bluuebunny/crossref_metadata_2025 huggingface dataset:
Lymphomas are sensitive to perforin-dependent cytotoxic pathways despite expression of PI-9 and overexpression of bcl-2
Authors: Godal Robert , Keilholz Ulrich , Uharek Lutz , Letsch Anne , Asemissen Anne Marie , Busse Antonia , Na Il-Kang , Thiel Eckhard , Scheibenbogen Carmen
Published: December 2005

There is considerable interest in immunotherapeutic approaches for lymphoma. The expression of proteinase inhibitor 9 (PI-9), a molecule that inactivates granzyme B, is considered an immune escape mechanism in lymphoma. Further, lymphomas frequently overexpress the antiapoptotic molecule bcl-2, which is able to inhibit perforin-dependent cytotoxic pathways. In this study, the impact of PI-9 and bcl-2 expression on the sensitivity of lymphomas to T- and natural killer (NK) cell–mediated cytotoxicity was analyzed. We found PI-9 expression in 10 of 18 lymphoma cell lines and in 9 of 14 primary lymphomas. Overexpression of bcl-2 was found in 8 of 18 cell lines and in 12 of 14 primary lymphomas. All lymphoma cells were sensitive to cytolysis by specific T cells and cytokine-activated NK cells, and no difference in sensitivity was observed with respect to PI-9 or bcl-2 expression. Cytolysis was mediated predominantly through perforin-dependent pathways despite expression of PI-9 and bcl-2. Interestingly, the majority of lymphoma cells were resistant to cytolysis by resting allogeneic NK cells. This was due to the failure of lymphomas to induce degranulation of resting NK cells. These results show that resistance to perforin-dependent pathways is not a relevant immune escape mechanism in lymphoma and therefore is unlikely to impair clinical outcome of immunotherapeutic approaches.
Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders
Authors: Passamonti Francesco , Rumi Elisa , Pietra Daniela , Porta Matteo G. Della , Boveri Emanuela , Pascutto Cristiana , Vanelli Laura , Arcaini Luca , Burcheri Sara , Malcovati Luca , Lazzarino Mario , Cazzola Mario
Published: December 2005

We studied the relationship between granulocyte JAK2 (V617F) mutation status, circulating CD34+ cells, and granulocyte activation in myeloproliferative disorders. Quantitative allele-specific polymerase chain reaction (PCR) showed significant differences between various disorders with respect to either the proportion of positive patients (53%-100%) or that of mutant alleles, which overall ranged from 1% to 100%. In polycythemia vera, JAK2 (V617F) was detected in 23 of 25 subjects at diagnosis and in 16 of 16 patients whose disease had evolved into myelofibrosis; median percentages of mutant alleles in these subgroups were significantly different (32% versus 95%, P < .001). Circulating CD34+ cell counts were variably elevated and associated with disease category and JAK2 (V617F) mutation status. Most patients had granulocyte activation patterns similar to those induced by administration of granulocyte colony-stimulating factor. A JAK2 (V617F) gene dosage effect on both CD34+ cell counts and granulocyte activation was clearly demonstrated in polycythemia vera, where abnormal patterns were mainly found in patients carrying more than 50% mutant alleles. These observations suggest that JAK2 (V617F) may constitutively activate granulocytes and by this means mobilize CD34+ cells. This exemplifies a novel paradigm in which a somatic gain-of-function mutation is initially responsible for clonal expansion of hematopoietic cells and later for their abnormal trafficking via an activated cell progeny.
ADAM-9 (MDC-9/meltrin-γ), a member of the adisintegrin and metalloproteinase family, regulates myeloma-cell–induced interleukin-6 production in osteoblasts by direct interaction with the αvβ5 integrin
Authors: Karadag Abdullah , Zhou Min , Croucher Peter I.
Published: December 2005

ADAM-9, a member of the adisintegrin and metalloproteinase family, contains both metalloproteinase and disintegrin domains. Myeloma cell lines express ADAM-9; however, its function and role in the pathophysiology of multiple myeloma is unknown. The aim of this study was to establish whether primary myeloma cells express ADAM-9, whether ADAM-9 regulates IL-6 production in human osteoblasts (hOBs), whether ADAM-9 interacts with specific integrin heterodimers, and the identity of downstream signaling pathways. Primary myeloma cells demonstrated increased expression of ADAM-9 (P < .01). ADAM-9 promoted a 5-fold increase in IL-6, but not IL-1β mRNA, and a dose- and time-dependent increase in IL-6 production by hOBs (P < .01). IL-6 induction was inhibited by an antibody to the αvβ5 integrin (P < .01) but not by antibodies to other integrin heterodimers. ADAM-9 was shown to bind directly to the αvβ5 integrin on hOBs. Antibodies to ADAM-9 and αvβ5 integrin inhibited myeloma cell–induced IL-6 production by hOBs (P < .01). Furthermore, inhibitors of p38 MAPK and cPLA2, but not NF-κB and JAK2, signaling pathways inhibited ADAM-9–induced IL-6 production by hOBs (P < .01). These data demonstrate that ADAM-9, expressed by myeloma cells, stimulates IL-6 production in hOBs by binding the αvβ5 integrin. This may have important consequences for the growth and survival of myeloma cells in bone.
Tumor vascular targeting therapy with viral vectors
Authors: Liu Yanzheng , Deisseroth Albert
Published: December 2005

