bluuebunny/crossref_metadata_2025_split huggingface dataset:
Maraviroc and Other HIV-1 Entry Inhibitors Exhibit a Class-Specific Redistribution Effect That Results in Increased Extracellular Viral Load
Authors: Kramer Victor G. , Schader Susan M. , Oliveira Maureen , Colby-Germinario Susan P. , Donahue Daniel A. , Singhroy Diane N. , Tressler Randy , Sloan Richard D. , Wainberg Mark A. 
Published: May 2012

ABSTRACT

HIV entry inhibitors, such as maraviroc (MVC), prevent cell-free viruses from entering the cells. In clinical trials, patients who were treated with MVC often displayed viral loads that were above the limit of conventional viral load detection compared to efavirenz-based regimens. We hypothesize that viruses blocked by entry inhibitors may be redistributed to plasma, where they artificially increase viral load measurements compared to those with the use of antiretroviral drugs (ARVs) that act intracellularly. We infected PM-1 cells with CCR5-tropic HIV-1 BaL or CXCR4-tropic HIV-1 NL4-3 in the presence of inhibitory concentrations of efavirenz, raltegravir, enfuvirtide, maraviroc, and AMD3100, the latter three being entry inhibitors. Supernatant viral load, reverse transcriptase enzyme activity, and intracellular nucleic acid levels were measured at times up to 24 h postinfection. Infectivity of redistributed dual-tropic HIV-1 was assessed using TZM-bl cells. Extracellular viral load analysis revealed that entry inhibitor-treated cells had higher levels of virus in the supernatant than the cells treated with other ARVs at 8 h postinfection. By 24 h, the supernatant viral load was still higher for entry inhibitors than other ARVs. We observed a correlation between viral load and the step of entry inhibition. Dual-tropic virus infectivity was undiminished utilizing the CCR5 coreceptor following redistribution by CXCR4 entry inhibition. This
in vitro
model indicates that entry inhibitors exhibit a redistribution effect unseen with intracellular ARV drugs. Based on these results, the effectiveness of some entry inhibitors may be underestimated if plasma viral load is used as a sole indicator of clinical success.
HIV gp120 H375 Is Unique to HIV-1 Subtype CRF01_AE and Confers Strong Resistance to the Entry Inhibitor BMS-599793, a Candidate Microbicide Drug
Authors: Schader Susan M. , Colby-Germinario Susan P. , Quashie Peter K. , Oliveira Maureen , Ibanescu Ruxandra-Ilinca , Moisi Daniela , Mespléde Thibault , Wainberg Mark A. 
Published: May 2012

ABSTRACTBMS-599793 is a small molecule entry inhibitor that binds to human immunodeficiency virus type 1 (HIV-1) gp120, resulting in the inhibition of CD4-dependent entry into cells. Since BMS-599793 is currently considered a candidate microbicide drug, we evaluated its efficacy against a number of primary patient HIV isolates from different subtypes and circulating recombinant forms (CRFs) and showed that activity varied between ∼3 ρM and 7 μM at 50% effective concentrations (EC50s). Interestingly, CRF01_AE HIV-1 isolates consistently demonstrated natural resistance against this compound. Genotypic analysis of >1,600 sequences (Los Alamos HIV sequence database) indicated that a single amino acid polymorphism in Env, H375, may account for the observed BMS-599793 resistance in CRF01_AE HIV-1. Results of site-directed mutagenesis experiments confirmed this hypothesis, andin silicodrug docking simulations identified a drug resistance mechanism at the molecular level. In addition, CRF01_AE viruses were shown to be resistant to multiple broadly neutralizing monoclonal antibodies. Thus, our results not only provide insight into how Env polymorphisms may contribute to entry inhibitor resistance but also may help to elucidate how HIV can evade some broadly neutralizing antibodies. Furthermore, the high frequency of H375 in CRF01_AE HIV-1, and its apparent nonoccurrence in other subtypes, could serve as a means for rapid identification of CRF01_AE infections.
Adverse Effects of Antimicrobials via Predictable or Idiosyncratic Inhibition of Host Mitochondrial Components
Authors: Barnhill Alison E. , Brewer Matt T. , Carlson Steve A. 
Published: May 2012

