bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of a Novel Genomic Island Conferring Resistance to Multiple Aminoglycoside Antibiotics in Campylobacter coli
Authors: Qin Shangshang , Wang Yang , Zhang Qijing , Chen Xia , Shen Zhangqi , Deng Fengru , Wu Congming , Shen Jianzhong 
Published: August 2012

ABSTRACT

Historically, the incidence of gentamicin resistance in
Campylobacter
has been very low, but recent studies reported a high prevalence of gentamicin-resistant
Campylobacter
isolated from food-producing animals in China. The reason for the high prevalence was unknown and was addressed in this study. PCR screening identified aminoglycoside resistance genes
aphA-3
and
aphA-7
and the
aadE–sat4–aphA-3
cluster among 41
Campylobacter
isolates from broiler chickens. Importantly, a novel genomic island carrying multiple aminoglycoside resistance genes was identified in 26 aminoglycoside resistant
Campylobacter coli
strains. Sequence analysis revealed that the genomic island was inserted between
cadF
and
COO1582
on the
C. coli
chromosome and consists of 14 open reading frames (ORFs), including 6 genes (the
aadE–sat4–aphA-3
cluster,
aacA-aphD
,
aac
, and
aadE
) encoding aminoglycoside-modifying enzymes. Analysis by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing indicated that the
C. coli
isolates carrying this unique genomic island were clonal, and the clone of PFGE subtype III and sequence type (ST) 1625 was particularly predominant among the
C. coli
isolates examined, suggesting that clonal expansion may be involved in dissemination of this resistance island. Additionally, we were able to transfer this genomic island from
C. coli
to a
Campylobacter jejuni
strain using natural transformation under laboratory conditions, and the transfer resulted in a drastic increase in aminoglycoside resistance in the recipient strain. These findings identify a previously undescribed genomic island that confers resistance to multiple aminoglycoside antibiotics. Since aminoglycoside antibiotics are used for treating occasional systemic infections caused by
Campylobacter
, the emergence and spread of this antibiotic resistance genomic island represent a potential concern for public health.
Population Pharmacokinetics of Conventional and Intermittent Dosing of Liposomal Amphotericin B in Adults: a First Critical Step for Rational Design of Innovative Regimens
Authors: Hope William W. , Goodwin Joanne , Felton Timothy W. , Ellis Michael , Stevens David A. 
Published: August 2012

ABSTRACT

There is increased interest in intermittent regimen of liposomal amphotericin B, which may facilitate use in ambulatory settings. Little is known, however, about the most appropriate dosage and schedule of administration. Plasma pharmacokinetic data were acquired from 30 patients receiving liposomal amphotericin B for empirical treatment of suspected invasive fungal infection. Two cohorts were studied. The first cohort received 3 mg of liposomal amphotericin B/kg of body weight/day; the second cohort received 10 mg of liposomal amphotericin B/kg at time zero, followed by 5 mg/kg at 48 and 120 h. The levels of liposomal amphotericin B were measured by high-pressure liquid chromatography (HPLC). The pharmacokinetics were estimated by using a population methodology. Monte Carlo simulations were performed. D-optimal design was used to identify maximally informative sampling times for both conventional and intermittent regimens for future studies. A three-compartment pharmacokinetic model best described the data. The pharmacokinetics for both conventional and intermittent dosing were linear. The estimates for the mean (standard deviation) for clearance and the volume of the central compartment were 1.60 (0.85) liter/h and 20.61 (15.27) liters, respectively. Monte Carlo simulations demonstrated considerable variability in drug exposure. Bayesian estimates for clearance and volume increased in a linear manner with weight, but only the former was statistically significant (
P
= 0.039). D-optimal design provided maximally informative sampling times for future pharmacokinetic studies. The pharmacokinetics of a conventional and an intermittently administered high-dose regimen liposomal amphotericin B are linear. Further pharmacokinetic-pharmacodynamic preclinical and clinical studies are required to identify safe and effective intermittent regimens.
Characterization of Hepatitis C Virus (HCV) Quasispecies Dynamics upon Short-Term Dual Therapy with the HCV NS5B Nucleoside Polymerase Inhibitor Mericitabine and the NS3/4 Protease Inhibitor Danoprevir
Authors: Le Pogam S. , Yan J. M. , Chhabra M. , Ilnicka M. , Kang H. , Kosaka A. , Ali S. , Chin D. J. , Shulman N. S. , Smith P. , Klumpp K. , Nájera I. 
Published: August 2012

