associated with increased mortality in individuals with diabetes.

Design

Population-based prospective cohort study.

Setting

Enrolment took place between 1992 and 2000 in four centres (Bilthoven, Heidelberg, Potsdam, Umeå) in a subcohort nested in the European Prospective Investigation into Cancer and Nutrition.

Participants

3257 individuals (mean ± SD age was 55.8±7.6 years and 42% women) with confirmed diagnosis of diabetes mellitus.

Primary outcome measure

The authors used Cox proportional hazards modelling to estimate HRs for total mortality controlling for age, centre, sex, educational level, body mass index, physical inactivity, smoking, insulin treatment, hypertension, hyperlipidaemia and history of myocardial infarction, stroke or cancer.

Results

During follow-up (mean follow-up ± SD was 8.6±2.3 years), 344 deaths (241 men/103 women) occurred. In a multivariate model, individuals with low SRH were at higher risk of mortality (HR 1.38, 95% CI 1.10 to 1.73) than those with high SRH. The association was mainly driven by increased 5-year mortality and was stronger among individuals with body mass index of <25 kg/m2than among obese individuals. In sex-specific analyses, the association was statistically significant in men only. There was no indication of heterogeneity across centres.

Conclusions

Low SRH was associated with increased mortality in individuals with diabetes after controlling for established risk factors. In patients with diabetes with low SRH, the physician should consider a more detailed consultation and intensified support.
Health systems and HIV treatment in sub-Saharan Africa: matching intervention and programme evaluation strategies
Authors: Bärnighausen Till , Bloom David E , Humair Salal
Published: February 2012

Objectives

International donors financing the delivery of antiretroviral treatment in developing countries have recently emphasised their commitment to rigorous evaluation of antiretroviral treatment impact on population health. At the same time frame, but for different reasons, they have announced that they will shift funding from vertically structured (ie, disease-specific) interventions to horizontally structured interventions (ie, staff, systems and infrastructure that can deliver care for many diseases). The authors analyse likely effects of the latter shift on the feasibility of impact evaluation.

Methods

The authors examine the effect of the shift in intervention strategy on (1) outcome measurement, (2) cost measurement, (3) study-design options and the (4) technical and (5) political feasibility of programme evaluation.

Results

As intervention structure changes from vertical to horizontal, outcome and cost measurements are likely to become more difficult (because the number of relevant outcomes and costs increases and the sources holding data on these measures become more diverse); study-design options become more limited (because it is often impossible to identify a rigorously defined counterfactual in horizontal interventions); the technical feasibility of interventions is reduced (because lag times between intervention and impact increase in length and effect-mediating and -modifying factors increase in number) and political feasibility of evaluation is decreased (because national policymakers may be reluctant to support the evaluation).

Conclusions

In the choice of intervention strategy, policymakers need to consider the effect of intervention strategy on impact evaluation. Methodological studies are needed to identify the best approaches to evaluate the population health impact of horizontal interventions.
Maintaining cost-effective access to antiretroviral drug therapy through a collaborative approach to drug procurement, consensus treatment guidelines and regular audit: the experience of London HIV commissioners and providers
Authors: Foreman Claire , Gazzard Brian , Johnson Margaret , Sharott Peter , Collins Simon
Published: February 2012

Background

In the UK, meeting the £20 billion efficiency challenge in the NHS requires new approaches to protect quality and improve productivity. In London, clinicians, people living with HIV and commissioners are collaborating to reduce the cost of antiretrovirals as part of the Quality Innovation Productivity and Prevention agenda.

Objectives

To describe how collaboration in antiretroviral procurement in 2011/2012 aimed to significantly reduce drug acquisition costs, ensure equity of prescribing and protect the quality and experience of care and treatment for patients.

Methods

Greater clinical leadership and engagement and involvement of patient representatives enabled an approach to drug procurement focused on clinical outcomes at a patient and population level while reducing cost. Consensus guidelines for implementation were developed and agreed by all London lead clinicians while people living with HIV produced a patient information leaflet to explain the tender process and outcomes. A planned audit is underway at all services to monitor prescribing changes and outcomes for those on treatment.

