bluuebunny/crossref_metadata_2025 huggingface dataset:
Shared Uncertainty in Measurement Error Problems, with Application to Nevada Test Site Fallout Data
Authors: Li Yehua , Guolo Annamaria , Hoffman F. Owen , Carroll Raymond J.
Published: May 2007

SummaryIn radiation epidemiology, it is often necessary to use mathematical models in the absence of direct measurements of individual doses. When complex models are used as surrogates for direct measurements to estimate individual doses that occurred almost 50 years ago, dose estimates will be associated with considerable error, this error being a mixture of (a) classical measurement error due to individual data such as diet histories and (b) Berkson measurement error associated with various aspects of the dosimetry system. In the Nevada Test Site(NTS) Thyroid Disease Study, the Berkson measurement errors are correlated within strata. This article concerns the development of statistical methods for inference about risk of radiation dose on thyroid disease, methods that account for the complex error structure inherence in the problem. Bayesian methods using Markov chain Monte Carlo and Monte‐Carlo expectation–maximization methods are described, with both sharing a key Metropolis–Hastings step. Regression calibration is also considered, but we show that regression calibration does not use the correlation structure of the Berkson errors. Our methods are applied to the NTS Study, where we find a strong dose–response relationship between dose and thyroiditis. We conclude that full consideration of mixtures of Berkson and classical uncertainties in reconstructed individual doses are important for quantifying the dose response and its credibility/confidence interval. Using regression calibration and expectation values for individual doses can lead to a substantial underestimation of the excess relative risk per gray and its 95% confidence intervals.
A Proportional Hazards Cure Model for the Analysis of Time to Event with Frequently Unidentifiable Causes
Authors: Dahlberg Suzanne E. , Wang Molin
Published: May 2007

SummaryWe propose a semiparametric method for the analysis of masked‐cause failure data that are also subject to a cure. We present estimators for the failure time distribution, the cure rate, and the covariate effect on each of these, assuming a proportional hazards cure model for the time to event of interest and we use the expectation–maximization algorithm to conduct the likelihood maximization. The method is applied to data from a breast cancer clinical trial.
Selective inhibition of prostacyclin synthase activity by rofecoxib
Authors: Griffoni Cristiana , Spisni Enzo , Strillacci Antonio , Toni Mattia , Bachschmid Markus Michael , Tomasi Vittorio
Published: May 2007

The development of cyclooxygenase‐2 (COX‐2) selective inhibitors prompted studies aimed at treating chronic inflammatory diseases and cancer by using this new generation of drugs.Yet, several recent reports pointed out that long‐term treatment of patients with COX‐2 selective inhibitors (especially rofecoxib) caused severe cardiovascular complicances. The aim of this study was to ascertain whether, in addition to inhibiting COX‐2, rofecoxib may also affect prostacyclin (PGI2) level by inhibiting PGI2 forming enzyme (prostacyclin synthase, PGIS). In order to evaluate if selective (celecoxib, rofecoxib) and non‐selective (aspirin, naproxen) anti‐inflammatory compounds could decrease PGI2 production in endothelial cells by inhibiting PGIS, we analyzed the effect of anti‐inflammatory compounds on the enzyme activity by ELISA assay after addition of exogenous substrate, on PGIS protein levels by Western blotting and on its subcellular distribution by confocal microscopy. We also analyzed the effect of rofecoxib on PGIS activity in bovine aortic microsomal fractions enriched in PGIS. This study demonstrates an inhibitory effect of rofecoxib on PGIS activity in human umbilical vein endothelial (HUVE) cells and in PGIS‐enriched bovine aortic microsomal fractions, which is not observed by using other anti‐inflammatory compounds. The inhibitory effect of rofecoxib is associated neither to a decrease of PGIS protein levels nor to an impairment of the enzyme intracellular localization. The results of this study may explain the absence of a clear relationship between COX‐2 selectivity and cardiovascular side effects. Moreover, in the light of these results we propose that novel selective COX‐2 inhibitors should be tested on PGI2 synthase activity inhibition.
Roles of CD147 on T lymphocytes activation and MMP‐9 secretion in Systemic Lupus Erythematosus
Authors: Pistol Gina , Matache Cristiana , Calugaru Ana , Stavaru Crina , Tanaseanu Stefanita , Ionescu Ruxandra , Dumitrache Sergiu , Stefanescu Maria
Published: May 2007

The cellular and molecular mechanisms involved in many abnormalities described in Systemic Lupus Erythematosus (SLE) are still unclear. Some of these abnormalities referred to the hyperactivation of T lymphocytes and the enhanced secretion of MMP‐9 by peripheral blood mononuclear cells (PBMCs). Therefore, in this paper we investigated the potential role of CD147 molecule in these abnormalities. Our results demonstrated that CD147 molecule is overexpressed on CD3+T lymphocytes from SLE patients when compared with CD3+T lymphocytes from healthy donors. Monoclonal anti‐CD147 antibodies, MEM‐M6/1 clone, were able to inhibit protein tyrosine phosphorylation only in CD3 × CD28 costimulated T lymphocytes from SLE patients. However, this monoclonal antibody was unable to inhibit the enhanced activity of MMP‐9 secreted by SLE PBMCs.
Hydrogen sulfide acts as a mediator of inflammation inacute pancreatitis: in vitro studies using isolated mouse pancreatic acinar cells
Authors: Tamizhselvi Ramasamy , Moore Philip K. , Bhatia Madhav
Published: May 2007