ABSTRACT
In the INFORM-1 study, 73 patients with chronic hepatitis C virus infection received mericitabine plus danoprevir for up to 13 days. Seventy-two patients experienced a continuous decline in HCV RNA levels during treatment, and of these patients, 14 had viral loads that remained >1,000 IU/ml by day 13 and 1 met the definition for viral breakthrough. In-depth NS5B and NS3/4A population and clonal sequencing studies and mericitabine and danoprevir drug susceptibility testing were performed to assess the variability and quasispecies dynamics before and upon monotherapy or dual therapy. Sequence analysis of the viral quasispecies indicated that the mericitabine resistance mutation S282T was not present at baseline, nor was it selected (even at a low level) during treatment. Protease inhibitor resistance mutations, either as predominant or as minority species, were detected in 18 patients at baseline. No enrichment of minority protease inhibitor-resistant variants present at baseline was observed during treatment; viral population samples were fully susceptible to mericitabine and/or danoprevir, despite the presence within their quasispecies of minority variants confirmed to have reduced susceptibility to danoprevir or other protease inhibitors. It was also observed that certain NS3 amino acid substitutions affected protease inhibitor drug susceptibility in a compound-specific manner and varied with the genetic context. In summary, the slower kinetics of viral load decline observed in some patients was not due to the selection of danoprevir or mericitabine resistance during treatment. Over 2 weeks' therapy, mericitabine suppressed the selection of danoprevir resistance, results that could differ upon longer treatment periods.
Daptomycin-Nonsusceptible Vancomycin-Intermediate Staphylococcus aureus Vertebral Osteomyelitis Cases Complicated by Bacteremia Treated with High-Dose Daptomycin and Trimethoprim-Sulfamethoxazole
Authors: Avery Lisa M. , Steed Molly E. , Woodruff Ashley E. , Hasan Muhammad , Rybak Michael J. 
Published: August 2012

ABSTRACT

We report two cases of daptomycin (DAP)-nonsusceptible (DNS) vancomycin-intermediate
Staphylococcus aureus
(VISA) vertebral osteomyelitis cases complicated by bacteremia treated with high-dose daptomycin and trimethoprim-sulfamethoxazole. Both patients responded rapidly and favorably to this combination. The clinical isolates from the two patients were tested
post hoc
in an
in vitro
pharmacokinetic/pharmacodynamic (PK/PD) model to confirm the bactericidal activity and enhancement of daptomycin and trimethoprim-sulfamethoxazole. The combination of high-dose daptomycin and trimethoprim-sulfamethoxazole should be explored further for the treatment of DNS VISA strains.
Preclinical Profile and Characterization of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir (BMS-650032)
Authors: McPhee Fiona , Sheaffer Amy K. , Friborg Jacques , Hernandez Dennis , Falk Paul , Zhai Guangzhi , Levine Steven , Chaniewski Susan , Yu Fei , Barry Diana , Chen Chaoqun , Lee Min S. , Mosure Kathy , Sun Li-Qiang , Sinz Michael , Meanwell Nicholas A. , Colonno Richard J. , Knipe Jay , Scola Paul 
Published: August 2012

ABSTRACT

Asunaprevir (ASV; BMS-650032) is a hepatitis C virus (HCV) NS3 protease inhibitor that has demonstrated efficacy in patients chronically infected with HCV genotype 1 when combined with alfa interferon and/or the NS5A replication complex inhibitor daclatasvir. ASV competitively binds to the NS3/4A protease complex, with

