bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antimicrobial and Anticoagulant Activities of
N
-Chlorotaurine,
N
,
N
-Dichloro-2,2-Dimethyltaurine, and
N
-Monochloro-2,2-Dimethyltaurine in Human Blood
Authors: Martini C. , Hammerer-Lercher A. , Zuck M. , Jekle A. , Debabov D. , Anderson M. , Nagl M. 
Published: January 2012

ABSTRACT

The aim of this study was to determine the potential application of
N
-chlorotaurine (NCT),
N
,
N
-dichloro-2,2-dimethyltaurine (NVC-422), and
N
-monochloro-2,2-dimethyltaurine (NVC-612) as catheter lock solutions for the prevention of catheter blockage and catheter-related bloodstream infections by testing their anticoagulant and broad-spectrum antimicrobial activities in human blood. NCT, NVC-422, NVC-612, and control compounds were serially diluted in fresh human blood to evaluate the effects on prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, and direct thrombin inhibition. Quantitative killing assays against pathogens, including methicillin-resistant
Staphylococcus aureus
,
Escherichia coli
, and
Candida albicans
, were performed in the presence of heparin and human blood. NCT and NVC-612 (1.38 mM each) and 1.02 mM NVC-422 prolonged prothrombin time (Quick value, 17 to 30%), activated partial thromboplastin time 3- to 4-fold to 76 to 125 s, and thrombin time 2- to 4-fold to 34 to 68 s. Fibrinogen decreased from 258 to 283 mg/dl (range of controls) to <40 mg/dl. No direct thrombin inhibition was observed by NVC-422 or NVC-612. Heparin did not influence the bactericidal activity of NCT. The microbicidal activities of NCT, NVC-422, and NVC-612 were maintained in diluted human blood. NCT, NVC-612, and NVC-422 have broad-spectrum antimicrobial activity in blood and anticoagulant activity targeting both intrinsic and extrinsic pathways of the coagulation system. These properties support their application as catheter lock solutions.
Pharmacokinetics of and Short-Term Virologic Response to Low-Dose 400-Milligram Once-Daily Raltegravir Maintenance Therapy
Authors: Ananworanich Jintanat , Gorowara Meena , Avihingsanon Anchalee , Kerr Stephen J. , van Heesch Nadine , Khongpetch Chuleeporn , Uanithirat Anuntaya , Hill Andrew , Ruxrungtham Kiat , Burger David M. 
Published: January 2012

ABSTRACT

Because studies showed similar viral suppression with lower raltegravir doses and because Asians usually have high antiretroviral concentrations, we explored low-dose raltegravir therapy in Thais. Nineteen adults on raltegravir at 400 mg twice daily (BID) with HIV RNA loads of <50 copies/ml were randomized to receive 400 mg once daily (QD) or 800 mg QD for 2 weeks, followed by the other dosing for 2 weeks. Intensive pharmacokinetic analyses were performed, and HIV RNA was monitored. Two patients were excluded from the 400-mg QD analysis due to inevaluable pharmacokinetic data. The mean patient weight was 58 kg. Mean pharmacokinetic values were as follows: for raltegravir given at 400 mg BID, the area under the concentration-time curve from 0 to 12 h (AUC
0-12
) was 15.6 mg/liter-h and the minimum plasma drug concentration (
C
trough
) was 0.22 mg/liter; for raltegravir given at 800 mg QD, the AUC
0-24
was 33.6 mg/liter-h and the
C
trough
was 0.06 mg/liter; and for raltegravir given at 400 mg QD, the AUC
0-24
was 18.6 mg/liter-h and the
C
trough
was 0.08 mg/liter. The HIV RNA load was <50 copies/ml at each dose level. Compared to the adjusted AUC
0-24
for Westerners on raltegravir at 400 mg BID, Thais on the same dose had double the AUC
0-24
and those on raltegravir at 400 mg QD had a similar AUC
0-24
. More patients had a
C
trough
of <0.021 mg/liter on raltegravir at 400 mg QD (9/17 patients) than on raltegravir at 800 mg QD (1/19 patients) or 400 mg BID (0/19 patients). Seventeen patients used raltegravir at 400 mg QD for a median of 35 weeks; two had confirmed HIV RNA loads between 50 and 200 copies/ml, and both had low
C
trough
values. Low-dose raltegravir could be a cost-saving option for maintenance therapy in Asians or persons with low body weight. However, raltegravir at 400 mg QD was associated with a low
C
trough
and with a risk for HIV viremia. Raltegravir at 200 or 300 mg BID should be studied, but new raltegravir formulations will be needed.
Mutation Analysis of Mycobacterial
rpoB
Genes and Rifampin Resistance Using Recombinant Mycobacterium smegmatis
Authors: Nakata Noboru , Kai Masanori , Makino Masahiko 
Published: January 2012