Hydrogen sulphide (H2S) is synthesized from L‐cysteine via the action of cystathionine‐γ‐lyase (CSE) and cystathionine‐β‐synthase (CBS). We have earlier shown that H2S acts as a mediator of inflammation. However the mechanism remains unclear. In this study, we investigated the presence of H2S and the expression of H2S synthesizing enzymes, CSE and CBS, in isolated mouse pancreatic acini. Pancreatic acinar cells from mice were incubated with or without caerulein (10−7 M for 30 and 60 min). Caerulein increased the levels of H2S and CSE mRNA expression while CBS mRNA expression was decreased. In addition, cells pre‐treated with DL‐propargylglycine (PAG, 3 mM), a CSE inhibitor, reduced the formation of H2S in caerulein treated cells, suggesting that CSE may be the main enzyme involved in H2S formation in mouse acinar cells. Furthermore, substance P (SP) concentration in the acini and expression of SP gene (preprotachykinin‐A, PPT‐A) and neurokinin‐1 receptor (NK‐1R), the primary receptor for SP, are increased in secretagogue caerulein‐treated acinar cells. Inhibition of endogenous production of H2S by PAG significantly suppressed SP concentration, PPT‐A expression and NK1‐R expression in the acini. To determine whether H2S itself provoked inflammation in acinar cells, the cells were treated with H2S donor drug, sodium hydrosulphide (NaHS), (10, 50 and 100 μM), that resulted in a significant increase in SP concentration and expression of PPT‐A and NK1‐R in acinar cells. These results suggest that the pro‐inflammatory effect of H2S may be mediated by SP‐NK‐1R related pathway in mouse pancreatic acinar cells.
The effect of Cyclosporine A on cardiomyocytes differentiation
Authors: Paslaru Liliana , Davidson Sean , Popescu Irinel , Morange Michel
Published: May 2007

Cyclosporine A (CsA) is a powerful immunosuppressive drug which significantly improved the success of organ transplantation; however, the major limiting factors for the drug's clinical use are its long and short term adverse effects. The present study was conducted to examine, in a dose‐dependent manner, in a model of cardiogenesis, the effect of CsA on cardiomyocytes differentiation.
Adaptive Underrelaxation of Picard Iterations in Ground Water Models
Authors: Durbin Timothy , Delemos David
Published: May 2007

This methods note examines the use of adaptive underrelaxation of Picard iterations to accelerate the solution convergence for nonlinear ground water flow problems. Ground water problems are nonlinear when drains, phreatophytes, stream aquifer, and similar features are simulated. Typically, simple Picard iterations are used to address such nonlinear problems. Nevertheless, the convergence rate can be slow, or convergence cannot be obtained. However, convergence often can be accelerated using Picard iterations with adaptive underrelaxation, and convergence often can be obtained where it otherwise would not occur.
A Hybrid Artificial Neural Network‐Numerical Model for Ground Water Problems
Authors: Szidarovszky Ferenc , Coppola Emery A. , Long Jingjie , Hall Anthony D. , Poulton Mary M.
Published: May 2007

Numerical models constitute the most advanced physical‐based methods for modeling complex ground water systems. Spatial and/or temporal variability of aquifer parameters, boundary conditions, and initial conditions (for transient simulations) can be assigned across the numerical model domain. While this constitutes a powerful modeling advantage, it also presents the formidable challenge of overcoming parameter uncertainty, which, to date, has not been satisfactorily resolved, inevitably producing model prediction errors. In previous research, artificial neural networks (ANNs), developed with more accessible field data, have achieved excellent predictive accuracy over discrete stress periods at site‐specific field locations in complex ground water systems. In an effort to combine the relative advantages of numerical models and ANNs, a new modeling paradigm is presented. The ANN models generate accurate predictions for a limited number of field locations. Appending them to a numerical model produces an overdetermined system of equations, which can be solved using a variety of mathematical techniques, potentially yielding more accurate numerical predictions. Mathematical theory and a simple two‐dimensional example are presented to overview relevant mathematical and modeling issues. Two of the three methods for solving the overdetermined system achieved an overall improvement in numerical model accuracy for various levels of synthetic ANN errors using relatively few constrained head values (i.e., cells), which, while demonstrating promise, requires further research. This hybrid approach is not limited to ANN technology; it can be used with other approaches for improving numerical model predictions, such as regression or support vector machines (SVMs).
Adapting the Environment to Age‐Related Sensory Losses
Authors: Winters Reng K. V.
Published: May 2007

Alteration of the environment to compensate for age‐related sensory losses as well as common pathological sensory losses is necessary to maintain the independent living of many elderly people. Thorough knowledge of the changes in vision, taste, smell, kinesthesia, touch, and hearing that accompany the aging process is essential to the nurse practitioner for accurately assessing environmental alteration. By applying Dorothea Orem's Self‐Care Deficit Nursing Theory, this article illustrates ways for the nurse practitioner to prevent hazards, adapt institutional settings, and support successful independent living. It focuses on adapting the environment to the normal sensory physiological changes that occur with aging, and identifies some common pathological processes that concur with these losses.
Ectopic Pregnancy: A Growing Concern
Authors: Warded Diane Wind
Published: May 2007

Ectopic pregnancy rates have increased threefold since 1970. Ectopic pregnancy continues to be the leading cause of maternal death in the first trimester of pregnancy. The identification of clients with ectopic pregnancies may be difficult. In this article, risk factors, assessment techniques, and treatment strategies are reviewed. A questionnaire is included for use during pregnancy verification to identify those clients who may be at risk of having an ectopic pregnancy. The role of the nurse practitioner in providing comprehensive care is also addressed.
Quality Changes of Shrimp during Boiling in Salt Solution
Authors: Niamnuy C. , Devahastin S. , Soponronnarit S.
Published: May 2007

