bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of a virtual source model for Monte Carlo dose calculations of a flattening filter free linac
Authors: Cashmore Jason , Golubev Sergey , Dumont Jose Luis , Sikora Marcin , Alber Markus , Ramtohul Mark
Published: May 2012

Purpose:

A linac delivering intensity‐modulated radiotherapy (IMRT) can benefit from a flattening filter free (FFF) design which offers higher dose rates and reduced accelerator head scatter than for conventional (flattened) delivery. This reduction in scatter simplifies beam modeling, and combining a Monte Carlo dose engine with a FFF accelerator could potentially increase dose calculation accuracy. The objective of this work was to model a FFF machine using an adapted version of a previously published virtual source model (VSM) for Monte Carlo calculations and to verify its accuracy.

Methods:

An Elekta Synergy linear accelerator operating at 6 MV has been modified to enable irradiation both with and without the flattening filter (FF). The VSM has been incorporated into a commercially available treatment planning system (Monaco™ v 3.1) as VSM 1.6. Dosimetric data were measured to commission the treatment planning system (TPS) and the VSM adapted to account for the lack of angular differential absorption and general beam hardening. The model was then tested using standard water phantom measurements and also by creating IMRT plans for a range of clinical cases.

Results:

The results show that the VSM implementation handles the FFF beams very well, with an uncertainty between measurement and calculation of <1% which is comparable to conventional flattened beams. All IMRT beams passed standard quality assurance tests with >95% of all points passing gamma analysis (γ < 1) using a 3%/3 mm tolerance.

Conclusions:

The virtual source model for flattened beams was successfully adapted to a flattening filter free beam production. Water phantom and patient specific QA measurements show excellent results, and comparisons of IMRT plans generated in conventional and FFF mode are underway to assess dosimetric uncertainties and possible improvements in dose calculation and delivery.
Investigating the dosimetric and tumor control consequences of prostate seed loss and migration
Authors: Knaup Courtney , Mavroidis Panayiotis , Esquivel Carlos , Stathakis Sotirios , Swanson Gregory , Baltas Dimos , Papanikolaou Nikos
Published: May 2012

Purpose:

Low dose‐rate brachytherapy is commonly used to treat prostate cancer. However, once implanted, the seeds are vulnerable to loss and movement. The goal of this work is to investigate the dosimetric and radiobiological effects of the types of seed loss and migration commonly seen in prostate brachytherapy.

Methods:

Five patients were used in this study. For each patient three treatment plans were created using Iodine‐125, Palladium‐103, and Cesium‐131 seeds. The three seeds that were closest to the urethra were identified and modeled as the seeds lost through the urethra. The three seeds closest to the exterior of prostatic capsule were identified and modeled as those lost from the prostate periphery. The seed locations and organ contours were exported from Prowess and used by in‐house software to perform the dosimetric and radiobiological evaluation. Seed loss was simulated by simultaneously removing 1, 2, or 3 seeds near the urethra 0, 2, or 4 days after the implant or removing seeds near the exterior of the prostate 14, 21, or 28 days after the implant.

Results:

Loss of one, two or three seeds through the urethra results in aD90 reduction of 2%, 5%, and 7% loss, respectively. Due to delayed loss of peripheral seeds, the dosimetric effects are less severe than for loss through the urethra. However, while the dose reduction is modest for multiple lost seeds, the reduction in tumor control probability was minimal.

Conclusions:

The goal of this work was to investigate the dosimetric and radiobiological effects of the types of seed loss and migration commonly seen in prostate brachytherapy. The results presented show that loss of multiple seeds can cause a substantial reduction ofD90 coverage. However, for the patients in this study the dose reduction was not seen to reduce tumor control probability.
Radiobiology for eye plaque brachytherapy and evaluation of implant duration and radionuclide choice using an objective function
Authors: Gagne Nolan L. , Leonard Kara L. , Rivard Mark J.
Published: May 2012

Purpose:

Clinical optimization of Collaborative Ocular Melanoma Study (COMS) eye plaque brachytherapy is currently limited to tumor coverage, consensus prescription dosage, and dose calculations to ocular structures. The biologically effective dose (BED) of temporary brachytherapy treatments is a function of both chosen radionuclideR and implant duration T. This study endeavored to evaluate BED delivered to the tumor volume and surrounding ocular structures as a function of plaque position P, prescription dose, R, and T.

Methods:

Plaque‐heterogeneity‐corrected dose distributions were generated with MCNP5 for the range of currently available COMS plaques loaded with sources using three available low‐energy radionuclides. These physical dose distributions were imported into thePINNACLE3 treatment planning system using the TG‐43 hybrid technique and used to generate dose volume histograms for a T = 7 day implant within a reference eye geometry including the ciliary body, cornea, eyelid, foveola, lacrimal gland, lens, optic disc, optic nerve, retina, and tumor at eight standard treatment positions. The equation of Dale and Jones was employed to create biologically effective dose volume histograms (BEDVHs), allowing for BED volumetric analysis of all ROIs. Isobiologically effective prescription doses were calculated for T = 5 days down to 0.01 days, with BEDVHs subsequently generated for all ROIs using correspondingly reduced prescription doses. Objective functions were created to evaluate the BEDVHs as a function of R and T. These objective functions are mathematically accessible and sufficiently general to be applied to temporary or permanent brachytherapy implants for a variety of disease sites.

