bluuebunny/crossref_metadata_2025 huggingface dataset:
Groundhog Day versus Alice in Wonderland, Red Herrings versus Swedish Fishes, and Hopefully Something Constructive: A Reply to Comments
Authors: Donnellan M. Brent , Trzesniewski Kali H.
Published: February 2010

In this reply to the comments on our original article, we identify common themes and respond to some specific issues that appear to be at the core of the debate over the evidence for “Generation Me.” In particular, we point out that generational studies have both applied and theoretical consequences and echo the sentiment that developmental considerations are likely to be more important than generational considerations when thinking about the attributes of today's young people. We also acknowledge that disagreements are inevitable, as this is a controversial issue of study. However, we reiterate our commitment to the interpretation of effect sizes rather than null hypothesis significance testing and emphasize the need for care when psychological scientists offer broad and often moralistic pronouncements about entire generations of young people.
Effect of Ti addition on morphology and size of primary M7C3 type carbide in hypereutectic high chromium cast iron
Authors: Huang Z. F. , Xing J. D. , Zhi X. H. , Gao Y. M.
Published: February 2010

Effect of Ti addition on the morphology and size of primary M7C3 type carbide in hypereutectic high chromium cast iron was investigated. The results indicated that the carbide is refined gradually, and its morphology becomes more equiaxed as titanium addition increases, but rather slowly when Ti addition exceeds 0·95. The qualitative measurement result indicated that value shape factor K increases clearly first and then changes little, and the average equivalent diameter D changes against K exactly. Furthermore, by TEM analysis and Brammit's theory calculation, the results also indicated that there are orientation relationships of [Formula: see text] TiC||[Formula: see text] M7C3 and [011]TiC||[0001]M7C3 between M7C3 type carbide and TiC, and the lattice misfit δ between [Formula: see text] TiC and [Formula: see text] M7C3 is 1·32, explaining that [Formula: see text] TiC may provide the effective substrate plane for [Formula: see text] M7C3 nucleation to ameliorate morphology and size of primary M7C3 type carbide.
Effect of ZnAl2O4 coating of whisker surface on Young's modulus of Al18B4O33w/Al composite
Authors: Yue H. Y. , Fei W. D. , Guo E. J. , Wang L. P. , Yu Z. M.
Published: February 2010

Pure aluminium matrix composites reinforced by ZnAl2O4 coated Al18B4O33 whiskers were fabricated by squeeze casting. The effect of ZnAl2O4 coating on the Young's modulus of the composite was investigated. The results show that the Young's modulus of the composite significantly increases with increasing ZnAl2O4 coating content. The influence mechanisms of ZnAl2O4 coating on the Young's modulus of the composite were analysed. The increase in load transfer area of whisker/matrix interface and the volume fraction of effective reinforcement with increasing ZnAl2O4 coating content can increase the Young's modulus of the composites. The steps can provide an additional load transfer from the matrix to whiskers during the tensile deformation of the composites.
Interaction of 308 stainless steel insert with A319 aluminium casting alloy
Authors: Khoonsari E. M. , Jalilian F. , Paray F. , Emadi D. , Drew R. A. L.
Published: February 2010

In the metallurgical connection of aluminium alloys to steels, it is important to restrain the formation and growth of hard and brittle intermetallic phases at the aluminium/steel interface to enhance the mechanical behaviour of the joint. The influence of two coating materials, electroless plated copper (for 20 and 40 min) and galvanised zinc (at 480 and 550°C), on the quality of the interface between 308 stainless steel and A319 aluminium matrix was investigated. Copper led to the formation of a compact, solid inhibition layer against the elemental diffusion at the aluminium–steel contact temperature, while zinc resulted in the formation of a composite intermetallic layer which was open in structure. Comparing all interfaces formed between the insert and Al matrix, the 40 min Cu coated steel revealed the lowest values in terms of the thickness and microhardness after immersion into the molten aluminium.
Insufficient evidence for association of NOD2/CARD15 or other inflammatory bowel disease–associated markers on GVHD incidence or other adverse outcomes in T-replete, unrelated donor transplantation
Authors: Nguyen Yume , Al-Lehibi Abed , Gorbe Elizabeth , Li Ellen , Haagenson Michael , Wang Tao , Spellman Stephen , Lee Stephanie J. , Davidson Nicholas O.
Published: February 2010

Previous European studies suggest NOD2/CARD15 and interleukin-23 receptor (IL-23R) donor or recipient variants are associated with adverse clinical outcomes in allogeneic hematopoietic stem cell transplantation. We reexamined these findings as well as the role of another inflammatory bowel disease (IBD) susceptibility gene (immunity-related GTPase family, M [IRGM]) on transplantation outcomes in 390 US patients and their matched unrelated donors, accrued between 1995 and 2004. Patients received T-replete grafts with mostly myeloablative conditioning regimens. Multivariate analyses were performed for overall survival, disease-free survival, transplantation-related mortality, relapse, and acute and chronic graft-versus-host disease. Of 390 pairs, NOD2/CARD15 variant single nucleotide polymorphisms (SNPs) were found in 14% of donors and 17% of recipients. In 3% both donor and recipient had a mutant SNP. Thirteen percent of donors and 16% of recipients had variant IL23R SNPs, with 3% having both donor and recipient variants. Twenty-three percent of both donors and recipients had variant IRGM SNPs. None of the 3 IBD-associated alleles showed a statistically significant association with any adverse clinical outcomes. Our results do not support an association between the 3 IBD-associated SNPs and adverse outcomes after matched unrelated donor hematopoietic cell transplantations in US patients.
Region-specific effects on brain metabolites of hypoxia and hyperoxia overlaid on cerebral ischemia in young and old rats: a quantitative proton magnetic resonance spectroscopy study
Authors: Macri Maria A , D'Alessandro Nicola , Di Giulio Camillo , Di Iorio Patrizia , Di Luzio Silvano , Giuliani Patricia , Esposito Ennio , Pokorski Mieczyslaw
Published: February 2010

