bluuebunny/crossref_metadata_2025 huggingface dataset:
Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes
Authors: Kasper Maria , Jaks Viljar , Are Alexandra , Bergström Åsa , Schwäger Anja , Svärd Jessica , Teglund Stephan , Barker Nick , Toftgård Rune
Published: February 2011

Chronic wounds and acute trauma constitute well-established risk factors for development of epithelial-derived skin tumors, although the underlying mechanisms are largely unknown. Basal cell carcinomas (BCCs) are the most common skin cancers displaying a number of features reminiscent of hair follicle (HF)-derived cells and are dependent on deregulated Hedgehog (Hh)/GLI signaling. Here we show, in a mouse model conditionally expressing GLI1 and in a model with homozygous inactivation of Ptch1, mimicking the situation in human BCCs, that the wound environment accelerates the initiation frequency and growth of BCC-like lesions. Lineage tracing reveals that both oncogene activation and wounding induce emigration of keratinocytes residing in the lower bulge and the nonpermanent part of the HFs toward the interfollicular epidermis (IFE). However, only oncogene activation in combination with a wound environment enables the participation of such cells in the initiation of BCC-like lesions at the HF openings and in the IFE. We conclude that, in addition to the direct enhancement of BCC growth, the tumor-promoting effect of the wound environment is due to recruitment of tumor-initiating cells originating from the neighboring HFs, establishing a link between epidermal wounds and skin cancer risk.
Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2
+
breast cancer patients
Authors: Scaltriti Maurizio , Eichhorn Pieter J. , Cortés Javier , Prudkin Ludmila , Aura Claudia , Jiménez José , Chandarlapaty Sarat , Serra Violeta , Prat Aleix , Ibrahim Yasir H. , Guzmán Marta , Gili Magui , Rodríguez Olga , Rodríguez Sonia , Pérez José , Green Simon R. , Mai Sabine , Rosen Neal , Hudis Clifford , Baselga José
Published: February 2011

Clinical benefits from trastuzumab and other anti-HER2 therapies in patients with HER2 amplified breast cancer remain limited by primary or acquired resistance. To identify potential mechanisms of resistance, we established trastuzumab-resistant HER2 amplified breast cancer cells by chronic exposure to trastuzumab treatment. Genomewide copy-number variation analyses of the resistant cells compared with parental cells revealed a focal amplification of genomic DNA containing the cyclin E gene. In a cohort of 34 HER2
+
patients treated with trastuzumab-based therapy, we found that cyclin E amplification/overexpression was associated with a worse clinical benefit (33.3% compared with 87.5%,
P
< 0.02) and a lower progression-free survival (6 mo vs. 14 mo,
P
< 0.002) compared with nonoverexpressing cyclin E tumors. To dissect the potential role of cyclin E in trastuzumab resistance, we studied the effects of cyclin E overexpression and cyclin E suppression. Cyclin E overexpression resulted in resistance to trastuzumab both in vitro and in vivo. Inhibition of cyclin E activity in cyclin E-amplified trastuzumab resistant clones, either by knockdown of cyclin E expression or treatment with cyclin-dependent kinase 2 (CDK2) inhibitors, led to a dramatic decrease in proliferation and enhanced apoptosis. In vivo, CDK2 inhibition significantly reduced tumor growth of trastuzumab-resistant xenografts. Our findings point to a causative role for cyclin E overexpression and the consequent increase in CDK2 activity in trastuzumab resistance and suggest that treatment with CDK2 inhibitors may be a valid strategy in patients with breast tumors with HER2 and cyclin E coamplification/overexpression.
Cargo recognition mechanism of myosin X revealed by the structure of its tail MyTH4-FERM tandem in complex with the DCC P3 domain
Authors: Wei Zhiyi , Yan Jing , Lu Qing , Pan Lifeng , Zhang Mingjie
Published: February 2011

Myosin X (MyoX), encoded by
Myo10
, is a representative member of the MyTH4–FERM domain-containing myosins, and this family of unconventional myosins shares common functions in promoting formation of filopodia/stereocilia structures in many cell types with unknown mechanisms. Here, we present the structure of the MyoX MyTH4–FERM tandem in complex with the cytoplasmic tail P3 domain of the netrin receptor DCC. The structure, together with biochemical studies, reveals that the MyoX MyTH4 and FERM domains interact with each other, forming a structural and functional supramodule. Instead of forming an extended β-strand structure in other FERM binding targets, DCC_P3 forms a single α-helix and binds to the αβ-groove formed by β5 and α1 of the MyoX FERM F3 lobe. Structure-based amino acid sequence analysis reveals that the key polar residues forming the inter-MyTH4/FERM interface are absolutely conserved in all MyTH4–FERM tandem-containing proteins, suggesting that the supramodular nature of the MyTH4–FERM tandem is likely a general property for all MyTH4–FERM proteins.
Efficiency of the CO
2
-concentrating mechanism of diatoms
Authors: Hopkinson Brian M. , Dupont Christopher L. , Allen Andrew E. , Morel François M. M.
Published: February 2011

