bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective, Observational Study of Voriconazole Therapeutic Drug Monitoring among Lung Transplant Recipients Receiving Prophylaxis: Factors Impacting Levels of and Associations between Serum Troughs, Efficacy, and Toxicity
Authors: Mitsani Dimitra , Nguyen M. Hong , Shields Ryan K. , Toyoda Yoshiya , Kwak Eun J. , Silveira Fernanda P. , Pilewski Joseph M. , Crespo Maria M. , Bermudez Christian , Bhama Jay K. , Clancy Cornelius J.
Published: February 2012

Voriconazole prophylaxis is common following lung transplantation, but the value of therapeutic drug monitoring is unknown. A prospective, observational study of lung transplant recipients (
n
= 93) receiving voriconazole prophylaxis was performed. Serum voriconazole troughs (
n
= 331) were measured by high-pressure liquid chromatography. The median initial and subsequent troughs were 1.91 and 1.46 μg/ml, respectively. The age of the patient directly correlated with initial troughs (
P
= 0.005). Patients that were ≥60 years old and cystic fibrosis patients were significantly more likely to have higher and lower initial troughs, respectively. In 95% (88/93) of patients, ≥2 troughs were measured. In 28% (25/88) and 32% (28/88) of these patients, all troughs were ≤1.5 μg/ml or >1.5 μg/ml, respectively. Ten percent (10/93) and 27% (25/93) of the patients developed invasive fungal infection (tracheobronchitis) and fungal colonization, respectively. The median troughs at the times of positive and negative fungal cultures were 0.92 and 1.72 μg/ml (
P
= 0.07). Invasive fungal infections or colonization were more likely with troughs of ≤1.5 μg/ml (
P
= 0.01) and among patients with no trough of >1.5 μg/ml (
P
= 0.007). Other cutoff troughs correlated less strongly with microbiologic outcomes. Troughs correlated directly with aspartate transferase levels (
P
= 0.003), but not with other liver enzymes. Voriconazole was discontinued due to suspected toxicity in 27% (25/93) of the patients. The troughs did not differ at the times of suspected drug-induced hepatotoxicity, central nervous system (CNS) toxicity, or nausea/vomiting and in the absence of toxicity. Voriconazole prophylaxis was most effective at troughs of >1.5 μg/ml. A cutoff for toxicity was not identified, but troughs of >4 μg/ml were rare. The data support a target range of >1.5 to 4 μg/ml.
Standardized Comparison of the Relative Impacts of HIV-1 Reverse Transcriptase (RT) Mutations on Nucleoside RT Inhibitor Susceptibility
Authors: Melikian George L. , Rhee Soo-Yon , Taylor Jonathan , Fessel W. Jeffrey , Kaufman David , Towner William , Troia-Cancio Paolo V. , Zolopa Andrew , Robbins Gregory K. , Kagan Ron , Israelski Dennis , Shafer Robert W.
Published: February 2012

Determining the phenotypic impacts of reverse transcriptase (RT) mutations on individual nucleoside RT inhibitors (NRTIs) has remained a statistical challenge because clinical NRTI-resistant HIV-1 isolates usually contain multiple mutations, often in complex patterns, complicating the task of determining the relative contribution of each mutation to HIV drug resistance. Furthermore, the NRTIs have highly variable dynamic susceptibility ranges, making it difficult to determine the relative effect of an RT mutation on susceptibility to different NRTIs. In this study, we analyzed 1,273 genotyped HIV-1 isolates for which phenotypic results were obtained using the PhenoSense assay (Monogram, South San Francisco, CA). We used a parsimonious feature selection algorithm, LASSO, to assess the possible contributions of 177 mutations that occurred in 10 or more isolates in our data set. We then used least-squares regression to quantify the impact of each LASSO-selected mutation on each NRTI. Our study provides a comprehensive view of the most common NRTI resistance mutations. Because our results were standardized, the study provides the first analysis that quantifies the relative phenotypic effects of NRTI resistance mutations on each of the NRTIs. In addition, the study contains new findings on the relative impacts of thymidine analog mutations (TAMs) on susceptibility to abacavir and tenofovir; the impacts of several known but incompletely characterized mutations, including E40F, V75T, Y115F, and K219R; and a tentative role in reduced NRTI susceptibility for K64H, a novel NRTI resistance mutation.
Epidemiological Cutoff Values for Azoles and Aspergillus fumigatus Based on a Novel Mathematical Approach Incorporating
cyp51A
Sequence Analysis
Authors: Meletiadis J. , Mavridou E. , Melchers W. J. G. , Mouton J. W. , Verweij P. E.
Published: February 2012

