bluuebunny/crossref_metadata_2025_split huggingface dataset:
Collimator design for experimental minibeam radiation therapy
Authors: Babcock Kerry , Sidhu Narinder , Kundapur Vijayananda , Ali Kaiser 
Published: March 2011

Purpose:To design and optimize a minibeam collimator for minibeam radiation therapy studies using a 250 kVp x‐ray machine as a simulated synchrotron source.Methods:A Philips RT250 orthovoltage x‐ray machine was modeled using the EGSnrc/BEAMnrc Monte Carlo software. The resulting machine model was coupled to a model of a minibeam collimator with a beam aperture of 1 mm. Interaperture spacing and collimator thickness were varied to produce a minibeam with the desired peak‐to‐valley ratio.Results:Proper design of a minibeam collimator with Monte Carlo methods requires detailed knowledge of the x‐ray source setup. For a cathode‐ray tube source, the beam spot size, target angle, and source shielding all determine the final valley‐to‐peak dose ratio.Conclusions:A minibeam collimator setup was created, which can deliver a 30 Gy peak dose minibeam radiation therapy treatment at depths less than 1 cm with a valley‐to‐peak dose ratio on the order of 23%.
Dosimetric validation of Acuros® XB with Monte Carlo methods for photon dose calculations
Authors: Bush K. , Gagne I. M. , Zavgorodni S. , Ansbacher W. , Beckham W. 
Published: March 2011

Purpose:The dosimetric accuracy of the recently released Acuros® XB advanced dose calculation algorithm (Varian Medical Systems, Palo Alto, CA) is investigated for single radiation fields incident on homogeneous and heterogeneous geometries, and a comparison is made to the analytical anisotropic algorithm (AAA).Methods:Ion chamber measurements for the 6 and 18 MV beams within a range of field sizes (from to ) are used to validate Acuros® XB dose calculations within a unit density phantom. The dosimetric accuracy of Acuros® XB in the presence of lung, low‐density lung, air, and bone is determined using BEAMnrc/DOSXYZnrc calculations as a benchmark. Calculations using the AAA are included for reference to a current superposition/convolution standard.Results:Basic open field tests in a homogeneous phantom reveal an Acuros® XB agreement with measurement to within ±1.9% in the inner field region for all field sizes and energies. Calculations on a heterogeneous interface phantom were found to agree with Monte Carlo calculations to within ±2.0% in lung and within ±2.9% in low‐density lung . In comparison, differences of up to 10.2% and 17.5% in lung and low‐density lung were observed in the equivalent AAA calculations. Acuros® XB dose calculations performed on a phantom containing an air cavity were found to be within the range of ±1.5% to ±4.5% of the BEAMnrc/DOSXYZnrc calculated benchmark in the tissue above and below the air cavity. A comparison of Acuros® XB dose calculations performed on a lung CT dataset with a BEAMnrc/DOSXYZnrc benchmark shows agreement within ±2%/2mm and indicates that the remaining differences are primarily a result of differences in physical material assignments within a CT dataset.Conclusions:By considering the fundamental particle interactions in matter based on theoretical interaction cross sections, the Acuros® XB algorithm is capable of modeling radiotherapy dose deposition with accuracy only previously achievable with Monte Carlo techniques.
Inhibition of Hepatitis C Virus Replicon RNA Synthesis by PSI-352938, a Cyclic Phosphate Prodrug of β-d-2′-Deoxy-2′-α-Fluoro-2′-β-C-Methylguanosine
Authors: Lam Angela M. , Espiritu Christine , Murakami Eisuke , Zennou Veronique , Bansal Shalini , Micolochick Steuer Holly M. , Niu Congrong , Keilman Meg , Bao Haiying , Bourne Nigel , Veselenak Ronald L. , Reddy P. Ganapati , Chang Wonsuk , Du Jinfa , Nagarathnam Dhanapalan , Sofia Michael J. , Otto Michael J. , Furman Phillip A. 
Published: March 2011