ABSTRACT:  Boiling shrimp in salt solution is an important step during the production of dried shrimp. In this study the effects of various boiling parameters, namely, concentration of salt solution (2, 3, and 4% w/v), mass ratio of shrimp to salt solution (1:2 and 1:3), boiling time (1, 3, 5, and 7 min), and shrimp size (small and large), on the various quality attributes of shrimp were investigated. The quality of boiled shrimp was evaluated in terms of its salt content, moisture content, which is in turn related to the other qualities, namely, protein content, colors, shrinkage, and texture (hardness and toughness), as well as microbiological quality. It was found that higher concentration of salt solution and longer boiling time and lower mass ratio of shrimp to salt solution led to higher salt content of shrimp but to lower levels of moisture and proteins, leading to higher values of hardness, toughness, shrinkage, and color changes of shrimp. However, the mass ratio of shrimp to salt solution alone did not significantly affect any qualities of boiled shrimp (P > 0.05). It was found that the minimum boiling time of 3 min was enough to reduce the number of microorganisms to a safe level and inactivate enzymes causing melanosis in boiled shrimp.
Numerical Analysis of Survival of Listeria monocytogenes during In‐Package Pasteurization of Frankfurters by Hot Water Immersion
Authors: Huang Lihan
Published: May 2007

ABSTRACT:  The objective of this research was to develop and validate a more accurate method to analyze and calculate the inactivation of Listeria monocytogenes in frankfurter packages during postlethality hot water immersion heating and the subsequent cooling processes. Finite difference analysis with implicit scheme was used to simulate the heat transfer process during in‐package pasteurization of frankfurters. A volumetrically distributed simulation method was developed to calculate the lethality of the thermal treatment. The simulation method was validated using frankfurter packages inoculated with a 4‐strain cocktail of L. monocytogenes. Experimental results showed that the numerical analysis model could accurately simulate the heat transfer process during heating and cooling of frankfurter packages. The simulated temperatures on the surface or in the middle of the package matched very closely with the experimental observations. Using the simulated temperature distribution in the packages, the integrated lethality simulation method, based on the volumetric distribution of bacteria, could accurately predict the reduction in the bacterial counts. The calculation results were on average within 0.3 log(CFU/g) difference from the experimental observations, while the General Method systematically underestimated the bacterial reductions by approximately 0.9 log(CFU/g). The study shows that the integrated lethality method is more accurate than the General Method in calculating the lethality of thermal processes for conduction‐heated foods.
Chemistry of Deep‐Fat Frying Oils
Authors: Choe E. , Min D.B.
Published: May 2007

ABSTRACT:  Deep‐fat frying produces desirable or undesirable flavor compounds and changes the flavor stability and quality of the oil by hydrolysis, oxidation, and polymerization. Tocopherols, essential amino acids, and fatty acids in foods are degraded during deep‐fat frying. The reactions in deep‐fat frying depend on factors such as replenishment of fresh oil, frying conditions, original quality of frying oil, food materials, type of fryer, antioxidants, and oxygen concentration. High frying temperature, the number of fryings, the contents of free fatty acids, polyvalent metals, and unsaturated fatty acids of oil decrease the oxidative stability and flavor quality of oil. Antioxidant decreases the frying oil oxidation, but the effectiveness of antioxidant decreases with high frying temperature. Lignan compounds in sesame oil are effective antioxidants in deep‐fat frying.
In Vitro Resistance Selection and In Vivo Efficacy of Morpholino Oligomers against West Nile Virus
Authors: Deas Tia S. , Bennett Corey J. , Jones Susan A. , Tilgner Mark , Ren Ping , Behr Melissa J. , Stein David A. , Iversen Patrick L. , Kramer Laura D. , Bernard Kristen A. , Shi Pei-Yong
Published: May 2007

We characterize in vitro resistance to and demonstrate the in vivo efficacy of two antisense phosphorodiamidate morpholino oligomers (PMOs) against West Nile virus (WNV). Both PMOs were conjugated with an Arg-rich peptide. One peptide-conjugated PMO (PPMO) binds to the 5′ terminus of the viral genome (5′-end PPMO); the other targets an essential 3′ RNA element required for genome cyclization (3′ conserved sequence I [3′ CSI] PPMO). The 3′ CSI PPMO displayed a broad spectrum of antiflavivirus activity, suppressing WNV, Japanese encephalitis virus, and St. Louis encephalitis virus, as demonstrated by reductions in viral titers of 3 to 5 logs in cell cultures, likely due to the absolute conservation of the 3′ CSI PPMO-targeted sequences among these viruses. The selection and sequencing of PPMO-resistant WNV showed that the 5′-end-PPMO-resistant viruses contained two to three mismatches within the PPMO-binding site whereas the 3′ CSI PPMO-resistant viruses accumulated mutations outside the PPMO-targeted region. The mutagenesis of a WNV infectious clone demonstrated that the mismatches within the PPMO-binding site were responsible for the 5′-end PPMO resistance. In contrast, a U insertion or a G deletion located within the 3′-terminal stem-loop of the viral genome was the determinant of the 3′ CSI PPMO resistance. In a mouse model, both the 5′-end and 3′ CSI PPMOs (administered at 100 or 200 μg/day) partially protected mice from WNV disease, with minimal to no PPMO-mediated toxicity. A higher treatment dose (300 μg/day) caused toxicity. Unconjugated PMOs (3 mg/day) showed neither efficacy nor toxicity, suggesting the importance of the peptide conjugate for efficacy. The results suggest that a modification of the peptide conjugate composition to reduce its toxicity yet maintain its ability to effectively deliver PMO into cells may improve PMO-mediated therapy.
Steady-State Disposition of the Nonpeptidic Protease Inhibitor Tipranavir when Coadministered with Ritonavir
Authors: Chen Linzhi , Sabo John P. , Philip Elsy , Mao Yanping , Norris Stephen H. , MacGregor Thomas R. , Wruck Jan M. , Garfinkel Sandra , Castles Mark , Brinkman Amy , Valdez Hernan
Published: May 2007