Epidemiological cutoff values (ECV) are commonly used to separate wild-type isolates from isolates with reduced susceptibility to antifungal drugs, thus setting the foundation for establishing clinical breakpoints for
Aspergillus fumigatus
. However, ECVs are usually determined by eye, a method which lacks objectivity, sensitivity, and statistical robustness and may be difficult, in particular, for extended and complex MIC distributions. We therefore describe and evaluate a statistical method of MIC distribution analysis for posaconazole, itraconazole, and voriconazole for 296
A. fumigatus
isolates utilizing nonlinear regression analysis, the normal plot technique, and recursive partitioning analysis incorporating
cyp51A
sequence data. MICs were determined by using the CLSI M38–A2 protocol (CLSI, CLSI document M38–A2, 2008) after incubation of the isolates for 48 h and were transformed into log
2
MICs. We found a wide distribution of MICs of all azoles, some ranging from 0.02 to 128 mg/liter, with median MICs of 32 mg/liter for itraconazole, 4 mg/liter for voriconazole, and 0.5 mg/liter for posaconazole. Of the isolates, 65% (192 of 296) had mutations in the
cyp51A
gene, and the majority of the mutants (90%) harbored tandem repeats in the promoter region combined with mutations in the
cyp51A
coding region. MIC distributions deviated significantly from normal distribution (D'Agostino-Pearson omnibus normality test
P
value, <0.001), and they were better described with a model of the sum of two Gaussian distributions (
R
2
, 0.91 to 0.96). The normal plot technique revealed a mixture of two populations of MICs separated by MICs of 1 mg/liter for itraconazole, 1 mg/liter for voriconazole, and 0.125 mg/liter for posaconazole. Recursive partitioning analysis confirmed these ECVs, since the proportions of isolates harboring
cyp51A
mutations associated with azole resistance were less than 20%, 20 to 30%, and >70% when the MICs were lower than, equal to, and higher than the above-mentioned ECVs, respectively.
Broad-Spectrum β-Lactam Antibiotics for Treating Experimental Peritonitis in Mice Due to Klebsiella pneumoniae Producing the Carbapenemase OXA-48
Authors: Mimoz Olivier , Grégoire Nicolas , Poirel Laurent , Marliat Manuella , Couet William , Nordmann Patrice
Published: February 2012

A lethal peritonitis model was induced in mice with a
Klebsiella pneumoniae
isolate producing the carbapenemase OXA-48. Administration of a single dose (up to 100 mg/kg) of the antibiotic piperacillin-tazobactam, imipenem-cilastatin, ertapenem, or cefotaxime had little or no impact on lethality. Ceftazidime had the highest efficacy
in vivo
, which mirrored its
in vitro
activity; this was not the case for carbapenems. Therefore, ceftazidime may be recommended for the treatment of infections due to OXA-48 producers if they do not coproduce an extended-spectrum β-lactamase or a plasmid-mediated AmpC cephalosporinase.
Antimicrobial Action and Cell Agglutination by the Eosinophil Cationic Protein Are Modulated by the Cell Wall Lipopolysaccharide Structure
Authors: Pulido David , Moussaoui Mohammed , Andreu David , Nogués M. Victòria , Torrent Marc , Boix Ester
Published: February 2012

Antimicrobial proteins and peptides (AMPs) are essential effectors of innate immunity, acting as a first line of defense against bacterial infections. Many AMPs exhibit high affinity for cell wall structures such as lipopolysaccharide (LPS), a potent endotoxin able to induce sepsis. Hence, understanding how AMPs can interact with and neutralize LPS endotoxin is of special relevance for human health. Eosinophil cationic protein (ECP) is an eosinophil secreted protein with high activity against both Gram-negative and Gram-positive bacteria. ECP has a remarkable affinity for LPS and a distinctive agglutinating activity. By using a battery of LPS-truncated
E. coli
mutant strains, we demonstrate that the polysaccharide moiety of LPS is essential for ECP-mediated bacterial agglutination, thereby modulating its antimicrobial action. The mechanism of action of ECP at the bacterial surface is drastically affected by the LPS structure and in particular by its polysaccharide moiety. We have also analyzed an N-terminal fragment that retains the whole protein activity and displays similar cell agglutination behavior. Conversely, a fragment with further minimization of the antimicrobial domain, though retaining the antimicrobial capacity, significantly loses its agglutinating activity, exhibiting a different mechanism of action which is not dependent on the LPS composition. The results highlight the correlation between the protein's antimicrobial activity and its ability to interact with the LPS outer layer and promote bacterial agglutination.
Preclinical Evaluation of the HIV-1 Fusion Inhibitor L'644 as a Potential Candidate Microbicide
Authors: Harman Sarah , Herrera Carolina , Armanasco Naomi , Nuttall Jeremy , Shattock Robin J.
Published: February 2012

Topical blockade of the gp41 fusogenic protein of HIV-1 is one possible strategy by which microbicides could prevent HIV transmission, working early against infection, by inhibiting viral entry into host cells. In this study, we examined the potential of gp41 fusion inhibitors (FIs) as candidate anti-HIV microbicides. Preclinical evaluation of four FIs, C34, T20, T1249, and L'644, was performed using cellular and
ex vivo
genital and colorectal tissue explant models. Increased and sustained activity was detected for L'644, a cholesterol-derivatized version of C34, relative to the other FIs. The higher potency of L'644 was further increased with sustained exposure of cells or tissue to the compound. The activity of L'644 was not affected by biological fluids, and the compound was still active when tissue explants were treated after viral exposure. L'644 was also more active than other FIs against a viral escape mutant resistant to reverse transcriptase inhibitors (RTIs), demonstrating the potential of L'644 to be included as part of a multiactive antiretroviral (ARV) combination-based microbicide. These data support the further development of L'644 for microbicide application.
Acyclovir Achieves a Lower Concentration in African HIV-Seronegative, Herpes Simplex Virus 2-Seropositive Women than in Non-African Populations
Authors: Lu Yanhui , Celum Connie , Wald Anna , Baeten Jared M. , Cowan Frances , Delany-Moretlwe Sinead , Reid Stewart E. , Hughes James P. , Wilcox Ellen , Corey Lawrence , Hendrix Craig W.
Published: February 2012

Acyclovir pharmacokinetics was evaluated in 68 HIV-seronegative, herpes simplex virus 2 (HSV-2)-seropositive African women, who received a single oral 400-mg dose of acyclovir, with plasma acyclovir concentrations measured over 8 h. Geometric mean peak concentration and area under the concentration-time curve were 0.31 μg/ml and 1.59 h · μg/ml, respectively, 54% and 52% lower than values from non-Africans. Lower acyclovir concentrations may partly explain the reduced acyclovir suppression of HSV-2 genital ulcer recurrence in HPTN 039 African women participants.
Artemisinin-Naphthoquine Combination Therapy for Uncomplicated Pediatric Malaria: a Tolerability, Safety, and Preliminary Efficacy Study
Authors: Benjamin John , Moore Brioni , Lee Sook Ting , Senn Michèle , Griffin Susan , Lautu Dulci , Salman Sam , Siba Peter , Mueller Ivo , Davis Timothy M. E.
Published: February 2012