Diatoms are responsible for a large fraction of CO
2
export to deep seawater, a process responsible for low modern-day CO
2
concentrations in surface seawater and the atmosphere. Like other photosynthetic organisms, diatoms have adapted to these low ambient concentrations by operating a CO
2
concentrating mechanism (CCM) to elevate the concentration of CO
2
at the site of fixation. We used mass spectrometric measurements of passive and active cellular carbon fluxes and model simulations of these fluxes to better understand the stoichiometric and energetic efficiency and the physiological architecture of the diatom CCM. The membranes of diatoms are highly permeable to CO
2
, resulting in a large diffusive exchange of CO
2
between the cell and external milieu. An active transport of carbon from the cytoplasm into the chloroplast is the main driver of the diatom CCM. Only one-third of this carbon flux is fixed photosynthetically, and the rest is lost by CO
2
diffusion back to the cytoplasm. Both the passive influx of CO
2
from the external medium and the recycling of the CO
2
leaking out of the chloroplast are achieved by the activity of a carbonic anhydrase enzyme combined with the maintenance of a low concentration of HCO
3
−
in the cytoplasm. To achieve the CO
2
concentration necessary to saturate carbon fixation, the CO
2
is most likely concentrated within the pyrenoid, an organelle within the chloroplast where the CO
2
-fixating enzyme is located.
Identification of the meiotic life cycle stage of
Trypanosoma brucei
in the tsetse fly
Authors: Peacock Lori , Ferris Vanessa , Sharma Reuben , Sunter Jack , Bailey Mick , Carrington Mark , Gibson Wendy
Published: February 2011

Elucidating the mechanism of genetic exchange is fundamental for understanding how genes for such traits as virulence, disease phenotype, and drug resistance are transferred between pathogen strains. Genetic exchange occurs in the parasitic protists
Trypanosoma brucei
,
T. cruzi
, and
Leishmania major
, but the precise cellular mechanisms are unknown, because the process has not been observed directly. Here we exploit the identification of homologs of meiotic genes in the
T. brucei
genome and demonstrate that three functionally distinct, meiosis-specific proteins are expressed in the nucleus of a single specific cell type, defining a previously undescribed developmental stage occurring within the tsetse fly salivary gland. Expression occurs in clonal and mixed infections, indicating that the meiotic program is an intrinsic but hitherto cryptic part of the developmental cycle of trypanosomes. In experimental crosses, expression of meiosis-specific proteins usually occurred before cell fusion. This is evidence of conventional meiotic division in an excavate protist, and the functional conservation of the meiotic machinery in these divergent organisms underlines the ubiquity and basal evolution of meiosis in eukaryotes.
Genetic manipulation of lignin reduces recalcitrance and improves ethanol production from switchgrass
Authors: Fu Chunxiang , Mielenz Jonathan R. , Xiao Xirong , Ge Yaxin , Hamilton Choo Y. , Rodriguez Miguel , Chen Fang , Foston Marcus , Ragauskas Arthur , Bouton Joseph , Dixon Richard A. , Wang Zeng-Yu
Published: February 2011

Switchgrass is a leading dedicated bioenergy feedstock in the United States because it is a native, high-yielding, perennial prairie grass with a broad cultivation range and low agronomic input requirements. Biomass conversion research has developed processes for production of ethanol and other biofuels, but they remain costly primarily because of the intrinsic recalcitrance of biomass. We show here that genetic modification of switchgrass can produce phenotypically normal plants that have reduced thermal-chemical (≤180 °C), enzymatic, and microbial recalcitrance. Down-regulation of the switchgrass caffeic acid
O
-methyltransferase gene decreases lignin content modestly, reduces the syringyl:guaiacyl lignin monomer ratio, improves forage quality, and, most importantly, increases the ethanol yield by up to 38% using conventional biomass fermentation processes. The down-regulated lines require less severe pretreatment and 300–400% lower cellulase dosages for equivalent product yields using simultaneous saccharification and fermentation with yeast. Furthermore, fermentation of diluted acid-pretreated transgenic switchgrass using
Clostridium thermocellum
with no added enzymes showed better product yields than obtained with unmodified switchgrass. Therefore, this apparent reduction in the recalcitrance of transgenic switchgrass has the potential to lower processing costs for biomass fermentation-derived fuels and chemicals significantly. Alternatively, such modified transgenic switchgrass lines should yield significantly more fermentation chemicals per hectare under identical process conditions.
Global land use change, economic globalization, and the looming land scarcity
Authors: Lambin Eric F. , Meyfroidt Patrick
Published: February 2011

A central challenge for sustainability is how to preserve forest ecosystems and the services that they provide us while enhancing food production. This challenge for developing countries confronts the force of economic globalization, which seeks cropland that is shrinking in availability and triggers deforestation. Four mechanisms—the displacement, rebound, cascade, and remittance effects—that are amplified by economic globalization accelerate land conversion. A few developing countries have managed a land use transition over the recent decades that simultaneously increased their forest cover and agricultural production. These countries have relied on various mixes of agricultural intensification, land use zoning, forest protection, increased reliance on imported food and wood products, the creation of off-farm jobs, foreign capital investments, and remittances. Sound policies and innovations can therefore reconcile forest preservation with food production. Globalization can be harnessed to increase land use efficiency rather than leading to uncontrolled land use expansion. To do so, land systems should be understood and modeled as open systems with large flows of goods, people, and capital that connect local land use with global-scale factors.
Polycystin-2 takes different routes to the somatic and ciliary plasma membrane
Authors: Hoffmeister Helen , Babinger Karin , Gürster Sonja , Cedzich Anna , Meese Christine , Schadendorf Karin , Osten Larissa , de Vries Uwe , Rascle Anne , Witzgall Ralph
Published: February 2011