Background

Both hypoxia and hyperoxia, deregulating the oxidative balance, may play a role in the pathology of neurodegenerative disorders underlain by cerebral ischemia. In the present study, quantitative proton magnetic resonance spectroscopy was used to evaluate regional metabolic alterations, following a 24-hour hypoxic or hyperoxic exposure on the background of ischemic brain insult, in two contrasting age-groups of rats: young - 3 months old and aged - 24 months old.

Methods

Cerebral ischemia was induced by ligation of the right common carotid artery. Concentrations of eight metabolites (alanine, choline-containing compounds, total creatine, γ-aminobutyric acid, glutamate, lactate, myo-inositol and N-acetylaspartate) were quantified from extracts in three different brain regions (fronto-parietal and occipital cortices and the hippocampus) from both hemispheres.

Results

In the control normoxic condition, there were significant increases in lactate and myo-inositol concentrations in the hippocampus of the aged rats, compared with the respective values in the young ones. In the ischemia-hypoxia condition, the most prevalent changes in the brain metabolites were found in the hippocampal regions of both young and aged rats; but the effects were more evident in the aged animals. The ischemia-hyperoxia procedure caused less dedicated changes in the brain metabolites, which may reflect more limited tissue damage.

Conclusions

We conclude that the hippocampus turns out to be particularly susceptible to hypoxia overlaid on cerebral ischemia and that old age further increases this susceptibility.
Expression profiling of mouse embryonic fibroblasts with a deletion in the helicase domain of the Werner Syndrome gene homologue treated with hydrogen peroxide
Authors: Labbé Adam , Turaga Ramachander VN , Paquet Éric R , Garand Chantal , Lebel Michel
Published: February 2010

Background

Werner Syndrome (WS) is a rare disorder characterized by the premature onset of a number of age-related diseases. The gene responsible for WS encodes a DNA helicase/exonuclease protein believed to affect different aspects of transcription, replication, and/or DNA repair. In addition to genomic instability, human WS cells exhibit oxidative stress. In this report, we have examined the impact of exogenous hydrogen peroxide on the expression profile of mouse embryonic fibroblasts lacking part of the helicase domain of the WRN homologue (here referred to as Wrn
Δhel/Δhel
).

Results

Wrn
Δhel/Δhel
mutant mouse embryonic fibroblasts exhibit increased oxidative stress. This was reflected by increased intracellular reactive oxygen species (ROS), increased oxidative damage in genomic DNA, changes in ATP/ADP ratios, and a disruption of the inner mitochondrial transmembrane potential when compared to wild type mouse embryonic fibroblasts. Expression profile analyses of hydrogen peroxide-treated wild type cells have indicated significant decreases in the expression of genes involved in mitosis, glycolysis, fatty acid metabolism, nucleic acid metabolism, and cell cycle control, as well as protein modification and stability. Such decreases in these biological processes were not observed in hydrogen peroxide-treated Wrn
Δhel/Δhel
cells. Importantly, untreated Wrn
Δhel/Δhel
cells already exhibited down regulation of several biological processes decreased in wild type cells that had been treated with hydrogen peroxide.

Conclusion

Expression profiling of Wrn
Δhel/Δhel
mutant cells revealed a very different response to exogenous addition of hydrogen peroxide in culture compared to wild type cells. This is due in part to the fact that Wrn
Δhel/Δhel
mutant cells already exhibited a modest chronic intracellular oxidative stress.
Analysis of a β-helical region in the p55 domain of Helicobacter pylori vacuolating toxin
Authors: Ivie Susan E , McClain Mark S , Algood Holly M Scott , Lacy D Borden , Cover Timothy L
Published: February 2010

Background

Helicobacter pylori is a gram-negative bacterium that colonizes the human stomach and contributes to the development of gastric cancer and peptic ulcer disease. VacA, a toxin secreted by H. pylori, is comprised of two domains, designated p33 and p55. Analysis of the crystal structure of the p55 domain indicated that its structure is predominantly a right-handed parallel β-helix, which is a characteristic of autotransporter passenger domains. Substitution mutations of specific amino acids within the p33 domain abrogate VacA activity, but thus far, it has been difficult to identify small inactivating mutations within the p55 domain. Therefore, we hypothesized that large portions of the p55 domain might be non-essential for vacuolating toxin activity. To test this hypothesis, we introduced eight deletion mutations (each corresponding to a single coil within a β-helical segment spanning VacA amino acids 433-628) into the H. pylori chromosomal vacA gene.

Results

All eight of the mutant VacA proteins were expressed by the corresponding H. pylori mutant strains and underwent proteolytic processing to yield ~85 kDa passenger domains. Three mutant proteins (VacA Δ484-504, Δ511-536, and Δ517-544) were secreted and induced vacuolation of mammalian cells, which indicated that these β-helical coils were dispensable for vacuolating toxin activity. One mutant protein (VacA Δ433-461) exhibited reduced vacuolating toxin activity compared to wild-type VacA. Other mutant proteins, including those containing deletions near the carboxy-terminal end of the β-helical region (amino acids Val559-Asn628), exhibited marked defects in secretion and increased susceptibility to proteolytic cleavage by trypsin, which suggested that these proteins were misfolded.