Artemisinin-naphthoquine (ART-NQ) is a fixed-dose coformulated antimalarial therapy recommended as a single-dose treatment and marketed in Papua New Guinea among other tropical countries. We conducted a tolerability, safety, and efficacy study of ART-NQ for Papua New Guinean children aged 5 to 12 years with uncomplicated malaria, comparing single-dose ART-NQ (15 and 6 mg/kg of body weight) given with water (group 1;
n
= 15), single-dose ART-NQ (22 and 9 mg/kg) given with milk (group 2;
n
= 17), or two daily doses of 22 and 9 mg/kg given with water (group 3;
n
= 16). Of the 48 children (45 with
Plasmodium falciparum
malaria, 2 with
Plasmodium vivax
malaria, and 1 with mixed-species malaria), 2 in group 2 did not attend all follow-up assessments. All regimens were well tolerated, with no serious adverse events. There were no clinically significant changes in pulse, blood pressure, rate-corrected electrocardiographic QT, routine biochemistry/hematology, or hearing after treatment. Fever clearance was prompt. Mean 50% parasite clearance times were 4, 4, and 5 h for groups 1, 2, and 3, respectively. One group 1 patient had PCR-confirmed
P. falciparum
recrudescence at day 23; four had PCR-confirmed
P. falciparum
reinfections on day 28 or 42; and three had
P. vivax
infections detected on day 42. The only recurrent parasitemia in groups 2 and 3 occurred in a group 2 child who developed a
P. vivax
infection on day 42. Day 14 gametocyte positivity levels were 20%, 27%, and 9% in groups 1, 2, and 3, respectively. The lower single ART-NQ dose was associated with relatively frequent recurrence of parasitemia, but the prolonged gametocytemia in all three groups has implications for the transmission of malaria.
Efficacy of Human Simulated Exposures of Ceftaroline against Phenotypically Diverse Enterobacteriaceae Isolates
Authors: Housman Seth T. , Keel Rebecca A. , Crandon Jared L. , Williams Gregory , Nicolau David P.
Published: February 2012

Ceftaroline fosamil, a new broad-spectrum cephalosporin, exhibits potent bactericidal activity against common Gram-negative pathogens, including
Enterobacteriaceae
, and Gram-positive pathogens, including methicillin-resistant
Staphylococcus aureus
and penicillin-resistant
Streptococcus pneumoniae
. The purpose of this study was to evaluate the efficacy of a human simulated dose of ceftaroline fosamil against clinical
Enterobacteriaceae
in both neutropenic and immunocompetent mouse thigh infection models. Thirty-five
Enterobacteriaceae
isolates with ceftaroline MICs ranging from 0.25 to 32 μg/ml were selected for the neutropenic model, and five
Escherichia coli
isolates were also tested in the immunocompetent model. Two hours after inoculation, the ceftaroline fosamil human simulated regimen of 600 mg intravenously (i.v.) every 12 h was administered. The change in log
10
CFU after 24 h was compared to that in 0 h controls. The human simulated regimen produced predictable efficacy against 18 of 20 isolates with a MIC of ≤1 μg/ml. Similar efficacy was seen in the immunocompetent model against isolates with a MIC of ≤2 μg/ml, and enhanced efficacy was observed against the isolate with a MIC of 4 μg/ml. Human simulated exposures to ceftaroline fosamil at 600 mg every 12 h provided predictable efficacy against
Enterobacteriaceae
with MICs of ≤1 μg/ml and enhanced efficacy within the immunocompetent model, supporting the clinical utility of ceftaroline fosamil against these organisms.
High Levels of Antibodies to Multiple Domains and Strains of VAR2CSA Correlate with the Absence of Placental Malaria in Cameroonian Women Living in an Area of High Plasmodium falciparum Transmission
Authors: Tutterrow Yeung L. , Avril Marion , Singh Kavita , Long Carole A. , Leke Robert J. , Sama Grace , Salanti Ali , Smith Joseph D. , Leke Rose G. F. , Taylor Diane W.
Published: February 2012

Placental malaria, caused by sequestration of
Plasmodium falciparum
-infected erythrocytes in the placenta, is associated with increased risk of maternal morbidity and poor birth outcomes. The parasite antigen VAR2CSA (variant surface antigen 2-chondroitin sulfate A) is expressed on infected erythrocytes and mediates binding to chondroitin sulfate A, initiating inflammation and disrupting homeostasis at the maternal-fetal interface. Although antibodies can prevent sequestration, it is unclear whether parasite clearance is due to antibodies to a single Duffy binding-like (DBL) domain or to an extensive repertoire of antibodies to multiple DBL domains and allelic variants. Accordingly, plasma samples collected longitudinally from pregnant women were screened for naturally acquired antibodies against an extensive panel of VAR2CSA proteins, including 2 to 3 allelic variants for each of 5 different DBL domains. Analyses were performed on plasma samples collected from 3 to 9 months of pregnancy from women living in areas in Cameroon with high and low malaria transmission. The results demonstrate that high antibody levels to multiple VAR2CSA domains, rather than a single domain, were associated with the absence of placental malaria when antibodies were present from early in the second trimester until term. Absence of placental malaria was associated with increasing antibody breadth to different DBL domains and allelic variants in multigravid women. Furthermore, the antibody responses of women in the lower-transmission site had both lower magnitude and lesser breadth than those in the high-transmission site. These data suggest that immunity to placental malaria results from high antibody levels to multiple VAR2CSA domains and allelic variants and that antibody breadth is influenced by malaria transmission intensity.
The CovS/CovR Acid Response Regulator Is Required for Intracellular Survival of Group B Streptococcus in Macrophages
Authors: Cumley Nicola J. , Smith Leanne M. , Anthony Mark , May Robin C.
Published: February 2012