Polycystin-2 (also called TRPP2), an integral membrane protein mutated in patients with cystic kidney disease, is located in the primary cilium where it is thought to transmit mechanical stimuli into the cell interior. After studying a series of polycystin-2 deletion mutants we identified two amino acids in loop 4 that were essential for the trafficking of polycystin-2 to the somatic (nonciliary) plasma membrane. However, polycystin-2 mutant proteins in which these two residues were replaced by alanine were still sorted into the cilium, thus indicating that the trafficking routes to the somatic and ciliary plasma membrane compartments are distinct. We also observed that the introduction of dominant-negative Sar1 mutant proteins and treatment of cells with brefeldin A prevented the transport into the ciliary plasma membrane compartment, whereas metabolic labeling experiments, light microscopical imaging, and high-resolution electron microscopy revealed that full-length polycystin-2 did not traverse the Golgi apparatus on its way to the cilium. These data argue that the transport of polycystin-2 to the ciliary and to the somatic plasma membrane compartments originates in a COPII-dependent fashion at the endoplasmic reticulum, that polycystin-2 reaches the cis side of the Golgi apparatus in either case, but that the trafficking to the somatic plasma membrane goes through the Golgi apparatus whereas transport vesicles to the cilium leave the Golgi apparatus at the cis compartment. Such an interpretation is supported by the finding that mycophenolic acid treatment resulted in the colocalization of polycystin-2 with GM130, a marker of the cis-Golgi apparatus. Remarkably, we also observed that wild-type Smoothened, an integral membrane protein involved in hedgehog signaling that under resting conditions resides in the somatic plasma membrane, passed through the Golgi apparatus, but the M2 mutant of Smoothened, which is constitutively located in the ciliary but not in the somatic plasma membrane, does not. Finally, a dominant-negative form of Rab8a, a BBSome-associated monomeric GTPase, prevented the delivery of polycystin-2 to the primary cilium whereas a dominant-negative form of Rab23 showed no inhibitory effect, which is consistent with the view that the ciliary trafficking of polycystin-2 is regulated by the BBSome.
Role for miR-204 in human pulmonary arterial hypertension
Authors: Courboulin Audrey , Paulin Roxane , Giguère Nellie J. , Saksouk Nehmé , Perreault Tanya , Meloche Jolyane , Paquet Eric R. , Biardel Sabrina , Provencher Steeve , Côté Jacques , Simard Martin J. , Bonnet Sébastien
Published: February 2011

Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs). Because microRNAs have been recently implicated in the regulation of cell proliferation and apoptosis, we hypothesized that these regulatory molecules might be implicated in the etiology of PAH. In this study, we show that miR-204 expression in PASMCs is down-regulated in both human and rodent PAH. miR-204 down-regulation correlates with PAH severity and accounts for the proliferative and antiapoptotic phenotypes of PAH-PASMCs. STAT3 activation suppresses miR-204 expression, and miR-204 directly targets SHP2 expression, thereby SHP2 up-regulation, by miR-204 down-regulation, activates the Src kinase and nuclear factor of activated T cells (NFAT). STAT3 also directly induces NFATc2 expression. NFAT and SHP2 were needed to sustain PAH-PASMC proliferation and resistance to apoptosis. Finally, delivery of synthetic miR-204 to the lungs of animals with PAH significantly reduced disease severity. This study uncovers a new regulatory pathway involving miR-204 that is critical to the etiology of PAH and indicates that reestablishing miR-204 expression should be explored as a potential new therapy for this disease.
Synthesis, characterization and capacitive performance of hydrous manganese dioxide nanostructures
Authors: Zhang Jintao , Chu Wei , Jiang Jianwen , Zhao X S
Published: February 2011

Hydrous manganese dioxide nanostructures were synthesized via a catalytic oxidation reaction mechanism at mild temperatures. It was found that the morphology of the manganese dioxide nanostructures was significantly influenced by the pH of the reaction system. With increasing pH the morphology of manganese dioxide nanostructures changed from urchin-like structures to nanobelts. The capacitive performance was investigated by using cycle voltammetry and galvanostatic charge/discharge techniques. Hydrous manganese dioxide nanostructures obtained from a basic solution exhibited a capacitance of 262 F g− 1at a current density of 250 mA g− 1and a capacitive retention of 75% after 1200 cycles, suggesting that this is a promising electrode material for supercapacitors. The high specific capacitance is attributed to the hydrous nature coupled with a high surface area (181 m2 g− 1) of the manganese dioxide nanostructure.
Improving SNP discovery by base alignment quality
Authors: Li Heng
Published: February 2011

Summary: I propose a new application of profile Hidden Markov Models in the area of SNP discovery from resequencing data, to greatly reduce false SNP calls caused by misalignments around insertions and deletions (indels). The central concept is per-Base Alignment Quality, which accurately measures the probability of a read base being wrongly aligned. The effectiveness of BAQ has been positively confirmed on large datasets by the 1000 Genomes Project analysis subgroup.