Results:

ReducingT from 7 to 0.01 days for a 10 mm plaque produced an average BED benefit of 26%, 20%, and 17% for 103Pd, 125I, and 131Cs, respectively, for all P; 16 and 22 mm plaque results were more position‐dependent. 103Pd produced a 16%–35% BED benefit over 125I, whereas 131Cs produced a 3%–7% BED detriment, independent of P, T, and plaque size. Additionally, corresponding organ at risk physical doses were lowest using 103Pd in all circumstances.

Conclusions:

The results suggest that shorter implant durations may correlate with more favorable outcomes compared to 7 day implants when treating small or medium intraocular lesions. The data also indicate that implant duration may be safely reduced if the prescription physical dose is likewise diminished and that103Pd offers a substantial radiobiological benefit over 125I and 131Cs irrespective of plaque position, implant duration, and tumor size.
Interferon-β Therapy Against EAE Is Effective Only When Development of the Disease Depends on the NLRP3 Inflammasome
Authors: Inoue Makoto , Williams Kristi L. , Oliver Timothy , Vandenabeele Peter , Rajan Jayant V. , Miao Edward A. , Shinohara Mari L.
Published: May 2012

Characterization of an animal model may explain why not all patients with multiple sclerosis respond to interferon-β.
Revisiting Channel Allostery: A Coherent Mechanism in IP
3
and Ryanodine Receptors
Authors: Hamada Kozo , Mikoshiba Katsuhiko
Published: May 2012

Structural analyses suggest a similar gating mechanism in the IP
3
and ryanodine receptors.
Pharmacodynamics of Itraconazole against Aspergillus fumigatus in an
In Vitro
Model of the Human Alveolus: Perspectives on the Treatment of Triazole-Resistant Infection and Utility of Airway Administration
Authors: Al-Nakeeb Zaid , Sudan Ajay , Jeans Adam R. , Gregson Lea , Goodwin Joanne , Warn Peter A. , Felton Timothy W. , Howard Susan J. , Hope William W.
Published: May 2012

Itraconazole is used for the prevention and treatment of infections caused by
Aspergillus fumigatus
. An understanding of the pharmacodynamics of itraconazole against wild-type and triazole-resistant strains provides a basis for innovative therapeutic strategies for treatment of infections. An
in vitro
model of the human alveolus was used to define the pharmacodynamics of itraconazole. Galactomannan was used as a biomarker. The effect of systemic and airway administration of itraconazole was assessed, as was a combination of itraconazole administered to the airway and systemically administered 5FC. Systemically administered itraconazole against the wild type induced a concentration-dependent decline in galactomannan in the alveolar and endothelial compartments. No exposure-response relationships were apparent for the L98H, M220T, or G138C mutant. The administration of itraconazole to the airway resulted in comparable exposure-response relationships to those observed with systemic therapy. This was achieved without detectable concentrations of drug within the endothelial compartment. The airway administration of itraconazole resulted in a definite but submaximal effect in the endothelial compartment against the L98H mutant. The administration of 5FC resulted in a concentration-dependent decline in galactomannan in both the alveolar and endothelial compartments. The combination of airway administration of itraconazole and systemically administered 5FC was additive. Systemic administration of itraconazole is ineffective against Cyp51 mutants. The airway administration of itraconazole is effective for the treatment of wild-type strains and appears to have some activity against the L98H mutants. Combination with other agents, such as 5FC, may enable the attainment of near-maximal antifungal activity.
Single-Dose Phase I Study To Evaluate the Pharmacokinetics of Posaconazole in New Tablet and Capsule Formulations Relative to Oral Suspension
Authors: Krishna Gopal , Ma Lei , Martinho Monika , O'Mara Edward
Published: May 2012

Posaconazole oral suspension, a marketed extended-spectrum triazole with proven efficacy as antifungal treatment and prophylaxis, should be taken with food to maximize absorption. New tablet and capsule formulations have been developed in an attempt to optimize absorption and bioavailability. The aims of this exploratory open-label, partially randomized, 2-part, 4-way, single-dose crossover study in 16 healthy adults were to characterize pharmacokinetics for posaconazole tablet and capsule formulations relative to those for posaconazole oral suspension under fasted and fed conditions and to assess safety and tolerability. Under fasted conditions, posaconazole exposures (area under the curve [AUC]) for the tablet and capsule formulations were similar (mean AUC from time zero to infinity [AUC0–∞], tablet A, 11,700 ng · h/ml [coefficient of variation {CV}, 26%]; tablet B, 11,300 ng · h/ml [CV, 22%]; capsule, 11,000 ng · h/ml [CV, 25%]) and were substantially higher than the exposure for the oral suspension (mean AUC0–∞, 3,420 ng · h/ml [CV, 44%]). Tablets and capsule showed less variability in exposure than the oral suspension. In fed subjects, tablets and capsule resulted in similar AUC values (mean AUC0–∞, tablet A, 11,900 ng · h/ml [23%]; tablet B, 12,400 ng · h/ml [CV, 25%]; capsule, 12,300 ng · h/ml [CV, 28%]) and slightly higher exposure than the oral suspension (mean AUC0–∞, 8,750 [CV, 24%]). Median times to the maximum concentration of drug in plasma were 4 to 5 h (fasted conditions) and 6 to 8 h (fed conditions). Mean half-lives values were similar for all formulations under fed and fasted conditions (23.1 to 29.2 h). Consistent with previous data, exposure for the oral suspension increased 2.5- to 3-fold when it was given with a high-fat meal. Conversely, exposures for tablets and capsule were not markedly affected by food. All formulations of posaconazole at 100 mg were safe and well tolerated.
Preclinical Characterization of JTK-853, a Novel Nonnucleoside Inhibitor of the Hepatitis C Virus RNA-Dependent RNA Polymerase
Authors: Ando Izuru , Adachi Tsuyoshi , Ogura Naoki , Toyonaga Yukiyo , Sugimoto Kazuyuki , Abe Hiroyuki , Kamada Masafumi , Noguchi Toru
Published: May 2012