Group B
Streptococcus
(GBS) is a leading cause of neonatal meningitis and septicemia. The ability of this organism to survive inside phagocytic cells is poorly understood but thought to be an important step for the establishment of disease in the host. Here, we demonstrate that GBS shows prolonged survival within J774 macrophages and that the capacity to survive is not significantly changed across a diverse range of strains representing different serotypes, multilocus sequence types (MLST), and sites of clinical isolation. Using staining for the lysosome-associated membrane protein (LAMP) and by pharmacological inhibition of phagosome acidification, we demonstrate that streptococci reside in a phagosome and that acidification of the phagosome is required for GBS to survive intracellularly. Moreover, we show that the GBS two-component system CovS/CovR, which is the major acid response regulator in this organism, is required for survival inside the phagosome.
Leptin Protects Host Cells from Entamoeba histolytica Cytotoxicity by a STAT3-Dependent Mechanism
Authors: Marie Chelsea S. , Verkerke Hans P. , Paul Shom N. , Mackey Aaron J. , Petri William A.
Published: February 2012

The adipocytokine leptin links nutritional status to immune function. Leptin signaling protects from amebiasis, but the molecular mechanism is not understood. We developed anin vitromodel of ameba-host cell interaction to test the hypothesis that leptin prevents ameba-induced apoptosis in host epithelial cells. We demonstrated that activation of mammalian leptin signaling increased cellular resistance to amebic cytotoxicity, including caspase-3 activation. Exogenous expression of the leptin receptor conferred resistance in susceptible cells, and leptin stimulation enhanced protection. A series of leptin receptor signaling mutants showed that resistance to amebic cytotoxicity was dependent on activation of STAT3 but not the Src homology-2 domain-containing tyrosine phosphatase (SHP-2) or STAT5. A common polymorphism in the leptin receptor (Q223R) that increases susceptibility to amebiasis in humans and mice was found to increase susceptibility to amebic cytotoxicity in single cells. The Q223R polymorphism also decreased leptin-dependent STAT3 activation by 21% relative to that of the wild-type (WT) receptor (P= 0.035), consistent with a central role of STAT3 signaling in protection. A subset of genes uniquely regulated by STAT3 in response to leptin was identified. Most notable were the TRIB1 and suppressor of cytokine signaling 3 (SOCS3) genes, which have opposing roles in the regulation of apoptosis. Overall apoptotic genes were highly enriched in this gene set (P< 1E−05), supporting the hypothesis that leptin regulation of host apoptotic genes via STAT3 is responsible for protection. This is the first demonstration of a mammalian signaling pathway that restricts amebic pathogenesis and represents an important advance in our mechanistic understanding of how leptin links nutrition and susceptibility to infection.
Involvement of Peptidylprolyl
cis
/
trans
Isomerases in Enterococcus faecalis Virulence
Authors: Reffuveille Fany , Connil Nathalie , Sanguinetti Maurizio , Posteraro Brunella , Chevalier Sylvie , Auffray Yanick , Rince Alain
Published: February 2012

Peptidylprolyl
cis
/
trans
isomerases (PPIases) are enzymes involved in protein folding. Analysis of the genome sequence of
Enterococcus faecalis
V583 allowed for identification of 3 PPIases carrying genes.
ef2898
encodes an intracellular PPIase which was not shown to be important for the
E. faecalis
stress response or virulence. The other two PPIases, the parvulin family rotamase EF0685 and the cyclophilin family member EF1534, are expected to be surface-exposed proteins. They were shown to be important for virulence and resistance to NaCl. A Δ
ef0685
Δ
ef1534
mutant was also more resistant to oxidative stress, was able to grow under a high manganese concentration, and showed altered resistance to ampicillin and quinolone antibiotics.
Effect of specific resistance training on forearm pain and work disability in industrial technicians: cluster randomised controlled trial
Authors: Andersen Lars L , Jakobsen Markus D , Pedersen Mogens T , Mortensen Ole S , Sjøgaard Gisela , Zebis Mette K
Published: February 2012

Objectives

To determine the effect of specific resistance training on forearm pain and work disability in industrial technicians.

Design and setting

Two-armed cluster randomised controlled trial of 20 weeks performed at two industrial production units in Copenhagen, Denmark.

Participants

Working-age industrial technicians both with and without pain and disability.

Interventions

The training group (n=282) performed specific resistance training for the shoulder, neck and arm muscles three times a week. The control group (n=255) was advised to continue normal physical activity.

Outcome

All participants rated forearm pain intensity (Visual Analogue Scale, 0–100 mm) once a week (primary outcome) and replied to a questionnaire on work disability (Disability of the Arm Shoulder and Hand, 0–100) at baseline and follow-up (secondary outcome).

Results

Questionnaires were sent to 854 workers of which 30 (n=282) and 27 (n=255) clusters were randomised to training and control, respectively. Of these, 211 and 237 participants, respectively, responded to the follow-up questionnaire. Intention-to-treat analyses including both individuals with and without pain showed that from baseline to follow-up, pain intensity and work disability decreased more in the training group than in the control group (4–5 on a scale of 0–100, p<0.01–0.001). Among those with pain >30 mm Visual Analogue Scale at baseline (n=54), the OR for complete recovery at follow-up in the training group compared with the control group was 4.6 (95% CI 1.2 to 17.9). Among those with work disability >30 at baseline (n=113), the OR for complete recovery at follow-up in the training group compared with the control group was 6.0 (95% CI 1.8 to 19.8).