Availability:  http://samtools.sourceforge.net

Contact:  hengli@broadinstitute.org
Cola in the German Democratic Republic. East German Fantasies on Western Consumption
Authors: Veenis Milena
Published: February 2011

Coca Cola is frequently used to signal the large-scale transformation from socialism to capitalism in eastern and middle Europe, which began in East Germany in the autumn of 1989. In the famous GermanWende-movieGoodbye Lenin, the caffeinated drink figures prominently. The main character in this movie is a middle-aged woman who has fallen into coma during one of the mass demonstrations in Berlin, in November 1989. When she finally wakes up, about one year later, her country no longer exists. Her children successfully hide this fact from her, surrounding her with the material remnants of the past. One day, when she gets out of bed, she sees people attaching a huge banner of Coca Cola to the large flat in front of her apartment bloc. The scene marks the beginning of her awareness that the world in which she used to live is definitively gone.
Population structure of a deep-water squaloid shark, the Portuguese dogfish (Centroscymnus coelolepis)
Authors: Veríssimo Ana , McDowell Jan R. , Graves John E.
Published: February 2011

Veríssimo, A., McDowell, J. R., and Graves, J. E. 2011. Population structure of a deep-water squaloid shark, the Portuguese dogfish (Centroscymnus coelolepis). – ICES Journal of Marine Science, 68: . The genetic population structure of the deep-water squaloid Centroscymnus coelolepis (the Portuguese dogfish) in the eastern Atlantic was investigated using eight polymorphic nuclear microsatellite markers and a 496-bp fragment of the mitochondrial DNA control region (mtDNA CR). Samples (20–50 individuals per location) were collected off Ireland, Portugal, Madeira, Mauritania, South Africa, and the Azores (Mid-Atlantic Ridge). High levels of genetic diversity were found at the nuclear microsatellite loci (mean A = 17.3; overall Ho = 0.77), although there was low diversity at the mtDNA CR (h = 0.65, π = 0.0018). Genetic diversity for the Portuguese dogfish was homogeneously distributed among sampling locations, resulting in low and non-significant indices of genetic differentiation (e.g. FST = −0.0013 to 0.0096, ΦST = −0.017 to 0.033; p > 0.5), consistent with the absence of population structure within the area sampled. The results indicate that C. coelolepis has a high dispersal potential within the eastern Atlantic, and its apparent spatial segregation by size and maturity stage suggest large-scale migration associated with the reproductive cycle.
Phenotypic and Genomic Analyses of a Fast Neutron Mutant Population Resource in Soybean
Authors: Bolon Yung-Tsi , Haun William J. , Xu Wayne W. , Grant David , Stacey Minviluz G. , Nelson Rex T. , Gerhardt Daniel J. , Jeddeloh Jeffrey A. , Stacey Gary , Muehlbauer Gary J. , Orf James H. , Naeve Seth L. , Stupar Robert M. , Vance Carroll P.
Published: February 2011

Mutagenized populations have become indispensable resources for introducing variation and studying gene function in plant genomics research. In this study, fast neutron (FN) radiation was used to induce deletion mutations in the soybean (Glycine max) genome. Approximately 120,000 soybean seeds were exposed to FN radiation doses of up to 32 Gray units to develop over 23,000 independent M2 lines. Here, we demonstrate the utility of this population for phenotypic screening and associated genomic characterization of striking and agronomically important traits. Plant variation was cataloged for seed composition, maturity, morphology, pigmentation, and nodulation traits. Mutants that showed significant increases or decreases in seed protein and oil content across multiple generations and environments were identified. The application of comparative genomic hybridization (CGH) to lesion-induced mutants for deletion mapping was validated on a midoleate x-ray mutant, M23, with a known FAD2-1A (for fatty acid desaturase) gene deletion. Using CGH, a subset of mutants was characterized, revealing deletion regions and candidate genes associated with phenotypes of interest. Exome resequencing and sequencing of PCR products confirmed FN-induced deletions detected by CGH. Beyond characterization of soybean FN mutants, this study demonstrates the utility of CGH, exome sequence capture, and next-generation sequencing approaches for analyses of mutant plant genomes. We present this FN mutant soybean population as a valuable public resource for future genetic screens and functional genomics research.
Fascin‐1 expression correlates with repression of E‐cadherin expression in hepatocellular carcinoma cells and augments their invasiveness in combination with matrix metalloproteinases
Authors: Hayashi Yoshihiro , Osanai Makoto , Lee Gang‐Hong
Published: February 2011

Expression of fascin‐1, an actin bundling protein, is a poor prognostic factor in hepatocellular carcinoma (HCC). However, its biological role in HCC cells remains unclear. Using human HCC tissues and cell lines HLE, Hep3B, and Huh7, we investigated whether fascin‐1 is involved in epithelial–mesenchymal transition (EMT) and increases invasiveness, thus serving as a promoter of cancer aggressiveness. Immunohistochemical analysis revealed that fascin‐1 expression in 19% of primary HCCs was associated with repression of E‐cadherin expression, indicating EMT. In vitro, HLE cells showed high fascin‐1 expression, loss of E‐cadherin, and efficient invasion through Matrigel. Knockdown of fascin‐1 significantly repressed invasiveness of the HLE cells and slightly induced E‐cadherin expression. In contrast, Huh7 cells had low fascin‐1 levels, high E‐cadherin expression, and were expectedly non‐invasive. However, forced overexpression of fascin‐1 conferred only modest invasiveness without E‐cadherin repression, indicating that fascin‐1 alone cannot effectively stimulate invasiveness or EMT. Furthermore, Hep3B cells were non‐invasive despite high fascin‐1 expression. Nevertheless, fascin‐1 overexpression dramatically increased the migratory potential of Huh7 cells. We then evaluated matrix metalloproteinases (MMPs) 2 and 9 from the HCC cell lines. Significant MMP secretion was only found in HLE cells. Although MMP levels were not elevated in fascin‐1‐overexpressing Huh7 cells, their invasiveness was remarkably augmented by coculture with HLE cells, and was suppressed in the presence of an MMP inhibitor. In conclusion, we propose that fascin‐1 primarily acts as a migration factor associated with EMT in HCC cells and facilitates their invasiveness in combination with MMPs. (Cancer Sci 2011; 102: 1228–1235)
Variability in the population pharmacokinetics of isoniazid in South African tuberculosis patients
Authors: Wilkins Justin J. , Langdon Grant , McIlleron Helen , Pillai Goonaseelan , Smith Peter J. , Simonsson Ulrika S. H.
Published: February 2011

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The pharmacokinetic properties of isoniazid are well characterized, having been studied in seminal work beginning in the early 1950s. Pharmacokinetic models have been published in other populations.