Tumor angiogenesis is crucial for the progression and metastasis of cancer. The vasculature of tumor tissue is different from normal vasculature. Therefore, tumor vascular targeting therapy could represent an effective therapeutic strategy with which to suppress both primary tumor growth and tumor metastasis. The use of viral vectors for tumor vascular targeting therapy is a promising strategy based on the unique properties of viral vectors. In order to circumvent the potential problems of antiviral neutralizing antibodies, poor access to extravascular tumor tissue, and toxicities to normal tissue, viral vectors need to be modified to target the tumor endothelial cells. Viral vectors that could be used for tumor vascular targeting therapy include adenoviral vectors, adeno-associated viral vectors, retroviral vectors, lentiviral vectors, measles virus, and herpes simplex viral vectors. In this review, we will summarize the strategies available for targeting viral vectors for tumor vascular targeting therapy.
A DNA-based cancer vaccine enhances lymphocyte cross talk by engaging the NKG2D receptor
Authors: Zhou He , Luo Yunping , Kaplan Charles D. , Krüger Jörg A. , Lee Sung-Hyung , Xiang Rong , Reisfeld Ralph A.
Published: December 2005

The NKG2D receptor is a stimulatory receptor expressed on NK cells and activated CD8 T cells. We previously demonstrated that engaging the NKG2D receptor markedly improved the efficacy of a survivin-based DNA vaccine. The combination vaccine, encoding both the NKG2D ligand H60 and survivin, activates innate and adaptive antitumor immunity and results in better protection against tumors of different origin and NKG2D expression levels. Here we demonstrate that the enhanced vaccine efficacy is in part attributable to increased cross talk between lymphocytes. Depletion of CD8 T cells during priming reduces the vaccine-induced activation of dendritic cells (DCs) and NK cell activity. Depletion of NK cells during priming leads to reduced DC activation and CTL activity. However, depletion of CD4 T cells results in the activation of DCs, NK cells, and CD8 T cells and enhances NK cell activity. The pH60/Survivin vaccine also increases DCs and NK cells but decreases CD4 T cell homing to Peyer patches, presumably as a result of changes in the homing receptor profile. Thus, by preferentially activating and attracting positive regulators and reducing negative regulators in Peyer patches, this dual-function DNA vaccine induces a microenvironment more suitable for NK cell activation and T cell priming.
Long-term air pollution exposure and living close to busy roads are associated with COPD in women
Authors: Schikowski Tamara , Sugiri Dorothea , Ranft Ulrich , Gehring Ulrike , Heinrich Joachim , Wichmann H-Erich , Krämer Ursula
Published: December 2005

Background

Lung function and exacerbations of chronic obstructive pulmonary disease (COPD) have been associated with short-term exposure to air pollution. However, the effect of long-term exposure to particulate matter from industry and traffic on COPD as defined by lung function has not been evaluated so far. Our study was designed to investigate the influence of long-term exposure to air pollution on respiratory symptoms and pulmonary function in 55-year-old women. We especially focused on COPD as defined by GOLD criteria and additionally compared the effects of air pollution on respiratory symptoms by questionnaire data and by lung function measurements.

Methods

In consecutive cross sectional studies conducted between 1985–1994, we investigated 4757 women living in the Rhine-Ruhr Basin of Germany. NO2 and PM10 exposure was assessed by measurements done in an 8 km grid, and traffic exposure by distance from the residential address to the nearest major road using Geographic Information System data. Lung function was determined and COPD was defined by using the GOLD criteria. Chronic respiratory symptoms and possible confounders were defined by questionnaire data. Linear and logistic regressions, including random effects were used to account for confounding and clustering on city level.

Results

The prevalence of COPD (GOLD stages 1–4) was 4.5%. COPD and pulmonary function were strongest affected by PM10 and traffic related exposure. A 7 μg/m3 increase in five year means of PM10 (interquartile range) was associated with a 5.1% (95% CI 2.5%–7.7%) decrease in FEV1, a 3.7% (95% CI 1.8%–5.5%) decrease in FVC and an odds ratio (OR) of 1.33 (95% CI 1.03–1.72) for COPD. Women living less than 100 m from a busy road also had a significantly decreased lung function and COPD was 1.79 times more likely (95% CI 1.06–3.02) than for those living farther away. Chronic symptoms as based on questionnaire information showed effects in the same direction, but less pronounced.