JTK-853 is a novel piperazine derivative nonnucleoside inhibitor of hepatitis C virus (HCV) RNA-dependent RNA polymerase. JTK-853 showed potent inhibitory activity against genotype 1 HCV polymerase, with a 50% inhibitory concentration in the nanomolar range, and showed potent antiviral activity against the genotype 1b replicon, with a 50% effective concentration of 0.035 μM. The presence of human serum at up to 40% had little effect on the antiviral activity of JTK-853. Structure analysis of HCV polymerase with JTK-853 revealed that JTK-853 associates with the palm site and β-hairpin region of HCV polymerase, and JTK-853 showed decreased antiviral activity against HCV replicons bearing the resistance mutations C316Y, M414T, Y452H, and L466V in the palm site region of HCV polymerase. JTK-853 showed an additive combination effect with other DAAs (direct antiviral agents), such as nucleoside polymerase inhibitor, thumb pocket-binding nonnucleoside polymerase inhibitor, NS5A inhibitor, and protease inhibitor. Collectively, these data demonstrate that JTK-853 is a potent and novel nonnucleoside palm site-binding HCV polymerase inhibitor, suggesting JTK-853 as a potentially useful agent in combination with other DAAs for treatment of HCV infections.
Identification of (+)-Erythro-Mefloquine as an Active Enantiomer with Greater Efficacy than Mefloquine against Mycobacterium avium Infection in Mice
Authors: Bermudez Luiz E. , Inderlied Clark B. , Kolonoski Peter , Chee Christopher B. , Aralar Priscilla , Petrofsky Mary , Parman Toufan , Green Carol E. , Lewin Anita H. , Ellis William Y. , Young Lowell S.
Published: May 2012

Infection caused by
Mycobacterium avium
is common in AIDS patients who do not receive treatment with highly active antiretroviral therapy (HAART) or who develop resistance to anti-HIV therapy. Mefloquine, a racemic mixture used for malaria prophylaxis and treatment, is bactericidal against
M. avium
in mice. MICs of (+)-erythro-, (−)-erythro-, (+)-threo-, and (−)-threo-mefloquine were 32 μg/ml, 32 μg/ml, 64 μg/ml, and 64 μg/ml, respectively. The postantibiotic effect for (+)-erythro-mefloquine was 36 h (MIC) and 41 h for a concentration of 4× MIC. The mefloquine postantibiotic effect was 25 h (MIC and 4× MIC). After baseline infection was established (7 days), the (+)- and (−)-isomers of the diastereomeric threo- and erythro-α-(2-piperidyl)-2,8-bis(trifluoromethyl)-4-quinolinemethanol were individually used to orally treat C57BL/6 bg
+
/bg
+
beige mice that were infected intravenously with
M. avium
. Mice were also treated with commercial mefloquine and diluent as controls. After 4 weeks of treatment, the mice were harvested, and the number of bacteria in spleen and liver was determined. Mice receiving (+)- or (−)-threo-mefloquine or (−)-erythro-mefloquine had numbers of bacterial load in tissues similar to those of untreated control mice at 4 weeks. Commercial mefloquine had a bactericidal effect. However, mice given the (+)-erythro-enantiomer for 4 weeks had a significantly greater reduction of bacterial load than those given mefloquine. Thus, (+)-erythro-mefloquine is the active enantiomer of mefloquine against
M. avium
and perhaps other mycobacteria.
Harmine Is a Potent Antimalarial Targeting Hsp90 and Synergizes with Chloroquine and Artemisinin
Authors: Shahinas Dea , MacMullin Gregory , Benedict Christan , Crandall Ian , Pillai Dylan R.
Published: May 2012

Previous studies have shown an antimalarial effect of total alkaloids extracted from leaves of
Guiera senegalensis
from Mali in West Africa. We independently observed that the beta-carboline alkaloid harmine obtained from a natural product library screen inhibited
Plasmodium falciparum
heat shock protein 90 (PfHsp90) ATP-binding domain. In this study, we confirmed harmine-PfHsp90-specific affinity using surface plasmon resonance analysis (dissociation constant [

K
d

] of 40 μM). In contrast, the related compound harmalol bound human Hsp90 (HsHsp90) (

K
d

of 224 μM) more tightly than PfHsp90 (

K
d

of 7,010 μM). Site-directed mutagenesis revealed that Arg98 in PfHsp90 is essential for harmine selectivity. In keeping with our model indicating that Hsp90 inhibition affords synergistic combinations with existing antimalarials, we demonstrated that harmine potentiates the effect of chloroquine and artemisinin
in vitro
and in the
Plasmodium berghei
mouse model. These findings have implications for the development of novel therapeutic combinations that are synergistic with existing antimalarials.
Impact of Antibiotic MIC on Infection Outcome in Patients with Susceptible Gram-Negative Bacteria: a Systematic Review and Meta-Analysis
Authors: Falagas Matthew E. , Tansarli Giannoula S. , Rafailidis Petros I. , Kapaskelis Anastasios , Vardakas Konstantinos Z.
Published: May 2012