ABSTRACTPSI-352938 is a novel cyclic phosphate prodrug of β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methylguanosine 5′-monophosphate that has potent activity against hepatitis C virus (HCV)in vitro. The studies described here characterize thein vitroanti-HCV activity of PSI-352938, alone and in combination with other inhibitors of HCV, and the cross-resistance profile of PSI-352938. The effective concentration required to achieve 50% inhibition for PSI-352938, determined using genotype 1a-, 1b-, and 2a-derived replicons stably expressed in the Lunet cell line, were 0.20, 0.13, and 0.14 μM, respectively. The active 5′-triphosphate metabolite, PSI-352666, inhibited recombinant NS5B polymerase from genotypes 1 to 4 with comparable 50% inhibitory concentrations. In contrast, PSI-352938 did not inhibit the replication of hepatitis B virus or human immunodeficiency virusin vitro. PSI-352666 did not significantly affect the activity of human DNA and RNA polymerases. PSI-352938 and its cyclic phosphate metabolites did not affect the cyclic GMP-mediated activation of protein kinase G. Clearance studies using replicon cells demonstrated that PSI-352938 cleared cells of HCV replicon RNA and prevented replicon rebound. An additive to synergistic effect was observed when PSI-352938 was combined with other classes of HCV inhibitors, including alpha interferon, ribavirin, NS3/4A inhibitors, an NS5A inhibitor, and nucleoside/nucleotide and nonnucleoside inhibitors. Cross-resistance studies showed that PSI-352938 remained fully active against replicons containing the S282T or the S96T/N142T amino acid alteration. Replicons that contain mutations conferring resistance to various classes of nonnucleoside inhibitors also remained sensitive to inhibition by PSI-352938. PSI-352938 is currently being evaluated in a phase I clinical study in genotype 1-infected individuals.
The Kinetic Effects on Thymidine Kinase 2 by Enzyme-Bound dTTP May Explain the Mitochondrial Side Effects of Antiviral Thymidine Analogs
Authors: Wang Liya , Sun Ren , Eriksson Staffan 
Published: March 2011

ABSTRACT
Mitochondrial thymidine kinase 2 (TK2) is a key enzyme in the salvage of pyrimidine deoxynucleosides needed for mitochondrial DNA synthesis. TK2 phosphorylates thymidine (dThd), deoxycytidine (dCyd), and many other antiviral pyrimidine nucleoside analogs. Zidovudine (AZT) is the first nucleoside analog approved for anti-HIV therapy, and it is still used in combination with other drugs. One of the side effects of long-term treatment with nucleoside analogs is mitochondrial DNA depletion, which has been ascribed to competition by AZT for the endogenous dThd phosphorylation carried out by TK2. Here we studied the kinetics of AZT and 3′-fluorothymidine phosphorylation by recombinant human TK2 and the effects of these and other pyrimidine nucleoside analogs on the phosphorylation of dThd and dCyd. Thymidine analogs strongly inhibited dThd phosphorylation but not dCyd phosphorylation, which instead was stimulated ∼30%. We found that recombinant human TK2 contained the feedback inhibitor dTTP in a 1:1 molar ratio and that incubation with dThd and AZT could completely remove the enzyme-bound dTTP, but dCyd was less efficient in this regard. The release of feedback inhibitor by dThd and dThd analogs most likely accounts for the observed kinetics. Similar effects were also observed with native rat liver mitochondrial TK2, strongly indicating a physiologic role for this process, which most likely is an important factor in the mitochondrial toxicity observed with antiviral nucleoside analogs.
Novel Inhibitors of the Pseudomonas aeruginosa Virulence Factor LasB: a Potential Therapeutic Approach for the Attenuation of Virulence Mechanisms in Pseudomonal Infection
Authors: Cathcart George R. A. , Quinn Derek , Greer Brett , Harriott Pat , Lynas John F. , Gilmore Brendan F. , Walker Brian 
Published: March 2011

