bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of pegylated interferon‐α2a monotherapy in Japanese children with chronic hepatitis C
Authors: Tsunoda Tomoyuki , Inui Ayano , Etani Yuri , Kiyohara Yuki , Sugiura Tokio , Ito Koichi , Miyazawa Reiko , Nagata Ikuo , Ida Shinobu , Fujisawa Tomoo ,   Working Group for the Study of Pegylated Monotherapy for Children with Chronic Hepatitis C in the Japan Society of Pediatric Hepatology
Published: April 2011

Aim:  There is little information available on the efficacy of pegylated interferon (PEG IFN) therapy for children with chronic hepatitis C. The aim of this study was to evaluate the efficacy and tolerability of PEG IFN‐α2a monotherapy for children infected by chronic hepatitis C virus (HCV).Methods:  From 2004–2006, we conducted a prospective, open‐label, multicenter study of 22 patients aged 4–18 years, including eight with genotype 1 and 14 with genotype 2. None had previously received IFN. The patients were treated with s.c. PEG IFN‐α2a at a dose of 3 µg/kg once a week for 48 weeks. Rapid virological response (RVR) was defined as: undetectable serum HCV RNA at week 4; early viral response (EVR) as a 2 or more log reduction or undetectable serum HCV RNA at week 12; and sustained viral response (SVR) as undetectable serum HCV RNA at 24 weeks after the cessation of treatment.Results:  SVR was achieved in 10 (45%) of the 22 patients (three with genotype 1, seven with genotype 2). Retrospectively, the patients with SVR included five with RVR (one with genotype 1, four with genotype 2) and five with EVR (two with genotype 1, three with genotype 2). PEG IFN‐α2a monotherapy was well tolerated, except in one patient in whom alanine aminotransferase activity flared (>500 IU/L) during treatment.Conclusion:  The efficacy of PEG IFN‐α2a monotherapy in children is similar to that for adults, while tolerability seems to be better in children than in adults.
Major role of apolipoprotein B in cycloheximide‐induced acute hepatic steatosis in mice
Authors: Murakami Mari , Bessho Kazuhiko , Mushiake Sotaro , Kondou Hiroki , Miyoshi Yoko , Ozono Keiichi 
Published: April 2011

Aim:  Hepatic steatosis accompanied by impaired protein synthesis is often observed in hepatic dysfunction. To assess whether protein synthesis inhibition directly induces hepatic steatosis, we investigated the molecular mechanisms of cycloheximide (CHX)‐induced fatty liver mice.Methods:  C57/BL6CR mice were i.p. administrated CHX (20 mg/kg) three times every 4 h to induce hepatic steatosis. Hepatic lipid secretion, fatty acid oxidation, hepatic lipogenesis and hepatic lipid uptake were evaluated.Results:  Twenty‐four hours after the first CHX injection, hepatic lipid levels increased in CHX‐treated mice to 1.8‐fold of that in controls but returned to normal within 48 h. The hepatic triglyceride (TG) secretion rate decreased significantly to 22% of controls, and the apolipoprotein B (apoB) protein level, but not microsomal TG transfer protein, decreased in CHX‐treated mice. The apob gene expression was not significantly different between controls and CHX‐treated mice. On the other hand, plasma free fatty acid and lipogenic protein levels did not increase and plasma β‐hydroxybutyrate level remained stable, suggesting that the coordinated balance between fatty acid oxidation, hepatic lipid uptake and lipogenesis was not disrupted in this model. Cellular lipid accumulation and decreased cellular and secreted apoB were also observed in CHX‐treated HepG2 cells. Knockdown of apoB in HepG2 cells also resulted in the cellular TG accumulation.Conclusion:  We demonstrated that decreased hepatic lipid secretion due to acute apoB reduction is involved in the pathogenesis of CHX‐induced liver steatosis.
Effect of the regulation of retinoid X receptor‐α gene expression on rat hepatic fibrosis
Authors: Wang Zheng , Xu Jiapeng , Zheng Yongchao , Chen Wei , Sun Yongwei , Wu Zhiyong , Luo Meng 
Published: April 2011

