bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetic-Pharmacodynamic Modeling of the In Vitro Activities of Oxazolidinone Antimicrobial Agents against Methicillin-ResistantStaphylococcus aureus
Authors: Schmidt Stephan , Sabarinath Sreedharan Nair , Barbour April , Abbanat Darren , Manitpisitkul Prasarn , Sha Sue , Derendorf Hartmut 
Published: September 2009

ABSTRACTLinezolid is the first FDA-approved oxazolidinone with activity against clinically important gram-positive pathogens, including methicillin (meticillin)-resistantStaphylococcus aureus(MRSA). RWJ-416457 is a new oxazolidinone with an antimicrobial spectrum similar to that of linezolid. The goal of the present study was to develop a general pharmacokinetic (PK)-pharmacodynamic (PD) model that allows the characterization and comparison of the in vitro activities of oxazolidinones, determined in time-kill curve experiments, against MRSA. The in vitro activities of RWJ-416457 and the first-in-class representative, linezolid, against MRSA OC2878 were determined in static and dynamic time-kill curve experiments over a wide range of concentrations: 0.125 to 8 μg/ml (MIC, 0.5 μg/ml) and 0.25 to 16 μg/ml (MIC, 1 μg/ml), respectively. After correction for drug degradation during the time-kill curve experiments, a two-subpopulation model was simultaneously fitted to all data in the NONMEM VI program. The robustness of the model and the precision of the parameter estimates were evaluated by internal model validation by nonparametric bootstrap analysis. A two-subpopulation model, consisting of a self-replicating, oxazolidinone-susceptible and a persistent, oxazolidinone-insusceptible pool of bacteria was appropriate for the characterization of the time-kill curve data. The PK-PD model identified was capable of accounting for saturation in growth, delays in the onsets of growth and drug-induced killing, as well as naturally occurring bacterial death. The simultaneous fit of the proposed indirect-response, maximum-effect model to the data resulted in concentrations that produced a half-maximum killing effect that were significantly (P< 0.05) lower for RWJ-416457 (0.41 μg/ml) than for linezolid (1.39 μg/ml). In combination with the appropriate PK data, the susceptibility-based two-subpopulation model identified may provide valuable guidance for the selection of oxazolidinone doses or dose regimens for use in clinical studies.
ADS-J1 Inhibits Human Immunodeficiency Virus Type 1 Entry by Interacting with the gp41 Pocket Region and Blocking Fusion-Active gp41 Core Formation
Authors: Wang Hongtao , Qi Zhi , Guo Angi , Mao Qinchao , Lu Hong , An Xiuli , Xia Chenglai , Li Xiaojuan , Debnath Asim K. , Wu Shuguang , Liu Shuwen , Jiang Shibo 
Published: September 2009

ABSTRACT
We previously identified a small-molecule anti-human immunodeficiency virus type 1 (anti-HIV-1) compound, ADS-J1, using a computer-aided molecular docking technique for primary screening and a sandwich enzyme-linked immunosorbent assay (ELISA) as a secondary screening method. In the present study, we demonstrated that ADS-J1 is an HIV-1 entry inhibitor, as determined by a time-of-addition assay and an HIV-1-mediated cell fusion assay. Further mechanism studies confirmed that ADS-J1 does not block gp120-CD4 binding and exhibits a marginal interaction with the HIV-1 coreceptor CXCR4. However, ADS-J1 inhibited the fusion-active gp41 core formation mimicked by peptides derived from the viral gp41 N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR), as determined by ELISA, native polyacrylamide gel electrophoresis, and circular dichroism analysis. Moreover, using a surface plasmon resonance assay, we found that ADS-J1 could bind directly to IQN17, a trimeric peptide containing the gp41 pocket region, resulting in the conformational change of IQN17 and the blockage of its interaction with a short D peptide, PIE7. The positively charged residue (K574) located in the gp41 pocket region is critical for the binding of ADS-J1 to NHR. These results suggest that ADS-J1 may bind to the viral gp41 NHR region through its hydrophobic and ionic interactions with the hydrophobic and positively charged resides located in the pocket region, subsequently blocking the association between the gp41 NHR and CHR regions to form the fusion-active gp41 core, thereby inhibiting HIV-1-mediated membrane fusion and virus entry.
Modifying Culture Conditions in Chemical Library Screening Identifies Alternative Inhibitors of Mycobacteria
Authors: Miller Christopher H. , Nisa Shahista , Dempsey Sandi , Jack Cameron , O'Toole Ronan 
Published: September 2009