Conclusion

Chronic exposure to PM10, NO2 and living near a major road might increase the risk of developing COPD and can have a detrimental effect on lung function.
The Gene Set Builder: collation, curation, and distribution of sets of genes
Authors: Yusuf Dimas , Lim Jonathan S , Wasserman Wyeth W
Published: December 2005

Background

In bioinformatics and genomics, there are many applications designed to investigate the common properties for a set of genes. Often, these multi-gene analysis tools attempt to reveal sequential, functional, and expressional ties. However, while tremendous effort has been invested in developing tools that can analyze a set of genes, minimal effort has been invested in developing tools that can help researchers compile, store, and annotate gene sets in the first place. As a result, the process of making or accessing a set often involves tedious and time consuming steps such as finding identifiers for each individual gene. These steps are often repeated extensively to shift from one identifier type to another; or to recreate a published set. In this paper, we present a simple online tool which – with the help of the gene catalogs Ensembl and GeneLynx – can help researchers build and annotate sets of genes quickly and easily.

Description

The Gene Set Builder is a database-driven, web-based tool designed to help researchers compile, store, export, and share sets of genes. This application supports the 17 eukaryotic genomes found in version 32 of the Ensembl database, which includes species from yeast to human. User-created information such as sets and customized annotations are stored to facilitate easy access. Gene sets stored in the system can be "exported" in a variety of output formats – as lists of identifiers, in tables, or as sequences. In addition, gene sets can be "shared" with specific users to facilitate collaborations or fully released to provide access to published results. The application also features a Perl API (Application Programming Interface) for direct connectivity to custom analysis tools. A downloadable Quick Reference guide and an online tutorial are available to help new users learn its functionalities.

Conclusion

The Gene Set Builder is an Ensembl-facilitated online tool designed to help researchers compile and manage sets of genes in a user-friendly environment. The application can be accessed via http://www.cisreg.ca/gsb/.
Avoiding inconsistencies over time and tracking difficulties in Applied Biosystems AB1700™/Panther™ probe-to-gene annotations
Authors: Noth Sebastian , Benecke Arndt ,   systems epigenomics group
Published: December 2005

Background

Significant inconsistencies between probe-to-gene annotations between different releases of probe set identifiers by commercial microarray platform solutions have been reported. Such inconsistencies lead to misleading or ambiguous interpretation of published gene expression results.

Results

We report here similar inconsistencies in the probe-to-gene annotation of Applied Biosystems AB1700 data, demonstrating that this is not an isolated concern. Moreover, the online information source PANTHER does not provide information required to track such inconsistencies, hence, even correctly annotated datasets, when resubmitted after PANTHER was updated to a new probe-to-gene annotation release, will generate differing results without any feedback on the origin of the change.

Conclusion

The importance of unequivocal annotation of microarray experiments can not be underestimated. Inconsistencies greatly diminish the usefulness of the technology. Novel methods in the analysis of transcriptome profiles often rely on large disparate datasets stemming from multiple sources. The predictive and analytic power of such approaches rapidly diminishes if only least-common subsets can be used for analysis. We present here the information that needs to be provided together with the raw AB1700 data, and the information required together with the biologic interpretation of such data to avoid inconsistencies and tracking difficulties.
Evolutionary programming as a platform for in silico metabolic engineering
Authors: Patil Kiran Raosaheb , Rocha Isabel , Förster Jochen , Nielsen Jens
Published: December 2005

Background

Through genetic engineering it is possible to introduce targeted genetic changes and hereby engineer the metabolism of microbial cells with the objective to obtain desirable phenotypes. However, owing to the complexity of metabolic networks, both in terms of structure and regulation, it is often difficult to predict the effects of genetic modifications on the resulting phenotype. Recently genome-scale metabolic models have been compiled for several different microorganisms where structural and stoichiometric complexity is inherently accounted for. New algorithms are being developed by using genome-scale metabolic models that enable identification of gene knockout strategies for obtaining improved phenotypes. However, the problem of finding optimal gene deletion strategy is combinatorial and consequently the computational time increases exponentially with the size of the problem, and it is therefore interesting to develop new faster algorithms.

Results

In this study we report an evolutionary programming based method to rapidly identify gene deletion strategies for optimization of a desired phenotypic objective function. We illustrate the proposed method for two important design parameters in industrial fermentations, one linear and other non-linear, by using a genome-scale model of the yeast Saccharomyces cerevisiae. Potential metabolic engineering targets for improved production of succinic acid, glycerol and vanillin are identified and underlying flux changes for the predicted mutants are discussed.