ABSTRACTPseudomonas elastase (LasB), a metalloprotease virulence factor, is known to play a pivotal role in pseudomonal infection. LasB is secreted at the site of infection, where it exerts a proteolytic action that spans from broad tissue destruction to subtle action on components of the host immune system. The former enhances invasiveness by liberating nutrients for continued growth, while the latter exerts an immunomodulatory effect, manipulating the normal immune response. In addition to the extracellular effects of secreted LasB, it also acts within the bacterial cell to trigger the intracellular pathway that initiates growth as a bacterial biofilm. The key role of LasB in pseudomonal virulence makes it a potential target for the development of an inhibitor as an antimicrobial agent. The concept of inhibition of virulence is a recently established antimicrobial strategy, and such agents have been termed “second-generation” antibiotics. This approach holds promise in that it seeks to attenuate virulence processes without bactericidal action and, hence, without selection pressure for the emergence of resistant strains. A potent inhibitor of LasB,N-mercaptoacetyl-Phe-Tyr-amide (Ki= 41 nM) has been developed, and its ability to block these virulence processes has been assessed. It has been demonstrated that thes compound can completely block the action of LasB on protein targets that are instrumental in biofilm formation and immunomodulation. The novel LasB inhibitor has also been employed in bacterial-cell-based assays, to reduce the growth of pseudomonal biofilms, and to eradicate biofilm completely when used in combination with conventional antibiotics.
Prospective, Open-Label Investigation of the Pharmacokinetics of Daptomycin during Cardiopulmonary Bypass Surgery
Authors: Nguyen Megan H. , Eells Samantha J. , Tan Jennifer , Sheth Corinne T. , Omari Bassam , Flores Margarita , Wang Jeffrey , Miller Loren G. 
Published: March 2011

ABSTRACT

As methicillin-resistant
Staphylococcus aureus
(MRSA) becomes more prevalent, vancomycin is becoming increasingly used as a prophylaxis against surgical-site infections for cardiothoracic surgeries. However, vancomycin administration can be challenging, and the pharmacokinetics of alternative antibiotics in this setting are poorly understood. The primary objective of this investigation was to describe the pharmacokinetics of daptomycin in patients undergoing coronary artery bypass graft surgery. We enrolled 15 patients undergoing coronary artery bypass surgery requiring cardiopulmonary bypass. Each subject was administered a single open-label dose of daptomycin (8 mg/kg of body weight) for surgical prophylaxis. Fourteen daptomycin plasma samples were collected. Safety outcomes between subjects who received daptomycin and 15 control subjects who received the standard-of-care antibiotic were compared. The mean maximal concentration of daptomycin (
C
max
) was 84.4 ± 27.1 μg/ml; the mean daptomycin concentration during the cardiopulmonary bypass procedure was 33.2 ± 11.4 μg/ml and was 30.9 ± 12.7 μg/ml at sternum closure. Mean daptomycin concentrations at 12, 18, 24, and 48 h were 22.7 ± 9.7, 16.2 ± 8.2, 12.0 ± 4.7, and 3.5 ± 2.3 μg/ml, respectively. Mean daptomycin concentrations were consistently above the MIC at which 90% of the tested isolates are inhibited (MIC
90
) for
S. aureus
and
S. epidermidis
during the cardiopulmonary bypass procedure. Daptomycin was not associated with surgical-site infections or differences in adverse events compared to findings for control subjects. We found that a single dose of daptomycin at 8 mg/kg was well tolerated and achieved adequate plasma concentrations against common pathogens associated with surgical-site infections after cardiothoracic surgery. Daptomycin may be considered an alternative surgical prophylaxis antibiotic for patients undergoing cardiothoracic bypass surgery who are unable to receive vancomycin.
Polyphasic Identification and Susceptibility to Seven Antifungals of 102 Aspergillus Isolates Recovered from Immunocompromised Hosts in Greece
Authors: Arabatzis Michael , Kambouris Manousos , Kyprianou Miltiades , Chrysaki Aikaterini , Foustoukou Maria , Kanellopoulou Maria , Kondyli Lydia , Kouppari Georgia , Koutsia-Karouzou Chrysa , Lebessi Evangelia , Pangalis Anastasia , Petinaki Efthimia , Stathi Ageliki , Trikka-Graphakos Eleftheria , Vartzioti Erriketi , Vogiatzi Aliki , Vyzantiadis Timoleon-Achilleas , Zerva Loukia , Velegraki Aristea 
Published: March 2011