The pharmacokinetic and metabolite profiles of the antiretroviral agent tipranavir (TPV), administered with ritonavir (RTV), in nine healthy male volunteers were characterized. Subjects received 500-mg TPV capsules with 200-mg RTV capsules twice daily for 6 days. They then received a single oral dose of 551 mg of TPV containing 90 μCi of [
14
C]TPV with 200 mg of RTV on day 7, followed by twice-daily doses of unlabeled 500-mg TPV with 200 mg of RTV for up to 20 days. Blood, urine, and feces were collected for mass balance and metabolite profiling. Metabolite profiling and identification was performed using a flow scintillation analyzer in conjunction with liquid chromatography-tandem mass spectrometry. The median recovery of radioactivity was 87.1%, with 82.3% of the total recovered radioactivity excreted in the feces and less than 5% recovered from urine. Most radioactivity was excreted within 24 to 96 h after the dose of [
14
C]TPV. Radioactivity in blood was associated primarily with plasma rather than red blood cells. Unchanged TPV accounted for 98.4 to 99.7% of plasma radioactivity. Similarly, the most common form of radioactivity excreted in feces was unchanged TPV, accounting for a mean of 79.9% of fecal radioactivity. The most abundant metabolite in feces was a hydroxyl metabolite, H-1, which accounted for 4.9% of fecal radioactivity. TPV glucuronide metabolite H-3 was the most abundant of the drug-related components in urine, corresponding to 11% of urine radioactivity. In conclusion, after the coadministration of TPV and RTV, unchanged TPV represented the primary form of circulating and excreted TPV and the primary extraction route was via the feces.
Amiodarone and Bepridil Inhibit Anthrax Toxin Entry into Host Cells
Authors: Sanchez Ana M. , Thomas Diane , Gillespie Eugene J. , Damoiseaux Robert , Rogers Joseph , Saxe Jonathan P. , Huang Jing , Manchester Marianne , Bradley Kenneth A.
Published: May 2007

Anthrax lethal toxin is one of the fundamental components believed to be responsible for the virulence of
Bacillus anthracis
. In order to find novel compounds with anti-lethal toxin properties, we used a cell-based assay to screen a collection of approximately 500 small molecules. Nineteen compounds that blocked lethal toxin-mediated killing of RAW 264.7 macrophages were identified, and we report here on the characterization of the two most potent antitoxic compounds, amiodarone and bepridil. These drugs are used to treat cardiac arrhythmia or angina in humans at doses similar to those that provide protection against lethal toxin in vitro. Our results support a model whereby the antitoxic properties of both drugs result from their ability to block endosomal acidification, thereby blocking toxin entry. Amiodarone was tested in vivo and found to significantly increase survival of lethal toxin-challenged Fischer rats.
Efficacy of Telavancin in the Treatment of Experimental Endocarditis Due to Glycopeptide-Intermediate
Staphylococcus aureus
Authors: Miró José M. , García-de-la-Mària Cristina , Armero Yolanda , de-Lazzari Elisa , Soy Dolors , Moreno Asunción , del Rio Ana , Almela Manel , Mestres Carlos A. , Gatell José M. , Jiménez-de-Anta María-Teresa , Marco Francesc
Published: May 2007

The efficacy of telavancin, a novel lipoglycopeptide, was evaluated in experimental endocarditis in rabbits using two clinical isolates of glycopeptide-intermediate
Staphylococcus aureus
: ATCC 700788 and HIP 5836. Infected rabbits were treated for 2 days with telavancin (10 mg/kg of body weight once daily intravenously) or vancomycin (1 g twice daily intravenously), administered with a computer-controlled infusion pump system simulating human serum kinetics. Vegetations were harvested at 16 h postinoculation in the control group and at the end of treatment in the drug-treated group. For ATCC 700788, MICs and minimal bactericidal concentrations (MBCs), respectively, were 1 mg/liter and 4 mg/liter for telavancin and 8 mg/liter and 128 mg/liter for vancomycin. For HIP 5836, MICs and MBCs, respectively, were 4 mg/liter and 8 mg/liter for telavancin and 8 mg/liter and 128 mg/liter for vancomycin. Peak and trough levels were 90 μg/ml and 6 μg/ml, respectively, for telavancin and 46 μg/ml and 6 μg/ml, respectively, for vancomycin. In glycopeptide-intermediate
S. aureus
ATCC 700788, telavancin sterilized 6 of 16 vegetations (37%), whereas vancomycin sterilized 4 of 20 (20%) (
P
= 0.29) compared with 0 of 17 in the control group. In HIP 5836 experiments, telavancin and vancomycin sterilized 5 of 16 (31%) and 1 of 15 (7%) vegetations (
P
= 0.17), respectively, compared with none in the control group. Telavancin reduced vegetation titers by 2.0 and 2.3 logs greater than vancomycin for the ATCC 700788 (4.6 [2.0 to 5.8] versus 6.6 [2.0 to 6.9] log CFU/g vegetation;
P
= 0.05) and HIP 5836 (4.4 [2.0 to 7.4] versus 6.7 [4.5 to 8.7] log CFU/g vegetation;
P
= 0.09) strains, respectively; these differences did not reach statistical significance. All isolates from vegetations remained susceptible to telavancin after therapy. The results suggest that telavancin may be an effective treatment for endocarditis caused by glycopeptide-intermediate
S. aureus
.
Transcriptional Response of
Candida parapsilosis
following Exposure to Farnesol
Authors: Rossignol Tristan , Logue Mary E. , Reynolds Kieran , Grenon Muriel , Lowndes Noel F. , Butler Geraldine
Published: May 2007