Aim:  To study the effect of retinoid X receptor‐α (RXR‐α) expression on rat hepatic fibrosis.Methods:  Rat hepatic fibrosis was induced by CCl4, and the rats were randomly divided into an early‐phase hepatic fibrosis group (2 weeks) and a sustained hepatic fibrosis group (8 weeks). They were then divided into four groups (normal control, hepatic fibrosis, negative control and RXR‐α groups). A recombinant lentiviral expression vector carrying the rat RXR‐α gene was injected into the rats to induce RXR‐α expression by intraportal infusion, hepatic tissue pathological examination was performed, and hydroxyproline content was detected. Hepatic stellate cells (HSC) were cultured in vitro, an RXR‐α lentivirus vector was used to activate HSC, and 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) activation was assayed to detect HSC proliferation.Results:  In vivo experiments indicated that in the sustained hepatic fibrosis group, there were significant differences in the hydroxyproline content, and expression of RXR‐α, α‐smooth muscle actin (α‐SMA) and type I collagen (P < 0.01). However, in the early‐phase hepatic fibrosis group, hydroxyproline content and the protein level of RXR‐α showed no significant difference compared with the normal control group (P > 0.05). In vitro studies revealed that expression of RXR‐α significantly inhibited expression of α‐SMA and type I collagen in activated HSC (P < 0.01), as well as HSC proliferation (P < 0.01).Conclusion:  The increased RXR‐α gene expression inhibited HSC activation and proliferation and the degree of hepatic fibrosis.
Effects of late evening snack including branched‐chain amino acid on the function of hepatic parenchymal cells in patients with liver cirrhosis
Authors: Koreeda Chizu , Seki Toshihito , Okazaki Kazuichi , Ha‐Kawa Sang Kil , Sawada Satoshi 
Published: April 2011

Aim:  A late evening snack (LES) improves protein‐energy malnutrition due to overnight starvation and the catabolic state in patients with liver cirrhosis. Our aim was to examine whether LES including a branched‐chain amino acid (BCAA) could maintain hepatic reserve and the function of hepatic parenchymal cells in patients with liver cirrhosis, including those in the early stage of disease.Methods:  Seventeen patients with liver cirrhosis received LES with a BCAA‐enriched nutrient mixture. During the study period, each patient was instructed on energy and protein intake. Indicators of liver function measured at 6 months included maximum asialoscintigraphic removal (Rmax: indicator of total liver receptors), asialoscintigraphic imaging grade, serum albumin, ammonia, tyrosine and BTR (molar ratio of branched‐chain amino acids to tyrosine).Results:  Serum albumin levels, BTR and tyrosine levels of the 17 patients were significantly improved after nutrient treatment. In patients with Rmax of 0.2 or higher, serum albumin level and tyrosine level were significantly improved.Conclusion:  LES with BCAA‐enriched nutrient therapy can improve protein malnutrition in patients with liver cirrhosis, and is more useful in the early stages of liver cirrhosis in improving hepatic parenchymal cell mass.
Strange duality of weighted homogeneous polynomials
Authors: Ebeling Wolfgang , Takahashi Atsushi 
Published: April 2011

AbstractWe consider a mirror symmetry between invertible weighted homogeneous polynomials in three variables. We define Dolgachev and Gabrielov numbers for them and show that we get a duality between these polynomials generalizing Arnold’s strange duality between the 14 exceptional unimodal singularities.
In Vivo
Efficacy of a Human-Simulated Regimen of Ceftaroline Combined with NXL104 against Extended-Spectrum-β-Lactamase (ESBL)-Producing and Non-ESBL-Producing Enterobacteriaceae
Authors: Wiskirchen Dora E. , Crandon Jared L. , Furtado Guilherme H. , Williams Gregory , Nicolau David P. 
Published: April 2011

ABSTRACT

Ceftaroline exhibits
in vitro
activity against extended-spectrum β-lactamase (ESBL)-, AmpC-, and KPC-producing
Enterobacteriaceae
when combined with the novel β-lactamase inhibitor NXL104. The purpose of this study was to evaluate the efficacy of a human-simulated regimen of ceftaroline plus NXL104 against
Enterobacteriaceae
in a murine thigh infection model.