The objective of this study was to analyze the impact of MIC values within the susceptible range of antibiotics on the outcomes of patients with Gram-negative infections. The PubMed and Scopus electronic databases were searched. We identified 13 articles (1,469 patients) that studied the impact of antibiotic MICs on the outcomes of infections; β-lactams were studied in 10 of them. Infections due to
Salmonella enterica
strains with high fluoroquinolone MICs were associated with more treatment failures than those due to strains with low MICs (relative risk [RR], 5.75; 95% confidence interval [CI], 1.77 to 18.71). Among non-
Salmonella
enterobacteriaceae, there was no difference in treatment failures depending on the MIC value (RR, 1.18; 95% CI, 0.71 to 1.97); however, a higher all-cause mortality was observed for patients infected with strains with high MICs (RR, 2.03; 95% CI, 1.05 to 3.92). More treatment failures were observed for patients infected with nonfermentative Gram-negative bacilli when strains had high MICs (RR, 5.54; 95% CI, 2.72 to 11.27). The mortality rate for patients with infections with Gram-negative nonfermentative bacilli with high MICs was also higher than for those with low MICs (RR, 2.39; 95% CI, 1.19 to 4.81). The limited available data suggest that there is an association between high MICs, within the susceptible range, and adverse outcomes for patients with Gram-negative infections.
High Risk of QT Interval Prolongation and Torsades de Pointes Associated with Intravenous Quinidine Used for Treatment of Resistant Malaria or Babesiosis
Authors: Wroblewski Heather A. , Kovacs Richard J. , Kingery Joanna R. , Overholser Brian R. , Tisdale James E.
Published: May 2012

Cardiac toxicity may be associated with drugs used for malaria. Torsades de pointes (TdP) is a well-known adverse effect of quinidine when used for atrial fibrillation. Intravenous quinidine doses for resistant malaria are 2 to 3 times higher than those used for arrhythmias. Among 6 patients receiving quinidine for malaria or babesiosis, 4 developed QT interval prolongation and 2 experienced TdP. Clinicians should be aware that recommended doses of quinidine for malaria carry a high TdP risk.
Application of a Loading Dose of Colistin Methanesulfonate in Critically Ill Patients: Population Pharmacokinetics, Protein Binding, and Prediction of Bacterial Kill
Authors: Mohamed Ami F. , Karaiskos Ilias , Plachouras Diamantis , Karvanen Matti , Pontikis Konstantinos , Jansson Britt , Papadomichelakis Evangelos , Antoniadou Anastasia , Giamarellou Helen , Armaganidis Apostolos , Cars Otto , Friberg Lena E.
Published: May 2012

A previous pharmacokinetic study on dosing of colistin methanesulfonate (CMS) at 240 mg (3 million units [MU]) every 8 h indicated that colistin has a long half-life, resulting in insufficient concentrations for the first 12 to 48 h after initiation of treatment. A loading dose would therefore be beneficial. The aim of this study was to evaluate CMS and colistin pharmacokinetics following a 480-mg (6-MU) loading dose in critically ill patients and to explore the bacterial kill following the use of different dosing regimens obtained by predictions from a pharmacokinetic-pharmacodynamic model developed from an
in vitro
study on
Pseudomonas aeruginosa
. The unbound fractions of colistin A and colistin B were determined using equilibrium dialysis and considered in the predictions. Ten critically ill patients (6 males; mean age, 54 years; mean creatinine clearance, 82 ml/min) with infections caused by multidrug-resistant Gram-negative bacteria were enrolled in the study. The pharmacokinetic data collected after the first and eighth doses were analyzed simultaneously with the data from the previous study (total, 28 patients) in the NONMEM program. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.026 and 2.2 h, respectively. For colistin, a one-compartment model was sufficient and the estimated half-life was 18.5 h. The unbound fractions of colistin in the patients were 26 to 41% at clinical concentrations. Colistin A, but not colistin B, had a concentration-dependent binding. The predictions suggested that the time to 3-log-unit bacterial kill for a 480-mg loading dose was reduced to half of that for the dose of 240 mg.
The Rickettsial OmpB β-Peptide of Rickettsia conorii Is Sufficient To Facilitate Factor H-Mediated Serum Resistance
Authors: Riley Sean P. , Patterson Jennifer L. , Martinez Juan J.
Published: May 2012

Pathogenic species of the spotted fever groupRickettsiaare subjected to repeated exposures to the host complement system through cyclic infections of mammalian and tick hosts. The serum complement machinery is a formidable obstacle for bacteria to overcome if they endeavor to endure this endozoonotic cycle. We have previously demonstrated that that the etiologic agent of Mediterranean spotted fever,Rickettsia conorii, is susceptible to complement-mediated killing only in the presence of specific monoclonal antibodies. We have also shown that in the absence of particular neutralizing antibody,R. conoriiis resistant to the effects of serum complement. We therefore hypothesized that the interactions between fluid-phase complement regulators and conserved rickettsial outer membrane-associated proteins are critical to mediate serum resistance. We demonstrate here thatR. conoriispecifically interacts with the soluble host complement inhibitor, factor H. Depletion of factor H from normal human serum rendersR. conoriimore susceptible to C3 and membrane attack complex deposition and to complement-mediated killing. We identified the autotransporter protein rickettsial OmpB (rOmpB) as a factor H ligand and further demonstrate that the rOmpB β-peptide is sufficient to mediate resistance to the bactericidal properties of human serum. Taken together, these data reveal an additional function for the highly conserved rickettsial surface cell antigen, rOmpB, and suggest that the ability to evade complement-mediated clearance from the hematogenous circulation is a novel virulence attribute for this class of pathogens.
Comparative Analysis of the Interaction of Helicobacter pylori with Human Dendritic Cells, Macrophages, and Monocytes
Authors: Fehlings Michael , Drobbe Lea , Moos Verena , Renner Viveros Pablo , Hagen Jana , Beigier-Bompadre Macarena , Pang Ervinna , Belogolova Elena , Churin Yuri , Schneider Thomas , Meyer Thomas F. , Aebischer Toni , Ignatius Ralf
Published: May 2012