Conclusion

We show that evolutionary programming enables solving large gene knockout problems in relatively short computational time. The proposed algorithm also allows the optimization of non-linear objective functions or incorporation of non-linear constraints and additionally provides a family of close to optimal solutions. The identified metabolic engineering strategies suggest that non-intuitive genetic modifications span several different pathways and may be necessary for solving challenging metabolic engineering problems.
Chaperone use during intimate examinations in primary care: postal survey of family physicians
Authors: Price David H , Tracy C Shawn , Upshur Ross EG
Published: December 2005

Background

Physicians have long been advised to have a third party present during certain parts of a physical examination; however, little is known about the frequency of chaperone use for those specific intimate examinations regularly performed in primary care. We aimed to determine the frequency of chaperone use among family physicians across a variety of intimate physical examinations for both male and female patients, and also to identify the factors associated with chaperone use.

Methods

Questionnaires were mailed to a randomly selected sample of 500 Ontario members of the College of Family Physicians of Canada. Participants were asked about their use of chaperones when performing a variety of intimate examinations, namely female pelvic, breast, and rectal exams and male genital and rectal exams.

Results

276 of 500 were returned (56%), of which 257 were useable. Chaperones were more commonly used with female patients than with males (t = 9.09 [df = 249], p < 0.001), with the female pelvic exam being the most likely of the five exams to be attended by a chaperone (53%). As well, male physicians were more likely to use chaperones for examination of female patients than were female physicians for the examination of male patients. Logistic regression analyses identified two independent factors – sex of physician and availability of a nurse – that were significantly associated with chaperone use. For female pelvic exam, male physicians were significantly more likely to report using a chaperone (adjusted Odds Ratio [OR] 40.62, 95% confidence interval [CI] 16.91–97.52). Likewise, having a nurse available also significantly increased the likelihood of a chaperone being used (adjusted OR 6.92, 95% CI 2.74–17.46). This pattern of results was consistent across the other four exams. Approximately two-thirds of respondents reported using nurses as chaperones, 15% cited the use of other office staff, and 10% relied on the presence of a family member.

Conclusion

Clinical practice concerning the use of chaperones during intimate exams continues to be discordant with the recommendations of medical associations and medico-legal societies. Chaperones are used by only a minority of Ontario family physicians. Chaperone use is higher for examinations of female patients than of male patients and is highest for female pelvic exams. The availability of a nurse in the clinic to act as a chaperone is associated with more frequent use of chaperones.
Protocol for Project FACT: a randomised controlled trial on the effect of a walking program and vitamin B supplementation on the rate of cognitive decline and psychosocial wellbeing in older adults with mild cognitive impairment [ISRCTN19227688]
Authors: van Uffelen Jannique GZ , Hopman-Rock Marijke , Chin A Paw Marijke JM , van Mechelen Willem
Published: December 2005

Background

the prevalence of individuals with cognitive decline is increasing since the number of elderly adults is growing considerably. The literature provides promising results on the beneficial effect of exercise and vitamin supplementation on cognitive function both in cognitively healthy as well as in the demented elderly.

Methods/Design

the design is a two-by-two factorial randomised controlled trial. The study population consists of independently living elderly, between 70 and 80 years old, with mild cognitive impairment (MCI). In the RCT the effect of two interventions, a walking program and vitamin supplementation, is examined. The walking program (WP) is a group-based program aimed at improving cardiovascular endurance; frequency two lessons a week; lesson duration one hour; program duration one year. Non-walking groups receive a placebo activity program (PAP) (i.e. low intensive non-aerobic group exercises, like stretching) with the same frequency, lesson and program duration. Vitamin supplementation consists of a single daily vitamin supplement containing 50 mg B6, 5 mg folic acid and 0,4 mg B12 for one year. Subjects not receiving vitamin supplements are daily taking an identically looking placebo pill, also for a year. Participants are randomised to four groups 1) WP and vitamin supplements; 2) WP and placebo supplements; 3) PAP and vitamin supplements; 4) PAP and placebo supplements. Primary outcome measures are measures of cognitive function. Secondary outcomes include psychosocial wellbeing, physical activity, cardiovascular endurance and blood vitamin levels.

Discussion

no large intervention study has been conducted yet on the effect of physical activity and vitamin supplementation in a population-based sample of adults with MCI. The objective of the present article is to describe the design of a randomised controlled trial examining the effect of a walking program and vitamin B supplementation on the rate of cognitive decline in older adults with MCI.
A randomised controlled trial of the effects of albendazole in pregnancy on maternal responses to mycobacterial antigens and infant responses to bacille Calmette-Guérin (BCG) immunisation [ISRCTN32849447]
Authors: Elliott Alison M , Namujju Proscovia B , Mawa Patrice A , Quigley Maria A , Nampijja Margaret , Nkurunziza Peter M , Belisle John T , Muwanga Moses , Whitworth James AG ,   the "Mother and Baby" study team
Published: December 2005

Background

Maternal schistosomiasis and filariasis have been shown to influence infant responses to neonatal bacille Calmette-Guérin (BCG) immunisation but the effects of maternal hookworm, and of de-worming in pregnancy, are unknown.