IMPORTANCE
Twelve
Enterobacteriaceae
isolates were tested with neutropenic ICR mice. Seven of these isolates were also tested with immunocompetent mice. Doses were given to simulate human free-drug exposures of ceftaroline (600 mg) plus NXL104 (600 mg) every 8 h over 24 h by targeting the percentage of time that free drug concentrations remain above the MIC, ƒ
T
>MIC. The change in log
10
CFU/ml compared with 0 h controls was observed after 24 h. Human-simulated exposures were achieved against all isolates (MICs of ≤0.015 to 1 μg/ml) in both the neutropenic and the immunocompetent host models, which was equivalent to a ƒ
T
>MIC of 100%. A 0.5 to ≥2 log CFU reduction was observed in the neutropenic thigh infection model. Furthermore, significantly greater reductions in bacterial density were observed for five of seven isolates studied in an immunocompetent model than in the neutropenic-host model. Regardless of immune status, ceftaroline (600 mg) combined with NXL104 (600 mg) every 8 h provided predictable efficacy against ESBL-, non-ESBL-, and KPC-producing isolates with an MIC of ≤1 μg/ml and could be useful in combating the growing threat of resistant
Enterobacteriaceae
.
Use of the NP-40 Detergent-Mediated Assay in Discovery of Inhibitors of β-Hematin Crystallization
Authors: Sandlin Rebecca D. , Carter Melissa D. , Lee Patricia J. , Auschwitz Jennifer M. , Leed Susan E. , Johnson Jacob D. , Wright David W. 
Published: April 2011

ABSTRACT

The protozoan parasite responsible for malaria affects over 500 million people each year. Current antimalarials have experienced decreased efficacy due to the development of drug-resistant strains of
Plasmodium
spp., resulting in a critical need for the discovery of new antimalarials. Hemozoin, a crystalline by-product of heme detoxification that is necessary for parasite survival, serves as an important drug target. The quinoline antimalarials, including amodiaquine and chloroquine, act by inhibiting the formation of hemozoin. The formation of this crystal does not occur spontaneously, and recent evidence suggests crystallization occurs in the presence of neutral lipid particles located in the acidic digestive vacuole of the parasite. To mimic these conditions, the lipophilic detergent NP-40 has previously been shown to successfully mediate the formation of β-hematin, synthetic hemozoin. Here, an NP-40 detergent-based assay was successfully adapted for use as a high-throughput screen to identify inhibitors of β-hematin formation. The resulting assay exhibited a favorable
Z
′ of 0.82 and maximal drift of less than 4%. The assay was used in a pilot screen of 38,400 diverse compounds at a screening concentration of 19.3 μM, resulting in the identification of 161 previously unreported β-hematin inhibitors. Of these, 48 also exhibited ≥90% inhibition of parasitemia in a
Plasmodium falciparum
whole-cell assay at a screening concentration of 23 μM. Eight of these compounds were identified to have nanomolar 50% inhibitory concentration values near that of chloroquine in this assay.
Selective Membrane Disruption: Mode of Action of C16G2, a Specifically Targeted Antimicrobial Peptide
Authors: Kaplan Christopher W. , Sim Jee Hyun , Shah Kevin R. , Kolesnikova-Kaplan Aida , Shi Wenyuan , Eckert Randal 
Published: April 2011

ABSTRACT

The specifically targeted antimicrobial peptide (STAMP) C16G2 was developed to target the cariogenic oral pathogen
Streptococcus mutans
. Because the design of this peptide was novel, we sought to better understand the mechanism through which it functioned. Compared to antimicrobial peptides (AMPs) with wide spectra of activity, the STAMP C16G2 has demonstrated specificity for
S. mutans
in a mixed-culture environment, resulting in the complete killing of
S. mutans
while having minimal effect on the other streptococci. In the current study, we sought to further confirm the selectivity of C16G2 and also compare its membrane activity to that of melittin B, a classical toxic AMP, in order to determine the STAMP's mechanism of cell killing. Disruption of
S. mutans
cell membranes by C16G2 was demonstrated by increased SYTOX green uptake and ATP efflux from the cells similar to those of melittin B. Treatment with C16G2 also resulted in a loss of membrane potential as measured by DiSC(3)5 fluorescence. In comparison, the individual moieties of C16G2 demonstrated no specificity and limited antimicrobial activity compared to those of the STAMP C16G2. The data suggest that C16G2 has a mechanism of action similar to that of traditional AMPs and kills
S. mutans
through disruption of the cell membrane, allowing small molecules to leak out of the cell, which is followed by a loss of membrane potential and cell death. Interestingly, this membrane activity is rapid and potent against
S. mutans
, but not other noncariogenic oral streptococci.
Fungicidal Monoclonal Antibody C7 Interferes with Iron Acquisition in Candida albicans
Authors: Brena Sonia , Cabezas-Olcoz Jonathan , Moragues María D. , Fernández de Larrinoa Iñigo , Domínguez Angel , Quindós Guillermo , Pontón José 
Published: April 2011