Helicobacter pylorimay cause chronic gastritis, gastric cancer, or lymphoma. Myeloid antigen-presenting cells (APCs) are most likely involved in the induction and expression of the underlying inflammatory responses. To study the interaction of human APC subsets withH. pylori, we infected monocytes, monocyte-derived dendritic cells (DCs), and monocyte-derived (classically activated; M1) macrophages withH. pyloriand analyzed phenotypic alterations, cytokine secretion, phagocytosis, and immunostimulation. Since we detected CD163+(alternatively activated; M2) macrophages in gastric biopsy specimens fromH. pylori-positive patients, we also included monocyte-derived M2 macrophages in the study. UponH. pyloriinfection, monocytes secreted interleukin-1β (IL-1β), IL-6, IL-10, and IL-12p40 (partially secreted as IL-23) but not IL-12p70. Infected DCs became activated, as shown by the enhanced expression of CD25, CD80, CD83, PDL-1, and CCR7, and secreted IL-1β, IL-6, IL-10, IL-12p40, IL-12p70, and IL-23. However, infection led to significantly downregulated CD209 and suppressed the constitutive secretion of macrophage migration inhibitory factor (MIF).H. pylori-infected M1 macrophages upregulated CD14 and CD32, downregulated CD11b and HLA-DR, and secreted mainly IL-1β, IL-6, IL-10, IL-12p40, and IL-23. Activation of DCs and M1 macrophages correlated with increased capacity to induce T-cell proliferation and decreased phagocytosis of dextran. M2 macrophages upregulated CD14 and CD206 and secreted IL-10 but produced less of the proinflammatory cytokines than M1 macrophages. Thus,H. pyloriaffects the functions of human APC subsets differently, which may influence the course and the outcome ofH. pyloriinfection. The suppression of MIF in DCs constitutes a novel immune evasion mechanism exploited byH. pylori.
Role of the Vpe Carbohydrate Permease in Escherichia coli Urovirulence and Fitness
In Vivo
Authors: Martinez-Jéhanne Vanessa , Pichon Christophe , du Merle Laurence , Poupel Olivier , Cayet Nadège , Bouchier Christiane , Le Bouguénec Chantal
Published: May 2012

Uropathogenic
Escherichia coli
(UPEC) strains are a leading cause of infections in humans, but the mechanisms governing host colonization by this bacterium remain poorly understood. Previous studies have identified numerous gene clusters encoding proteins involved in sugar transport, in pathogen-specific islands. We investigated the role in fitness and virulence of the
vpe
operon encoding an EII complex of the phosphotransferase (PTS) system, which is found more frequently in human strains from infected urine and blood (45%) than in
E. coli
isolated from healthy humans (15%). We studied the role of this locus
in vivo
, using the UPEC
E. coli
strain AL511, mutants, and complemented derivatives in two experimental mouse models of infection. Mutant strains displayed attenuated virulence in a mouse model of sepsis. A role in kidney colonization was also demonstrated by coinfection experiments in a mouse model of pyelonephritis. Electron microscopy examinations showed that the
vpeBC
mutant produced much smaller amounts of a capsule-like surface material than the wild type, particularly when growing in human urine. Complementation of the
vpeBC
mutation led to an increase in the amount of exopolysaccharide, resistance to serum killing, and virulence. It was therefore clear that the loss of
vpe
genes was responsible for all the observed phenotypes. We also demonstrated the involvement of the
vpe
locus in gut colonization in the streptomycin-treated mouse model of intestinal colonization. These findings confirm that carbohydrate transport and metabolism underlie the ability of UPEC strains to colonize the host intestine and to infect various host sites.
The Sphingosine-1-Phosphate Analogue FTY720 Impairs Mucosal Immunity and Clearance of the Enteric Pathogen Citrobacter rodentium
Authors: Murphy Carola T. , Hall Lindsay J. , Hurley Grainne , Quinlan Aoife , MacSharry John , Shanahan Fergus , Nally Kenneth , Melgar Silvia
Published: May 2012

The sphingosine-1-phosphate (S1P) analogue FTY720 is therapeutically efficacious in multiple sclerosis and in the prevention of transplant rejection. It prevents the migration of lymphocytes to sites of pathology by trapping them within the peripheral lymph nodes, mesenteric lymph nodes (MLNs), and Peyer's patches. However, evidence suggests that its clinical use may increase the risk of mucosal infections. We investigated the impact of FTY720 treatment on susceptibility to gastrointestinal infection with the mouse enteric pathogen
Citrobacter rodentium
. This attaching and effacing bacterium induces a transient bacterial colitis in immunocompetent mice that resembles human infection with pathogenic
Escherichia coli
. FTY720 treatment induced peripheral blood lymphopenia, trapped lymphocytes in the MLNs, and prevented the clearance of bacteria when mice were infected with luciferase-tagged
C. rodentium
. FTY720-treated
C. rodentium
-infected mice had enhanced colonic inflammation, with significantly higher colon mass, colon histopathology, and neutrophil infiltration than vehicle-infected animals. In addition, FTY720-treated infected mice had significantly lower numbers of colonic dendritic cells, macrophages, and T cells. Gene expression analysis demonstrated that FTY720-treated infected mice had an impaired innate immune response and a blunted mucosal adaptive immune response, including Th1 cytokines. The data demonstrate that the S1P analogue FTY720 adversely affects the immune response to and clearance of
C. rodentium
.
The epileptic singers of belle époque Paris
Authors: Baxendale Sallie , Marshall Fiona
Published: May 2012