Conclusions

These results indicate that within the β-helical segment of the VacA p55 domain, there are regions of plasticity that tolerate alterations without detrimental effects on protein secretion or activity, as well as a carboxy-terminal region in which similar alterations result in protein misfolding and impaired secretion. We propose that non-essential β-helical coils and a carboxy-terminal β-helical segment required for proper protein folding and secretion are features shared by numerous autotransporter passenger domains.
Salicylic acid alleviates decreases in photosynthesis under heat stress and accelerates recovery in grapevine leaves
Authors: Wang Li-Jun , Fan Ling , Loescher Wayne , Duan Wei , Liu Guo-Jie , Cheng Jian-Shan , Luo Hai-Bo , Li Shao-Hua
Published: February 2010

Background

Although the effect of salicylic acid (SA) on photosynthesis of plants including grapevines has been investigated, very little is yet known about the effects of SA on carbon assimilation and several components of PSII electron transport (donor side, reaction center and acceptor side). In this study, the impact of SA pretreatment on photosynthesis was evaluated in the leaves of young grapevines before heat stress (25°C), during heat stress (43°C for 5 h), and through the following recovery period (25°C). Photosynthetic measures included gas exchange parameters, PSII electron transport, energy dissipation, and Rubisco activation state. The levels of heat shock proteins (HSPs) in the chloroplast were also investigated.

Results

SA did not significantly (P< 0.05) influence the net photosynthesis rate (Pn) of leaves before heat stress. But, SA did alleviate declines inPnand Rubisco activition state, and did not alter negative changes in PSII parameters (donor side, acceptor side and reaction center QA) under heat stress. Following heat treatment, the recovery ofPnin SA-treated leaves was accelerated compared with the control (H2O-treated) leaves, and, donor and acceptor parameters of PSII in SA-treated leaves recovered to normal levels more rapidly than in the controls. Rubisco, however, was not significantly (P< 0.05) influenced by SA. Before heat stress, SA did not affect level of HSP 21, but the HSP21 immune signal increased in both SA-treated and control leaves during heat stress. During the recovery period, HSP21 levels remained high through the end of the experiment in the SA-treated leaves, but decreased in controls.

Conclusion

SA pretreatment alleviated the heat stress induced decrease inPnmainly through maintaining higher Rubisco activition state, and it accelerated the recovery ofPnmainly through effects on PSII function. These effects of SA may be related in part to enhanced levels of HSP21.
Hybrid capture vs. PCR screening of cervical human papilloma virus infections. Cytological and histological associations in 1270 women
Authors: Tsiodras Sotirios , Georgoulakis John , Chranioti Aikaterini , Voulgaris Zanis , Psyrri Amanda , Tsivilika Angeliki , Panayiotides John , Karakitsos Petros
Published: February 2010

Background

We evaluated two molecular methods of HPV detection and their correlation with cytological and histological diagnosis in a large sample of Greek women.

Methods

All women with liquid-based cytology performed at a University Hospital between 2000 and 2003 were included. The Hybrid Capture 2 (HC2) kit and in house Polymerase Chain Reaction (PCR) were used for HPV DNA detection. Cervical biopsy was performed for women with ASCUS+ cytology, HPV detection, or abnormal colposcopy. Positive (PLR) and negative (NLR) likelihood ratios were calculated for cytology and HPV molecular testing for the prediction of CIN2 and greater histology.

Results

Of the 1270 women evaluated 241 (18.5%) had abnormal cytology. Cytology diagnosed high-grade squamous intraepithelial lesion (HSIL) or invasive carcinoma in 21(1.7%) cases whereas 26 (2%) women had CIN2+ or greater histology. PCR detected HPV in 397/1270 (31.3%) and HC2 in 260/1270 (20.4%) samples. Both molecular tests exhibited high reproducibility (Cohen's kappa value 0.691, 95% CI: 0.664 - 0.718). Positive likelihood ratios (PLR) of 9.4, 3.8 and 3.4 and negative likelihood ratios of 0.13, 0.21, and 0 were noted for ≥ LSIL, any positive HC2 or any positive PCR-HPV testing, for predicting CIN2+ histology, respectively. All CIN 3+ lesions harbored high risk oncogenic HPV type infections.

Conclusions

HPV infection was found in a large proportion of this population and was associated with CIN 2/3 lesions and infiltrating carcinomas. Thin prep testing and HPV detection by HC2 or PCR performed very well with regards to identifying high grade lesions in an environment with experienced examiners.
In vitro and in vivo characterization of highly purified Human Mesothelioma derived cells
Authors: Melotti Alice , Daga Antonio , Marubbi Daniela , Zunino Annalisa , Mutti Luciano , Corte Giorgio
Published: February 2010

Background

Malignant pleural mesothelioma is a rare disease known to be resistant to conventional therapies. A better understanding of mesothelioma biology may provide the rationale for new therapeutic strategies. In this regard, tumor cell lines development has been an important tool to study the biological properties of many tumors. However all the cell lines established so far were grown in medium containing at least 10% serum, and it has been shown that primary cell lines cultured under these conditions lose their ability to differentiate, acquire gene expression profiles that differ from that of tissue specific stem cells or the primary tumor they derive from, and in some cases are neither clonogenic nor tumorigenic. Our work was aimed to establish from fresh human pleural mesothelioma samples cell cultures maintaining tumorigenic properties.