Results

HIV clinicians, pharmacists and patient representatives were directly involved in this novel therapeutic tendering approach to antiretroviral drug procurement. Modelling indicates that £8–£10 million savings will be released through the process over 2 years.

Conclusions

Clinically led therapeutic tendering of antiretroviral drugs provides an opportunity to protect quality and improve productivity in HIV. The approach is novel in HIV in the UK, and the emergent learning has implications for quality and cost improvement in HIV spending in the UK and potentially in other countries.
MEAN-FIELD CRITICAL BEHAVIOR AND ERGODICITY BREAK IN A NONEQUILIBRIUM ONE-DIMENSIONAL RSOS GROWTH MODEL
Authors: MENDONÇA J. RICARDO G.
Published: February 2012

We investigate the nonequilibrium roughening transition of a one-dimensional restricted solid-on-solid model by directly sampling the stationary probability density of a suitable order parameter as the surface adsorption rate varies. The shapes of the probability density histograms suggest a typical Ginzburg–Landau scenario for the phase transition of the model, and estimates of the "magnetic" exponent seem to confirm its mean-field critical behavior. We also found that the flipping times between the metastable phases of the model scale exponentially with the system size, signaling the breaking of ergodicity in the thermodynamic limit. Incidentally, we discovered that a closely related model not considered before also displays a phase transition with the same critical behavior as the original model. Our results support the usefulness of off-critical histogram techniques in the investigation of nonequilibrium phase transitions. We also briefly discuss in the appendix a good and simple pseudo-random number generator used in our simulations.
DECAY/GROWTH RATE ESTIMATION USING INSTANTANEOUS LYAPUNOV EXPONENT
Authors: TOTOKI YUSUKE , MATSUO TAKAMI
Published: February 2012

The Lyapunov exponent gives a measure of the mean decay/growth rates of the flows of nonlinear systems. However, the Lyapunov exponent needs an infinite time interval of flows and the Jacobian matrix of system dynamics. In this paper, we propose an instantaneous decay/growth rate that is a kind of generalized Lyapunov exponent and call the instantaneous Lyapunov exponent (ILE) with respect to a decay function. The instantaneous Lyapunov exponent is one of the measures that estimate the decay and growth rates of flows of nonlinear systems by assigning a comparison function and can apply a stable system whose decay rate is slower than an exponential function. Moreover, we propose a synchronization measure of two signals using the ILE.
BIFURCATIONS OF EXACT TRAVELING WAVE SOLUTIONS FOR THE (2 + 1)-DIMENSIONAL mKP EQUATION
Authors: XU YUANFEN , DAI ZHENXIANG
Published: February 2012

For the (2 + 1)-dimensional mKP equation, what is the dynamical behavior of its traveling wave solutions and how does it depend on the parameters of the systems? This paper will answer these questions by using the methods of dynamical systems. Thirteen exact explicit parametric representations of the traveling wave solutions are given. Bifurcations of phase portraits of the corresponding singular traveling wave system are shown.
THE REAL PROBLEM WITH MOND
Authors: DODELSON SCOTT
Published: February 2012

Gravitational potentials in the cosmos are deeper than expected from observed visible objects, a phenomenon usually attributed to dark matter, presumably in the form of a new fundamental particle. Until such a particle is observed, the jury remains out on dark matter, and modified gravity models must be considered. The class of models reducing to modified Newtonian dynamics (MOND) in the weak field limit does an excellent job fitting the rotation curves of galaxies, predicting the relation between baryonic mass and velocity in gas-dominated galaxies, and explaining the properties of the local group. Several of the initial challenges facing MOND have been overcome, while others remain. Here we point out the most severe challenge facing MOND.
ON THE MEASURE OF SPACETIME AND GRAVITY
Authors: DADHICH NARESH
Published: February 2012