In
Candida albicans
, the quorum-sensing molecule farnesol inhibits the transition from yeast to hyphae but has no effect on cellular growth. We show that the addition of exogenous farnesol to cultures of
Candida parapsilosis
causes the cells to arrest, but not at a specific stage in the cell cycle. The cells are not susceptible to additional farnesol. However, the cells do eventually recover from arrest. Unlike in
C. albicans
, in
C. parapsilosis
sterols are localized to the tips of budding cells, and this polarization is disrupted by the addition of farnesol. We used the results of a genome sequence survey to design and manufacture partial genomic microarrays that were applied to determining the transcriptional response of
C. parapsilosis
to the presence of exogenous farnesol. In both
C. albicans
and
C. parapsilosis
, exposure to farnesol results in increased expression of the oxidoreductases
GRP2
and
ADH7
and altered expression of genes involved in sterol metabolism. There is no effect on expression of
C. parapsilosis
orthologs of genes involved in hyphal growth in
C. albicans.
Farnesol therefore differs significantly in its effects on
C. parapsilosis
and
C. albicans
.
Systematic Comparison of the Population Pharmacokinetics and Pharmacodynamics of Piperacillin in Cystic Fibrosis Patients and Healthy Volunteers
Authors: Bulitta J. B. , Duffull S. B. , Kinzig-Schippers M. , Holzgrabe U. , Stephan U. , Drusano G. L. , Sörgel F.
Published: May 2007

Respiratory tract infections cause 90% of premature mortality in patients with cystic fibrosis (CF). Treatment ofPseudomonas aeruginosainfection is often very problematic. Piperacillin-tazobactam has good activity againstP. aeruginosa, but its pharmacokinetics (PK) in CF patients has not been compared to the PK in healthy volunteers in a controlled clinical study. Therefore, we compared the population PK and pharmacodynamics (PD) of piperacillin between CF patients and healthy volunteers. We studied 8 adult (median age, 20 years) CF patients (average total body weight [WT], 43.1 ± 7.8 kg) and 26 healthy volunteers (WT, 71.1 ± 11.8 kg) who each received 4 g piperacillin as a 5-min intravenous infusion. We determined piperacillin levels by high-performance liquid chromatography, and we used NONMEM for population PK and Monte Carlo simulation. We used a target time of nonprotein-bound concentration above the MIC of 50%, which represents near-maximal bacterial killing. Unscaled total clearance was 25% lower, and the volume of distribution was 31% lower in CF patients. Allometric scaling by lean body mass reduced the unexplained (random) between-subject variability in clearance by 26% compared to the variability of linear scaling by WT. A standard dosage regimen of 3 g/70 kg body WT every 4 h as a 30-min infusion (daily dose, 18 g) achieved a robust (≥90%) probability-of-target attainment (PTA) for MICs of ≤12 mg/liter in CF patients and ≤16 mg/liter in healthy volunteers. Alternative modes of administration allowed a marked dose reduction to 9 g daily. Prolonged (4-h) infusions of 3 g/70 kg WT every 8 h and continuous infusion (daily dose, 9 g), achieved a robust PTA for MICs of ≤16 mg/liter in both groups. Piperacillin achieved PTA expectation values of 64% and 89% againstP. aeruginosainfection in CF patients, based on susceptibility data from two German CF clinics.
Babesial Vector Tick Defensin againstBabesiasp. Parasites
Authors: Tsuji Naotoshi , Battsetseg Badgar , Boldbaatar Damdinsuren , Miyoshi Takeharu , Xuan Xuenan , Oliver James H. , Fujisaki Kozo
Published: May 2007

Antimicrobial peptides are major components of host innate immunity, a well-conserved, evolutionarily ancient defensive mechanism. Infectious disease-bearing vector ticks are thought to possess specific defense molecules against the transmitted pathogens that have been acquired during their evolution. We found in the tickHaemaphysalis longicornisa novel parasiticidal peptide named longicin that may have evolved from a common ancestral peptide resembling spider and scorpion toxins.H. longicornisis the primary vector forBabesiasp. parasites in Japan. Longicin also displayed bactericidal and fungicidal properties that resemble those of defensin homologues from invertebrates and vertebrates. Longicin showed a remarkable ability to inhibit the proliferation of merozoites, an erythrocyte blood stage of equineBabesia equi, by killing the parasites. Longicin was localized at the surface of theBabesiasp. parasites, as demonstrated by confocal microscopic analysis. In an in vivo experiment, longicin induced significant reduction of parasitemia in animals infected with the zoonotic and murineB. microti. Moreover, RNA interference data demonstrated that endogenous longicin is able to directly kill the canineB. gibsoni, thus indicating that it may play a role in regulating the vectorial capacity in the vector tickH. longicornis. Theoretically, longicin may serve as a model for the development of chemotherapeutic compounds against tick-borne disease organisms.
The prevalence of syndrome Z (the interaction of obstructive sleep apnoea with the metabolic syndrome) in a teaching hospital in Singapore
Authors: Venkateswaran Sridhar , Shankar Praveen
Published: May 2007

Background

Syndrome Z describes the interaction of obstructive sleep apnoea (OSA) with the metabolic syndrome.

Purpose of study

A pilot study to determine the prevalence of syndrome Z in a teaching hospital in Singapore.