ABSTRACT

Rifampin is a major drug used to treat leprosy and tuberculosis. The rifampin resistance of
Mycobacterium leprae
and
Mycobacterium tuberculosis
results from a mutation in the
rpoB
gene, encoding the β subunit of RNA polymerase. A method for the molecular determination of rifampin resistance in these two mycobacteria would be clinically valuable, but the relationship between the mutations and susceptibility to rifampin must be clarified before its use. Analyses of mutations responsible for rifampin resistance using clinical isolates present some limitations. Each clinical isolate has its own genetic variations in some loci other than
rpoB
, which might affect rifampin susceptibility. For this study, we constructed recombinant strains of
Mycobacterium smegmatis
carrying the
M. leprae
or
M. tuberculosis rpoB
gene with or without mutation and disrupted their own
rpoB
genes on the chromosome. The rifampin and rifabutin susceptibilities of the recombinant bacteria were measured to examine the influence of the mutations. The results confirmed that several mutations detected in clinical isolates of these two pathogenic mycobacteria can confer rifampin resistance, but they also suggested that some mutations detected in
M. leprae
isolates or rifampin-resistant
M. tuberculosis
isolates are not involved in rifampin resistance.
Population Pharmacokinetics of Telavancin in Healthy Subjects and Patients with Infections
Authors: Samara Emil , Shaw Jeng-Pyng , Barriere Steven L. , Wong Shekman L. , Worboys Philip 
Published: January 2012

ABSTRACT
A population pharmacokinetic model of telavancin, a lipoglycopeptide antibiotic, was developed and used to identify sources of interindividual variability. Data were obtained from healthy subjects (seven phase 1 studies), patients with complicated skin and skin structure infections (cSSSI; two phase 2 and two phase 3 studies), and patients with hospital-acquired pneumonia (HAP; two phase 3 studies). A two-compartment open model with zero-order input best fit the telavancin data from healthy individuals and patients with cSSSI or HAP. Telavancin clearance was highly correlated with renal function and, to a lesser extent, with body weight. Other covariates were related to at least one parameter in cSSSI (gender, bacterial eradication, and surgery) or HAP (age of ≥75 years) but did not markedly affect exposure. These analyses support current dosing recommendations for telavancin based on patient weight and renal function.
Case-Control Study Comparing
De Novo
and Daptomycin-Exposed Daptomycin-Nonsusceptible Enterococcus Infections
Authors: Kelesidis Theodoros , Chow Angela L. P. , Humphries Romney , Uslan Daniel Z. , Pegues David 
Published: January 2012

ABSTRACT

Understanding factors associated with
de novo
daptomycin-nonsusceptible
Enterococcus
(DNSE) infections will aid in better understanding the mechanisms of daptomycin nonsusceptibility. We conducted a case-control study to compare patients with DNSE infections who were daptomycin treatment naïve (
n
= 9) and those with DNSE infections who had exposure to daptomycin (
n
= 13). Less frequent exposure to antimicrobials, increased susceptibility to nitrofurantoin and gentamicin, and shorter duration of hospitalization were associated with
de novo
DNSE infection, suggesting a potential community reservoir.
NDM-4 Metallo-β-Lactamase with Increased Carbapenemase Activity from Escherichia coli
Authors: Nordmann Patrice , Boulanger Anne E. , Poirel Laurent 
Published: January 2012

ABSTRACT

A clinical
Escherichia coli
isolate resistant to all β-lactams, including carbapenems, expressed a novel metallo-β-lactamase (MBL), NDM-4, differing from NDM-1 by a single amino acid substitution (Met154Leu). NDM-4 possessed increased hydrolytic activity toward carbapenems and several cephalosporins compared to that of NDM-1. This amino acid substitution was not located in the known active sites of NDM-1, indicating that remote amino acid substitutions might also play a role in the extended activity of this MBL.
Differential Use of CCR5 by HIV-1 Clinical Isolates Resistant to Small-Molecule CCR5 Antagonists
Authors: Henrich Timothy J. , Lewine Nicolas R. P. , Lee Sun-Hee , Rao Suhas S. P. , Berro Reem , Gulick Roy M. , Moore John P. , Tsibris Athe M. N. , Kuritzkes Daniel R. 
Published: January 2012