ABSTRACT
This minireview explores mitochondria as a site for antibiotic-host interactions that lead to pathophysiologic responses manifested as nonantibacterial side effects. Mitochondrion-based side effects are possibly related to the notion that these organelles are archaic bacterial ancestors or commandeered remnants that have co-evolved in eukaryotic cells; thus, this minireview focuses on mitochondrial damage that may be analogous to the antibacterial effects of the drugs. Special attention is devoted to aminoglycosides, chloramphenicol, and fluoroquinolones and their respective single side effects related to mitochondrial disturbances. Linezolid/oxazolidinone multisystemic toxicity is also discussed. Aminoglycosides and oxazolidinones are inhibitors of bacterial ribosomes, and some of their side effects appear to be based on direct inhibition of mitochondrial ribosomes. Chloramphenicol and fluoroquinolones target bacterial ribosomes and gyrases/topoisomerases, respectively, both of which are present in mitochondria. However, the side effects of chloramphenicol and the fluoroquinolones appear to be based on idiosyncratic damage to host mitochondria. Nonetheless, it appears that mitochondrion-associated side effects are a potential aspect of antibiotics whose targets are shared by prokaryotes and mitochondria—an important consideration for future drug design.
A Chimeric Toxin Vaccine Protects against Primary and Recurrent Clostridium difficile Infection
Authors: Wang Haiying , Sun Xingmin , Zhang Yongrong , Li Shan , Chen Kevin , Shi Lianfa , Nie Weijia , Kumar Raj , Tzipori Saul , Wang Jufang , Savidge Tor , Feng Hanping 
Published: May 2012

ABSTRACT

The global emergence of
Clostridium difficile
infection (CDI) has contributed to the recent surge in severe antibiotic-associated diarrhea and colonic inflammation.
C. difficile
produces two homologous glucosylating exotoxins, TcdA and TcdB, both of which are pathogenic and require neutralization to prevent disease occurrence. However, because of their large size and complex multifunctional domain structures, it has been a challenge to produce native recombinant toxins that may serve as vaccine candidates. Here, we describe a novel chimeric toxin vaccine that retains major neutralizing epitopes from both toxins and confers complete protection against primary and recurrent CDI in mice. Using a nonpathogenic
Bacillus megaterium
expression system, we generated glucosyltransferase-deficient holotoxins and demonstrated their loss of toxicity. The atoxic holotoxins induced potent antitoxin neutralizing antibodies showing little cross-immunogenicity or protection between TcdA and TcdB. To facilitate simultaneous protection against both toxins, we generated an active clostridial toxin chimera by switching the receptor binding domain of TcdB with that of TcdA. The toxin chimera was fully cytotoxic and showed potent proinflammatory activities. This toxicity was essentially abolished in a glucosyltransferase-deficient toxin chimera, cTxAB. Parenteral immunization of mice or hamsters with cTxAB induced rapid and potent neutralizing antibodies against both toxins. Complete and long-lasting disease protection was conferred by cTxAB vaccinations against both laboratory and hypervirulent
C. difficile
strains. Finally, prophylactic cTxAB vaccination prevented spore-induced disease relapse, which constitutes one of the most significant clinical issues in CDI. Thus, the rational design of recombinant chimeric toxins provides a novel approach for protecting individuals at high risk of developing CDI.
Neutrophils Are Essential for Containment of Vibrio cholerae to the Intestine during the Proinflammatory Phase of Infection
Authors: Queen Jessica , Satchell Karla J. Fullner 
Published: May 2012

ABSTRACTCholera is classically considered a noninflammatory diarrheal disease, in comparison to invasive enteric organisms, although there is a low-level proinflammatory response during early infection withVibrio choleraeand a strong proinflammatory reaction to live attenuated vaccine strains. Using an adult mouse intestinal infection model, this study examines the contribution of neutrophils to host defense to infection. Nontoxigenic El Tor O1V. choleraeinfection is characterized by the upregulation of interleukin-6 (IL-6), IL-10, and macrophage inflammatory protein 2 alpha in the intestine, indicating an acute innate immune response. Depletion of neutrophils from mice with anti-Ly6G IA8 monoclonal antibody led to decreased survival of mice. The role of neutrophils in protection of the host is to limit the infection to the intestine and control bacterial spread to extraintestinal organs. In the absence of neutrophils, the infection spread to the spleen and led to increased systemic levels of IL-1β and tumor necrosis factor alpha, suggesting the decreased survival in neutropenic mice is due to systemic shock. Neutrophils were found not to contribute to either clearance of colonizing bacteria or to alter the local immune response. However, when genes for secreted accessory toxins were deleted, the colonizing bacteria were cleared from the intestine, and this clearance is dependent upon neutrophils. Thus, the requirement for accessory toxins in virulence is negated in neutropenic mice, which is consistent with a role of accessory toxins in the evasion of innate immune cells in the intestine. Overall, these data support that neutrophils impact disease progression and suggest that neutrophil effectiveness can be manipulated through the deletion of accessory toxins.
Antiphagocytic Function of an IgG Glycosyl Hydrolase from Streptococcus equi subsp.
equi
and Its Use as a Vaccine Component
Authors: Flock Margareta , Frykberg Lars , Sköld Markus , Guss Bengt , Flock Jan-Ingmar 
Published: May 2012