K
i

values of 0.4 and 0.24 nM against recombinant enzymes representing genotypes 1a (H77) and 1b (J4L6S), respectively. Selectivity was demonstrated by the absence of any significant activity against the closely related GB virus-B NS3 protease and a panel of human serine or cysteine proteases. In cell culture, ASV inhibited replication of HCV replicons representing genotypes 1 and 4, with 50% effective concentrations (EC
50
s) ranging from 1 to 4 nM, and had weaker activity against genotypes 2 and 3 (EC
50
, 67 to 1,162 nM). Selectivity was again demonstrated by the absence of activity (EC
50
, >12 μM) against a panel of other RNA viruses. ASV exhibited additive or synergistic activity in combination studies with alfa interferon, ribavirin, and/or inhibitors specifically targeting NS5A or NS5B. Plasma and tissue exposures
in vivo
in several animal species indicated that ASV displayed a hepatotropic disposition (liver-to-plasma ratios ranging from 40- to 359-fold across species). Twenty-four hours postdose, liver exposures across all species tested were ≥110-fold above the inhibitor EC
50
s observed with HCV genotype-1 replicons. Based on these virologic and exposure properties, ASV holds promise for future utility in a combination with other anti-HCV agents in the treatment of HCV-infected patients.
Herb-Drug Interaction between Echinacea purpurea and Etravirine in HIV-Infected Patients
Authors: Moltó José , Valle Marta , Miranda Cristina , Cedeño Samandhy , Negredo Eugenia , Clotet Bonaventura 
Published: August 2012

ABSTRACT

The aim of this open-label, fixed-sequence study was to investigate the potential of the botanical supplement
Echinacea purpurea
to interact with etravirine, a nonnucleoside reverse transcriptase inhibitor of HIV. Fifteen HIV-infected patients receiving antiretroviral therapy with etravirine (400 mg once daily) for at least 4 weeks were included.
E. purpurea
root/extract-containing capsules were added to the antiretroviral treatment (500 mg every 8 h) for 14 days. Etravirine concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, 12, and 24 h after a morning dose of etravirine on day 0 and etravirine plus
E. purpurea
on day 14. Individual etravirine pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 by means of the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 46 years (interquartile range, 41 to 50), and the median body weight was 76 kg (interquartile range, 68 to 92). Echinacea was well tolerated, and all participants completed the study. The GMR for etravirine coadministered with
E. purpurea
relative to etravirine alone was 1.07 (90% CI, 0.81 to 1.42) for the maximum concentration, 1.04 (90% CI, 0.79 to 1.38) for the area under the concentration-time curve from 0 to 24 h, and 1.04 (90% CI, 0.74 to 1.44) for the concentration at the end of the dosing interval. In conclusion, the coadministration of
E. purpurea
with etravirine was safe and well tolerated in HIV-infected patients; our data suggest that no dose adjustment for etravirine is necessary.
Pyrazinamide May Improve Fluoroquinolone-Based Treatment of Multidrug-Resistant Tuberculosis
Authors: Chang Kwok-Chiu , Leung Chi-Chiu , Yew Wing-Wai , Leung Eric Chung-Ching , Leung Wai-Man , Tam Cheuk-Ming , Zhang Ying 
Published: August 2012