ABSTRACTIn this study, application of a dual absorbance/fluorescence assay to a chemical library screen identified several previously unknown inhibitors of mycobacteria. In addition, growth conditions had a significant effect on the activity profile of the library. Some inhibitors such as Se-methylselenocysteine were detected only when screening was performed under nutrient-limited culture conditions as opposed to nutrient-rich culture conditions. We propose that multiple culture condition library screening is required for complete inhibitory profiling and for maximal antimycobacterial compound detection.
Susceptibilities of Human Cytomegalovirus Clinical Isolates and Other Herpesviruses to New Acetylated, Tetrahalogenated Benzimidazole
d
-Ribonucleosides
Authors: Hwang Jae-Seon , Schilf Rita , Drach John C. , Townsend Leroy B. , Bogner Elke 
Published: September 2009

ABSTRACT

Recently we characterized two inhibitors targeting the human cytomegalovirus (HCMV) terminase, 2-bromo-4,5,6-trichloro-1-(2,3,5-tri-
O
-acetyl-β-
d
-ribofuranosyl) benzimidazole (BTCRB) and 2,4,5,6-tetrachloro-1-(2,3,5-tri-
O
-acetyl-β-
d
-ribofuranosyl) benzimidazole (Cl
4
RB). The terminase consists of the ATP-hydrolyzing subunit pUL56 and the subunit pUL89 required for duplex nicking. Because mammalian cell DNA replication does not involve cleavage of concatemeric DNA by a terminase, these compounds represent attractive alternative HCMV antivirals. We now have tested these previously identified benzimidazole ribonucleosides in order to determine if they are active against HCMV clinical isolates as well as those of herpes simplex virus type 1, mouse cytomegalovirus, rat cytomegalovirus (RCMV), and varicella-zoster virus (VZV). Antiviral activity was quantified by measurement of viral plaque formation (plaque reduction) and by viral growth kinetics. Interestingly, both BTCRB and Cl
4
RB had an inhibitory effect in ganciclovir (GCV)-sensitive and GCV-resistant clinical isolates, with the best effect produced by Cl
4
RB. Electron microscopy revealed that in cells infected with GCV-sensitive or GCV-resistant isolates, B capsids and dense bodies were formed mainly. Furthermore, pulsed-field gel electrophoresis showed that cleavage of concatenated DNA was inhibited in clinical isolates. In addition, the antiviral effect on other herpesviruses was determined. Interestingly, in plaque reduction assays, BTCRB was active against all tested herpesviruses. The best effects were observed on VZV- and RCMV-infected cells. These results demonstrate that the new compounds are highly active against GCV-resistant and GCV-sensitive clinical isolates and slightly active against other herpesviruses.
Paradoxical Growth of
Candida dubliniensis
Does Not Preclude In Vivo Response to Echinocandin Therapy
Authors: Mariné Marçal , Pastor F. Javier , Sahand Ismail H. , Pontón José , Quindós Guillermo , Guarro Josep 
Published: September 2009

ABSTRACT

Candida dubliniensis
commonly shows paradoxical or trailing growth effects in vitro in the presence of echinocandins. We tested the in vitro activities of anidulafungin, caspofungin, and micafungin against clinical isolates of
C. dubliniensis
and evaluated the efficacy of these drugs in two murine models of systemic infection. The three echinocandins were similarly effective in the treatment of experimental disseminated infections with
C. dubliniensis
strains showing or not showing abnormal growth in vitro.
Bacterial Toxins Induce Sustained mRNA Expression of the Silencing Transcription Factor
klf2
via Inactivation of RhoA and Rhophilin 1
Authors: Dach Kristina , Zovko Josip , Hogardt Michael , Koch Isabel , van Erp Katrin , Heesemann Jürgen , Hoffmann Reinhard 
Published: September 2009