ABSTRACT

In this study, the first such study in Greece, we used polyphasic identification combined with antifungal susceptibility study to analyze
Aspergillus
clinical isolates comprising 102 common and rare members of sections Fumigati, Flavi, Terrei, Nidulantes, Nigri, Circumdati, Versicolores, and Usti. High amphotericin B MICs (>2 μg/ml) were found for 17.6% of strains. Itraconazole, posaconazole, and voriconazole MICs of >4 μg/ml were shown in 1%, 5%, and 0% of the isolates, respectively. Anidulafungin, micafungin, and caspofungin minimum effective concentrations (MECs) of ≥2 μg/ml were correspondingly recorded for 4%, 9%, and 33%, respectively, of the strains.
Emergence of Escherichia coli Sequence Type ST131 Carrying both the
bla
GES-5
and
bla
CTX-M-15
Genes
Authors: Kim Juwon , Hong Seong Geun , Bae Il Kwon , Kang Ji Roung , Jeong Seok Hoon , Lee Wookeun , Lee Kyungwon 
Published: March 2011

ABSTRACT

Escherichia coli
clinical isolate BD07372 of sequence type ST131 recovered from a bed sore specimen exhibited high-level resistance to ceftazidime and cefotaxime but exhibited susceptibility to imipenem and meropenem. The isolate harbored two β-lactamase genes, the
bla
CTX-M-15
gene carried by an ∼250-kbp plasmid carrying the FIA and FIC replicons and the
bla
GES-5
gene carried by a class 1 integron in the chromosome.
Induction of Antimalaria Immunity by Pyrimethamine Prophylaxis during Exposure to Sporozoites Is Curtailed by Parasite Resistance
Authors: Friesen Johannes , Borrmann Steffen , Matuschewski Kai 
Published: March 2011

ABSTRACT

Each year, infections with the protozoan parasite
Plasmodium falciparum
kill 1 million people, mostly children in Africa. Intermittent preventive treatment (IPT) with sulfadoxine-pyrimethamine (SP) reduces the incidence of malaria and aims to prevent mortality in infants, children, and pregnant women. There is contradictory evidence as to whether this strategy may generate additional protection against reinfection beyond the limited duration of the intervention. Previous work established that ablation of either liver-stage maturation or subsequent life cycle conversion by causal prophylactic drugs elicits protective immune responses against reinfections when drugs are no longer present. Here we show in the rodent malaria model that pyrimethamine, a component of SP, inhibits liver-stage development
in vitro
and
in vivo
, confirming the causal prophylactic activity of pyrimethamine. Repeated exposure to high doses of
Plasmodium berghei
sporozoites during pyrimethamine prophylaxis induced complete protection in C57BL/6 mice against challenge with high doses of sporozoites delivered intravenously 35 to 199 days later. Immunizations by infectious mosquito bites induced limited, inoculation-dependent protection against subsequent challenge by infected mosquito bites but provided partial protection against experimental cerebral malaria. Short-term pyrimethamine prophylaxis during intravenous transmission of sporozoites from a pyrimethamine-resistant strain delayed, but did not prevent, blood-stage infection. Our data provide a rationale for the notion of sustained protective efficacy of IPT based on the capacity of arrested, drug-sensitive liver-stage and/or suppressed blood-stage parasites to mount lasting protection.
Characteristics of NDM-1-Producing Escherichia coli Isolates That Belong to the Successful and Virulent Clone ST131
Authors: Peirano Gisele , Schreckenberger Paul C. , Pitout Johann D. D. 
Published: March 2011