Conclusion

Specific resistance training of the shoulder, neck and arm reduces forearm pain and work disability among industrial technicians.

Trial registration number

NCT01071980.
Where do patients known to a community palliative care service die?
Authors: Capel Margred , Gazi Terri , Vout Lauren , Wilson Nicola , Finlay Ilora
Published: February 2012

Objectives

The majority of people would prefer to die at home and National Health Service policy aims to support this concept. This service evaluation compared the preferred and actual place of death of patients known to a specialist community palliative care service.

Design

All deaths of patients (n=788) known to the specialist palliative care service from 1 January 2009 to 31 December 2010 were examined in a service evaluation to compare the actual place of death with the preferred place of death previously identified by the patient. Triggers for admission were established when patients did not achieve this preference.

Results

69% of patients (n=263) who expressed a preference to die at home and 82% of patients (n=93) who expressed a preference to die as inpatients in the hospice fulfilled these preferences. 71% of patients (n=298) who wanted to die in their current place of residence achieved this preference.

54% of patients (n=121) who declined to express a preference for end-of-life care subsequently died in hospital, reflecting the importance of advance care planning.

Conclusions

The perceived lack of social support for patients dying at home is a significant trigger for admission to a hospice. The provision of sitters to support patients dying at home may ensure people achieve their preference. Commissioners consider preferred place of care to be a marker of quality, but clinical events that precipitate admission are often outside the influence of the palliative care team.
Development of Prognosis in Palliative care Study (PiPS) predictor models to improve prognostication in advanced cancer: prospective cohort study
Authors: Gwilliam Bridget , Keeley Vaughan , Todd Chris , Gittins Matthew , Roberts Chris , Kelly Laura , Barclay Stephen , Stone Patrick C
Published: February 2012

Objective

To develop a novel prognostic indicator for use in patients with advanced cancer that is significantly better than clinicians' estimates of survival.

Design

Prospective multicentre observational cohort study.

Setting

18 palliative care services in the UK (including hospices, hospital support teams, and community teams).

Participants

1018 patients with locally advanced or metastatic cancer, no longer being treated for cancer, and recently referred to palliative care services.

Main outcome measures

Performance of a composite model to predict whether patients were likely to survive for “days” (0-13 days), “weeks” (14-55 days), or “months+” (>55 days), compared with actual survival and clinicians' predictions.

Results

On multivariate analysis, 11 core variables (pulse rate, general health status, mental test score, performance status, presence of anorexia, presence of any site of metastatic disease, presence of liver metastases, C reactive protein, white blood count, platelet count, and urea) independently predicted both two week and two month survival. Four variables had prognostic significance only for two week survival (dyspnoea, dysphagia, bone metastases, and alanine transaminase), and eight variables had prognostic significance only for two month survival (primary breast cancer, male genital cancer, tiredness, loss of weight, lymphocyte count, neutrophil count, alkaline phosphatase, and albumin). Separate prognostic models were created for patients without (PiPS-A) or with (PiPS-B) blood results. The area under the curve for all models varied between 0.79 and 0.86. Absolute agreement between actual survival and PiPS predictions was 57.3% (after correction for over-optimism). The median survival across the PiPS-A categories was 5, 33, and 92 days and survival across PiPS-B categories was 7, 32, and 100.5 days. All models performed as well as, or better than, clinicians' estimates of survival.

Conclusions

In patients with advanced cancer no longer being treated, a combination of clinical and laboratory variables can reliably predict two week and two month survival.
Quality for home palliative care: an Italian metropolitan multicentre JCI-certified model
Authors: Rizzi Franco , Pizzuto Massimo , Lodetti Laura , Corli Oscar , Da Col Daria , Damiani Maria Eugenia , Mihali Dorian , Piva Laura , Saita Luigi , Vinci Maria , Bonaldi Antonio
Published: February 2012

Background

Assessing the quality of care and service delivery through the analysis of ad hoc indicators is a relevant process for quality monitoring and improvement with a view to providing patients, the community and administrators alike with appropriate elements of evaluation. This paper describes the key results of a certification process based on the Joint Commission International (JCI) criteria for the home hospitalisation model implemented by the palliative care units of seven Milan hospitals for terminally ill patients with cancer.

Methods

In 2006, the interhospital working team implemented a certification project based on the JCI Disease or Condition-Specific Care (DSCS) programme. Thirty standards subdivided into five functional areas with 150 measurable elements were the starting-point for periodic improvement plans within and across participating hospitals. Programme compliance was analysed in terms of annual performance improvement and consistency across the seven PCUs involved in achieving set goals. The JCI standards were applied on 3316 terminally ill patients with cancer treated at home from 2005 to 2009.

Results

As a result of the work carried out, the JCI survey conducted 3 years after project implementation demonstrated full compliance with the established standards, leading to the JCI certification award (for the first time in this clinical setting internationally).