WHAT THIS PAPER ADDS

• This work provides a population model for isoniazid pharmacokinetics in a South African population from a tuberculosis‐endemic region, of potential use in investigating the complex exposure‐response relationships found in the first line treatment of pulmonary tuberculosis. Previous work has been performed in smaller groups of healthy volunteers or predominantly Caucasian or Asian patients, but the pharmacokinetics of isoniazid in the population in this study are significantly different from those previously reported in other populations. The developed model will provide a basis for estimation of optimal doses in children.

AIM This study was designed to characterize the population pharmacokinetics of isoniazid in South African pulmonary tuberculosis patients.

METHODS Concentration–time measurements obtained from 235 patients receiving oral doses of isoniazid as part of routine tuberculosis chemotherapy in two clinical studies were pooled and subjected to nonlinear mixed‐effects analysis.

RESULTS A two‐compartmental model, including first‐order absorption and elimination with allometric scaling, was found to describe the observed dose‐exposure relationship for oral isoniazid adequately. A mixture model was used to characterize dual rates of isoniazid elimination. Estimates of apparent clearance in slow and fast eliminators were 9.70 and 21.6 l h−1, respectively. The proportion of fast eliminators in the population was estimated to be 13.2%. Central volume of distribution was estimated to be 10% smaller in female patients and clearance was found to be 17% lower in patients with HIV. Variability in absorption rate (90%) was completely interoccasional in nature, whereas in relative bioavailability, interoccasional variability (8.4%) was lower than interindividual variability (26%). Oral doses, given once daily according to dosing policies at the time, were sufficient to reach therapeutic concentrations in the majority of the studied population, regardless of eliminator phenotype. Simulations suggested that current treatment guidelines (5 mg kg−1) may be suboptimal in fast eliminators with low body weight.

CONCLUSIONS A population pharmacokinetic model was developed to characterize the highly variable pharmacokinetics of isoniazid in a South African pulmonary tuberculosis patient population. Current treatment guidelines may lead to underexposure in rapid isoniazid eliminators.
Influence of genetic, biological and pharmacological factors on warfarin dose in a Southern Brazilian population of European ancestry
Authors: Botton Mariana Rodrigues , Bandinelli Eliane , Rohde Luis Eduardo Paim , Amon Luis Carlos , Hutz Mara Helena
Published: February 2011

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Warfarin is an oral anticoagulant widely used for thromboembolic disease prophylaxis. The pharmacokinetics and pharmacodynamics of this drug vary with environmental and genetic factors. Several algorithms including genetic and non‐genetic factors have been developed for different populations. These investigations have shown that polymorphisms in CYP2C9 and VKORC1 genes are related to warfarin dose variation.

WHAT THIS STUDY ADDS

• This study confirms that CYP2C9 and VKORC1 genes are the main predictors of warfarin dose, but there are other genes with smaller effects that can improve the algorithm for better dose prediction.

• This study observed for the first time an effect of the F2 gene on warfarin dose prediction.

• The inclusion for the first time of co‐medication with amlodipine, carbamazepine, β‐adrenoceptor blockers and diuretics refined the construction of an algorithm for dose prediction.

AIMS To investigate the influence of polymorphisms in CYP2C9, VKORC1, CYP4F2 and F2 genes on warfarin dose–response and develop a model including genetic and non‐genetic factors for warfarin dose prediction needed for each patient.

METHODS A total of 279 patients of European ancestry on warfarin medication were investigated. Genotypes for −1639G>A, 1173C>T, and 3730G>A SNPs in the VKORC1 gene, CYP2C9*2 and CYP2C9*3, 1347C>T in the CYP4F2 gene and 494C>T in the F2 gene were determined by allelic discrimination with Taqman 5'‐nuclease assays.

RESULTS The CYP2C9*2 and CYP2C9*3 polymorphisms in the CYP2C9 gene, −1639G>A and 1173C>T in the VKORC1 gene and 494C>T in the F2 gene are responsible for lower anticoagulant doses. In contrast, 1347C>T in the CYP4F2 gene and 3730G>A in the VKORC1 gene are responsible for higher doses of warfarin. An algorithm including genetic, biological and pharmacological factors that explains 63.3% of warfarin dose variation was developed.

CONCLUSION The model suggested has one of the highest coefficients of determination among those described in the literature.
A cautious iodization programme bringing iodine intake to a low recommended level is associated with an increase in the prevalence of thyroid autoantibodies in the population
Authors: Pedersen Inge B. , Knudsen Nils , Carlé Allan , Vejbjerg Pernille , Jørgensen Torben , Perrild Hans , Ovesen Lars , Rasmussen Lone B. , Laurberg Peter
Published: February 2011

Autoantibodies against the thyroid gland with thyroid peroxidase antibody (TPO‐Ab) and thyroglobulin antibody (Tg‐Ab) as the most common can often be demonstrated in serum. The effect of public iodization programmes on antibody prevalence is uncertain.

Aim  To measure the concentrations of thyroid autoantibodies in the Danish population before and after mandatory iodization of salt.