In late 19th century Paris, people with epilepsy were treated alongside those with hysteria in the now famous Salpêtrière Hospital, where both conditions were deemed to have a neurological basis. When Jean Martin Charcot became chief physician at the Salpêtrière Hospital in 1862, he described himself ‘in possession of a kind of museum of living pathology whose holdings were virtually inexhaustible’. He opened the doors of his ‘living museum’ and exhibited his prize specimens to all of Paris. By putting his patients on display, Charcot introduced a vogue for pathology that permeated well beyond the world of medical enquiry and into the public psyche and vernacular. Not only did Charcot's demonstrations provide the inspiration for high culture in the form of operas, plays and novels, they also provided the inspiration for the ‘gommeuses epileptiques’ (epileptic singers), who entertained the masses at the café concerts. This paper explores the foundations of our current medical approaches to mental illness and epilepsy, with a particular focus on the boundaries that emerged between hysteria and epilepsy in 19th century Paris. These clinical boundaries were both shaped by and reflected in the popular entertainments in the city.
LYAPUNOV SPECTRUM OF NONAUTONOMOUS LINEAR STOCHASTIC DIFFERENTIAL ALGEBRAIC EQUATIONS OF INDEX-1
Authors: CONG NGUYEN DINH , THE NGUYEN THI
Published: May 2012

We introduce a concept of Lyapunov exponents and Lyapunov spectrum of a stochastic differential algebraic equation (SDAE) of index-1. The Lyapunov exponents are defined samplewise via the induced two-parameter stochastic flow generated by inherent regular stochastic differential equations. We prove that Lyapunov exponents are nonrandom.
THE CENTRAL LIMIT THEOREM FOR UNIFORMLY STRONG MIXING MEASURES
Authors: HAYDN NICOLAI
Published: May 2012

The theorem of Shannon–McMillan–Breiman states that for every generating partition on an ergodic system, the exponential decay rate of the measure of cylinder sets equals the metric entropy almost everywhere (provided the entropy is finite). In this paper we prove that the measure of cylinder sets are lognormally distributed for strongly mixing systems and infinite partitions and show that the rate of convergence is polynomial provided the fourth moment of the information function is finite. Also, unlike previous results by Ibragimov and others which only apply to finite partitions, here we do not require any regularity of the conditional entropy function. We also obtain the law of the iterated logarithm and the weak invariance principle for the information function.
THE EFFECT OF THRESHOLD VALUE ON THE ARCHITECTURAL PARAMETERS AND STIFFNESS OF HUMAN CANCELLOUS BONE IN MICRO CT ANALYSIS
Authors: YAN YA-BO , QI WEI , QIU TIAN-XIA , TEO EE-CHON , LEI WEI
Published: May 2012

In this study, the effects of threshold variation in image segmentation of micro CT images of cancellous bone in the determination of the architectural parameters and stiffness were investigated. A total of 42 samples of 6 × 6 × 6 mm3 cubes with threshold values set between 500–1100 greyscale in increment of 100 of CT images of six human C5 vertebral bodies were analyzed. Threshold value of 800, based on Otsu's method, was set for the control group. From various threshold values, the respective architectural parameters, and the corresponding stiffness in three orthotropic directions (Exx, Eyy, Ezz) of each cube were computed from the voxel-based micro-finite element models under compressive simulation. The results showed that 1% variation of threshold value resulted in a 3.4% variation in BV/TV, 2% in Tb.N, 3.1% in Tb.Th, 2.9% in BS/BV, 1.8% in Tb.Sp, 29.2% in Exx, 28.7% Eyy and 27.7% in Ezz. Statistical analysis showed that 2.9% threshold variation caused significant change in BV/TV, Tb.Th, Exx, Eyy and Ezz values. The study shows that with threshold variation of more than 2.9%, significant differences in the architectural parameters and stiffness compared to those based on Otsu's method.
The N-End Rule Pathway
Authors: Tasaki Takafumi , Sriram Shashikanth M. , Park Kyong Soo , Kwon Yong Tae
Published: May 2012

The N-end rule pathway is a proteolytic system in which N-terminal residues of short-lived proteins are recognized by recognition components (N-recognins) as essential components of degrons, called N-degrons. Known N-recognins in eukaryotes mediate protein ubiquitylation and selective proteolysis by the 26S proteasome. Substrates of N-recognins can be generated when normally embedded destabilizing residues are exposed at the N terminus by proteolytic cleavage. N-degrons can also be generated through modifications of posttranslationally exposed pro-N-degrons of otherwise stable proteins; such modifications include oxidation, arginylation, leucylation, phenylalanylation, and acetylation. Although there are variations in components, degrons, and hierarchical structures, the proteolytic systems based on generation and recognition of N-degrons have been observed in all eukaryotes and prokaryotes examined thus far. The N-end rule pathway regulates homeostasis of various physiological processes, in part, through interaction with small molecules. Here, we review the biochemical mechanisms, structures, physiological functions, and small-molecule-mediated regulation of the N-end rule pathway.
The Structural Basis for Control of Eukaryotic Protein Kinases
Authors: Endicott Jane A. , Noble Martin E.M. , Johnson Louise N.
Published: May 2012