Conclusion

The work carried out with a view to certification has confirmed the possibility that facilities spread across different hospitals can actually share common processes and standardise the activities for the care of end-of-life patients with cancer at home as if they were one single service provider.
Use of qualitative methods to identify solutions to selected equine welfare problems in Ireland
Authors: Collins J. A. , More S. J. , Hanlon A. , Wall P. G. , McKenzie K. , Duggan V.
Published: February 2012

This paper explores the views of those in the Irish equine industry, organisations and government regarding necessary improvements to equine welfare in Ireland at unregulated gatherings and during the disposal process. Three qualitative research methods were employed, namely semistructured interviews, focus groups and a structured, facilitated workshop. Representatives from industry, welfare societies, socially disadvantaged groupings and government engaged with this process and shared their views regarding horse welfare and implementable solutions with merit to address welfare problems. A consensus was achieved that equine welfare in Ireland could be improved by the development of a comprehensive identification system, a Code of Practice for horse gatherings, a horse licensing scheme, ring‐fenced funding to promote responsible, humane horse disposal and better means of raising awareness of the value of safeguarding horse welfare for the benefit of all parties.
Malley diabase dykes of the Slave craton, Canadian Shield: U–Pb age, paleomagnetism, and implications for continental reconstructions in the early Paleoproterozoic1Geological Survey of Canada Contribution 20110114.
Authors: Buchan Kenneth L. , LeCheminant Anthony N. , van Breemen Otto
Published: February 2012

The NE-trending Malley dyke swarm, dated herein at 2231 ± 2 Ma (U–Pb baddeleyite), extends from the central Slave craton to the vicinity of the Kilohigok basin, and may continue farther to the northeast as the geochemically similar Brichta dyke swarm, having been offset sinistrally along the prominent Bathurst fault. It carries a characteristic high unblocking temperature paleomagnetic component of single polarity directed up SE (mean direction: D = 138.3°, I = –53.8°), with corresponding paleopole at 50.8°S, 50.0°W. Lower unblocking temperature components, in some cases directed down SE, similar to ca 1.75 Ga post-Hudsonian overprints, are easily removed using combined alternating field (AF) thermal demagnetization, but difficult to remove using AF cleaning alone. The characteristic remanence has not been demonstrated primary, but is significantly older than 2.03 Ga, the age of Lac de Gras dykes, based on a baked contact test at a Lac de Gras – Malley dyke intersection. In addition, an E- to ESE-trending dyke carries a down WNW remanence, typical of 2.19 Ga Dogrib dykes near Yellowknife, suggesting that regional overprinting has not affected the study area since Dogrib emplacement, and that the Malley remanence was acquired at or shortly after Malley emplacement. Comparing Malley and Lac de Gras paleopoles with the 2.22–2.00 Ga Superior craton apparent polar wander path indicates that the two cratons were (i) not in their present relative orientation at 2.23 or 2.03 Ga, and (ii) likely not drifting in close proximity to one another as parts of a single (super)continent throughout the 2.23–2.03 Ga interval.
Vertebrate fossils (Dinosauria) from the Bonnet Plume Formation, Yukon Territory, Canada
Authors: Evans David C. , Vavrek Matthew J. , Braman Dennis R. , Campione Nicolás E. , Dececchi T. Alexander , Zazula Grant D.
Published: February 2012

Dinosaurs and other terrestrial vertebrates are poorly documented in the Mesozoic of the Canadian polar region. Here, we provide a complete review of the Upper Cretaceous (Maastrichtian) vertebrate fauna of the Bonnet Plume Formation in the northeastern Yukon Territory, Canada, which includes the description of the first newly collected dinosaur bones from this unit in almost half a century. Previously reported fragmentary dinosaur remains collected in the early 1960’s pertain to an indeterminate hadrosaurid. New material includes a poorly preserved forelimb bone and a pedal phalanx. These new remains pertain to at least one species of non-hadrosaurid ornithischian dinosaur, and the humerus is tentatively referred to a small-bodied basal ornithopod. The new vertebrate fossils from the Bonnet Plume Formation provide further evidence of vertebrates from this unit. However, directed field surveys in 2008 and 2009 suggest that vertebrate fossils are not abundant. A review of the known localities of terrestrial Mesozoic vertebrates from the Canadian Arctic indicate that it had a relatively diverse community of terrestrial vertebrates, including dinosaurs, during the Late Cretaceous, but emphasizes our limited knowledge of the Mesozoic Arctic and considerable potential for future exploration and discovery.
Mafic and ultrapotassic rocks from the Canyon domain (central Grenville Province): geochemistry and tectonic implications
Authors: Valverde Cardenas Carolina , Indares Aphrodite , Jenner George
Published: February 2012

The Canyon domain and the Banded complex in the Manicouagan area of the Grenville Province preserve a record of magmatic activity from ∼1.4 to 1 Ga. This study focuses on 1.4–1.2 Ga mafic rocks and 1 Ga ultrapotassic dykes. Geochemistry and Sm–Nd isotopic signatures were used to constrain the origin of these rocks and evaluate the changing role of the mantle with time and tectonic setting from the late evolution of the Laurentian margin to the Grenvillian orogeny, in the Manicouagan area. The mafic rocks include layers inferred to represent flows, homogeneous bodies in mafic migmatite, and deformed dykes, all of which were recrystallized under granulite-facies conditions during the Grenvillian orogeny. In spite of the complexities inherent in these deformed and metamorphosed mafic rocks, we were able to recognize suites with distinctive geochemical and isotopic signatures. Integration of this data along with available ages is consistent with a 1.4 Ga continental arc cut by 1.2 Ga non-arc basalts derived from depleted asthenospheric mantle, with varied degrees of crustal contamination and inferred to represent magmatism in an extensional environment. The 1 Ga ultrapotassic dykes postdate the Grenvillian metamorphism. They are extremely enriched in incompatible elements, have negative Nb anomalies, relatively unradiogenic Sr-isotopic compositions (initial 87Sr/86Sr ~ 0.7040) and εNd –3 to –15. Some dykes have compositional characteristics consistent with derivation from the mantle, ruling out crustal contamination as a major process in their petrogenesis. The most likely source region for the ultrapotassic dykes is a metasomatized subcontinental lithospheric mantle, with thermal input from the asthenosphere in association with post-orogenic delamination.
Therapeutic efficacy of Hypericum perforatum L. extract for mice infected with an influenza A virus
Authors: Xiuying Pu , Jianping Liang , Ruofeng Shang , Liye Zhou , Xuehong Wang , Yan Li
Published: February 2012