ABSTRACT

EndoSe from
Streptococcus equi
subsp.
equi
is an enzyme hydrolyzing glycosyl groups on IgG, analogous to EndoS from
Streptococcus pyogenes
. We here show that the activity of EndoSe leads to an antiphagocytic function and may thus be a contributory factor to immune evasion of
S. equi
. Despite the damaging effect that EndoSe has on IgG, antibodies against EndoSe can neutralize its function. Antibodies against EndoSe restored the opsonic activity of specific opsonizing antibodies. Mice infected with either
S. equi
subsp.
equi
or subsp.
zooepidemicus
or
S. pyogenes
could be protected by vaccination with EndoSe. It is speculated that EndoSe could be a suitable vaccine candidate against streptococcal infections.
Appetite regulation genes are associated with body mass index in black South African adolescents: a genetic association study
Authors: Lombard Zané , Crowther Nigel J , van der Merwe Lize , Pitamber Punita , Norris Shane A , Ramsay Michèle 
Published: May 2012

BackgroundObesity is a complex trait with both environmental and genetic contributors. Genome-wide association studies have identified several variants that are robustly associated with obesity and body mass index (BMI), many of which are found within genes involved in appetite regulation. Currently, genetic association data for obesity are lacking in Africans—a single genome-wide association study and a few replication studies have been published in West Africa, but none have been performed in a South African population.ObjectiveTo assess the association of candidate loci with BMI in black South Africans. The authors focused on single nucleotide polymorphisms (SNPs) in theFTO,LEP,LEPR,MC4R,NPY2RandPOMCgenes.DesignA genetic association study.Participants990 randomly selected individuals from the larger Birth to Twenty cohort (a longitudinal birth cohort study of health and development in Africans).MeasuresThe authors genotyped 44 SNPs within the six candidate genes that included known BMI-associated SNPs and tagSNPs based on linkage disequilibrium in an African population forFTO,LEPandNPY2R. To assess population substructure, the authors included 18 ancestry informative markers. Weight, height, sex, sex-specific pubertal stage and exact age collected during adolescence (13 years) were used to identify loci that predispose to obesity early in life.ResultsSex, sex-specific pubertal stage and exact age together explain 14.3% of the variation in log(BMI) at age 13. After adjustment for these factors, four SNPs were individually significantly associated with BMI:FTOrs17817449 (p=0.022),LEPrs10954174 (p=0.0004),LEPrs6966536 (p=0.012) andMC4Rrs17782313 (p=0.045). Together the four SNPs account for 2.1% of the variation in log(BMI). Each risk allele was associated with an estimated average increase of 2.5% in BMI.ConclusionsThe study highlighted SNPs inFTOandMC4Ras potential genetic markers of obesity risk in South Africans. The association with two SNPs in the 3′ untranslated region of theLEPgene is novel.
Discontinuation of statin therapy in older people: does a cancer diagnosis make a difference? An observational cohort study using data linkage
Authors: Stavrou Efty P , Buckley Nicholas , Olivier Jake , Pearson Sallie-Anne 
Published: May 2012

ObjectiveThe aim was to examine statin discontinuation rates in a cohort of elderly Australians with newly diagnosed cancer using population-based secondary health data.DesignObservational cohort study.SettingNew South Wales, the largest jurisdiction in Australia. The Pharmaceutical Benefits and Repatriation Pharmaceutical Benefits Schemes are national programmes subsidising prescription drugs to the Australian population and Australian Government Department of Veterans' Affairs clients.ParticipantsThe cohort comprised 1731 cancer patients aged ≥65 years with evidence of statin use in the 90 days prior to diagnosis. They were matched to 3462 non-cancer patients prescribed statins in the same period.Main outcome measureThe authors compared statin discontinuation rates up to 4 years post-diagnosis and examined the factors associated with statin discontinuation.ResultsThe proportion of cancer patients discontinuing statin therapy at 4 years (27%) was comparable to the comparison cohort; however, significantly higher proportions of the cancer cohort discontinued statins than the comparison cohort at 3, 6 and 12 months of follow-up (9.7% vs 7.4% at 12 months, respectively). More than 30% of cancer patients who died were dispensed statins within 30 days of death. Discontinuation of statin therapy in cancer patients was associated with regionalised and distant disease spread at diagnosis (p<0.001), older age (p=0.006), upper gastrointestinal organs and liver cancer (aHR 2.95, 95% CI 1.92 to 4.53) and cancer of the lung, bronchus and trachea (aHR 1.99, 95% CI 1.32 to 3.00) and poorer survival.ConclusionsMedications should be rationalised at the time of a cancer diagnosis, especially in the setting of a poor prognosis. At least for some patients in our cohort, statin therapy may be inappropriately continued which adds unnecessarily to therapeutic burden.
Palliative care for the management of chronic illness: a systematic review study protocol
Authors: Effiong Andem , Effiong Andem I 
Published: May 2012