ABSTRACT
How HIV-1 resistant to small-molecule CCR5 antagonists uses the coreceptor for entry has been studied in a limited number of isolates. We characterized dependence on the N terminus (NT) and the second extracellular loop (ECL2) of CCR5 of three vicriviroc (VCV)-resistant clinical isolates broadly cross-resistant to other CCR5 antagonists. Pseudoviruses were constructed to assess CCR5 use by VCV-sensitive and -resistant envelopes of subtype B and C viruses. We determined the extent of entry inhibition by monoclonal antibodies (MAbs) directed against the NT and ECL2 in the presence and absence of VCV and the capacity of these pseudoviruses to use CCR5 mutants that contained scanning alanine substitutions in the CCR5 NT and ECL2 domains. Sensitive and resistant viruses were completely and competitively inhibited by the ECL2-specific MAb 2D7, whereas the NT-specific MAb CTC5 led to partial noncompetitive inhibition. VCV-resistant clones showed greater sensitivity to 2D7 than VCV-sensitive clones, but in the presence of saturating VCV concentrations, the 2D7 susceptibilities of two VCV-resistant viruses were similar to that of VCV-sensitive virus. The entry of VCV-sensitive and -resistant isolates was impaired to differing degrees by alanine mutations in CCR5; substitutions in NT had the greatest effect on viral entry. HIV-1 clinical isolates broadly resistant to CCR5 antagonists demonstrated significant heterogeneity in their use of CCR5. This heterogeneity makes it difficult to draw general conclusions about the relationship between patterns of CCR5 antagonist resistance and the use of specific CCR5 domains for entry.
Treatment Outcome of Bacteremia Due to KPC-Producing Klebsiella pneumoniae: Superiority of Combination Antimicrobial Regimens
Authors: Qureshi Zubair A. , Paterson David L. , Potoski Brian A. , Kilayko Mary C. , Sandovsky Gabriel , Sordillo Emilia , Polsky Bruce , Adams-Haduch Jennifer M. , Doi Yohei 
Published: January 2012

ABSTRACT

Klebsiella pneumoniae
producing
Klebsiella pneumoniae
carbapenemase (KPC) has been associated with serious infections and high mortality. The optimal antimicrobial therapy for infection due to KPC-producing
K. pneumoniae
is not well established. We conducted a retrospective cohort study to evaluate the clinical outcome of patients with bacteremia caused by KPC-producing
K. pneumoniae
. A total of 41 unique patients with blood cultures growing KPC-producing
K. pneumoniae
were identified at two medical centers in the United States. Most of the infections were hospital acquired (32; 78%), while the rest of the cases were health care associated (9; 22%). The overall 28-day crude mortality rate was 39.0% (16/41). In the multivariate analysis, definitive therapy with a combination regimen was independently associated with survival (odds ratio, 0.07 [95% confidence interval, 0.009 to 0.71],
P
= 0.02). The 28-day mortality was 13.3% in the combination therapy group compared with 57.8% in the monotherapy group (
P
= 0.01). The most commonly used combinations were colistin-polymyxin B or tigecycline combined with a carbapenem. The mortality in this group was 12.5% (1/8). Despite
in vitro
susceptibility, patients who received monotherapy with colistin-polymyxin B or tigecycline had a higher mortality of 66.7% (8/12). The use of combination therapy for definitive therapy appears to be associated with improved survival in bacteremia due to KPC-producing
K. pneumoniae
.
Infection with Anaplasma phagocytophilum Activates the Phosphatidylinositol 3-Kinase/Akt and NF-κB Survival Pathways in Neutrophil Granulocytes
Authors: Sarkar Arup , Hellberg Lars , Bhattacharyya Asima , Behnen Martina , Wang Keqing , Lord Janet M. , Möller Sonja , Kohler Maja , Solbach Werner , Laskay Tamás 
Published: January 2012