Eukaryotic protein kinases are key regulators of cell processes. Comparison of the structures of protein kinase domains, both alone and in complexes, allows generalizations to be made about the mechanisms that regulate protein kinase activation. Protein kinases in the active state adopt a catalytically competent conformation upon binding of both the ATP and peptide substrates that has led to an understanding of the catalytic mechanism. Docking sites remote from the catalytic site are a key feature of several substrate recognition complexes. Mechanisms for kinase activation through phosphorylation, additional domains or subunits, by scaffolding proteins and by kinase dimerization are discussed.
Programming of DNA Methylation Patterns
Authors: Cedar Howard , Bergman Yehudit
Published: May 2012

DNA methylation represents a form of genome annotation that mediates gene repression by serving as a maintainable mark that can be used to reconstruct silent chromatin following each round of replication. During development, germline DNA methylation is erased in the blastocyst, and a bimodal pattern is established anew at the time of implantation when the entire genome gets methylated while CpG islands are protected. This brings about global repression and allows housekeeping genes to be expressed in all cells of the body. Postimplantation development is characterized by stage- and tissue-specific changes in methylation that ultimately mold the epigenetic patterns that define each individual cell type. This is directed by sequence information in DNA and represents a secondary event that provides long-term expression stability. Abnormal methylation changes play a role in diseases, such as cancer or fragile X syndrome, and may also occur as a function of aging or as a result of environmental influences.
Pluripotency and Nuclear Reprogramming
Authors: Dejosez Marion , Zwaka Thomas P.
Published: May 2012

Pluripotency is a “blank” cellular state characteristic of specific cells within the early embryo (e.g., epiblast cells) and of certain cells propagated in vitro (e.g., embryonic stem cells, ESCs). The terms pluripotent cell and stem cell are often used interchangeably to describe cells capable of differentiating into multiple cell types. In this review, we discuss the prevailing molecular and functional definitions of pluripotency and the working parameters employed to describe this state, both in the context of cells residing within the early embryo and cells propagated in vitro.
Ubiquitin and Membrane Protein Turnover: From Cradle to Grave
Authors: MacGurn Jason A. , Hsu Pi-Chiang , Emr Scott D.
Published: May 2012

From the moment of cotranslational insertion into the lipid bilayer of the endoplasmic reticulum (ER), newly synthesized integral membrane proteins are subject to a complex series of sorting, trafficking, quality control, and quality maintenance systems. Many of these processes are intimately controlled by ubiquitination, a posttranslational modification that directs trafficking decisions related to both the biosynthetic delivery of proteins to the plasma membrane (PM) via the secretory pathway and the removal of proteins from the PM via the endocytic pathway. Ubiquitin modification of integral membrane proteins (or “cargoes”) generally acts as a sorting signal, which is recognized, captured, and delivered to a specific cellular destination via specialized trafficking events. By affecting the quality, quantity, and localization of integral membrane proteins in the cell, defects in these processes contribute to human diseases, including cystic fibrosis, circulatory diseases, and various neuropathies. This review summarizes our current understanding of how ubiquitin modification influences cargo trafficking, with a special emphasis on mechanisms of quality control and quality maintenance in the secretory and endocytic pathways.
The Ubiquitin Code
Authors: Komander David , Rape Michael
Published: May 2012

The posttranslational modification with ubiquitin, a process referred to as ubiquitylation, controls almost every process in cells. Ubiquitin can be attached to substrate proteins as a single moiety or in the form of polymeric chains in which successive ubiquitin molecules are connected through specific isopeptide bonds. Reminiscent of a code, the various ubiquitin modifications adopt distinct conformations and lead to different outcomes in cells. Here, we discuss the structure, assembly, and function of this ubiquitin code.
Lipid Droplets and Cellular Lipid Metabolism
Authors: Walther Tobias C. , Farese Robert V.
Published: May 2012

Among organelles, lipid droplets (LDs) uniquely constitute a hydrophobic phase in the aqueous environment of the cytosol. Their hydrophobic core of neutral lipids stores metabolic energy and membrane components, making LDs hubs for lipid metabolism. In addition, LDs are implicated in a number of other cellular functions, ranging from protein storage and degradation to viral replication. These processes are functionally linked to many physiological and pathological conditions, including obesity and related metabolic diseases. Despite their important functions and nearly ubiquitous presence in cells, many aspects of LD biology are unknown. In the past few years, the pace of LD investigation has increased, providing new insights. Here, we review the current knowledge of LD cell biology and its translation to physiology.
The MPS1 Family of Protein Kinases
Authors: Liu Xuedong , Winey Mark
Published: May 2012

MPS1 protein kinases are found widely, but not ubiquitously, in eukaryotes. This family of potentially dual-specific protein kinases is among several that regulate a number of steps of mitosis. The most widely conserved MPS1 kinase functions involve activities at the kinetochore in both the chromosome attachment and the spindle checkpoint. MPS1 kinases also function at centrosomes. Beyond mitosis, MPS1 kinases have been implicated in development, cytokinesis, and several different signaling pathways. Family members are identified by virtue of a conserved C-terminal kinase domain, though the N-terminal domain is quite divergent. The kinase domain of the human enzyme has been crystallized, revealing an unusual ATP-binding pocket. The activity, level, and subcellular localization of Mps1 family members are tightly regulated during cell-cycle progression. The mitotic functions of Mps1 kinases and their overexpression in some tumors have prompted the identification of Mps1 inhibitors and their active development as anticancer drugs.
Endoplasmic Reticulum Stress and Type 2 Diabetes
Authors: Back Sung Hoon , Kaufman Randal J.
Published: May 2012