By following the general guiding principle that nothing should be prescribed or imposed on the universal entity, spacetime, we establish that it is the homogeneity (by which we mean homogeneity and isotropy of space and homogeneity of time) that requires not only a universally constant invariant velocity but also an invariant length given by its constant curvature, Λ and spacetime is completely free of dynamics. Thus c and Λ are the only two true constants of the spacetime structure and no other physical constant could claim this degree of fundamentalness. When matter is introduced, the spacetime becomes inhomogeneous and dynamic, and its curvature then determines by the Bianchi differential identity, the equation of motion for the Einstein gravity. The homogeneity thus demands that the natural state of free spacetime is of constant curvature and the cosmological constant thus emerges as a clear prediction which seems to be borne out by the observations of accelerating expansion of the Universe. However it has no relation to the vacuum energy and it could be envisioned that in terms of the Planck area, the Universe measures 10120 units!
RINDLER FORCE AT LARGE DISTANCES
Authors: GRUMILLER D. , PREIS F.
Published: February 2012

Given some assumptions, it is possible to derive the most general post-general relativistic theory of gravity for the distant field of a point mass. The force law derived from this theory contains a Rindler term in addition to well-known contributions, a Schwarzschild mass and a cosmological constant. The same force law recently was confronted with solar system precision data. The Rindler force, if present in Nature, has intriguing consequences for gravity at large distances. In particular, the Rindler force is capable of explaining about 10% of the Pioneer anomaly and simultaneously ameliorates the shape of galactic rotation curves.
CAN THE GRAVITON HAVE A MASS?
Authors: KOYAMA KAZUYA , NIZ GUSTAVO , TASINATO GIANMASSIMO
Published: February 2012

In this essay, we address two long-standing problems of massive gravity: The ghost mode found by Boulware and Deser, and the incompatibility with General Relativity in the massless limit, better known as the vDVZ discontinuity. We present a recent candidate for a ghost-free theory, and show how Einstein's gravity is recovered within a certain macroscopic radius from a mass source, via the Vainshtein mechanism. We also exhibit an exact solution which could account for the late time acceleration of the Universe by means of a small graviton mass.
PERSISTENCE OF BLACK HOLES THROUGH A COSMOLOGICAL BOUNCE
Authors: CARR B. J. , COLEY A. A.
Published: February 2012

We discuss whether black holes could persist in a universe which recollapses and then bounces into a new expansion phase. Whether the bounce is of classical or quantum gravitational origin, such cosmological models are of great current interest. In particular, we investigate the mass range in which black holes might survive a bounce and ways of differentiating observationally between black holes formed just after and just before the last bounce. We also discuss the consequences of the universe going through a sequence of dimensional changes as it passes through a bounce.
APPARENT VERSUS TRUE VALUE OF THE COSMOLOGICAL CONSTANT
Authors: ROMANO ANTONIO ENEA , CHEN PISIN
Published: February 2012

Supernovae observations strongly support the presence of a cosmological constant, but its value, which we will call apparent, is normally determined assuming that the universe can be accurately described by a homogeneous model. Even in the presence of a cosmological constant we cannot exclude nevertheless the presence of a small local inhomogeneity which could affect the apparent value of the cosmological constant. Neglecting the presence of the inhomogeneity can in fact introduce a systematic misinterpretation of cosmological data, leading to the distinction between an apparent and the true value of the cosmological constant. But is such a difference distinguishable? Recently we set out to model the local inhomogeneity with a ΛLTB solution and computed the relation between the apparent and the true value of the cosmological constant. In this essay we reproduce the essence of our model with the emphasis on its physical implications.
STIMULATED CREATION OF QUANTA DURING INFLATION AND THE OBSERVABLE UNIVERSE
Authors: AGULLO IVAN , PARKER LEONARD
Published: February 2012