ABSTRACT
The role of pyrazinamide in the current treatment of multidrug-resistant (MDR) tuberculosis (TB) is uncertain. From a territory-wide registry of MDR-TB cases diagnosed between 1995 and 2009, we assembled a cohort of 194 patients with MDR pulmonary TB given fluoroquinolone-containing regimens. Stratified by pyrazinamide use and susceptibility, there were 83 users with pyrazinamide-susceptible MDR-TB (subgroup A), 24 users with pyrazinamide-resistant MDR-TB (subgroup B), 40 nonusers with pyrazinamide-susceptible MDR-TB (subgroup C), and 47 nonusers with pyrazinamide-resistant MDR-TB (subgroup D). We estimated the adjusted risk ratio (ARR) of early sputum culture conversion (ARR-culture) that occurred within 90 days posttreatment and that of cure or treatment completion (ARR-success) that occurred by 2 years posttreatment due to pyrazinamide use with susceptibility. In comparison with subgroup B, ARR-culture and ARR-success were 1.38 (95% confidence interval [CI], 0.89 to 2.12) and 1.38 (95% confidence interval [CI], 0.88 to 2.17), respectively. Corresponding findings were 0.99 (95% CI, 0.81 to 1.22) and 0.99 (95% CI, 0.78 to 1.26) in comparison with subgroup C and 1.09 (95% CI, 0.84 to 1.42) and 0.94 (95% CI, 0.74 to 1.20) in comparison with subgroup D. Early culture conversion significantly increased the incidence proportion of cure or treatment completion by 71% (95% CI, 26% to 133%). Selection bias among pyrazinamide nonusers might have underestimated the role of pyrazinamide. Comparison of pyrazinamide users showed that pyrazinamide increased the incidence proportion of early culture conversion and that of cure or treatment completion by a best estimate of 38% for both. This magnitude of change exceeded the 15 to 20% increase in the 2-month culture conversion rate of drug-susceptible TB that results from adding pyrazinamide to isoniazid and rifampin. Pyrazinamide is likely important in fluoroquinolone-based treatment of MDR-TB.
Mutation in the Plasmodium falciparum CRT Protein Determines the Stereospecific Activity of Antimalarial Cinchona Alkaloids
Authors: Griffin Carol E. , Hoke Jonathan M. , Samarakoon Upeka , Duan Junhui , Mu Jianbing , Ferdig Michael T. , Warhurst David C. , Cooper Roland A. 
Published: August 2012

ABSTRACT

The
Cinchona
alkaloids are quinoline aminoalcohols that occur as diastereomer pairs, typified by (−)-quinine and (+)-quinidine. The potency of (+)-isomers is greater than the (−)-isomers
in vitro
and
in vivo
against
Plasmodium falciparum
malaria parasites. They may act by the inhibition of heme crystallization within the parasite digestive vacuole in a manner similar to chloroquine. Earlier studies showed that a K76I mutation in the digestive vacuole-associated protein, PfCRT (
P. falciparum
chloroquine resistance transporter), reversed the normal potency order of quinine and quinidine toward
P. falciparum
. To further explore PfCRT-alkaloid interactions in the malaria parasite, we measured the
in vitro
susceptibility of eight clonal lines of
P. falciparum
derived from the 106/1 strain, each containing a unique
pfcrt
allele, to four
Cinchona
stereoisomer pairs: quinine and quinidine; cinchonidine and cinchonine; hydroquinine and hydroquinidine; 9-epiquinine and 9-epiquinidine. Stereospecific potency of the
Cinchona
alkaloids was associated with changes in charge and hydrophobicity of mutable PfCRT amino acids. In isogenic chloroquine-resistant lines, the IC
50
ratio of (−)/(+) CA pairs correlated with side chain hydrophobicity of the position 76 residue. Second-site PfCRT mutations negated the K76I stereospecific effects: charge-change mutations C72R or Q352K/R restored potency patterns similar to the parent K76 line, while V369F increased susceptibility to the alkaloids and nullified stereospecific differences between alkaloid pairs. Interactions between key residues of the PfCRT channel/transporter with (−) and (+) alkaloids are stereospecifically determined, suggesting that PfCRT binding plays an important role in the antimalarial activity of quinine and other
Cinchona
alkaloids.
Reproductive outcomes following induced abortion: a national register-based cohort study in Scotland
Authors: Bhattacharya Siladitya , Lowit Alison , Bhattacharya Sohinee , Raja Edwin Amalraj , Lee Amanda Jane , Mahmood Tahir , Templeton Allan 
Published: August 2012