Given the functional importance of the endoplasmic reticulum (ER), an organelle that performs folding, modification, and trafficking of secretory and membrane proteins to the Golgi compartment, the maintenance of ER homeostasis in insulin-secreting β-cells is very important. When ER homeostasis is disrupted, the ER generates adaptive signaling pathways, called the unfolded protein response (UPR), to maintain homeostasis of this organelle. However, if homeostasis fails to be restored, the ER initiates death signaling pathways. New observations suggest that both chronic hyperglycemia and hyperlipidemia, known as important causative factors of type 2 diabetes (T2D), disrupt ER homeostasis to induce unresolvable UPR activation and β-cell death. This review examines how the UPR pathways, induced by high glucose and free fatty acids (FFAs), interact to disrupt ER function and cause β-cell dysfunction and death.
ALKoma: A Cancer Subtype with a Shared Target
Authors: Mano Hiroyuki
Published: May 2012

Anaplastic lymphoma kinase (ALK) is a receptor-type protein tyrosine kinase that is currently the focus of much attention in oncology. ALK is rendered oncogenic as a result of its fusion to NPM1 in anaplastic large cell lymphoma, to TPM3 or TPM4 in inflammatory myofibroblastic tumor, to EML4 in non–small cell lung carcinoma, and to VCL in renal medullary carcinoma. It is also activated as a result of missense mutations in neuroblastoma and anaplastic thyroid cancer. Whereas these various tumors arise in different organs, they share activated ALK, and a marked clinical efficacy with ALK inhibitors has already been shown for some of the tumors with ALK fusions. One of such compound, crizotinib, is now approved in the United States for the treatment of lung cancer positive for ALK rearrangement. I propose that tumors carrying abnormal ALK as an essential growth driver be collectively termed “ALKoma.”

Significance: ALK acquires transforming ability through gene fusion or missense mutation in a wide range of human cancers. Some of these cancers, which I propose be collectively referred to as “ALKoma,” may all be effectively treated with small compounds or antibodies targeted to activated ALKs. Cancer Discov; 2(6); 495–502. © 2012 AACR.
Atorvastatin Inhibits Myocardin Expression in Vascular Smooth Muscle Cells
Authors: Li Jingjing , Jiang Jixin , Yin Hao , Wang Lifeng , Tian Ruijuan , Li Haijie , Wang Zengyong , Li Dong , Wang Yuebing , Gui Yu , Walsh Michael P. , Zheng Xi-Long
Published: May 2012

Atorvastatin (ATV), an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, is widely prescribed as a lipid-lowering drug. It also inhibits the RhoA-Rho–associated kinase pathway in vascular smooth muscle (SM) cells and critically inhibits SM function. Myocardin is a coactivator of serum response factor, which upregulates SM contractile proteins. The RhoA-Rho–associated kinase pathway, which directly triggers SM contraction, also increases
myocardin
gene expression. Therefore, we investigated whether ATV inhibits
myocardin
gene expression in SM cells. In mice injected with ATV (IP 20 μg/g per day) for 5 days, myocardin gene expression was significantly downregulated in aortic and carotid arterial tissues with decreased expression of
myocardin
target genes
SM α-actin
and
SM22
. Correspondingly, the contractility of aortic rings in mice treated with ATV or the Rho–associated kinase inhibitor Y-27632 was reduced in response to treatment with either KCl or phenylephrine. In cultured mouse and human aortic SM cells, KCl treatment stimulated the expression of myocardin, SM α-actin, and SM22. These stimulatory effects were prevented by ATV treatment. ATV-induced inhibition of
myocardin
expression was prevented by pretreatment with either mevalonate or geranylgeranylpyrophosphate but not farnesylpyrophosphate. Treatment with Y-27632 mimicked ATV effects on the gene expression of
myocardin
,
SM α-actin
, and
SM22
, further suggesting a role for the RhoA-Rho–associated kinase pathway in ATV effects. Furthermore, ATV treatment inhibited RhoA membrane translocation and activation; these effects were prevented by pretreatment with mevalonate. We conclude that ATV inhibits
myocardin
gene expression in vivo and in vitro, suggesting a novel mechanism for ATV inhibition of vascular contraction.
Changes in the Duration of European Wet and Dry Spells during the Last 60 Years
Authors: Zolina Olga , Simmer Clemens , Belyaev Konstantin , Gulev Sergey K. , Koltermann Peter
Published: May 2012

Daily rain gauge data over Europe for the period from 1950 to 2009 were used to analyze changes in the duration of wet and dry spells. The duration of wet spells exhibits a statistically significant growth over northern Europe and central European Russia, which is especially pronounced in winter when the mean duration of wet periods increased by 15%–20%. In summer wet spells become shorter over Scandinavia and northern Russia. The duration of dry spells decreases over Scandinavia and southern Europe in both winter and summer. For the discrimination between the roles of a changing number of wet days and of a regrouping of wet and dry days for the duration of the period, the authors suggest a fractional truncated geometric distribution. The changing numbers of wet days cannot explain the long-term variability in the duration of wet and dry periods. The observed changes are mainly due to the regrouping of wet and dry days. The tendencies in duration of wet and dry spells have been analyzed for a number of European areas. Over the Netherlands both wet and dry periods are extended in length during the cold and the warm season. A simultaneous shortening of wet and dry periods is found in southern Scandinavia in summer. Over France and central southern Europe during both winter and summer and over the Scandinavian Atlantic coast in summer, opposite tendencies in the duration of wet and dry spells were identified. Potential mechanisms that might be responsible for the changing durations of wet and dry periods and further perspectives are discussed.