Hypericum perforatum L., a plant used in Chinese herbal medicine, has been proven effective against many viral diseases. In the present study, the therapeutic efficacy of an extract of H. perforatum (HPE) against influenza A virus (IAV) was investigated in mice. Whether HPE would be a promising agent for influenza treatment was evaluated by measuring the protection rate, mean survival days, lung index, and viral titer, as well as the secretion of IL-6, interleukin-10 (IL-10), tumour necrosis factor-α (TNF-α), and interferon-gamma (IFN-γ) in lung tissue and serum on days 3 and 5 post-infection. The results showed that HPE could reduce the lung index and viral titer of mice infected with IAV, decrease mortality, and prolong the mean survival time. HPE decreased the concentration of IL-6 and TNF-α in lung tissue and serum on day 5 post-infection. In contrast, HPE enhanced the lung and serum levels of IL-10 and IFN-γ on the days 3 and 5 post-infection. Our study indicates that HPE has significant therapeutic efficacy for mice infected with IAV. The possible reasons for these results were concluded to be pertaining to up-regulating the expression of IL-10 and IFN-γ, and down-regulating the secretion of IL-6 and TNF-α in lung and serum.
Endothelin-1 induces neutrophil recruitment in adaptive inflammation via TNFα and CXCL1/CXCR2 in mice
Authors: Zarpelon Ana C. , Pinto Larissa G. , Cunha Thiago M. , Vieira Silvio M. , Carregaro Vanessa , Souza Guilherme R. , Silva João S. , Ferreira Sérgio H. , Cunha Fernando Q. , Verri Waldiceu A.
Published: February 2012

Endothelin mediates neutrophil recruitment during innate inflammation. Herein we address whether endothelin-1 (ET-1) is involved in neutrophil recruitment in adaptive inflammation in mice, and its mechanisms. Pharmacological treatments were used to determine the role of endothelin in neutrophil recruitment to the peritoneal cavity of mice challenged with antigen (ovalbumin) or ET-1. Levels of ET-1, tumour necrosis factor α (TNFα), and CXC chemokine ligand 1 (CXCL1) were determined by enzyme-linked immunosorbent assay. Neutrophil migration and flow cytometry analyses were performed 4 h after the intraperitoneal stimulus. ET-1 induced dose-dependent neutrophil recruitment to the peritoneal cavity. Treatment with the non-selective ETA/ETBreceptor antagonist bosentan, and selective ETAor ETBreceptor antagonists BQ-123 or BQ-788, respectively, inhibited ET-1- and ovalbumin-induced neutrophil migration to the peritoneal cavity. In agreement with the above, the antigen challenge significantly increased levels of ET-1 in peritoneal exudates. The ET-1- and ovalbumin-induced neutrophil recruitment were reduced in TNFR1 deficient mice, and by treatments targeting CXCL1 or CXC chemokine receptor 2 (CXCR2); further, treatment with bosentan, BQ-123, or BQ-788 inhibited ET-1- and antigen-induced production of TNFα and CXCL1. Furthermore, ET-1 and ovalbumin challenge induced an increase in the number of cells expressing the Gr1+markers in the granulocyte gate, CD11c+markers in the monocyte gate, and CD4+and CD45+(B220) markers in the lymphocyte gate in an ETA- and ETB-dependent manner, as determined by flow cytometry analysis, suggesting that ET-1 might be involved in the recruitment of neutrophils and other cells in adaptive inflammation. Therefore, the present study demonstrates that ET-1 is an important mediator for neutrophil recruitment in adaptive inflammation via TNFα and CXCL1/CXCR2-dependent mechanism.
Blood pressure reducing effects ofPhalaris canariensisin normotensive and spontaneously hypertensive rats
Authors: Passos Clévia Santos , Carvalho Lucimeire Nova , Pontes Roberto Braz , Campos Ruy Ribeiro , Ikuta Olinda , Boim Mirian Aparecida
Published: February 2012

The birdseed Phalaris canariensis (Pc) is popularly used as an antihypertensive agent. The aqueous extract of Pc (AEPc) was administered in adult normotensive Wistar rats and spontaneously hypertensive rats (SHR) and in prehypertensive young SHR (SHRY, 3 weeks old). Animals received AEPc (400 mg·kg–1·day–1, by gavage) for 30 days, then groups were divided into 2 subgroups: one was treated for another 30 days and the other received water instead of AEPc for 30 days. AEPc reduced systolic blood pressure (SBP) in both adult groups; however, treatment interruption was followed by a gradual return of the SBP to baseline levels. SHRYbecame hypertensive 30 days after weaning. AEPc minimized the increase in SBP in SHRY, but blood pressure rose to levels similar to those in the untreated group with treatment interruption. There were no changes in renal function, diuresis, or Na+excretion. Pc is rich in tryptophan, and the inhibition of the metabolism of tryptophan to kynurenine, a potential vasodilator factor, prevented the blood pressure reducing effect of AEPc. Moreover, AEPc significantly reduced sympathoexcitation. Data indicate that the metabolic derivative of tryptophan, kinurenine, may be a mediator of the volume-independent antihypertensive effect of Pc, which was at least in part mediated by suppression of the sympathetic tonus.
Choice of diet impacts the incidence of stroke-related symptoms in the spontaneously hypertensive stroke-prone rat model
Authors: Slemmer Jennifer E. , Shaughnessy Kevin S. , Scanlan Adam P. , Sweeney Marva I. , Gottschall-Pass Katherine T.
Published: February 2012