Methods

The primary cell cultures, obtained from four human pleural mesotheliomas, were expanded in vitro in a low serum proliferation-permissive medium and the expression of different markers as well as the tumorigenicity in immunodeficient mice was evaluated.

Results

The established mesothelioma cell cultures are able to engraft, after pseudo orthotopic intraperitoneal transplantation, in immunodeficient mouse and maintain this ability to after serial transplantation. Our cell cultures were strongly positive for CD46, CD47, CD56 and CD63 and were also strongly positive for some markers never described before in mesothelioma cell lines, including CD55, CD90 and CD99. By real time PCR we found that our cell lines expressed high mRNA levels of typical mesothelioma markers as mesothelin (MSLN) and calretinin (CALB2), and of BMI-1, a stemness marker, and DKK1, a potent Wingless [WNT] inhibitor.

Conclusions

These cell cultures may provide a valuable in vitro and in vivo model to investigate mesothelioma biology. The identification of new mesothelioma markers may be useful for diagnosis and/or prognosis of this neoplasia as well as for isolation of mesothelioma tumor initiating cells.
Association of shared decision-making with type of breast cancer surgery: a cross-sectional study
Authors: Lee Myung Kyung , Noh Dong Young , Nam Seok Jin , Ahn Se Hyun , Park Byeong Woo , Lee Eun Sook , Yun Young Ho
Published: February 2010

Background

Although some studies examined the association between shared decision-making (SDM) and type of breast cancer surgery received, it is little known how treatment decisions might be shaped by the information provided by physicians. The purpose of this study was to identify the associations between shared decision making (SDM) and surgical treatment received.

Methods

Questionnaires on SDM were administered to 1,893 women undergoing primary curative surgery for newly diagnosed stage 0-II localized breast cancer at five hospitals in Korea. Questions included being informed on treatment options and the patient's own opinion in decision-making.

Results

Patients more likely to undergo mastectomy were those whose opinions were respected in treatment decisions (adjusted odds ratio, aOR), 1.40; 95% confidence interval (CI), 1.14-1.72) and who were informed on chemotherapy (aOR, 2.57; CI, 2.20-3.01) or hormone therapy (aOR, 2.03; CI, 1.77-2.32). In contrast, patients less likely to undergo mastectomy were those who were more informed on breast surgery options (aOR, 0.34; CI, 0.27-0.42). In patients diagnosed with stage 0-IIa cancer, clinical factors and the provision of information on treatment by the doctor were associated with treatment decisions. In patients diagnosed with stage IIb cancer, the patient's opinion was more respected in treatment decisions.

Conclusion

Our population-based study suggested that women's treatment decisions might be shaped by the information provided by physicians, and that women might request different information from their physicians based on their preferred treatment options. These results might need to be confirmed in other studies of treatment decisions.
The influence of the rural health security schemes on health utilization and household impoverishment in rural China: data from a household survey of western and central China
Authors: Shi Wuxiang , Chongsuvivatwong Virasakdi , Geater Alan , Zhang Junhua , Zhang Hong , Brombal Daniele
Published: February 2010

Background

The New Rural Cooperative Medical Scheme (NRCMS, voluntary health insurance) and the Medical Financial Assistance (MFA, financial relief program) were established in 2003 for rural China. The aim of this study was to document their coverage, assess their effectiveness on access to in-patient care and protection against financial catastrophe and household impoverishment due to health spending, and identify the factors predicting impoverishment with and without these schemes.

Methods

A cross-sectional household survey was conducted in 2008 in Hebei and Shaanxi provinces and the Inner Mongolia Autonomous Region using a multi-stage sampling technique. Information on personal demographic characteristics, chronic illness status, health care use, household expenditure, and household health spending were collected by interview.

Results

NRCMS covered 90.8% of the studied individuals and among the designated poor, 7.6% had their premiums paid by MFA. Of those referred for hospitalization in the year prior to the interview, 34.3% failed to comply, mostly (80.2%) owing to financial constraints. There was no significant difference in the unmet need for admission between the insured with NRCMS and the uninsured. Before reimbursement, the incidence of catastrophic health payment (household health spending more than 40% of household's capacity to pay) and medical impoverishment (household per capita income falling below the poverty line due to medical expense) was 14.3% and 8.2%, respectively. NRCMS prevented 9.9% of the households from financial catastrophe and 7.7% from impoverishment, whereas MFA kept just one household from impoverishment and had no effect on financial catastrophe. Household per capita expenditure and household chronic disease proportion (proportion of members of a household with chronic illness) were the most important determinants of the unmet need for admission, risk of being impoverished and the chance of not being saved from impoverishment.

Conclusion

The coverage of NRCMS among the rural population was high but not adequate to improve access to in-patient care and protect against financial catastrophe and household impoverishment due to health payment, especially for the poor and the chronically ill. Furthermore, MFA played almost no such role; therefore, the current schemes need to be improved.
A potential tocopherol acetate loaded palm oil esters-in-water nanoemulsions for nanocosmeceuticals
Authors: Teo Brian Sheng Xian , Basri Mahiran , Zakaria Mohd Rezuwan Shah , Salleh Abu Bakar , Rahman Raja Noor Zaliha Raja Abdul , Rahman Mohd Basyaruddin Abdul
Published: February 2010

Background

Cosmeceuticals are cosmetic-pharmaceutical hybrids intended to enhance health and beauty of the skin. Nanocosmeceuticals use nano-sized system for the delivery of active ingredients to the targeted cells for better penetration. In this work, nanoemulsion from palm oil esters was developed as a delivery system to produce nanocosmeceuticals. The stability of the resulting formulation was tested using various methods. In addition, the effect of components i.e. Vitamin E and Pluronic F-68 on the formulation was also studied.