Methods

Patients (age ⩾18 years) recruited for this prospective study had to satisfy three of the following five inclusion criteria: fasting glucose >6.1 mmol/l, blood pressure ⩾130/85 mm Hg, HDL cholesterol <1.04 mmol/l in men and <1.2 mmol/l in women, triglycerides ⩾1.7 mmol/l, and a waist circumference >102 cm in men and >88 cm in women. All subjects underwent standard overnight polysomnography. Overnight fasting glucose and lipid levels were measured and baseline anthropometric data recorded. All sleep studies were scored and reported by a sleep physician. OSA was deemed to be present if the respiratory disturbance index (RDI) was ⩾5, with mild, moderate and severe categories classified according to the Chicago criteria.

Results

There were 24 patients (19 males and five females) of whom 10 were Chinese, eight Malay and five of Indian origin, with one other. Mean age was 48±13.5 years, mean body mass index was 34.9±6.1 kg/m2 and mean waist circumference was 111.3±15.7 cm. 23 (95.8%) of the patients had OSA with a mean RDI of 39.6±22.4 events/h with 15 patients (62.5%) in the severe category. The five patients who fulfilled all five criteria for diagnosis of the metabolic syndrome had severe OSA.

Conclusion

The prevalence of OSA in our studied population exhibiting the metabolic syndrome is very high. Therefore, a polysomnogram should always be considered for this subset of patients.
Comparison of P-POSSUM and O-POSSUM in predicting mortality after oesophagogastric resections
Authors: Nagabhushan J S , Srinath S , Weir F , Angerson W J , Sugden B A , Morran C G
Published: May 2007

Background

P-POSSUM (Physiological and Operative Severity Score for the enumeration of Mortality and morbidity) predicts mortality and morbidity in general surgical patients providing an adjunct to surgical audit. O-POSSUM was designed specifically to predict mortality and morbidity in patients undergoing oesophagogastric surgery.

Aim

To compare P-POSSUM and O-POSSUM in predicting surgical mortality in patients undergoing elective oesophagogastric cancer resections.

Methods

Elective oesophagogastric cancer resections in a district general hospital from 1990 to 2002 were scored by P-POSSUM and O-POSSUM methods. Observed mortality rates were compared to predicted mortality rates in six risk groups for each model using the Hosmer–Lemeshow goodness-of-fit test. The power to discriminate between patients who died and those who survived was assessed using the area under the receiver–operator characteristic (ROC) curve.

Results

313 patients underwent oesophagogastric resections. 32 died within 30 days (10.2%). P-POSSUM predicted 36 deaths (χ2 = 15.19, df = 6, p = 0.019, Hosmer–Lemeshow goodness-of-fit test), giving a standardised mortality ratio (SMR) of 0.89. O-POSSUM predicted 49 deaths (χ2 = 16.51, df = 6, p = 0.011), giving an SMR of 0.65. The area under the ROC curve was 0.68 (95% confidence interval 0.59 to 0.76) for P-POSSUM and 0.61 (95% confidence interval 0.50 to 0.72) for O-POSSUM.

Conclusion

Neither model accurately predicted the risk of postoperative death. P-POSSUM provided a better fit to observed results than O-POSSUM, which overpredicted total mortality. P-POSSUM also had superior discriminatory power.
The role of the Intra-aortic balloon pump in supporting children with acute cardiac failure
Authors: Paul Collison Sathiakar , Singh Dagar Kulbhusan
Published: May 2007

Acute heart failure occurs in children following the operative correction of a congenital anomaly, as an acute change in a child with a congenital anomaly, or in a structurally normal heart with acute myocarditis. Acute heart failure in children justifies aggressive treatment because of the high potential for complete recovery. The options for providing mechanical support to the failing heart in a child include extracorporeal membrane oxygenation, left ventricular assist devices and the use of the intra-aortic balloon pump (IABP). The principles of intra-aortic balloon pump usage are described, and the literature regarding the indications and outcome of its use in children is reviewed.
Is cocaine use recognised as a risk factor for acute coronary syndrome by doctors in the UK?
Authors: Wood David M , Hill Duncan , Gunasekera Awini , Greene Shaun L , Jones Alison L , Dargan Paul I
Published: May 2007

Background

Cocaine is a sympathomimetic agent that can cause coronary artery vasospasm leading to myocardial ischaemia, acute coronary syndrome and acute myocardial infarction (ACS/AMI). The management of cocaine-induced ACS/AMI is different to classical atheromatous ACS/MI, because the mechanisms are different.

Methods

Knowledge study—Junior medical staff were given a scenario of a patient with ACS and asked to identify potential risk factors for ACS and which ones they routinely asked about in clinical practice. Retrospective study—Retrospective notes reviews of patients with suspected and proven (elevated troponin T concentration) ACS were undertaken to determine the recording of cocaine use/non-use in clinical notes.

Results

Knowledge study—There was no significant difference in the knowledge that cocaine was a risk factor compared to other “classical” cardiovascular risk factors, but juniors doctors were less likely to ask routinely about cocaine use compared to other “classical” risk factors (52.9% vs >90%, respectively). Retrospective study—Cocaine use or non-use was documented in 3.7% (4/109) and 4% (2/50) of clinical notes of patients with suspected and proven ACS, respectively.

Discussion

Although junior medical staff are aware that cocaine is a risk factor for ACS/AMI, they are less likely to ask about it in routine clinical practice or record its use/non-use in clinical notes. It is essential that patients presenting with suspected ACS are asked about cocaine use, since the management of these patients is different to those with ACS secondary to “classical” cardiovascular risk factors.
The challenge of providing mentorship in primary care
Authors: MacLeod Sheona
Published: May 2007

In the changing National Health Service, there is an increasing awareness of stress related problems in the medical workforce. Mentorship has been shown to help with both stress reduction and adaptation to change. There are recognised difficulties with providing mentorship for doctors but there are ways in which these can be overcome. The medical profession is now considering revalidation, re-certification, and the standards required for these. Perhaps it is also time to consider ways in which mentorship can be provided to support the medical workforce, promote ongoing development and thus improve our ability to care for patients.
False cardiac arrests: the right time to turn away?
Authors: Kenward Gary , Robinson Alan , Bradburn Sandra , Steeds Richard
Published: May 2007

Aim

Cardiac arrest teams may be activated only to find that the patient does not require cardiac or respiratory resuscitation. Members of the cardiac arrest team are drawn from medical personnel with other responsibilities who may disperse quickly, leaving ongoing care of the patient to existing ward staff. The outcome for such false cardiac arrests, however, is rarely reported. The objective of this study was to determine the causes of false cardiac arrest team alerts (FCAs) and to assess the outcome of these patients relative to the general hospital population.