ABSTRACT

We have developed a monoclonal antibody (MAb), C7, that reacts with the Als3p and enolase present in the
Candida albicans
cell wall and exerts three anti-
Candida
activities: candidacidal activity and inhibition of both adhesion and filamentation. To investigate the mode of action of MAb C7 on fungal viability, we examined changes in the genome-wide gene expression profile of
C. albicans
grown in the presence of a subinhibitory concentration of MAb C7 (12.5 μg/ml) by using microarrays. A total of 49 genes were found to be differentially expressed upon treatment with MAb C7. Of these, 28 were found to be upregulated and 21 were found to be downregulated. The categories of upregulated genes with the largest number of variations were those involved in iron uptake or related to iron homeostasis (42.86%), while the energy-related group accounted for 38.10% of the downregulated genes (8/21). Results were validated by real-time PCR. Since these effects resembled those found under iron-limited conditions, the activity of MAb C7 on
C. albicans
mutants with deletions in key genes implicated in the three iron acquisition systems described in this yeast was also assessed. Only mutants lacking the
TPK1
gene and, to a lesser extent, the
TPK2
gene were less sensitive to the candidacidal effect of MAb C7. FeCl
3
or hemin at concentrations of ≥7.8 μM reversed the candidacidal effect of MAb C7 on
C. albicans
in a concentration-dependent manner. The results presented in this study provide evidence that the candidacidal effect of MAb C7 is related to the blockage of the reductive iron uptake pathway of
C. albicans
.
Modest but Variable Effect of Rifampin on Steady-State Plasma Pharmacokinetics of Efavirenz in Healthy African-American and Caucasian Volunteers
Authors: Kwara Awewura , Tashima Karen T. , Dumond Julie B. , Poethke Pamela , Kurpewski Jaclyn , Kashuba Angela D. M. , Court Michael H. , Greenblatt David J. 
Published: April 2011

ABSTRACTEfavirenz-based antiretroviral regimen is preferred during rifampin-containing tuberculosis therapy. However, current pharmacokinetic data are insufficient to guide optimized concurrent dosing. This study aimed to better characterize the effects of rifampin on efavirenz pharmacokinetics. Subjects were randomized to receive 600 mg efavirenz/day or 600 mg efavirenz with 600 mg rifampin/day for 8 days, with plasma samples collected for pharmacokinetic analysis over 24 h on day 8. Treatments were then crossed over after at least a 2-week washout period, and procedures were repeated. Efavirenz concentrations were determined by high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were estimated by noncompartmental analysis. Efavirenz pharmacokinetic differences between treatment periods were evaluated by pairedttest. The coefficients of variation in efavirenz plasma AUC0-24(area under the concentration-time curve from 0 to 24 h) were 50% and 56% in the absence and presence of rifampin, respectively. Of the 11 evaluable subjects (6 white, 5 black; 6 women, 5 men), the geometric mean AUC0-24ratio on/off rifampin (90% confidence interval) was 0.82 (0.72, 0.92), with individual AUC0-24ratios varying from 0.55 to 1.18. Five subjects had a 24-hour efavirenz concentration (C24) of <1,000 ng/ml on rifampin. They were more likely to have received a lower dose in milligrams/kilogram of body weight and to have lower efavirenz AUC0-24values in the basal state. Although rifampin resulted in a modest reduction in efavirenz plasma exposure in subjects as a whole, there was high variability in responses between subjects, suggesting that efavirenz dose adjustment with rifampin may need to be individualized. Body weight and genetic factors will be important covariates in dosing algorithms.
Transcriptional Profiling of Azole-Resistant Candida parapsilosis Strains
Authors: Silva A. P. , Miranda I. M. , Guida A. , Synnott J. , Rocha R. , Silva R. , Amorim A. , Pina-Vaz C. , Butler G. , Rodrigues A. G. 
Published: April 2011