Methods

In Entebbe, Uganda, we conducted a randomised, double-blind, placebo-controlled trial of a single dose of 400 mg of albendazole in the second trimester of pregnancy. Neonates received BCG. Interferon-gamma (IFN-γ) and interleukin (IL)-5 responses to a mycobacterial antigen (crude culture filtrate proteins (CFP) ofMycobacterium tuberculosis) were measured in a whole blood assay. We analysed results for binary variables using χ2tests and logistic regression. We analysed continuous variables using Wilcoxon's tests.

Results

Maternal hookworm was associated with reduced maternal IFN-γ responses to CFP (adjusted odds ratio for IFN-γ > median response: 0.14 (95% confidence interval 0.02–0.83, p = 0.021). Conversely, maternal hookworm was associated with subsequent increased IFN-γ responses in their one-year-old infants (adjusted OR 17.65 (1.20–258.66; p = 0.013)). Maternal albendazole tended to reduce these effects.

Conclusion

Untreated hookworm infection in pregnancy was associated with reduced maternal IFN-γ responses to mycobacterial antigens, but increased responses in their infants one year after BCG immunisation. The mechanisms of these effects, and their implications for protective immunity remain, to be determined.
Cloxacillin versus vancomycin for presumed late-onset sepsis in the Neonatal Intensive Care Unit and the impact upon outcome of coagulase negative staphylococcal bacteremia: a retrospective cohort study
Authors: Lawrence Sarah L , Roth Virginia , Slinger Robert , Toye Baldwin , Gaboury Isabelle , Lemyre Brigitte
Published: December 2005

Background

Coagulase negative staphylococcus (CONS) is the main cause of late-onset sepsis in Neonatal Intensive Care Units (NICU). Although CONS rarely causes fulminant sepsis, vancomycin is frequently used as empiric therapy. Indiscriminate use of vancomycin has been linked to the emergence of vancomycin resistant organisms. The objective of this study was to compare duration of CONS sepsis and mortality before and after implementation of a policy of selective vancomycin use and compare use of vancomycin between the 2 time periods.

Methods

A retrospective study was conducted of infants ≥4 days old, experiencing signs of sepsis with a first positive blood culture for CONS, during two 12-month periods. Late-onset sepsis was treated empirically with vancomycin and gentamicin during period 1, and cloxacillin and gentamicin during period 2. The confidence interval method was used to assess non-inferiority of the outcomes between the two study groups.

Results

There were 45 episodes of CONS sepsis during period 1 and 37 during period 2. Duration of sepsis was similar between periods (hazard ratio of 1.00, 95%CI: 0.64, 1.57). One death during period 2 was possibly related to CONS sepsis versus none in period 1. Vancomycin was used in 97.8% of episodes in period 1 versus 81.1% of episodes in period 2.

Conclusion

Although we failed to show non-inferiority of duration of sepsis in the cloxacillin and gentamicin group compared to the vancomycin and gentamicin group, duration of sepsis was clinically similar. Restricting vancomycin for confirmed cases of CONS sepsis resistant to oxacillin appears effective and safe, and significantly reduces vancomycin use in the NICU.
An automated, broad-based, near real-time public health surveillance system using presentations to hospital Emergency Departments in New South Wales, Australia
Authors: Muscatello David J , Churches Tim , Kaldor Jill , Zheng Wei , Chiu Clayton , Correll Patricia , Jorm Louisa
Published: December 2005

Background

In a climate of concern over bioterrorism threats and emergent diseases, public health authorities are trialling more timely surveillance systems. The 2003 Rugby World Cup (RWC) provided an opportunity to test the viability of a near real-time syndromic surveillance system in metropolitan Sydney, Australia. We describe the development and early results of this largely automated system that used data routinely collected in Emergency Departments (EDs).

Methods

Twelve of 49 EDs in the Sydney metropolitan area automatically transmitted surveillance data from their existing information systems to a central database in near real-time. Information captured for each ED visit included patient demographic details, presenting problem and nursing assessment entered as free-text at triage time, physician-assigned provisional diagnosis codes, and status at departure from the ED. Both diagnoses from the EDs and triage text were used to assign syndrome categories. The text information was automatically classified into one or more of 26 syndrome categories using automated "naïve Bayes" text categorisation techniques. Automated processes were used to analyse both diagnosis and free text-based syndrome data and to produce web-based statistical summaries for daily review. An adjusted cumulative sum (cusum) was used to assess the statistical significance of trends.

Results

During the RWC the system did not identify any major public health threats associated with the tournament, mass gatherings or the influx of visitors. This was consistent with evidence from other sources, although two known outbreaks were already in progress before the tournament. Limited baseline in early monitoring prevented the system from automatically identifying these ongoing outbreaks. Data capture was invisible to clinical staff in EDs and did not add to their workload.