ABSTRACT

Yersiniae bearing the
Yersinia
virulence plasmid pYV impact the transcriptome of J774A.1 macrophage-like cells in two distinct ways: (i) by suppressing, in a
Yersinia
outer protein P (YopP)-dependent manner, the induction of inflammatory response genes and (ii) by mRNA induction of the silencing transcription factor
klf2
. Here we show that
klf2
induction by
Yersinia enterocolitica
occurs in several cell lines of macrophage and squamous and upper gastrointestinal epithelial origin as well as in bone marrow-derived dendritic cells. Several strains of
Pseudomonas aeruginosa
and
Staphylococcus aureus
are equally effective as
Y. enterocolitica
in inducing
klf2
expression. Screening of mutant strains or incubation with recombinant toxins identified the rho-inactivating toxins YopT from
Yersinia
spp., ExoS from
Pseudomonas aeruginosa
, EDIN-B from
Staphylococcus aureus
, and C3bot from
Clostridium botulinum
as bacterial inducers of
klf2
mRNA.
klf2
mRNA induction by these toxins does not require de novo protein synthesis. Serum response factor or actin depolymerization does not seem to be involved in regulating
klf2
expression in response to bacterial infection. Instead, short hairpin RNA-mediated inactivation of RhoA and its effector rhophilin 1 is sufficient to induce long-term
klf2
expression. Thus, bacteria exploit the RhoA-rhophilin signaling cascade to mediate sustained expression of the immunosuppressive transcription factor
klf2
.
Vaccine Potentials of an Intrinsically Unstructured Fragment Derived from the Blood Stage-Associated
Plasmodium falciparum
Protein PFF0165c
Authors: Olugbile S. , Kulangara C. , Bang G. , Bertholet S. , Suzarte E. , Villard V. , Frank G. , Audran R. , Razaname A. , Nebie I. , Awobusuyi O. , Spertini F. , Kajava A. V. , Felger I. , Druilhe P. , Corradin G. 
Published: September 2009

ABSTRACT

We have identified new malaria vaccine candidates through the combination of bioinformatics prediction of stable protein domains in the
Plasmodium falciparum
genome, chemical synthesis of polypeptides, in vitro biological functional assays, and association of an antigen-specific antibody response with protection against clinical malaria. Within the predicted open reading frame of
P. falciparum
hypothetical protein PFF0165c, several segments with low hydrophobic amino acid content, which are likely to be intrinsically unstructured, were identified. The synthetic peptide corresponding to one such segment (P27A) was well recognized by sera and peripheral blood mononuclear cells of adults living in different regions where malaria is endemic. High antibody titers were induced in different strains of mice and in rabbits immunized with the polypeptide formulated with different adjuvants. These antibodies recognized native epitopes in
P. falciparum
-infected erythrocytes, formed distinct bands in Western blots, and were inhibitory in an in vitro antibody-dependent cellular inhibition parasite-growth assay. The immunological properties of P27A, together with its low polymorphism and association with clinical protection from malaria in humans, warrant its further development as a malaria vaccine candidate.
oxyR
, a LysR-Type Regulator Involved in
Klebsiella pneumoniae
Mucosal and Abiotic Colonization
Authors: Hennequin Claire , Forestier Christiane 
Published: September 2009

ABSTRACT

Colonization of the gastrointestinal tract is the first event in
Klebsiella pneumoniae
nosocomial infections, followed by colonization of the bladder or respiratory tract or entry into the bloodstream. To survive in the host, bacteria must harbor specific traits and overcome multiple stresses. OxyR is a conserved bacterial transcription factor with a key role both in the upregulation of defense mechanisms against oxidative stress and in pathogenesis by enhancing biofilm formation, fimbrial expression, and mucosal colonization. A homolog of
oxyR
was detected in silico in the
K. pneumoniae
sequenced genome and amplified from the LM21 wild-type strain. To determine the role of
oxyR
in
K. pneumoniae
host-interaction processes, an
oxyR
isogenic mutant was constructed, and its behavior was assessed. At concentrations lower than 10
7
ml
−1
,
oxyR
-deficient organisms were easily killed by micromolar concentrations of H
2
O
2
and exhibited typical aerobic phenotypes. The
oxyR
mutant was impaired in biofilm formation and types 1 and 3 fimbrial gene expression. In addition, the
oxyR
mutant was unable to colonize the murine gastrointestinal tract, and in vitro assays showed that it was defective in adhesion to Int-407 and HT-29 intestinal epithelial cells. The behavior of the
oxyR
mutant was also determined under hostile conditions, reproducing stresses encountered in the gastrointestinal environment: deletion of
oxyR
resulted in higher sensitivity to bile and acid stresses but not to osmotic stress. These results show the pleiotropic role of
oxyR
in
K. pneumoniae
gastrointestinal colonization.
The Enteropathogenic
Escherichia coli
Effector Cif Induces Delayed Apoptosis in Epithelial Cells
Authors: Samba-Louaka Ascel , Nougayrède Jean-Philippe , Watrin Claude , Oswald Eric , Taieb Frédéric 
Published: September 2009