IntroductionChronic illnesses are marked by fluctuations and variations over time. Individuals with chronic illness experience pain and other symptoms that are not always adequately managed. Their caregivers often have to deal with enormous burden as the illness progresses. Palliative care can serve as an intervention to manage chronic illness, not just at the end of life but also in the early phases of illness.Methods and analysisRandomised and non-randomised studies will be included in the systematic review. The focus will be on non-cancer chronic illness. Sources of data will be from PubMed and other databases and will include the reference list of studies included in the systematic review. The primary outcome will be to assess the efficacy of palliative care on chronic illness. Secondary outcomes will include health-related quality of life, care giver burden, quality of care and cost-effectiveness of interventions. The study population will consist of patients aged 18 years or over.Ethics and disseminationFor purposes of privacy and confidentiality, the systematic review will be limited to studies with de-identified data. The systematic review will be published in a peer-reviewed journal. It will also be disseminated electronically and in print. Brief reports of review findings will be disseminated directly to appropriate audiences via email and other modes of communication. Updates of the review will be conducted to inform and guide healthcare practice and policy.Trial registration numberPROSPEROCRD42011001794.
The International Community-Acquired Pneumonia (CAP) Collaboration Cohort (ICCC) study: rationale, design and description of study cohorts and patients
Authors: Myint Phyo Kyaw , Kwok Chun Shing , Majumdar Sumit R , Eurich Dean T , Clark Allan B , España Pedro P , Man Shin Yan , Huang David T , Yealy Donald M , Angus Derek C , Capelastegui Alberto , Rainer Timothy H , Marrie Thomas J , Fine Michael J , Loke Yoon K 
Published: May 2012

ObjectiveTo improve the understanding of the determinants of prognosis and accurate risk stratification in community-acquired pneumonia (CAP).DesignMulticentre collaboration of prospective cohorts.Setting6 cohorts from the USA, Canada, Hong Kong and Spain.ParticipantsFrom a published meta-analysis of risk stratification studies in CAP, the authors identified and pooled individual patient-level data from six prospective cohort studies of CAP (three from the USA, one each from Canada, Hong Kong and Spain) to create the International CAP Collaboration Cohort. Initial essential inclusion criteria of meta-analysis were (1) prospective design, (2) in English language, (3) reported 30-day mortality and transfer to an intensive or high dependency care and (4) minimum 1000 participants. Common baseline patient characteristics included demographics, history and physical examination findings, comorbidities and laboratory and radiographic findings.Primary and secondary outcome measuresThis paper reports the rationale, hypotheses and analytical framework and also describes study cohorts and patients. The authors aim to (1) compare the prognostic accuracy of existing CAP risk stratification tools, (2) assess patient-level determinants of prognosis, (3) improve risk stratification by combined use of scoring systems and (4) understand prognostic factors for specific patient groups.ResultsThe six cohorts assembled from 1991 to 2007 included 13 784 patients (median age 71 years, 54% men). Aside from one randomised controlled study, the remaining five were cohort studies, but all had similar inclusion criteria. Overall, there was 0%–6% missing data. A total of 6159 (44%) had severe pneumonia by Pneumonia Severity Index class IV/V. Mortality at 30 days was 8% (1036). Admission to intensive care or high dependency unit was also 8% (1059).ConclusionsInternational CAP Collaboration Cohort provides a pooled multicentre data set of patients with CAP, which will help us to better understand the prognosis of CAP.
THE POTENTIAL POINT OF VIEW FOR RENORMALIZATION
Authors: BARAVIERA ALEXANDRE , LEPLAIDEUR RENAUD , LOPES ARTUR O. 
Published: May 2012