Results

Both vitamin E and Pluronic F-68 were found to co-emulsify and co-stabilized the formulations. The best formulation was found to be the one having the composition of 10% Palm Oil Esters (POEs), 10% vitamin E, 24% Tween 80, 2.4% Pluronic F-68 and 53.6% deionised water. Those compositions are considered to be the best as a nanocosmeceutical product due to the small particle size (94.21 nm), low occurrence of Ostwald ripening and stable at different storing temperatures (5, 25 and 45°C) for four weeks.

Conclusions

Palm oil esters-in-water nanoemulsions loaded with vitamin E was successfully formulated and has the potential for the use as nanocosmeceuticals.
Coupling of receptor interference and a host-dependent post-binding entry deficiency in a gammaretroviral envelope protein
Authors: Bahrami Shervin , Ejegod Ditte , Sørensen Karina Dalsgaard , Pedersen Finn Skou
Published: February 2010

Background

SL3-2 is a unique polytropic murine gammaretroviral isolate that is only able to infect murine cells. We have previously shown that two mutations R212G and T213I located on the surface of the receptor binding domain in a region designated the VR3 loop can alter the species tropism of this envelope protein. This location suggests that the VR3 loop composition has an influence on receptor interaction and thereby affects binding as well as superinfection resistance. In order to investigate this further, we have studied the binding and interference patterns of the SL3-2 envelope and its mutants.

Results

We find unexpectedly that wild type SL3-2 envelope binds equally well to both permissive and non-permissive cells, indicating a post binding defect when interacting with the human Xpr1. Using replication competent viruses containing envelopes from SL3-2 or its mutants we find that the same amino acid mutations can dramatically alter the interference profile of this polytropic ENV, suggesting that the same amino acid changes that cause the post binding defect also influence interaction with the receptor.

Conclusions

The envelope protein of SL3-2 MLV shows an entry defect on non-murine cells. This is coupled to a dramatically reduced ability to interfere with entry of other polytropic viruses. Two point mutations in the VR3 loop of the receptor binding domain of this envelope result both in a much increased interference ability and in removing the post-binding defect on non-murine cells, suggesting that both of these phenotypes are a consequence of insufficient interaction between the envelope and the receptor
A real-time RT-PCR for detection of clade 1 and 2 H5N1 Influenza A virus using Locked Nucleic Acid (LNA) TaqMan probes
Authors: Tran Tan Thanh , Pawestri Hana Apsari , My Ngoc Nghiem , Minh Hien Vo , Syahrial Harun , Vu Trung Nguyen , van Doorn H Rogier , Wertheim Heiman FL , Van Vinh Chau Nguyen , Quang Ha Do , Farrar Jeremy J , Tinh Hien Tran , Sedyaningsih Endang R , de Jong Menno D
Published: February 2010

Background

The emergence and co-circulation of two different clades (clade 1 and 2) of H5N1 influenza viruses in Vietnam necessitates the availability of a diagnostic assay that can detect both variants.

Results

We developed a single real-time RT-PCR assay for detection of both clades of H5N1 viruses, directly from clinical specimens, using locked nucleic acid TaqMan probes. Primers and probe used in this assay were designed based on a highly conserved region in the HA gene of H5N1 viruses. The analytical sensitivity of the assay was < 0.5 PFU and 10 - 100 ssDNA plasmid copies. A total of 106 clinical samples (58 from patients infected with clade 1, 2.1 or 2.3 H5N1 viruses and 48 from uninfected or seasonal influenza A virus-infected individuals) were tested by the assay. The assay showed 97% concordance with initial diagnostics for H5 influenza virus infection with a specificity of 100%.

Conclusions

This assay is a useful tool for diagnosis of H5N1 virus infections in regions where different genetic clades are co-circulating.
Impact of HIV‐1 viral subtype on disease progression and response to antiretroviral therapy
Authors: Easterbrook Philippa J , Smith Mel , Mullen Jane , O'Shea Siobhan , Chrystie Ian , de Ruiter Annemiek , Tatt Iain D , Geretti Anna Maria , Zuckerman Mark
Published: February 2010

Background

Our intention was to compare the rate of immunological progression prior to antiretroviral therapy (ART) and the virological response to ART in patients infected with subtype B and four non‐B HIV‐1 subtypes (A, C, D and the circulating recombinant form, CRF02‐AG) in an ethnically diverse population of HIV‐1‐infected patients in south London.

Methods

A random sample of 861 HIV‐1‐infected patients attending HIV clinics at King's and St Thomas' hospitals' were subtyped using an in‐house enzyme‐linked immunoassay and env sequencing. Subtypes were compared on the rate of CD4 cell decline using a multi‐level random effects model. Virological response to ART was compared using the time to virological suppression (< 400 copies/ml) and rate of virological rebound (> 400 copies/ml) following initial suppression.