Setting

Tertiary care hospital.

Participants

Patients subject to a cardiac arrest call who were found not to require basic or advanced cardiac life support on arrival.

Results

In 512 events over a 1-year period, patients suffering FCAs were more likely to survive compared to patients suffering cardiac arrest (15% vs 73%, odds ratio (OR) 14.95; χ2 p⩽0.0001), but significantly less likely to survive than the general hospitalised population (73% vs 97%, OR 14.15; χ2 p⩽0.0001). The cause of the FCA was often minimised as collapse or vasovagal syncope; in 58% (87/150) of cases no further action was taken by the attending medical team. Patients suffering FCAs tended to be long-stay patients with a worse outcome at weekends.

Conclusion

In areas lacking a medical alert, outreach or patient at risk system, particular attention should be paid to optimising care of those suffering FCAs.
Hypervirulent strains of Clostridium difficile
Authors: Cookson Barry
Published: May 2007

North America has seen increasing numbers of hospitalised patients and others in nursing homes and the community, with more severe Clostridium difficile associated diarrhoea. This is also described in Northern Europe and surveillance systems are being developed or improved to monitor the situation. One strain (ribotype O27) is described in detail and, like other emerging strains, is demonstrating increasing antimicrobial resistance, notably to quinolone antibiotics. However, its association with increased virulence is not straightforward, probably reflecting the interactions with differing patient case mix. There are many subtypes of the strain and more sophisticated typing and virulence assessment systems need to be developed using isolates carefully collected to test different epidemiological hypotheses. There are also environmental factors relating to treatment such as antimicrobials, cytotoxics and proton pump inhibitors. An emerging theme is the importance of aspects of healthcare delivery in contributing to the problem; this includes poorly maintained and cleaned healthcare premises, overcrowded hospitals and increased staffing workloads leading to poor compliance with infection control.
Can we detect the development of baroreflex sensitivity in humans between 11 and 20 years of age?
Authors: Zavodna Eva , Honzikova Natasa , Hrstkova Hana , Novakova Zuzana , Moudr Jiri , Jira Miroslav , Fiser Bohumil
Published: May 2007

The aim of the study was to determine changes of baroreflex sensitivity in humans between 11 and 20 years of age. Continuous 5 min blood pressure recordings using a Finapres were taken in 415 healthy subjects while in a sitting, resting position (breathing at a frequency of 0.33 Hz). Beat-by-beat values of interbeat intervals (IBI) or heart rate, and systolic and diastolic blood pressures were measured. Baroreflex sensitivity in ms/mmHg (BRS) and in mHz/mmHg (BRSf) was determined at an average frequency of 0.1 Hz by spectral analysis. BRS did not correlate with age, but BRSf significantly decreased with age (p < 0.001). BRS correlated with mean IBI (p < 0.001) in all subjects and also in the particular subgroups, but BRSf was IBI-independent. Results of multiregression equations were BRS = 1.37 – 0.56 × age (years) + 0.02 × IBI (ms) (p < 0.001 for BRS vs. age and for BRS vs. IBI); BRSf = 34.74 – 0.97 × age (years) – 0.001 × IBI (ms) (p < 0.001 only for BRS vs. age), where age was measured in years and IBI was measured in ms. The limits of BRS were estimated for the total group: 5th percentile, 3.9; 50th percentile, 9.1; and 95th percentile, 18.7 ms/mmHg; and limits for BRSf were 5th percentile, 8.5; 50th percentile, 16.4; and 95th percentile, 33.6 mHz/mmHg. We conclude that IBI-dependent BRS was unchanged in the particular age groups, but the standardization of BRS on IBI decreased with age. BRSf was IBI-independent and better reflected the development of the BRS.
Increased expression of endothelial nitric oxide synthase and caveolin-1 in the aorta of rats with isoproterenol-induced cardiac hypertrophy
Authors: Krenek P. , Klimas J. , Kroslakova M. , Gazova A. , Plandorova J. , Kucerova D. , Fecenkova A. , Svec P. , Kyselovic J.
Published: May 2007