ABSTRACT

An NDM-1 carbapenemase-producing
Escherichia coli
isolate of sequence type 131 (ST131) that belonged to phylogenetic group B2 was obtained from a patient with a urinary tract infection who returned to the United States after a recent hospitalization while visiting India. NDM-1-producing
E. coli
ST131 had significantly more virulence factors than NDM-1-producing
E. coli
ST101, previously isolated from a patient in Canada. The presence of NDM β-lactamases in a very successful and virulent
E. coli
sequence type is of concern.
Inhibitory Effect of a Triterpenoid Compound, with or without Alpha Interferon, on Hepatitis C Virus Infection
Authors: Watanabe Takako , Sakamoto Naoya , Nakagawa Mina , Kakinuma Sei , Itsui Yasuhiro , Nishimura-Sakurai Yuki , Ueyama Mayumi , Funaoka Yusuke , Kitazume Akiko , Nitta Sayuri , Kiyohashi Kei , Murakawa Miyako , Azuma Seishin , Tsuchiya Kiichiro , Oooka Shinya , Watanabe Mamoru 
Published: March 2011

ABSTRACT
A lack of patient response to alpha interferon (α-IFN) plus ribavirin (RBV) treatment is a major problem in eliminating hepatitis C virus (HCV). We screened chemical libraries for compounds that enhanced cellular responses to α-IFN and identified a triterpenoid, toosendanin (TSN). Here, we studied the effects and mechanisms of action of TSN on HCV replication and its effect on α-IFN signaling. We treated HCV genotype 1b replicon-expressing cells and HCV-J6/JFH-infected cells with TSN, with or without α-IFN, and the level of HCV replication was quantified. To study the effects of TSN on α-IFN signaling, we detected components of the interferon-stimulated gene factor 3 (ISGF3), phosphorylated signal transducer and activator of transcription 1 (STAT1), and STAT2 by Western blotting analysis; expression levels of mRNA of interferon regulatory factor 9 using real-time reverse transcription-PCR (RT-PCR); and interferon-stimulated response element reporter activity and measured the expression levels of interferon-inducible genes for 2′,5′-oligoadenylate synthetase, MxA, protein kinase R, and p56 using real-time RT-PCR. TSN alone specifically inhibited expression of the HCV replicon (50% effective concentration = 20.6 nM, 50% cytotoxic concentration > 3 μM, selectivity index > 146). Pretreatment with TSN prior to α-IFN treatment was more effective in suppressing HCV replication than treatment with either drug alone. Although TSN alone did not activate the α-IFN pathway, it significantly enhanced the α-IFN-induced increase of phosphorylated STATs, interferon-stimulated response element activation, and interferon-stimulated gene expression. TSN significantly increased baseline expression of interferon regulatory factor 9, a component of interferon-stimulated gene factor 3. Antiviral effects of treatment with α-IFN can be enhanced by pretreatment with TSN. Its mechanisms of action could potentially be important to identify novel molecular targets to treat HCV infection.
Mutations in
gidB
Confer Low-Level Streptomycin Resistance in Mycobacterium tuberculosis
Authors: Wong Sharon Y. , Lee Jong Seok , Kwak Hyun Kyung , Via Laura E. , Boshoff Helena I. M. , Barry Clifton E. 
Published: March 2011