Results

Complete subtype and epidemiological data were available for 679 patients, of whom 357 (52.6%) were white and 230 (33.9%) were black African. Subtype B (n = 394) accounted for the majority of infections, followed by subtypes C (n = 125), A (n = 84), D (n = 51) and CRF02‐AG (n = 25). There were no significant differences in rate of CD4 cell decline, initial response to highly active antiretroviral therapy and subsequent rate of virological rebound for subtypes B, A, C and CRF02‐AG. However, a statistically significant four‐fold faster rate of CD4 decline (after adjustment for gender, ethnicity and baseline CD4 count) was observed for subtype D. In addition, subtype D infections showed a higher rate of virological rebound at six months (70%) compared with subtypes B (45%, p = 0.02), A (35%, p = 0.004) and C (34%, p = 0.01)

Conclusions

This is the first study from an industrialized country to show a faster CD4 cell decline and higher rate of subsequent virological failure with subtype D infection. Further studies are needed to identify the molecular mechanisms responsible for the greater virulence of subtype D.
Renin-angiotensin system activation correlates with microvascular dysfunction in a prospective cohort study of clinical sepsis
Authors: Doerschug Kevin C , Delsing Angela S , Schmidt Gregory A , Ashare Alix
Published: February 2010

Introduction

Microvascular dysregulation characterized by hyporesponsive vessels and heterogeneous bloodflow is implicated in the pathogenesis of organ failure in sepsis. The renin-angiotensin system (RAS) affects the microvasculature, yet the relationships between RAS and organ injury in clinical sepsis remain unclear. We tested our hypothesis that systemic RAS mediators are associated with dysregulation of the microvasculature and with organ failure in clinical severe sepsis.

Methods

We studied 30 subjects with severe sepsis, and 10 healthy control subjects. Plasma was analyzed for plasma renin activity (PRA) and angiotensin II concentration (Ang II). Using near-infrared spectroscopy, we measured the rate of increase in the oxygen saturation of thenar microvascular hemoglobin after five minutes of induced forearm ischemia. In so doing, we assessed bulk microvascular hemoglobin influx to the tissue during reactive hyperemia. We studied all subjects 24 hours after the development of organ failure. We studied a subset of 12 subjects at an additional timepoint, eight hours after recognition of organ failure (early sepsis).

Results

After 24 hours of resuscitation to clinically-defined endpoints of preload and arterial pressure, Ang II and PRA were elevated in septic subjects and the degree of elevation correlated negatively with the rate of microvascular reoxygenation during reactive hyperemia. Early RAS mediators correlated with microvascular dysfunction. Early Ang II also correlated with the extent of organ failure realized during the first day of sepsis.

Conclusions

RAS is activated in clinical severe sepsis. Systemic RAS mediators correlate with measures of microvascular dysregulation and with organ failure.
First-Line Trastuzumab Plus Epirubicin and Cyclophosphamide Therapy in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer: Cardiac Safety and Efficacy Data From the Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) Trial
Authors: Untch Michael , Muscholl Michael , Tjulandin Sergei , Jonat Walter , Meerpohl Hans-Gerd , Lichinitser Mikhail , Manikhas Alexey G. , Coumbos Alexandra , Kreienberg Rolf , du Bois Andreas , Harbeck Nadia , Jackisch Christian , Müller Volkmar , Pauschinger Matthias , Thomssen Christoph , Lehle Michaela , Catalani Olivier , Lück Hans-Joachim
Published: February 2010

Purpose

A high incidence of congestive heart failure (CHF) has been observed in patients with metastatic breast cancer (MBC) receiving doxorubicin-based chemotherapy and trastuzumab. The Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) trial evaluated trastuzumab plus cyclophosphamide and the less cardiotoxic anthracycline epirubicin.

Patients and Methods

This prospective trial combined a phase I dose-finding stage with a phase II randomized stage. In total, 120 patients with human epidermal growth factor receptor 2 (HER2) –positive MBC and adequate cardiac function received first-line trastuzumab (4 mg/kg intravenous loading dose, then 2 mg/kg every week) plus cyclophosphamide (600 mg/m2) and either epirubicin 60 mg/m2 (HEC-60) or 90 mg/m2 (HEC-90) for six cycles, followed by trastuzumab monotherapy until progression. Sixty patients with HER2-negative disease received epirubicin (90 mg/m2) and cyclophosphamide (EC-90) alone. The primary end point was dose-limiting cardiotoxicity (DLC).

Results

Incidence of DLC was 5.0%, 1.7%, and 0% in the HEC-90, HEC-60, and EC-90 arms, respectively. All DLC events were manageable. There were no cardiac-related deaths. Other adverse-event profiles were comparable across the three arms, except febrile neutropenia, which was reported in 10% of the HEC-90 arm compared with 3% of the other arms. Tumor response rates were 57%, 60%, and 25% in the HEC-60, HEC-90, and EC-90 arms, respectively; median time to progression was 12.5, 10.1, and 7.6 months, respectively.

Conclusion

The HEC regimen is a promising treatment option for patients with HER2-positive MBC. The lower incidence of DLC with HEC, compared with the historic incidence associated with trastuzumab plus doxorubicin, supports further evaluation of the regimen, especially in adjuvant or neoadjuvant settings.
Thymidylate Synthase But Not Excision Repair Cross-Complementation Group 1 Tumor Expression Predicts Outcome in Patients With Malignant Pleural Mesothelioma Treated With Pemetrexed-Based Chemotherapy
Authors: Righi Luisella , Papotti Mauro G. , Ceppi Paolo , Billè Andrea , Bacillo Elisa , Molinaro Luca , Ruffini Enrico , Scagliotti Giorgio V. , Selvaggi Giovanni
Published: February 2010

Purpose

The relationship between thymidylate synthase (TS) expression and outcome in patients with malignant pleural mesothelioma (MPM) treated with pemetrexed (P) was retrospectively evaluated.