Isoproterenol-induced cardiac hypertrophy is associated with increased expression of endothelial nitric oxide synthase in the aorta but without signs of improved endothelial function. The aim was to examine the hypothesis that increased expression of eNOS allosteric inhibitor caveolin-1 could be associated with unimproved endothelium-dependent relaxations. Rats received isoproterenol (5 mg/kg body mass, i.p., n = 13) or its vehicle (n = 14) during 1 week. Systolic blood pressure (SBP) and heart rate (HR) were measured by the tail-cuff method. Expression of eNOS and caveolin-1 was measured using immunoblotting analysis. Relaxations of isolated aorta to acetylcholine and sodium nitroprusside were evaluated ex vivo. After 1 week of isoproterenol administration, basal SBP and HR were decreased (SBP 110 ± 3 vs. 126 ± 3 mmHg, p < 0.05; HR 342 ± 8 vs. 366 ± 6 beats/min, p < 0.05). Isoproterenol increased the mass of the left ventricle (+33% ± 4% vs. control; p < 0.05) and right ventricle (+40% ± 9%; p < 0.05). Isoproterenol administration increased the expression of eNOS (+53% ± 12%; p < 0.05) and caveolin-1 (+54% ± 20%, p < 0.05) in the aorta. Relaxation of isolated aorta to acetylcholine and sodium nitroprusside showed a trend towards a worsened endothelial function and a lower sensitivity to exogenous NO. Thus, 1 week of isoproterenol administration led to increased eNOS expression in the aorta without amelioration of endothelial vasorelaxation function. Concomitant increase in caveolin-1 expression may be responsible for this paradox.
hPepT1 selectively transports muramyl dipeptide but not Nod1-activating muramyl peptides
Authors: Ismair Manfred G. , Vavricka Stephan R. , Kullak-Ublick Gerd A. , Fried Michael , Mengin-Lecreulx Dominique , Girardin Stephen E.
Published: May 2007

Muramyl peptides derived from bacterial peptidoglycan are detected intracellularly by Nod1 and Nod2, 2 members of the newly characterized nod-like receptor (NLR) family of pattern recognition molecules. In the absence of bacterial invasion into the host cytosolic compartment, it remains unclear whether muramyl peptides can cross the plasma membrane and localize into the cytosol. We have recently demonstrated that the plasma membrane transporter, hPepT1, was able to efficiently translocate muramyl dipeptide (MDP), a specific Nod2-activating molecule, into host cells. We aimed to characterize the transport properties of hPepT1 towards a spectrum of muramyl peptides, including Nod1-activating molecules. To do so, we designed an original procedure based on the ectopic expression of hPepT1 in oocytes from Xenopus laevis . Our results demonstrated that hPepT1 transports MDP but no other Nod2-activating molecule. Moreover, we observed that Nod1-stimulating muramyl peptides were not transported by hPepT1. Since hPepT1 expression is strongly associated with intestinal epithelial cells, where Nod1 and Nod2 have been shown to play a key role, these observations suggest a distinct contribution of Nod1 and Nod2 in mucosal homeostasis following the cellular uptake of muramyl peptides by hPepT1.
Methylglyoxal, oxidative stress, and hypertension
Authors: Chang Tuanjie , Wu Lingyun
Published: May 2007

Pathogenic mechanisms for essential hypertension are unclear despite striking efforts from numerous research teams over several decades. Increased production of reactive oxygen species (ROS) has been associated with the development of hypertension and the role of ROS in hypertension has been well documented in recent years. In this context, it is important to better understand pathways and triggering factors for increased ROS production in hypertension. This review draws a causative linkage between elevated methylglyoxal level, methylglyoxal-induced production of ROS, and advanced glycation end products in the development of hypertension. It is proposed that elevated methylglyoxal level and resulting protein glycation and ROS production may be the upstream links in the chain reaction leading to the development of hypertension.
Expression of breast cancer resistance protein (BCRP/ABCG2) in human placenta throughout gestation and at term before and after labor
Authors: Yeboah D. , Sun M. , Kingdom J. , Baczyk D. , Lye S.J. , Matthews S.G. , Gibb W.
Published: May 2007

Breast cancer resistance protein, BCRP, is a multidrug resistance protein that is highly expressed in the human placenta. In cancer tissues, this protein actively extrudes a wide variety of chemically and structurally unrelated chemotherapeutic drugs and other compounds. Studies in mice have shown that in the absence of BCRP activity in the placenta, there is a 2-fold increase in the uptake in BCRP substrates into fetus. This suggests that in the placenta, BCRP extrudes compounds that would otherwise cross the syncytiotrophoblast cells into fetal circulation. The purpose of this study was to examine the expression and localization of BCRP in the human placenta throughout gestation. Tissues from 6–13, 16–19, 24–29, 32–35, and 38–41 weeks of gestation were used. Real time RT-PCR analysis demonstrated that the mRNA levels of BCRP in the placenta do not change significantly as gestation progressed. However, Western blot analysis revealed that the protein levels increased towards the end of gestation. We demonstrated that BCRP is localized to the syncytiotrophoblast of the placenta and in some fetal blood vessels within the placenta. Tissues from the early stages of pregnancy (6–13 weeks) showed fewer BCRP positive blood vessels than term tissues (38–41 weeks).
Antinociceptive, anti-inflammatory and antipyretic properties ofMelastoma malabathricumleaves aqueous extract in experimental animals
Authors: Zakaria Z.A. , Raden Mohd. Nor R.N.S. , Hanan Kumar G. , Abdul Ghani Z.D.F. , Sulaiman M.R. , Rathna Devi G. , Mat Jais A.M. , Somchit M.N. , Fatimah C.A.
Published: May 2007

The present study was carried out to establish the antinociceptive, anti-inflammatory, and antipyretic properties of the aqueous extract of Melastoma malabathricum leaves in experimental animals. The antinociceptive activity was measured using abdominal constriction, hot-plate, and formalin tests, whereas the anti-inflammatory and antipyretic activities were measured using carrageenan-induced paw edema and brewer’s yeast-induced pyrexia tests, respectively. The extract, which was obtained after soaking the air-dried leaves in distilled water for 72 h and then preparing in concentrations of 10%, 50%, and 100% (v/v), was administered subcutaneously 30 min prior to subjection to the above mentioned assays. At all concentrations tested, the extract was found to exhibit significant (P < 0.05) antinociceptive, anti-inflammatory, and antipyretic activities in a concentration-independent manner. Our findings that the aqueous extract of M. malabathricum possesses antinociceptive, anti-inflammatory, and antipyretic activities supports previous claims on its traditional uses to treat various ailments.