ABSTRACT

Anaplasma phagocytophilum
, a Gram-negative, obligate intracellular bacterium infects primarily neutrophil granulocytes. Infection with
A. phagocytophilum
leads to inhibition of neutrophil apoptosis and consequently contributes to the longevity of the host cells. Previous studies demonstrated that the infection inhibits the executionary apoptotic machinery in neutrophils. However, little attempt has been made to explore which survival signals are modulated by the pathogen. The aim of the present study was to clarify whether the phosphatidylinositol 3-kinase (PI3K)/Akt and NF-κB signaling pathways, which are considered as important survival pathways in neutrophils, are involved in
A. phagocytophilum
-induced apoptosis delay. Our data show that infection of neutrophils with
A. phagocytophilum
activates the PI3K/Akt pathway and suggest that this pathway, which in turn maintains the expression of the antiapoptotic protein Mcl-1, contributes to the infection-induced apoptosis delay. In addition, the PI3K/Akt pathway is involved in the activation of NF-κB in
A. phagocytophilum
-infected neutrophils. Activation of NF-κB leads to the release of interleukin-8 (IL-8) from infected neutrophils, which, in an autocrine manner, delays neutrophil apoptosis. In addition, enhanced expression of the antiapoptotic protein cIAP2 was observed in
A. phagocytophilum
-infected neutrophils. Taken together, the data indicate that upstream of the apoptotic cascade, signaling via the PI3K/Akt pathway plays a major role for apoptosis delay in
A. phagocytophilum
-infected neutrophils.
Correlating Levels of Type III Secretion and Secreted Proteins with Fecal Shedding of Escherichia coli O157:H7 in Cattle
Authors: Sharma V. K. , Sacco R. E. , Kunkle R. A. , Bearson S. M. D. , Palmquist D. E. 
Published: January 2012

ABSTRACT

The locus of enterocyte effacement (LEE) of
Escherichia coli
O157:H7 (O157) encodes a type III secretion system (T3SS) for secreting LEE-encoded and non-LEE-encoded virulence proteins that promote the adherence of O157 to intestinal epithelial cells and the persistence of this food-borne human pathogen in bovine intestines. In this study, we compared
hha sepB
and
hha
mutants of O157 for LEE transcription, T3SS activity, adherence to HEp-2 cells, persistence in bovine intestines, and the ability to induce changes in the expression of proinflammatory cytokines. LEE transcription was upregulated in the
hha sepB
and
hha
mutant strains compared to that in the wild-type strain, but the secretion of virulence proteins in the
hha sepB
mutant was severely compromised. This reduced secretion resulted in reduced adherence of the
hha sepB
mutant to Hep-2 cells, correlating with a significantly shorter duration and lower magnitude of fecal shedding in feces of weaned (
n
= 4 per group) calves inoculated with this mutant strain. The levels of LEE transcription, T3SS activity, and adherence to HEp-2 cells were much lower in the wild-type strain than in the
hha
mutant, but no significant differences were observed in the duration or the magnitude of fecal shedding in calves inoculated with these strains. Examination of the rectoanal junction (RAJ) tissues from three groups of calves showed no adherent O157 bacteria and similar proinflammatory cytokine gene expression, irrespective of the inoculated strain, with the exception that interleukin-1β was upregulated in calves inoculated with the
hha sepB
mutant. These results indicate that the T3SS is essential for intestinal colonization and prolonged shedding, but increased secretion of virulence proteins did not enhance the duration and magnitude of fecal shedding of O157 in cattle or have any significant impact on the cytokine gene expression in RAJ tissue compared with that in small intestinal tissue from the same calves.
Plasmodium falciparum Malaria in the Peruvian Amazon, a Region of Low Transmission, Is Associated with Immunologic Memory
Authors: Clark Eva H. , Silva Claudia J. , Weiss Greta E. , Li Shanping , Padilla Carlos , Crompton Peter D. , Hernandez Jean N. , Branch OraLee H. 
Published: January 2012

ABSTRACTThe development of clinical immunity toPlasmodium falciparummalaria is thought to require years of parasite exposure, a delay often attributed to difficulties in developing protective antibody levels. In this study, we evaluated severalP. falciparumvaccine candidate antigens, including apical membrane antigen 1 (AMA-1), circumsporozoite protein (CSP), erythrocyte binding antigen 175 (EBA-175), and the 19-kDa region of merozoite surface protein 1 (MSP119). After observing a more robust antibody response to MSP119, we evaluated the magnitude and longevity of IgG responses specific to this antigen in Peruvian adults and children before, during, and afterP. falciparuminfection. In this low-transmission region, even one reported prior infection was sufficient to produce a positive anti-MSP119IgG response for >5 months in the absence of reinfection. We also observed an expansion of the total plasmablast (CD19+CD27+CD38high) population in the majority of individuals shortly after infection and detected MSP1-specific memory B cells in a subset of individuals at various postinfection time points. This evidence supports our hypothesis that effective antimalaria humoral immunity can develop in low-transmission regions.
Nonhuman Primate Model of Pertussis
Authors: Warfel Jason M. , Beren Joel , Kelly Vanessa K. , Lee Gloria , Merkel Tod J. 
Published: January 2012