Patients and Methods

Sixty histologically confirmed patients with MPM previously treated with P and platinum (45 of 60) or as single agent (15 of 60) were retrospectively considered. Eighty-one control patients with MPM not P-treated were also evaluated. TS and excision repair cross-complementation group 1 (ERCC1) gene expression levels were evaluated by real-time polymerase chain reaction and by immunohistochemistry using the H-score.

Results

Median TS H-score value was 90 (range, 5 to 240). A significant correlation between low TS protein expression and longer time to progression (TTP; 17.9 v 7.9 months; hazard ratio [HR], 2.05, 95% CI, 1.19 to 3.77; P = .02) or overall survival (OS; 30 v 16.7 months; HR, 2.38; 95% CI, 1.15 to 4.91; P = .019) was found when patients were divided according to median H-score. Conversely, TS mRNA levels were not significantly correlated with outcome. In platinum-treated patients (n = 45), no correlation was found with survival according to ERCC1 median H-score, but patients in the lower tertile had a significantly shorter survival (HR, 3.06; 95% CI, 1.08 to 8.69; P = .035). In control MPMs, TS had no prognostic role. At multivariate analysis, TS protein levels were the only independent prognostic factor for both TTP (HR, 2.71; 95% CI, 1.13 to 6.49; P = .02) and OS (HR, 6.91; 95% CI, 1.90 to 25.07; P = .003).

Conclusion

In patients with MPM treated with P-based chemotherapy, low TS protein levels are predictive of improved TTP and OS. The role of TS assessment is worth of prospective validation in future studies on MPM.
Thyroid-Stimulating Hormone, a Novel, Locally Produced Modulator of Human Epidermal Functions, Is Regulated by Thyrotropin-Releasing Hormone and Thyroid Hormones
Authors: Bodó Enikő , Kany Benedikt , Gáspár Erzsébet , Knüver Jana , Kromminga Arno , Ramot Yuval , Bíró Tamás , Tiede Stephan , van Beek Nina , Poeggeler Burkhard , Meyer Katja C. , Wenzel Björn E. , Paus Ralf
Published: February 2010

Several elements of the hypothalamic-pituitary-thyroid axis (HPT) reportedly are transcribed by human skin cell populations, and human hair follicles express functional receptors for TSH. Therefore, we asked whether the epidermis of normal human skin is yet another extrathyroidal target of TSH and whether epidermis even produces TSH. If so, we wanted to clarify whether intraepidermal TSH expression is regulated by TRH and/or thyroid hormones and whether TSH alters selected functions of normal human epidermis in situ. TSH and TSH receptor (TSH-R) expression were analyzed in the epidermis of normal human scalp skin by immunohistochemistry and PCR. In addition, full-thickness scalp skin was organ cultured and treated with TSH, TRH, or thyroid hormones, and the effect of TSH treatment on the expression of selected genes was measured by quantitative PCR and/or quantitative immunohistochemistry. Here we show that normal human epidermis expresses TSH at the mRNA and protein levels in situ and transcribes TSH-R. It also contains thyrostimulin transcripts. Intraepidermal TSH immunoreactivity is up-regulated by TRH and down-regulated by thyroid hormones. Although TSH-R immunoreactivity in situ could not be documented within the epidermis, but in the immediately adjacent dermis, TSH treatment of organ-cultured human skin strongly up-regulated epidermal expression of involucrin, loricrin, and keratins 5 and 14. Thus, normal human epidermis in situ is both an extrapituitary source and (possibly an indirect) target of TSH signaling, which regulates defined epidermal parameters. Intraepidermal TSH expression appears to be regulated by the classical endocrine controls that determine the systemic HPT axis.
Dehydroepiandrosterone Administration or Gαq Overexpression Induces β-Catenin/T-Cell Factor Signaling and Growth via Increasing Association of Estrogen Receptor-β/Dishevelled2 in Androgen-Independent Prostate Cancer Cells
Authors: Liu Xunxian , Arnold Julia T. , Blackman Marc R.
Published: February 2010

β-Catenin/T-cell factor signaling (β-CTS) plays multiple critical roles in carcinogenesis and is blocked by androgens in androgen receptor (AR)-responsive prostate cancer (PrCa) cells, primarily via AR sequestration of β-catenin from T-cell factor. Dehydroepiandrosterone (DHEA), often used as an over-the-counter nutritional supplement, is metabolized to androgens and estrogens in humans. The efficacy and safety of unregulated use of DHEA are unclear. We now report that DHEA induces β-CTS via increasing association of estrogen receptor (ER)-β with Dishevelled2 (Dvl2) in AR nonresponsive human PrCa DU145 cells, a line of androgen-independent PrCa (AiPC) cells. The induction is temporal, as assessed by measuring kinetics of the association of ERβ/Dvl2, protein expression of the β-CTS targeted genes, c-Myc and cyclin D1, and cell growth. However, in PC-3 cells, another human AiPC cell line, DHEA exerts no detectible effects, partly due to their lower expression of Gα-subunits and DHEA down-regulation of ERβ/Dvl2 association. When Gαq is overexpressed in PC-3 cells, β-CTS is constitutively induced, including increasing c-Myc and cyclin D1 protein expression. This effect involved increasing associations of Gαq/Dvl2 and ERβ/Dvl2 and promoted cell growth. These activities require ERβ in DU-145 and PC-3 cells because they are blocked by ICI 182–780 treatment inactivating ERβ, small interfering RNA administration depleting ERβ, or AR overexpression arresting ERβ. These data suggest that novel pathways activating β-CTS play roles in the progression of AiPC. Although DHEA may enhance PrCa cell growth via androgenic or estrogenic pathways, the effects of DHEA administration on clinical prostate function remain to be determined.
Silencing of the Insulin Receptor Isoform A Favors Formation of Type 1 Insulin-Like Growth Factor Receptor (IGF-IR) Homodimers and Enhances Ligand-Induced IGF-IR Activation and Viability of Human Colon Carcinoma Cells
Authors: Brierley G. V. , Macaulay S. L. , Forbes B. E. , Wallace J. C. , Cosgrove L. J. , Macaulay V. M.
Published: February 2010