ObjectiveTo investigate reproductive outcomes in women following induced abortion (IA).DesignRetrospective cohort study.SettingHospital admissions between 1981 and 2007 in Scotland.ParticipantsData were extracted on all women who had an IA, a miscarriage or a live birth from the Scottish Morbidity Records. A total of 120 033, 457 477 and 47 355 women with a documented second pregnancy following an IA, live birth and miscarriage, respectively, were identified.OutcomesObstetric and perinatal outcomes, especially preterm delivery in a second ongoing pregnancy following an IA, were compared with those in primigravidae, as well as those who had a miscarriage or live birth in their first pregnancy. Outcomes after surgical and medical termination as well as after one or more consecutive IAs were compared.ResultsIA in a first pregnancy increased the risk of spontaneous preterm birth compared with that in primigravidae (adjusted RR (adj. RR) 1.37, 95% CI 1.32 to 1.42) or women with an initial live birth (adj. RR 1.66, 95% CI 1.58 to 1.74) but not in comparison with women with a previous miscarriage (adj. RR 0.85, 95% CI 0.79 to 0.91). Surgical abortion increased the risk of spontaneous preterm birth compared with medical abortion (adj. RR 1.25, 95% CI 1.07 to 1.45). The adjusted RRs (95% CI) for spontaneous preterm delivery following two, three and four consecutive IAs were 0.94 (0.81 to 1.10), 1.06 (0.76 to 1.47) and 0.92 (0.53 to 1.61), respectively.ConclusionsThe risk of preterm birth after IA is lower than that after miscarriage but higher than that in a first pregnancy or after a previous live birth. This risk is not increased further in women who undergo two or more consecutive IAs. Surgical abortion appears to be associated with an increased risk of spontaneous preterm birth in comparison with medical termination of pregnancy. Medical termination was not associated with an increased risk of preterm delivery compared to primigravidae.
Poor uptake of primary healthcare registration among recent entrants to the UK: a retrospective cohort study
Authors: Stagg Helen R , Jones Jane , Bickler Graham , Abubakar Ibrahim 
Published: August 2012

ObjectivesUptake of healthcare among migrants is a complex and controversial topic; there are multiple recognised barriers to accessing primary care. Delays in presentation to healthcare services may result in a greater burden on costly emergency care, as well as increased public health risks. This study aimed to explore some of the factors influencing registration of new entrants with general practitioners (GPs).DesignRetrospective cohort study.SettingPort health screening at Heathrow and Gatwick airports, primary care.Participants252 559 new entrants to the UK, whose entry was documented by the port health tuberculosis screening processes at Heathrow and Gatwick. 191 had insufficient information for record linkage.Primary outcome measureRegistration with a GP practice within the UK, as measured through record linkage with the Personal Demographics Service (PDS) database.ResultsOnly 32.5% of 252 368 individuals were linked to the PDS, suggesting low levels of registration in the study population. Women were more likely to register than men, with a RR ratio of 1.44 (95% CI 1.41 to 1.46). Compared with those from Europe, individuals of nationalities from the Americas (0.43 (0.39 to 0.47)) and Africa (0.74 (0.69 to 0.79)) were less likely to register. Similarly, students (0.83 (0.81 to 0.85)), long-stay visitors (0.82 (0.77 to 0.87)) and asylum seekers (0.46 (0.42 to 0.51)) were less likely to register with a GP than other migrant groups.ConclusionsLevels of registration with GPs within this selected group of new entrants, as measured through record linkage, are low. Migrant groups with the lowest proportion registered are likely to be those with the highest health needs. The UK would benefit from a targeted approach to identify the migrants least likely to register for healthcare and to promote access among both users and service providers.
Frequent PVT1 Rearrangement and Novel Chimeric Genes PVT1-NBEA and PVT1-WWOX Occur in Multiple Myeloma with 8q24 Abnormality
Authors: Nagoshi Hisao , Taki Tomohiko , Hanamura Ichiro , Nitta Masakazu , Otsuki Takemi , Nishida Kazuhiro , Okuda Keiko , Sakamoto Natsumi , Kobayashi Satoru , Yamamoto-Sugitani Mio , Tsutsumi Yasuhiko , Kobayashi Tsutomu , Matsumoto Yosuke , Horiike Shigeo , Kuroda Junya , Taniwaki Masafumi 
Published: August 2012