ABSTRACT

The global threat posed by drug-resistant strains of
Mycobacterium tuberculosis
demands a greater understanding of the genetic basis and molecular mechanisms that govern how such strains develop resistance against various antituberculous drugs. In this report, we examine a new genetic basis for resistance to one of the oldest and most widely used second-line drugs employed in tuberculosis therapy, streptomycin (SM). This marker for SM resistance was first discovered on the basis of genomic data obtained from drug-resistant
M. tuberculosis
strains collected in Japan, wherein an association was observed between SM resistance and a mutation in
gidB
, a putative 16S rRNA methyltransferase. By evaluating an isogenic Δ
gidB
mutant strain constructed from strain H37Rv, we demonstrate the causal role of
gidB
in conferring a low-level SM-resistant phenotype in
M. tuberculosis
with a 16-fold increase in the MIC over the parent strain. Among clinical isolates, the modest increase in SM resistance conferred by a
gidB
mutation leads to an MIC distribution of
gidB
mutation-containing strains that spans the recommended SM breakpoint concentration currently used in drug susceptibility testing protocols. As such, some
gidB
mutation-containing isolates are found to be SM sensitive, while others are SM resistant. On the basis of a pharmacodynamic analysis and Monte Carlo simulation, those isolates that are found to be SM sensitive should still respond favorably to SM treatment, while nearly half of those found to be SM resistant will likely respond poorly. This report provides the first microbiological evidence for the contribution of
gidB
in streptomycin resistance and examines the clinical implications of mutations in the
gidB
gene.
Transitions to palliative care in acute hospitals in England: qualitative study: Table 1
Authors: Gott Merryn , Ingleton Christine , Bennett Michael I , Gardiner Clare 
Published: March 2011

ObjectiveTo explore how transitions to a palliative care approach are perceived to be managed in acute hospital settings in England.DesignQualitative study.SettingSecondary or primary care settings in two contrasting areas of England.Participants58 health professionals involved in the provision of palliative care in secondary or primary care.ResultsParticipants identified that a structured transition to a palliative care approach of the type advocated in UK policy guidance is seldom evident in acute hospital settings. In particular they reported that prognosis is not routinely discussed with inpatients. Achieving consensus among the clinical team about transition to palliative care was seen as fundamental to the transition being effected; however, this was thought to be insufficiently achieved in practice. Secondary care professionals reported that discussions about adopting a palliative care approach to patient management were not often held with patients; primary care professionals confirmed that patients were often discharged from hospital with “false hope” of cure because this information had not been conveyed. Key barriers to ensuring a smooth transition to palliative care included the difficulty of “standing back” in an acute hospital situation, professional hierarchies that limited the ability of junior medical and nursing staff to input into decisions on care, and poor communication.ConclusionSignificant barriers to implementing a policy of structured transitions to palliative care in acute hospitals were identified by health professionals in both primary and secondary care. These need to be addressed if current UK policy on management of palliative care in acute hospitals is to be established.
T'ai chi for the treatment of osteoarthritis: a systematic review and meta-analysis
Authors: Kang Jung Won , Lee Myeong Soo , Posadzki Paul , Ernst Edzard 
Published: March 2011

ObjectivesTo summarise and critically evaluate the evidence from randomised clinical trials (RCTs) of t'ai chi as a treatment for patients with osteoarthritis (OA).DesignEleven databases were searched from their inception to July 2010. RCTs testing t'ai chi against any type of controls in human patients with OA localised in any joints that assessed any type of clinical outcome measures were considered. Two reviewers independently performed the selection of the studies, data abstraction and validations. The risk of bias was assessed using Cochrane criteria.ResultsNine RCTs met the inclusion criteria, and most of them had significant methodological weaknesses. Six RCTs tested the effects of t'ai chi compared with that of an attention-control programme, a waiting list and routine care or self-help programmes in patients with OA in the knee. The meta-analysis suggested that t'ai chi has favourable effects on pain (n=256; standard mean difference (SMD), −0.79; 95% CI −1.19 to −0.39; p=0.0001; I2=55%), physical function (n=256; SMD, −0.86; 95% CI −1.20 to −0.52; p<0.00001; I2=38%) and joint stiffness (n=256; SMD, −0.53; 95% CI −0.99 to −0.08; p=0.02; I2=67%).ConclusionThe results are encouraging and suggest that t'ai chi may be effective in controlling pain and improving physical function in patients with OA in the knee. However, owing to the small number of RCTs with a low risk of bias, the evidence that t'ai chi is effective in patients with OA is limited.