Insulin receptor (IR) overexpression is common in cancers, with expression of the A isoform (IR-A, exon 11−) predominating over the B isoform. The IR-A signals a proliferative, antiapoptotic response to IGF-II, which itself can be secreted by tumors to establish an autocrine proliferative loop. Therefore, IGF-II signaling via the IR-A could mediate resistance to type 1 IGF receptor (IGF-IR) inhibitory drugs that are currently in development. This study addressed the role of the IR-A, using a small interfering RNA-based approach in SW480 human colon adenocarcinoma cells that coexpress the IGF-IR. Clonogenic survival was inhibited by depletion of the IGF-IR but not the IR-A, and dual receptor depletion had no greater effect than IGF-IR knockdown alone, suggesting that the IR-A could not compensate for IGF-IR loss. IGF-IR knockdown also resulted in a decrease in viability, whereas IR-A depletion resulted in increased viability. Consistent with this, upon IR-A depletion, we found a concomitant enhancement of IGF-IR activation by IGF-I and IGF-II, reduced formation of IGF-IR:IR-A hybrid receptors and increased IGF-IR homodimer formation. Together, these results suggest that IGF bioactivity is mediated more effectively by the IGF-IR than by the IR-A or receptor hybrids and that signaling via the IGF-IR is dominant to the IR-A in colon cancer cells that express both receptors.
Maternal control of early mouse development
Authors: Li Lei , Zheng Ping , Dean Jurrien
Published: February 2010

The hiatus between oocyte and embryonic gene transcription dictates a role for stored maternal factors in early mammalian development. Encoded by maternal-effect genes, these factors accumulate during oogenesis and enable the activation of the embryonic genome, the subsequent cleavage stages of embryogenesis and the initial establishment of embryonic cell lineages. Recent studies in mice have yielded new findings on the role of maternally provided proteins and multi-component complexes in preimplantation development. Nevertheless, significant gaps remain in our mechanistic understanding of the networks that regulate early mammalian embryogenesis, which provide an impetus and opportunities for future investigations.
Endothelial β1 integrins regulate sprouting and network formation during vascular development
Authors: Malan Daniela , Wenzel Daniela , Schmidt Annette , Geisen Caroline , Raible Axel , Bölck Birgit , Fleischmann Bernd K. , Bloch Wilhelm
Published: February 2010

β1 integrins are important regulators of vascular differentiation and development, as their endothelial-specific deletion results in embryonic lethality. In the present study, we investigated the molecular mechanisms underlying the prominent vascular abnormalities that occur in the absence of β1 integrins. Because of the early embryonic lethality of knockout mice, we studied endothelial cell and vessel development in β1-integrin-deficient murine embryonic stem cells to gain novel insights into the role of β1 integrins in vasculo-angiogenesis. We found that vessel development was strongly defective in the mutant embryoid bodies (EBs), as only primitive and short sprouts developed from clusters of vascular precursors in β1 integrin−/− EBs, whereas complex network formation of endothelial tubes was observed in wild-type EBs. The vascular defect was due to deficient β1 integrin expression in endothelial cells, as its endothelial-specific re-expression rescued the phenotype entirely. The mechanism responsible for defective vessel formation was found to be reduced endothelial cell maturation, migration and elongation. Moreover, the lower number of endothelial cells in β1 integrin−/− EBs was due to an increased apoptosis versus proliferation rate. The enhanced apoptosis and proliferation of β1 integrin−/− endothelial cells was related to the elevation of peNOS and pAKT signaling molecules, respectively. Our data demonstrate that endothelial β1 integrins are determinants of vessel formation and that this effect is mediated via different signaling pathways.
The Dynamics of Interorganizational Careers
Authors: Bidwell Matthew , Briscoe Forrest
Published: February 2010

How do workers build careers across organizations? We propose that increased worker mobility means that workers may now build their careers using interorganizational career ladders, working in certain kinds of organizations earlier in a career and in other kinds of organizations later in the career. We develop a matching framework that predicts such interorganizational moves based on how systematic changes in workers' needs and resources over the course of their careers alter the kinds of organizations they will best match. We specifically propose that workers will be more likely to work for organizations that provide more training early in their careers, and work for organizations that have higher demands for skills later in their careers. We use this argument to make three broad predictions: first, that interorganizational transitions are more likely to take place from larger to smaller workplaces, and into organizations in industries that employ a higher proportion of workers in the focal occupation; second, that such skill-based career paths are more common where the labor market provides more opportunities that reward those skills; and third, that the nature of external opportunities will disproportionately affect turnover from organizations on the lower rungs of the career ladder. Data from the career histories of college-educated information technology workers support our hypotheses.