ABSTRACT

The cycle inhibiting factor (Cif) belongs to a family of bacterial toxins, the cyclomodulins, which modulate the host cell cycle. Upon injection into the host cell by the type III secretion system of enteropathogenic
Escherichia coli
(EPEC), Cif induces both G
2
and G
1
cell cycle arrests. The cell cycle arrests correlate with the accumulation of p21
waf1
and p27
kip1
proteins that inhibit CDK-cyclin complexes, whose activation is required for G
1
/S and G
2
/M transitions. Increases of p21 and p27 levels are independent of p53 transcriptional induction and result from protein stabilization through inhibition of the ubiquitin/proteasome degradation pathway. In this study, we show that Cif not only induces cell cycle arrest but also eventually provokes a delayed cell death. Indeed, 48 h after infection with EPEC expressing Cif, cultured IEC-6 intestinal cells were positive for extracellular binding of annexin V and exhibited high levels of cleaved caspase-3 and lactate dehydrogenase release, indicating evidence of apoptosis. Cif was necessary and sufficient for inducing this late apoptosis, and the cysteine residue of the catalytic site was required for Cif activity. These results highlight a more complex role of Cif than previously thought, as a cyclomodulin but also as an apoptosis inducer.
Efficacy of low dose dexamethasone in severe thrombocytopenia caused by dengue fever: a placebo controlled study
Authors: Kularatne S A M , Walathara C , Mahindawansa S I , Wijesinghe S , Pathirage M M K , Kumarasiri P V R , Dissanayake A M S D M 
Published: September 2009

Abstract

Background
The use of corticosteroids in the management of thrombocytopenia in dengue fever remains untested.

Objectives
To test whether intravenous low dose dexamethasone is efficacious in increasing platelet count in acute severe thrombocytopenia in dengue infection.

Methods
We undertook a placebo controlled study at the Teaching Hospital, Peradeniya, Sri Lanka in July 2004. Patients with thrombocytopenia (platelet count &lt;50×109/l) were allocated to the treatment and placebo groups using the sealed envelop method. The treatment group received an initial intravenous dose of 4 mg dexamethasone, followed by 2 mg doses every 8 h for 24 h, and the placebo group received normal saline. The primary outcome was the degree of mean platelet count rise.

Results
Each group comprised 100 patients and their baseline data and other variables (headaches, nausea, flush, temperature, pulse, blood pressure, haematocrit, white cell count and haemoglobin) were similar. The primary outcome—mean platelet count (×109/l)—increased steadily in both groups from day 1 to 4 and showed no significant difference between the two groups (p&gt;0.05): day 1, 35 vs 35 (p = 0.70); day 2, 47 vs 43 (p = 0.19); day 3, 64 vs 59 (p = 0.31); day 4, 72 vs 78 (p = 0.55). Analysis of variance (ANOVA) statistics showed a significant linear association of mean platelet counts by days in either group (p&lt;0.001). Regression analysis identified the day of the illness and patient age as the independent predictors of platelet count change.

Conclusion
At a low dose regimen, dexamethasone was not effective in achieving a higher rise of platelet count in dengue infection.
Narrow complex (supraventricular) tachycardias
Authors: Linton N W F , Dubrey S W 
Published: September 2009

Abstract
Patients experiencing a narrow complex tachycardia are usually at a lower risk than those in whom a broad complex tachycardia occurs. Therefore, in the UK cardiologists are frequently involved in broad complex dysrhythmias at an early stage, while general physicians and general practitioners will often have greater involvement in the management of patients with narrow complex arrhythmias. We describe the management of narrow complex arrhythmias likely to be encountered, including the ubiquitous atrial fibrillation.
The ethical imperative to scale up health care services for people with severe mental disorders in low and middle income countries
Authors: Patel V , Bloch S 
Published: September 2009

AbstractMost mentally ill people in low and middle income countries, where clinical services are typically scarce and mental health legal provisions often inadequate, do not receive requisite evidence based treatment. The unfortunate consequence is compromised health and well-being and lack of social integration in the community. Recent initiatives, such as the Movement for Global Mental Health, aim to improve the situation and, in so doing, take into account ethical factors that play a role in the face of inadequate care and mental health legislative frameworks. Two composite case vignettes based on the narratives of actual patients living in India are used to show how family carers resort to measures like deception, coercion and physical restraint in order to deal with challenging behaviours stemming from severe and enduring mental disorders. These actions, while violating patients’ fundamental human rights, are also the consequence of the utter frustration and despair experienced by families. Scaling up mental health care based on the principle of cost effectiveness is not only a clinical imperative, but also a pivotal means to ensure that the severely mentally ill are accorded the same universal rights as those enjoyed by others.
Modulatory action of potassium channel openers on field potential and histamine release from rat peritoneal mast cells
Authors: Yeung Chi-Kong , Law Jessica Ka-Yan , Sam Sze-Wing , Ingebrandt Sven , Lau Hang-Yung Alaster , Rudd John Anthony , Chan Mansun 
Published: September 2009