For the shift σ in Σ = {0, 1}ℕ, we define the renormalization for potentials by [Formula: see text] We show that for a good H, there is a unique fixed point for [Formula: see text]. It is the Hofbauer potential V*.We show that the stable set of the Hofbauer potential, i. e. the set of potentials V such that [Formula: see text] converges to V* is characterized by the germ of these potentials close to 0∞= 000….Then, we make connections with the Manneville–Pomeau map f : [0, 1]↺. In particular we show that the lift in Σ of log f′ is in the stable set of V*.In the second part, we characterize "good" H, such that σ2◦ H = H ◦ σ.In the last part, we study the thermodynamic formalism for some special potentials in the stable set of V*. They are called virtual Manneville–Pomeau maps.
Emerging Paradigms for Complex Iron-Sulfur Cofactor Assembly and Insertion
Authors: Peters John W. , Broderick Joan B. 
Published: May 2012

[FeFe]-hydrogenses and molybdenum (Mo)-nitrogenase are evolutionarily unrelated enzymes with unique complex iron-sulfur cofactors at their active sites. The H cluster of [FeFe]-hydrogenases and the FeMo cofactor of Mo-nitrogenase require specific maturation machinery for their proper synthesis and insertion into the structural enzymes. Recent insights reveal striking similarities in the biosynthetic pathways of these complex cofactors. For both systems, simple iron-sulfur cluster precursors are modified on assembly scaffolds by the activity of radical S-adenosylmethionine (SAM) enzymes. Radical SAM enzymes are responsible for the synthesis and insertion of the unique nonprotein ligands presumed to be key structural determinants for their respective catalytic activities. Maturation culminates in the transfer of the intact cluster assemblies to a cofactor-less structural protein recipient. Required roles for nucleotide binding and hydrolysis have been implicated in both systems, but the specific role for these requirements remain unclear. In this review, we highlight the progress on [FeFe]-hydrogenase H cluster and nitrogenase FeMo-cofactor assembly in the context of these emerging paradigms.
Molecular Pathways: Interferon/Stat1 Pathway: Role in the Tumor Resistance to Genotoxic Stress and Aggressive Growth
Authors: Khodarev Nikolai N. , Roizman Bernard , Weichselbaum Ralph R. 
Published: May 2012

Abstract
STAT1 is activated by IFNs and other cell signals. Following activation, STAT1 is translocated to the nuclei and activates transcription of IFN-stimulated genes. Although the activation of STAT1 by IFNs is classically associated with antiviral defense and tumor-suppressive functions, emerging data indicate that expression of the STAT1 pathway confers cellular resistance to DNA-damaging agents and mediates aggressive tumor growth. Recent advances in the development of Janus-activated kinase/Stat inhibitors and peptide inhibitors specific for individual Stat proteins may provide new insights into the controversial functions of this pathway. Clin Cancer Res; 18(11); 3015–21. ©2012 AACR.
Electrocardiographic Characteristics of Potential Organ Donors and Associations With Cardiac Allograft Use
Authors: Khush Kiran K. , Menza Rebecca , Nguyen John , Goldstein Benjamin A. , Zaroff Jonathan G. , Drew Barbara J. 
Published: May 2012

Background—
Current regulations require that all cardiac allograft offers for transplantation must include an interpreted 12-lead electrocardiogram (ECG). However, little is known about the expected ECG findings in potential organ donors or the clinical significance of any identified abnormalities in terms of cardiac allograft function and suitability for transplantation.

Methods and Results—
A single experienced reviewer interpreted the first ECG obtained after brain stem herniation in 980 potential organ donors managed by the California Transplant Donor Network from 2002 to 2007. ECG abnormalities were summarized, and associations between specific ECG findings and cardiac allograft use for transplantation were studied. ECG abnormalities were present in 51% of all cases reviewed. The most common abnormalities included voltage criteria for left ventricular hypertrophy, prolongation of the corrected QT interval, and repolarization changes (ST/T wave abnormalities). Fifty-seven percent of potential cardiac allografts in this cohort were accepted for transplantation. Left ventricular hypertrophy on ECG was a strong predictor of allograft nonuse. No significant associations were seen among corrected QT interval prolongation, repolarization changes, and allograft use for transplantation after adjusting for donor clinical variables and echocardiographic findings.

Conclusions—
We have performed the first comprehensive study of ECG findings in potential donors for cardiac transplantation. Many of the common ECG abnormalities seen in organ donors may result from the heightened state of sympathetic activation that occurs after brain stem herniation and are not associated with allograft use for transplantation.