Conclusion

We have demonstrated the feasibility and potential utility of syndromic surveillance using routinely collected data from ED information systems. Key features of our system are its nil impact on clinical staff, and its use of statistical methods to assign syndrome categories based on clinical free text information. The system is ongoing, and has expanded to cover 30 EDs. Results of formal evaluations of both the technical efficiency and the public health impacts of the system will be described subsequently.
Comparison of foot orthoses made by podiatrists, pedorthists and orthotists regarding plantar pressure reduction in The Netherlands
Authors: Guldemond Nick A , Leffers Pieter , Schaper Nicolaas C , Sanders Antal P , Nieman Fred HM , Walenkamp Geert HIM
Published: December 2005

Background

There is a need for evidence of clinical effectiveness of foot orthosis therapy. This study evaluated the effect of foot orthoses made by ten podiatrists, ten pedorthists and eleven orthotists on plantar pressure and walking convenience for three patients with metatarsalgia. Aims were to assess differences and variability between and within the disciplines. The relationship between the importance of pressure reduction and the effect on peak pressure was also evaluated.

Methods

Each therapist examined all three patients and was asked to rate the 'importance of pressure reduction' through a visual analogue scale. The orthoses were evaluated twice in two sessions while the patient walked on a treadmill. Plantar pressures were recorded with an in-sole measuring system. Patients scored walking convenience per orthosis. The effects of the orthoses on peak pressure reduction were calculated for the whole plantar surface of the forefoot and six regions: big toe and metatarsal one to five.

Results

Within each discipline there was an extensive variation in construction of the orthoses and achieved peak pressure reductions. Pedorthists and orthotists achieved greater maximal peak pressure reductions calculated over the whole forefoot than podiatrists: 960, 1020 and 750 kPa, respectively (p < .001). This was also true for the effect in the regions with the highest baseline peak pressures and walking convenience rated by patients A and B. There was a weak relationship between the 'importance of pressure reduction' and the achieved pressure reduction for orthotists, but no relationship for podiatrists and pedorthotists.

Conclusion

The large variation for various aspects of foot orthoses therapy raises questions about a consistent use of concepts for pressures management within the professional groups.
An indirect enzyme-linked immunosorbent assay for rapid and quantitative assessment of Type III virulence phenotypes of Pseudomonas aeruginosa isolates
Authors: Li Li , Ledizet Michel , Kar Kalipada , Koski Raymond A , Kazmierczak Barbara I
Published: December 2005

Background

The presence of a Type III secretion system in clinical isolates of Pseudomonas aeruginosa is associated with severe disease and poor outcomes in infections caused by this pathogen. We describe an indirect enzyme-linked immunosorbent assay that rapidly and quantitatively detects two exotoxins, ExoU and ExoT, and two structural components, PopD and PcrV, of the P. aeruginosa Type III secretion system after in-vitro growth in a calcium-free minimal medium.

Methods

We used this assay to characterize the Type III secretion phenotype of 74 clinical isolates of P. aeruginosa. Findings were compared with results of standard immunoblotting and correlated with Type III secretion-dependent virulence of isolates toward cultured epithelial cells.

Results

Results of the ELISA assay were concordant with immunoblot detection of the secreted antigens for 73 of 74 isolates. The Type III secretion phenotype assessed by this immunoassay predicted bacterial virulence toward epithelial cells in vitro for all but five of the clinical isolates.

Conclusion

The availability of an ELISA assay for rapid detection of Type III secreted virulence factors will facilitate large clinical studies to examine whether the Type III secretion phenotype of a P. aeruginosa isolate predicts the course of clinical disease in a patient and should be taken into account in determining optimal treatment strategies for infected patients.
The diagnostic value of biomarkers (SteatoTest) for the prediction of liver steatosis
Authors: Poynard Thierry , Ratziu Vlad , Naveau Sylvie , Thabut Dominique , Charlotte Frederic , Messous Djamila , Capron Dominique , Abella Annie , Massard Julien , Ngo Yen , Munteanu Mona , Mercadier Anne , Manns Michael , Albrecht Janice
Published: December 2005

Background

Biopsy is the usual gold standard for liver steatosis assessment. The aim of this study was to identify a panel of biomarkers (SteatoTest), with sufficient predictive values, for the non-invasive diagnosis of steatosis in patients with or without chronic liver disease. Biomarkers and panels were assessed in a training group of consecutive patients with chronic hepatitis C and B, alcoholic liver disease, and non-alcoholic fatty liver disease, and were validated in two independent groups including a prospective one. Steatosis was blindly assessed by using a previously validated scoring system.