To determine whether changes in membrane potential affect the extent of mast cell degranulation, compound 48/80 was added to rat peritoneal mast cell suspensions in the absence or presence of potassium channel openers (KCOs). Changes were compared between the field potential (FP) and the amount of histamine released. The results demonstrated that (i) the onset and duration of FP, which reflects the hyperpolarizing nature of the response, increased as the concentration of compound 48/80 increased; (ii) both FP and the amount of histamine released increased as the concentration of compound 48/80 increased; (iii) although both KCOs (SDZ PCO400, a benzopyran derivative, and P1060, a cyanoguanidine derivative) potentiated compound 48/80-induced increases in FP and histamine release, without compound 48/80, they had no effect on either parameter; (iv) both glibenclamide and charybdotoxin significantly attenuated the compound 48/80-induced increase in FP; and (v) glibenclamide was able to attenuate the KCO-induced potentiation of FP. The results show that drugs presumably causing hyperpolarization can affect histamine release from rat peritoneal mast cells. The effect of KCOs on compound 48/80-induced response appears to be potentiation in nature rather than synergism. It is possible that KCO hyperpolarizes the cell membrane, enhances Ca2+ influx, and thus increases histamine release. As such, selective blockers of K+ channels may be useful for the treatment of immunological disorders.
Cardioprotective roles of aged garlic extract, grape seed proanthocyanidin, and hazelnut on doxorubicin-induced cardiotoxicity
Authors: Demirkaya Erkan , Avci Aslıhan , Kesik Vural , Karslioglu Yıldırım , Oztas Emin , Kismet Erol , Gokcay Erdal , Durak Ilker , Koseoglu Vedat 
Published: September 2009

Doxorubicin (DXR) is a chemotherapeutic agent used effectively in the treatment of several childhood malignancies. During treatment, cardiotoxicity caused by cell damage due to the free oxygen radicals that are generated is a major limiting factor. This study was undertaken to determine whether DXR-induced cardiotoxicity could be prevented by natural foods with antioxidant properties such as aged garlic extract (AGEX), grape seed proanthocyanidin (PA), and hazelnut. Wistar albino male rats were assigned randomly to 9 groups each consisting of 15 rats. AGEX, PA, and hazelnut groups received these antioxidants in addition to their standard rat diet. They were also treated with cumulative intraperitoneal (i.p.) injections according to 2 different regimens: either a high-dose of 15 mg/kg DXR (3.75 mg/kg per week for 4 weeks) or a low-dose of 7.5 mg/kg DXR (1.875 mg/kg per week for 4 weeks). The control group received i.p. 0.9% saline. AGEX, PA, or hazelnut supplements were given orally to the groups for a 6-week period starting 1 week before the DXR treatment and ending 1 week after the treatment. One week after the last DXR injection, heart tissue samples were analyzed to determine malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and xanthine oxidase (XO) levels, and serum samples were taken for creatine kinase (CK). There were no significant changes in MDA levels among the control, DXR-treated groups, or supplemented groups that received additional natural antioxidant foods. SOD enzyme levels were decreased in rats treated with DXR. PA prevented the decrease at low doses of DXR. DXR treatment decreased CAT enzyme levels, but additional PA and hazelnut consumption increased these levels at low cumulative doses. XO enzyme levels were decreased in AGEX and hazelnut groups, but PA prevented the decrease. CK levels were elevated after DXR administration, indicating myocardial injury, but PA significantly reversed this. Although there were no differences histopathologically between AGEX, PA, and hazelnut groups, the protective effects of AGEX and PA were evident in electron microscopy. In conclusion, the positive effects of natural antioxidant foods on the prevention of DXR-induced cardiac injury could not be clearly shown on the basis of antioxidant enzymes. However, the electron microscopic changes clearly demonstrated the protective effects of AGEX and PA. The supplementation of these antioxidant foods over longer periods may show more definitive results. Human studies with different doses are needed to evaluate the effects of these foods on the human heart.