Inflation provides a natural mechanism to account for the origin of cosmic structures. The generation of primordial inhomogeneities during inflation can be understood via the spontaneous creation of quanta from the vacuum. We show that when the corresponding stimulated creation of quanta is considered, the characteristics of the state of the universe at the onset of inflation are not diluted by the inflationary expansion and can be imprinted in the spectrum of primordial inhomogeneities. The non-gaussianities (particularly in the so-called squeezed configuration) in the cosmic microwave background and galaxy distribution can then tell us about the state of the universe that existed at the time when quantum field theory in curved spacetime first emerged as a plausible effective theory.
RELATIVE LOCALITY: A DEEPENING OF THE RELATIVITY PRINCIPLE
Authors: AMELINO-CAMELIA GIOVANNI , FREIDEL LAURENT , KOWALSKI-GLIKMAN JERZY , SMOLIN LEE
Published: February 2012

We describe a recently introduced principle of relative locality which we propose governs a regime of quantum gravitational phenomena accessible to experimental investigation. This regime comprises phenomena in which ℏ and GN may be neglected, while their ratio, the Planck mass [Formula: see text], is important. We propose that Mp governs the scale at which momentum space may have a curved geometry. We find that there are striking consequences for the concept of locality. The description of events in spacetime now depends on the energy used to probe it. But there remains an invariant description of physics in phase space. There is furthermore a reasonable expectation that the geometry of momentum space can be measured experimentally using astrophysical observations.
ASPECTS OF SPHERICAL SHELLS IN A D-DIMENSIONAL BACKGROUND
Authors: EIROA ERNESTO F. , SIMEONE CLAUDIO
Published: February 2012

In this work, shells are mathematically constructed by applying the cut and paste procedure to D-dimensional spherically symmetric geometries. The weak energy condition for the matter on the shells is briefly analyzed. The dynamical evolution is studied, and the general formalism for the stability of static solutions is presented. Several examples corresponding to different spacetime dimensions and values of the parameters are considered.
INSURANCE THEORY AND CHALLENGES FACING THE DEVELOPMENT OF MICROINSURANCE MARKETS
Authors: BRAU JAMES C. , MERRILL CRAIG , STAKING KIM B.
Published: February 2012

Microinsurance institutions and instruments have developed rapidly over the last decade, with policies covering tens of millions at the base of the economic pyramid. Ranging from simple policies providing life or health insurance to complex policies covering catastrophic risks for small landholders, it is a market with proven potential that demands closer attention. This paper provides a review of the nascent academic literature and then suggests some critical elements of insurance theory that may help us understand the challenges facing microinsurance markets and how these markets can better serve the needs of their customers. Although the basic theory is well known, application to microinsurance markets reveals interesting variations on known results.
THE DETERMINANTS OF RISK PREMIUM: THE CASE OF BANK LINES OF CREDIT GRANTED TO SMEs
Authors: ST-PIERRE JOSÉE , BAHRI MOUJIB
Published: February 2012

The goal of this paper is to gain a better understanding of the factors that determine the risk premium on bank lines of credit obtained by SMEs, and whether firm size, which may be used by banks to segment their client base, also has an impact on credit costs. An analysis of data from 406 SMEs in Canada showed the main determinants of risk premium were firm size, line of credit size, ability to repay, the relationship between banker and entrepreneur, and the length of the relationship with the bank. These determinants change according to the market segment in which the potential borrower operates. Banks appear to use a transactional approach for smaller borrowers, where credit terms are based on quantitative financial data, and a relational approach for larger firms, where relationship length and quality become significant.
A RESEARCH NOTE ON INSTITUTIONAL LOGICS AND ENTREPRENEURIAL ACTION: THE CASE OF BLACK CHURCH ORGANIZATIONS
Authors: HAYES RICHARD N. , ROBINSON JEFFREY A.
Published: February 2012

What role do institutions play in the development of entrepreneurial ventures? What factors influence whether organizations will engage in entrepreneurial activity? While research has examined the individual and group-level characteristics of entrepreneurs, this paper explores the role of institutions and organizations in the development of entrepreneurial ventures. Using the "Black Church" as an institutional context, we predict entrepreneurial activity patterns of individual congregations based on denomination-specific institutional logics — rules and norms that either facilitate or constrain organizational action.