Abstract
Chromosome 8q24 rearrangements are occasionally found in multiple myeloma and are associated with tumor progression. The 8q24 rearrangements were detected by FISH in 12 of 54 patients with multiple myeloma (22.2%) and in 8 of 11 multiple myeloma cell lines (72.7%). The breakpoints of 8q24 in 10 patients with multiple myeloma and in all multiple myeloma cell lines were assigned to a 360 kb segment, which was divided into 4 regions: approximately 120 kb centromeric to MYC (5′ side of MYC), the region centromerically adjacent to PVT1 (∼ 170 kb region, including MYC, of 5′ side of PVT1), the PVT1 region, and the telomeric region to PVT1. PVT1 rearrangements were most common and found in 7 of 12 patients (58.3%) and 5 of 8 cell lines (62.5%) with 8q24 abnormalities. A combination of spectral karyotyping (SKY), FISH, and oligonucleotide array identified several partner loci of PVT1 rearrangements, such as 4p16, 4q13, 13q13, 14q32, and 16q23-24. Two novel chimeric genes were identified: PVT1-NBEA in the AMU-MM1 cell line harboring t(8;13)(q24;q13) and PVT1-WWOX in RPMI8226 cell line harboring der(16)t(16;22)ins(16;8)(q23;q24). The PVT1-NBEA chimera in which PVT1 exon 1 was fused to NBEA exon 2 and the PVT1-WWOX in which PVT1 exon 1 was fused to WWOX exon 9 were associated with the expression of abnormal NBEA and WWOX lacking their N-terminus, respectively. These findings suggest that PVT1 rearrangements may represent a novel molecular paradigm underlying the pathology of 8q24 rearrangement–positive multiple myeloma. Cancer Res; 72(19); 4954–62. ©2012 AACR.
Intravesical Delivery of Small Activating RNA Formulated into Lipid Nanoparticles Inhibits Orthotopic Bladder Tumor Growth
Authors: Kang Moo Rim , Yang Glen , Place Robert F. , Charisse Klaus , Epstein-Barash Hila , Manoharan Muthiah , Li Long-Cheng 
Published: August 2012

Abstract
Practical methods for enhancing protein production in vivo remain a challenge. RNA activation (RNAa) is emerging as one potential solution by using double-stranded RNA (dsRNA) to increase endogenous gene expression. This approach, although related to RNA interference (RNAi), facilitates a response opposite to gene silencing. Duplex dsP21-322 and its chemically modified variants are examples of RNAa-based drugs that inhibit cancer cell growth by inducing expression of tumor suppressor p21WAF1/CIP1 (p21). In this study, we investigate the therapeutic potential of dsP21-322 in an orthotopic model of bladder cancer by formulating a 2′-fluoro-modified derivative (dsP21-322-2′F) into lipid nanoparticles (LNP) for intravesical delivery. LNP composition is based upon clinically relevant formulations used in RNAi-based therapies consisting of PEG-stabilized unilamellar liposomes built with lipid DLin-KC2-DMA. We confirm p21 induction, cell-cycle arrest, and apoptosis in vitro following treatment with LNP-formulated dsP21-322-2′F (LNP-dsP21-322-2′F) or one of its nonformulated variants. Both 2′-fluoro modification and LNP formulation also improve duplex stability in urine. Intravesical delivery of LNP-dsP21-322-2′F into mouse bladder results in urothelium uptake and extends survival of mice with established orthotopic human bladder cancer. LNP-dsP21-322-2′F treatment also facilitates p21 activation in vivo leading to regression/disappearance of tumors in 40% of the treated mice. Our results provide preclinical proof-of-concept for a novel method to treat bladder cancer by intravesical administration of LNP-formulated RNA duplexes. Cancer Res; 72(19); 5069–79. ©2012 AACR.