ABSTRACTHerein we describe the changes in the gene expression profile ofCandida parapsilosisassociated with the acquisition of experimentally induced resistance to azole antifungal drugs. Three resistant strains ofC. parapsilosiswere obtained following prolongedin vitroexposure of a susceptible clinical isolate to constant concentrations of fluconazole, voriconazole, or posaconazole. We found that after incubation with fluconazole or voriconazole, strains became resistant to both azoles but not to posaconazole, although susceptibility to this azole decreased, whereas the strain incubated with posaconazole displayed resistance to the three azoles. The resistant strains obtained after exposure to fluconazole and to voriconazole have increased expression of the transcription factorMRR1, the major facilitator transporterMDR1, and several reductases and oxidoreductases. Interestingly, and similarly to what has been described inC. albicans, upregulation ofMRR1andMDR1is correlated with point mutations inMRR1in the resistant strains. The resistant strain obtained after exposure to posaconazole shows upregulation of two transcription factors (UPC2andNDT80) and increased expression of 13 genes involved in ergosterol biosynthesis. This is the first study addressing global molecular mechanisms underlying azole resistance inC. parapsilosis; the results suggest that similarly toC. albicans, tolerance to azoles involves the activation of efflux pumps and/or increased ergosterol synthesis.
Efficacy of Caspofungin in a Juvenile Mouse Model of Central Nervous System Candidiasis
Authors: Flattery Amy M. , Hickey Emily , Gill Charles J. , Powles Mary Ann , Misura Andrew S. , Galgoci Andrew M. , Ellis Joan D. , Zhang Rena , Sandhu Punam , Ronan John , Abruzzo George K. 
Published: April 2011

ABSTRACTNeonatal candidiasis is an increasingly common occurrence causing significant morbidity and mortality and a higher risk of dissemination to the central nervous system (CNS) than that seen with older patients. The current understanding of optimal antifungal therapy in this setting is limited. We have developed a model of disseminated candidiasis with CNS involvement in juvenile mice to assess the efficacy of the echinocandin caspofungin relative to amphotericin B (AmB). Juvenile mice were inoculated intravenously with 5.64 × 104CFU ofCandida albicansMY1055. Treatment with caspofungin at 1, 2, 4, and 8 mg/kg of body weight/day, AmB at 1 mg/kg/day, or a vehicle control (VC) was initiated 30 h after infection and continued for 7 days. Pharmacokinetic parameters for caspofungin were also determined. Culture and histology showed evidence of disseminated candidiasis with multifocal encephalitis at the start of antifungal therapy. Survival was 100% in all treated groups, while mortality was 100% in the VC by day 11 after infection. By day 5, all mice in the caspofungin treatment (four doses) groups showed reductions in kidney and brain burden relative to the VC, while AmB treatment reduced kidney burden but gave no reduction of brain fungal burden. Systemic levels of caspofungin were similar in infected and uninfected mice, while brain levels were higher in infected animals. In this juvenile mouse model, caspofungin demonstrated dose-dependent activity, equivalent to or better than that of AmB at 1 mg/kg, against disseminated candidiasis with CNS involvement.
Pharmacokinetics of Intravenous and Oral Linezolid in Adults with Cystic Fibrosis
Authors: Keel Rebecca A. , Schaeftlein Andre , Kloft Charlotte , Pope J. Samuel , Knauft R. Frederic , Muhlebach Marianne , Nicolau David P. , Kuti Joseph L. 
Published: April 2011

ABSTRACT

Linezolid is a treatment option for methicillin-resistant
Staphylococcus aureus
(MRSA) infections in cystic fibrosis (CF) patients. Little is known, however, about its pharmacokinetics in this population. Eight adults with CF were randomized to receive intravenous (i.v.) and oral linezolid at 600 mg twice daily for 9 doses in a crossover design with a 9-day washout. Plasma samples were collected after the first and ninth doses of each phase. Population pharmacokinetic analyses were performed by nonlinear mixed-effects modeling using a previously described 2-compartment model with time-dependent clearance inhibition. Monte Carlo simulation was performed to assess the activities of the linezolid dosing regimens against 42 contemporary MRSA isolates recovered from CF patients. The following pharmacokinetic parameter estimates were observed for the population: absorption rate constant, 1.91 h
−1
; clearance, 9.54 liters/h; volume of central compartment, 26.8 liters; volume of peripheral compartment, 17.3 liters; and intercompartmental clearance, 104 liters/h. Linezolid demonstrated nonlinear clearance after 9 doses, which was reduced by a mean of 38.9% (range, 28.8 to 59.9%). Mean bioavailability was 85% (range, 47 to 131%). At steady state, 600 mg given twice daily produced 93.0% and 87.2% probabilities of obtaining the target pharmacodynamic exposure against the MRSA isolates for the i.v. and oral formulations, respectively. Thrice-daily dosing increased the probabilities to 97.0% and 95.6%, respectively. Linezolid pharmacokinetics in these adults with CF were well described by a 2-compartment model with time-dependent clearance inhibition. Standard i.v. and oral dosing regimens should be sufficient to reliably attain pharmacodynamic targets against most MRSA isolates; however, more frequent dosing may be required for isolates with MICs of ≥2 μg/ml.