Results

310 patients were included in the training group; 434 in three validation groups; and 140 in a control group. SteatoTest was constructed using a combination of the 6 components of FibroTest-ActiTest plus body mass index, serum cholesterol, triglycerides, and glucose adjusted for age and gender. SteatoTest area under the ROC curves was 0.79 (SE = 0.03) in the training group; 0.80 (0.04) in validation group 1; 0.86 (0.03) in validation group 2; and 0.72 (0.05) in the validation group 3 – all significantly higher than the standard markers: γ-glutamyl-transpeptidase or alanine aminotransferase. The median SteatoTest value was 0.13 in fasting controls; 0.16 in non-fasting controls; 0.31 in patients without steatosis; 0.39 in grade 1 steatosis (0–5%); 0.58 in grade 2 (6–32%); and 0.74 in grade 3–4 (33–100%). For the diagnosis of grade 2–4 steatosis, the sensitivity of SteatoTest at the 0.30 cut-off was 0.91, 0.98, 1.00 and 0.85 and the specificity at the 0.70 cut-off was 0.89, 0.83, 0.92, 1.00, for the training and three validation groups, respectively.

Conclusion

SteatoTest is a simple and non-invasive quantitative estimate of liver steatosis and may reduce the need for liver biopsy, particularly in patients with metabolic risk factor.
Dynamic 3D echocardiography in virtual reality
Authors: van den Bosch Annemien E , Koning Anton HJ , Meijboom Folkert J , McGhie Jackie S , Simoons Maarten L , van der Spek Peter J , Bogers Ad JJC
Published: December 2005

Background

This pilot study was performed to evaluate whether virtual reality is applicable for three-dimensional echocardiography and if three-dimensional echocardiographic 'holograms' have the potential to become a clinically useful tool.

Methods

Three-dimensional echocardiographic data sets from 2 normal subjects and from 4 patients with a mitral valve pathological condition were included in the study. The three-dimensional data sets were acquired with the Philips Sonos 7500 echo-system and transferred to the BARCO (Barco N.V., Kortrijk, Belgium) I-space. Ten independent observers assessed the 6 three-dimensional data sets with and without mitral valve pathology. After 10 minutes' instruction in the I-Space, all of the observers could use the virtual pointer that is necessary to create cut planes in the hologram.

Results

The 10 independent observers correctly assessed the normal and pathological mitral valve in the holograms (analysis time approximately 10 minutes).

Conclusion

this report shows that dynamic holographic imaging of three-dimensional echocardiographic data is feasible. However, the applicability and use-fullness of this technology in clinical practice is still limited.
Discontinuation of treatment of schizophrenic patients is driven by poor symptom response: a pooled post-hoc analysis of four atypical antipsychotic drugs
Authors: Liu-Seifert Hong , Adams David H , Kinon Bruce J
Published: December 2005

Background

Stopping antipsychotic treatment can interrupt improvement and exacerbate the illness. The reasons for discontinuing treatment during controlled clinical trials were analyzed to explore this phenomenon.

Methods

A post-hoc, pooled analysis was made of 4 randomized, double-blind clinical trials, 24–28 weeks in duration, involving 1627 patients with schizophrenia or a related disorder. Analyses combined all the atypical antipsychotic treatment groups in the studies.

Results

The majority of patients (53%) stopped their treatment at an early stage. Poor psychiatric response along with worsening symptoms was the most frequently given reason for discontinuing the course (36%), which was substantially more common than discontinuation due to poor tolerability of the medication (12%). This phenomenon was corroborated by less improvement in patients who discontinued treatment compared with those who completed, based on the PANSS total scores. Discontinuation due to poor response was, apparently, more predominantly linked to patient perception than to physicians' conclusions alone (80% vs. 20%). Discontinuation due to patient perception of poor response appeared to occur particularly early in the course of treatment. Patients who discontinued due to poor toleration of the medication responded in a more comparable manner with completers.

Conclusion

Discontinuing treatment may lead to exacerbation of symptoms, undermining therapeutic progress. In these studies, poor response to treatment and worsening of underlying psychiatric symptoms, and to a lesser extent, intolerability to medication were the primary contributors to treatment being discontinued. Our findings suggest that adherence may be enhanced by effective symptom control, as objectively measured and as subjectively perceived. Such strategies may improve patients' willingness to undertake long-term therapy and increase the likelihood of a better prognosis.
Neurogenetic interactions and aberrant behavioral co-morbidity of attention deficit hyperactivity disorder (ADHD): dispelling myths
Authors: Comings David E , Chen Thomas JH , Blum Kenneth , Mengucci Julie F , Blum Seth H , Meshkin Brian
Published: December 2005

Background

Attention Deficit Hyperactivity Disorder, commonly referred to as ADHD, is a common, complex, predominately genetic but highly treatable disorder, which in its more severe form has such a profound effect on brain function that every aspect of the life of an affected individual may be permanently compromised. Despite the broad base of scientific investigation over the past 50 years supporting this statement, there are still many misconceptions about ADHD. These include believing the disorder does not exist, that all children have symptoms of ADHD, that if it does exist it is grossly over-diagnosed and over-treated, and that the treatment is dangerous and leads to a propensity to drug addiction. Since most misconceptions contain elements of truth, where does the reality lie?