ABSTRACT

Pertussis is a highly contagious, acute respiratory illness caused by the bacterial pathogen
Bordetella pertussis
. Despite nearly universal vaccine coverage, pertussis rates in the United States have been rising steadily over the last 20 years. Our failure to comprehend and counteract this important public health concern is due in large part to gaps in our knowledge of the disease and the mechanisms of vaccine-mediated protection. Important questions about pertussis pathogenesis and mechanisms of vaccine effectiveness remain unanswered due to the lack of an animal model that replicates the full spectrum of human disease. Because current animal models do not meet these needs, we set out to develop a nonhuman primate model of pertussis. We inoculated rhesus macaques and olive baboons with wild-type
B. pertussis
strains and evaluated animals for clinical disease. We found that only 25% of rhesus macaques developed pertussis. In contrast, 100% of inoculated baboons developed clinical pertussis. A strong anamnestic response was observed when convalescent baboons were infected 6 months following recovery from a primary infection. Our results demonstrate that the baboon provides an excellent model of clinical pertussis that will allow researchers to investigate pertussis pathogenesis and disease progression, evaluate currently licensed vaccines, and develop improved vaccines and therapeutics.
Roles of the Nuclear Lamina in Stable Nuclear Association and Assembly of a Herpesviral Transactivator Complex on Viral Immediate-Early Genes
Authors: Silva Lindsey , Oh Hyung Suk , Chang Lynne , Yan Zhipeng , Triezenberg Steven J. , Knipe David M. 
Published: January 2012

ABSTRACT

Little is known about the mechanisms of gene targeting within the nucleus and its effect on gene expression, but most studies have concluded that genes located near the nuclear periphery are silenced by heterochromatin. In contrast, we found that early herpes simplex virus (HSV) genome complexes localize near the nuclear lamina and that this localization is associated with reduced heterochromatin on the viral genome and increased viral immediate-early (IE) gene transcription. In this study, we examined the mechanism of this effect and found that input virion transactivator protein, virion protein 16 (VP16), targets sites adjacent to the nuclear lamina and is required for targeting of the HSV genome to the nuclear lamina, exclusion of heterochromatin from viral replication compartments, and reduction of heterochromatin on the viral genome. Because cells infected with the VP16 mutant virus
in
1814 showed a phenotype similar to that of lamin A/C
−/−
cells infected with wild-type virus, we hypothesized that the nuclear lamina is required for VP16 activator complex formation. In lamin A/C
−/−
mouse embryo fibroblasts, VP16 and Oct-1 showed reduced association with the viral IE gene promoters, the levels of VP16 and HCF-1 stably associated with the nucleus were lower than in wild-type cells, and the association of VP16 with HCF-1 was also greatly reduced. These results show that the nuclear lamina is required for stable nuclear localization and formation of the VP16 activator complex and provide evidence for the nuclear lamina being the site of assembly of the VP16 activator complex.

IMPORTANCE
The targeting of chromosomes in the cell nucleus is thought to be important in the regulation of expression of genes on the chromosomes. The major documented effect of intranuclear targeting has been silencing of chromosomes at sites near the nuclear periphery. In this study, we show that targeting of the herpes simplex virus DNA genome to the nuclear periphery promotes formation of transcriptional activator complexes on the viral genome, demonstrating that the nuclear periphery also has sites for activation of transcription. These results highlight the importance of the nuclear lamina, the structure that lines the inner nuclear membrane, in both transcriptional activation and repression. Future studies defining the molecular structures of these two types of nuclear sites should define new levels of gene regulation.
Development of a solid polymer electrolyte membrane based on sulfonated poly(ether ether)ketone and polysulfone for fuel cell applications
Authors: Guhan Srinivasan , Muruganantham Rethinasabapathy , Sangeetha Dharmalingam 
Published: January 2012

Polymer electrolyte membranes made of sulfonated poly(ether ether)ketone (SPEEK) and polysulfone (PSf) (2–10 wt %) were prepared by a solution casting method. The characteristic properties of the SPEEK/PSf polymer blend membranes were investigated using thermogravimetric analysis (TGA), scanning electron microscopy (SEM), and the AC impedance method. The SPEEK/PSf blend membranes showed good thermal and mechanical properties and appreciable ionic conductivity. It was revealed that the addition of PSf into the SPEEK matrix could markedly improve the electrochemical properties of the resulting membranes, which can be accomplished by a simple blend method. As a result, the SPEEK/PSf blends appear to be good candidates for the proton exchange membrane fuel cell (PEMFC) and direct methanol fuel cell (DMFC) applications. These blend membranes, having various amounts of PSf (2–10 wt %), were investigated in PEMFC and DMFC. The power densities were about 400 and 50 mW/cm2 for PEMFC and DMFC, respectively. This makes PSf-based DMFC and PEMFC suitable for application in portable devices and transportation, respectively.