Methods  Two identical cross‐sectional population studies were performed before (Cohort 1 (C1), year 1997–1998, n = 4649, median urinary iodine 61 μg/l) and 4–5 years after (Cohort 2 (C2), year 2004–2005, n = 3570, median urinary iodine 101 μg/l) mandatory iodine fortification of salt was implemented in Denmark. Blood tests were analysed for TPO‐Ab and Tg‐Ab using sensitive assays.

Results  Antibodies were more frequent in C2 than in C1: TPO‐Ab > 30 U/ml, C1 vs C2: 14·3 vs 23·8% (P < 0·001) and Tg‐Ab > 20 U/ml, C1 vs C2: 13·7 vs 19·9% (P < 0·001). The C2 vs C1 effect was confirmed in multivariate regression models (C1 reference): TPO‐Ab: OR (95% CI): 1·80 (1·59–2·04) and Tg‐Ab: 1·49 (1·31–1·69). The increase in the frequency of thyroid antibodies was most pronounced in young women and especially observed at low concentrations of antibodies.

Conclusion  The prevalence of both TPO‐Ab and Tg‐Ab was higher 4–5 years after a cautious iodine fortification of salt was introduced in Denmark. The increase was most pronounced in young women and in the low concentrations of antibody. Further studies are needed to evaluate the long‐term effects of increased iodine intake on thyroid autoimmunity in the population.
Investigation of the significance of Oil Red O‐positive macrophage excess in bronchoalveolar lavage fluid during HIV infection
Authors: Lacoste‐Collin L. , Martin‐Blondel G. , Basset‐Léobon C. , Lauwers‐Cancès V. , d’Aure D. , Aziza J. , Berry A. , Marchou B , Delisle M. B. , Courtade‐Saïdi M.
Published: February 2011

L. Lacoste‐Collin, G. Martin‐Blondel, C. Basset‐Léobon, V. Lauwers‐Cancès, D. d’Aure, J. Aziza, A. Berry, B Marchou, M.B. Delisle and M. Courtade‐Saïdi

Investigation of the significance of Oil Red O‐positive macrophage excess in bronchoalveolar lavage fluid during HIV infection

Objective:  To assess the significance of increased levels of Oil Red O‐positive macrophages (ORO‐PM) in bronchoalveolar lavage fluids (BALFs) from HIV‐positive patients.

Methods:  Cytological data for seventy BALF samples from 66 consecutive HIV‐infected patients were analysed according to antiretroviral therapy regimen, presence of Pneumocystis jiroveci infection, blood CD4+T cell count, HIV‐1 viral load and plasma lipid levels. Non‐parametric tests were used to compare the values between groups.

Results:  The percentages of ORO‐PM were high in this group: 40% [6–80] (median [interquartile range]). They were positively correlated with the BALF total cell count, 21% [5–48.5] for <300 cells/mm3 and 60% [26.5–80] for >300 cells/mm3 (P < 0.01) but inversely correlated with the percentage of BALF lymphocytes, 50% [20–80] for <15% lymphocytes and 11.5% [2–47] for ≥15% lymphocytes (P < 0.01). Antiretroviral therapy with or without protease inhibitors, plasma lipid levels, HIV‐1 viral load, blood CD4+T cell count or presence of a Pneumocystis jiroveci infection were not correlated with the ORO‐PM status.

Conclusion:  Significantly increased numbers of ORO‐PM were correlated with high total cell counts and low lymphocyte counts in BALF, irrespective of disease activity or treatment. Extended work on a larger series of patients needs to be conducted.
A Taiwanese version of the International Consultation on Incontinence Questionnaire – Urinary Incontinence Short Form for pregnant women: instrument validation
Authors: Chang Shiow‐Ru , Chen Kuang‐Ho , Chang Ting‐Chen , Lin Ho‐Hsiung
Published: February 2011

Aim.  To translate the International Consultation on Incontinence Questionnaire – Urinary Incontinence Short Form (ICIQ‐UI SF) from English to Taiwanese and to evaluate its reliability and validity for pregnant Taiwanese women.

Background.  Urinary incontinence in pregnant women has been little investigated in Taiwan. A validated assessment instrument for urinary incontinence is needed for pregnant Taiwanese women.

Design.  A non‐experimental design was used to test the psychometric properties of the Taiwanese version of the ICIQ‐UI SF.

Method.  The internal consistency reliability and construct validity of the Taiwanese version of the ICIQ‐UI SF for pregnant women were evaluated in a random sample of 121 pregnant women at a medical center in Taiwan. Test–retest reliability was assessed for a sample of 55 pregnant women who completed this version at two time points in four weeks. Construct validity was verified with three questions and seven urinary‐leakage situations by factor analysis.

Results.  The Taiwanese version of the ICIQ‐UI SF showed adequate test–retest reliability in pregnant Taiwanese women. The Pearson’s correlation coefficient of the total score was 0·75, kappa statistics showed excellent or good reproducibility for most items and McNemar’s test confirmed that there was no significant difference in the test–retest pair for each item of the scale. The internal consistency reliability of the scale was good, with Cronbach’s α = 0·80. Three factors were extracted and identified with an eigenvalue ≥1·04, explaining 65·64% the total variance. The first, second and third factors were ‘symptom and quality of life’, ‘stress incontinence or other types’ and ‘urge or overflow incontinence’.

Conclusions.  The results provide evidence of the validity and reliability of the psychometric properties of the Taiwanese version of the ICIQ‐UI SF for pregnant women.