The spontaneously hypertensive stroke-prone (SHRSP) rat is a commonly used model of cerebrovascular disease and hypertension. SHRSP rats have been shown to develop stroke-related symptoms (SRS) by age 14 weeks when fed a purified diet, such as AIN-93G, supplemented with 1% NaCl. We conducted a pathology pilot study to compare the incidence of SRS in SHRSP rats fed either AIN-93G (with 1% NaCl in drinking water) or commercially available rat chow (with 4% NaCl in the diet), starting at 8 weeks of age. These results prompted us to analyze data from 5 earlier feeding trials using SHRSP rats. Overall, we found that SHRSP rats fed AIN-93G purified diet for 8 or 17 weeks did not demonstrate SRS (n = 18), whereas all SHRSP rats fed lab chow exhibited SRS at age 15.1 ± 0.6 weeks (n = 23). In addition, SHRSP rats fed lab chow had decreased mass gain starting at age 13 weeks, as well as decreased feed efficiencies after the first 5 weeks of feeding (p < 0.05). In conclusion, our data suggest that diet composition is a major contributor to the onset of stroke in SHRSP rats and that diet choice should be critically evaluated based on endpoint measures in the SHRSP model.
Effects of resveratrol on the amelioration of insulin resistance in KKAy mice
Authors: Chen Sifan , Li Jinghua , Zhang Zili , Li Wenxue , Sun Yanshuang , Zhang Quanxin , Feng Xiang , Zhu Wei
Published: February 2012

Resveratrol (Res) has attracted great interest regarding its effects related to metabolic syndrome, especially for lipid metabolic disorder or insulin resistance; however, the underlying mechanisms remain elusive. To explore the effects of Res on insulin sensitivity and the underlying mechanism, insulin-resistant KKAy mice were treated with 2 and 4 g/kg diets of Res for 12 weeks. After the treatment, blood glucose, serum insulin, glucose tolerance, and insulin tolerance, as well as other indices such as adiponectin mRNA in epididymal adipose tissues, silent information regulator 1 (Sirt1), AMP-activated protein kinase (AMPK), insulin receptor substrate 1 (IRS1), and phosphorylated protein kinase B (PKB/AKT) proteins in liver and soleus muscles, were investigated. The results indicate that Res intervention reduces blood glucose and serum insulin levels, improves insulin and glucose tolerance, increases serum adiponectin and adiponectin mRNA levels in epididymal adipose tissues, and more importantly, elevates Sirt1, p-AMPK, p-IRS1, and p-AKT levels in liver and soleus muscles. In conclusion, Res could improve insulin sensitivity and ameliorate insulin resistance in KKAy mice, which may be associated with the upregulation of Sirt1 protein in liver and soleus muscles and consequent AMPK activation, as well as insulin-signaling related proteins.
Folic acid supplementation attenuates high fat diet induced hepatic oxidative stress via regulation of NADPH oxidase
Authors: Sarna Lindsei K. , Wu Nan , Wang Pengqi , Hwang Sun-Young , Siow Yaw L. , O Karmin
Published: February 2012

Diets high in saturated fat and cholesterol facilitate weight gain, a predisposing factor that contributes to the onset of obesity and metabolic disorders. Hepatic oxidative stress is commonly reported in various animal models of obesity and has been associated with enhanced expression of NADPH oxidase. We have previously reported several antioxidant mechanisms through which folic acid confers protection during hyperhomocysteinemia-induced oxidative stress. The objective of the present study was to investigate whether folic acid supplementation ameliorates high-fat diet induced oxidative stress in the liver, and to identify the underlying mechanisms. Male C57BL/6J mice were fed a control diet, a high-fat diet, or a high-fat diet supplemented with folic acid for 12 weeks. A high-fat diet led to increased body mass, hepatic lipid peroxidation, and liver injury. There was a significant increase in hepatic NADPH oxidase activity, which was associated with enhanced expression of several NADPH-oxidase subunits. Folic acid supplementation had a protective effect against high-fat diet induced hepatic oxidative stress and liver injury. Further analysis revealed that the antioxidant effect of folic acid was attributed, in part, to transcriptional regulation of NADPH oxidase. These results suggested that folic acid supplementation may be hepatoprotective from liver injury associated with a high-fat diet.
Activation of proteolytic enzymes and depression of the sarcolemmal Na+/K+-ATPase in ischemia–reperfused heart may be mediated through oxidative stress
Authors: Singh Raja B. , Hryshko Larry , Freed Darren , Dhalla Naranjan S.
Published: February 2012

We tested whether the activation of proteolytic enzymes, calpain, and matrix metalloproteinases (MMPs) during ischemia–reperfusion (I/R) is mediated through oxidative stress. For this purpose, isolated rat hearts were subjected to a 30 min global ischemia followed by a 30 min reperfusion. Cardiac function was monitored and the activities of Na+/K+-ATPase, Mg2+-ATPase, calpain, and MMP were measured. Depression of cardiac function and Na+/K+-ATPase activity in I/R hearts was associated with increased calpain and MMP activities. These alterations owing to I/R were similar to those observed in hearts perfused with hypoxic medium, H2O2 and xanthine plus xanthine oxidase. The I/R-induced changes were attenuated by ischemic preconditioning as well as by perfusing the hearts with N-acetylcysteine or mercaptopropionylglycine. Inhibition of MMP activity in hearts treated with doxycycline depressed the I/R-induced changes in cardiac function and Na+/K+-ATPase activity without affecting the calpain activation. On the other hand, inhibition of calpain activity upon treatment with leupeptin or MDL 28170 significantly reduced the MMP activity in addition to attenuating the I/R-induced alterations in cardiac function and Na+/K+-ATPase activity. These results suggest that the I/R-induced depression in Na+/K+-ATPase and cardiac function may be a consequence of the increased activities of both calpain and MMP because of oxidative stress in the heart.