Relevance to clinical practice.  This questionnaire is a suitable instrument for evaluating urinary incontinence in pregnant Taiwanese women.
Use of polyurethane foam inside plaster casts to prevent the onset of heel sores in the population at risk. A controlled clinical study
Authors: Forni Cristiana , Loro Loretta , Tremosini Morena , Mini Sandra , Pignotti Elettra , Bigoni Ombretta , Guzzo Giuseppe , Bellini Laura , Trofa Carmela , Di Cataldo Anna M , Guzzi Marilena
Published: February 2011

Aim.  The aim of this study was to test the effectiveness of polyurethane foam in contact with the heel inside a plaster cast to decrease the rate of pressure sores in the population at most risk.

Background.  The rate of pressure sores caused by the plaster cast is reported to be 14–15% in the paediatric population, 33·3% in patients having undergone chemotherapy for bone tumours and 43% in orthopaedic patients who already have sore skin when the cast is applied (grade 1 lesion) to the heel.

Design.  Controlled clinical trial.

Methods.  From November 2007–January 2009, all consecutive subjects requiring lower limb casts having undergone chemotherapy and/or presenting heel soreness received polyurethane foam in contact with the skin of the heel before applying the cast. The results were compared with those of patients with the same risk factors but were not administered the foam and were enrolled from May 2005–August 2006.

Results.  In total, 156 patients were enrolled, 85 in the control group and 71 in the experimental group. In the experimental group, 2 of the 56 patients (3·6%) with sore skin developed a pressure sore compared with 21 of 49 (42·9%) in the control group without polyurethane foam (p < 0·0005). In the experimental group, one of the 24 patients (4·2%) patients undergoing chemotherapy developed a pressure sore compared with 18 of 54 (33·3%) in the control group (p = 0·005).

Conclusions.  Placing polyurethane foam in contact with the skin of the heel inside a plaster cast prevents the formation of pressure sores.

Relevance to clinical practice.  This study provides evidence that using polyurethane foam to prevent sores even inside plaster casts in populations at most risk is a simple and cost‐effective strategy and decreases the discomfort, pain and risks in these patients.
The adoption, local implementation and assimilation into routine nursing practice of a national quality improvement programme: the Productive Ward in England
Authors: Robert Glenn , Morrow Elizabeth , Maben Jill , Griffiths Peter , Callard Lynn
Published: February 2011

Aim and objective.  To explore why innovations in service and delivery are adopted and how they are then successfully implemented and eventually assimilated into routine nursing practice.

Background.  The ‘Productive Ward’ is a national quality improvement programme that aims to engage nursing staff in the implementation of change at ward level.

Design.  Mixed methods (analysis of routine data, online survey, interviews) to apply an evidence‐based diffusion of innovations framework.

Method.  (1) Broad and narrow indicators of the timing of ‘decisions to adopt’ the Productive Ward were applied. (2) An online survey explored the perceptions of 150 respondents involved with local implementation. (3) Fifty‐eight interviews in five organisational case studies to explore the process of assimilation in each context.

Results.  Since the launch of the programme in May 2008 staff in approximately 85% of NHS acute hospitals had either downloaded Productive Ward materials or formally purchased a support package (as of March 2009). On a narrower measure, 40% (140) of all NHS hospitals had adopted the programme (i.e. purchased a support package) with large variation between geographical regions. Four key interactions in the diffusion of innovations framework appeared central to the rapid adoption of the programme. Despite widespread perception of significant benefits, frontline nursing staff report that more needs to be carried out to ensure that impact can be demonstrated in quantifiable terms and include patient perspectives.

Conclusions.  The programme has been rapidly adopted by NHS hospitals in England. A variety of implementation approaches are being employed, which are likely to have implications for the successful assimilation of the programme into routine nursing practice.

Relevance to clinical practice.  This paper summarises the perceived benefits of the Productive Ward programme and highlights important lessons for nurse leaders who are designing (or adapting) and then implementing quality improvement programmes locally, particularly in terms of how to frame such initiatives – and provide support to – ward‐level staff.
Effects of a home‐based aerobic exercise programme in children with type 1 diabetes mellitus
Authors: Wong Ching‐Hsiang , Chiang Yi‐Chien , Wai Jackson Pui Man , Lo Fu‐Sung , Yeh Chao‐Hsing , Chung Shih‐Chi , Chang Chi‐Wen
Published: February 2011

Aims.  To explore the effects of exercise programme on glycosylated haemoglobin and peak oxygen uptake in children and adolescents with type 1 diabetes mellitus.

Background.  Regular exercise has been shown to be effective in blood glucose control, which includes improving glucose tolerance and insulin sensitivity, decreasing glycosylated haemoglobin levels and improving cardiorespiratory fitness.

Design.  Quasi‐experimental design with a twelve‐week home‐based aerobic exercise programme.

Method.  Twenty‐eight participants completed the study: 12 in the home‐based exercise group, 11 in the non‐exercise control group and five in the self‐directed exercise group. A mixed model was used to capture longitudinal change in glycosylated haemoglobin levels.

Results.  The home‐based aerobic exercise group showed no significant effect on glycemic control and peak oxygen uptake in this study across assessment times. However, a group difference in glycosylated haemoglobin levels at the nine‐month follow‐up was significant (general linear model: F = 4·06, p = 0·03). A Bonferroni test indicated that glycosylated haemoglobin levels in the home‐based exercise group were higher than in the self‐directed exercise group (p < 0·05) and higher in the control group than in the self‐directed exercise group (p < 0·05) at the nine‐month follow‐up. Home‐based aerobic exercise showed no significant effect on peak oxygen uptake in this study.

Conclusions.  A three‐month home‐based aerobic exercise programme has no significant effect on glycosylated haemoglobin and peak oxygen uptake levels in children with type 1 diabetes mellitus.

Relevance to clinical practice.  Our exercise programme has designed that children can practice exercise at home and is a viable component of self‐care intervention to improve patient’s self‐care skill and diabetes care control. However, how to encourage patients to adhere the exercise programme is a challenge for health care providers.
The effect of patient education and home monitoring on medication compliance, hypertension management, healthy lifestyle behaviours and BMI in a primary health care setting
Authors: Hacihasanoğlu Rabia , Gözüm Sebahat
Published: February 2011

Aim.  The aim of this study was to determine the effect of anti‐hypertensive patient‐oriented education and in‐home monitoring for medication adherence and management of hypertension in a primary care setting, by providing education on healthy lifestyle behaviours and medication adherence.

Background.  Hypertension is the third most common cause of death worldwide. Prevalence of hypertension in Turkey is approximately 30% in the general population and 45–50% in population over 50.

Design.  Randomised controlled study.

Methods.  This study conducted in Turkey used a study group comprised of 120 subjects (40 Group A, 40 Group B, 40 controls), all previously diagnosed with hypertension and who started medication therapy at least one year prior to start of study. The study was conducted between February–November 2006 at public primary health care facilities and homes of the study participants. Participants in Group A and B received a total of six monthly education sessions, four times during clinic visits and two home visits. Medication adherence education for Groups A and B and education about healthy lifestyle behaviours for Group B were administered in a structured and individualised format. The control group was routinely monitored in health care facilities.

Results.  Healthy lifestyle behaviours and perception of self‐efficacy regarding medication adherence showed improvement after education sessions in Groups A and B. Systolic and diastolic blood pressures of subjects in Group A and B showed a significant decrease compared with those of the control group; the blood pressure decrease in Group B was greater than in Group A.

Conclusion.  Nurses play an important role in uncontrolled hypertension detection and can improve medication adherence and healthy lifestyle behaviours.

Relevance to clinical practice.  Patient education medication adherence alone and in combination with healthy lifestyle behaviour teaching is an effective tool for blood pressure reduction in the hypertensive population in primary health care settings.
Physical exercise: does it help in relieving pain and increasing mobility among older adults with chronic pain?
Authors: Tse Mimi MY , Wan Vanessa TC , Ho Suki SK
Published: February 2011

Aim.  To provide a physical exercise programme for older adults living in nursing homes.

Background.  Pain is common among older persons and for those already in long‐term care and having difficulty in coping with pain will be at risk of further reducing their optimal independent function.

Design.  A quasi‐experimental single group pretest‐posttest design.

Method.  Older persons from a nursing home were invited to join an eight‐week physical exercise programme. Each session lasted an hour and sessions were conducted once a week by physiotherapist and nurses. Physical exercise programme consisted of stretching, strengthening, balancing, towel dancing and self‐administered massage to various acupressure points. On completion of each session, older persons were given a pamphlet with pictures to illustrate the exercise of the day and they were encouraged to practise these exercises by themselves. Outcome measures including pain intensity, range of movement, activities of daily living and mobility were collected before and after the physical exercise programme.

Results.  There were 75 older adult participants (57 female and 18 male, mean age 85·14 SD 5·30). Seventy‐three percent (n = 55) of them had pain in the previous three months and were referred as pain group, while 25% (n = 20) were no pain group. Pain scores of 4·89 (on a 10‐point scale) indicated medium pain intensity before the intervention for the pain group; the location of pain was mainly in the knee, back and shoulder. On completion of the physical exercise programme, there was a significant decrease in pain intensity to 2·89 (SD 2·14) (p < 0·01). There was a significant increase in range of movement in the neck, shoulder, back, hip and knee rotation, flex and abduction (p < 0·01). Mobility level was significantly increased post intervention, yet activities of daily living remained unchanged.

Conclusions.  The present study demonstrated the effectiveness of a physical exercise programme in relieving pain and enhancing functional mobility for older persons.

Relevance to clinical practice.  It is important to educate older persons, especially those living in nursing homes, on the importance of engaging in regular physical exercise and maintaining mobility.
Predictors of postpartum stress
Authors: Hung Chich‐Hsiu , Lin Chia‐Ju , Stocker Joel , Yu Ching‐Yun
Published: February 2011

Aim.  To predict important factors in women’s postpartum stress.

Background.  The transition to motherhood is often accompanied by stress, but research on predictors of postpartum stress is scant.

Design.  A cross‐sectional survey was used in the study.

Methods.  Proportional stratified quota sampling based on births at 11 registered general hospitals and seven specialty clinics in the Kaohsiung area of southern Taiwan was used to obtain a high degree of representation. Eight hundred and fifty‐nine women participated in the study within six weeks postpartum. The Hung postpartum stress scale, the social support scale and the 12‐item Chinese Health Questionnaire were used in this study.

Results.  Women with minor psychiatric morbidity, one or two children, junior college educational level, formula feeding for their infants, preference for an infant boy and a low level of social support were important predictors for women’s postpartum stress.

Conclusion.  Our findings provide information and data for service planning and community care for the prevention and amelioration of postpartum stress.

Relevance to clinical practice.  Postpartum women face a constellation of factors that could put them at risk for high levels of postpartum stress. Postpartum stress could significantly negatively impact women’s health status. Nursing interventions should be tailored to decrease women’s postpartum stress as a means of promoting postpartum women’s pursuit of well‐being.