Results

We have reviewed the literature to evaluate some of the claims and counter-claims. The evidence suggests that ADHD is primarily a polygenic disorder involving at least 50 genes, including those encoding enzymes of neurotransmitter metabolism, neurotransmitter transporters and receptors. Because of its polygenic nature, ADHD is often accompanied by other behavioral abnormalities. It is present in adults as well as children, but in itself it does not necessarily impair function in adult life; associated disorders, however, may do so. A range of treatment options is reviewed and the mechanisms responsible for the efficacy of standard drug treatments are considered.

Conclusion

The genes so far implicated in ADHD account for only part of the total picture. Identification of the remaining genes and characterization of their interactions is likely to establish ADHD firmly as a biological disorder and to lead to better methods of diagnosis and treatment.
Hormone replacement therapy and false positive recall in the Million Women Study: patterns of use, hormonal constituents and consistency of effect
Authors: Banks Emily , Reeves Gillian , Beral Valerie , Bull Diana , Crossley Barbara , Simmonds Moya , Hilton Elizabeth , Bailey Stephen , Barrett Nigel , Briers Peter , English Ruth , Jackson Alan , Kutt Elizabeth , Lavelle Janet , Rockall Linda , Wallis Matthew G , Wilson Mary , Patnick Julietta
Published: December 2005

Introduction

Current and recent users of hormone replacement therapy (HRT) have an increased risk of being recalled to assessment at mammography without breast cancer being diagnosed ('false positive recall'), but there is limited information on the effects of different patterns of HRT use on this. The aim of this study is to investigate in detail the relationship between patterns of use of HRT and false positive recall.

Methods

A total of 87,967 postmenopausal women aged 50 to 64 years attending routine breast cancer screening at 10 UK National Health Service Breast Screening Units from 1996 to 1998 joined the Million Women Study by completing a questionnaire before screening and were followed for their screening outcome.

Results

Overall, 399 (0.5%) participants were diagnosed with breast cancer and 2,629 (3.0%) had false positive recall. Compared to never users of HRT, the adjusted relative risk (95% CI) of false positive recall was: 1.62 (1.43–1.83), 1.80 (1.62–2.01) and 0.76 (0.52–1.10) in current users of oestrogen-only HRT, oestrogen-progestagen HRT and tibolone, respectively (p (heterogeneity) < 0.0001); 1.65 (1.43–1.91), 1.49 (1.22–1.81) and 2.11 (1.45–3.07) for current HRT used orally, transdermally or via an implant, respectively (p (heterogeneity) = 0.2); and 1.84 (1.67–2.04) and 1.75 (1.49–2.06) for sequential and continuous oestrogen-progestagen HRT, respectively (p (heterogeneity) = 0.6). The relative risk of false positive recall among current users appeared to increase with increasing time since menopause, but did not vary significantly according to any other factors examined, including duration of use, hormonal constituents, dose, whether single- or two-view screening was used, or the woman's personal characteristics.

Conclusion

Current use of oestrogen-only and oestrogen-progestagen HRT, but not tibolone, increases the risk of false positive recall at screening.
Sex-Dependent Effect of Melatonin on Systemic Erythematosus Lupus Developed in Mrl/Mpj-Faslpr Mice: It Ameliorates the Disease Course in Females, whereas It Exacerbates It in Males
Authors: Jimenez-Caliani Antonio J. , Jimenez-Jorge Silvia , Molinero Patrocinio , Fernandez-Santos Jose M. , Martin-Lacave Ines , Rubio Amalia , Guerrero Juan M. , Osuna Carmen
Published: December 2005

In this study, the effect of chronic administration of melatonin on MRL/MpJ-Faslpr mice has been studied. These mice spontaneously develop an autoimmune disease that has many features resembling human systemic lupus erythematosus. In fact, histological studies showed that all female mice and most male mice exhibited glomerular abnormalities, arteritic lesions, and cellular interstitial inflammatory infiltrate ranging from mild to severe patterns. Treatment with melatonin improved the histological pattern in females and worsened it in males. Moreover, female mice treated with melatonin showed a diminution of titers of total serum IgG, IgM, and anti-double-stranded DNA and anti-CII autoantibodies; a decrease in proinflammatory cytokines (IL-2, IL-6, interferon-γ, TNF-α, and IL-1β), an increase in antiinflammatory cytokines (IL-10), and a decrease in nitrite/nitrate. In male mice, treatment with melatonin exhibited the opposite effect, worsening all the immunological parameters with an elevation of titers of autoantibodies and a prevalence of proinflammatory vs. antiinflammatory cytokines. Similar results were obtained when lymphocytes from spleen and lymph nodes were cultured. Again, melatonin treatment in females decreased proinflammatory cytokines and increased antiinflammatory cytokines produced by lymphocytes; in males, the effect was the opposite. These findings suggest that melatonin action in MRL/MpJ-Faslpr mice is gender dependent, probably through modulation and inhibition of sex hormones.
Calcitonin Gene-Related Peptide Receptor Activation by Receptor Activity-Modifying Protein-1 Gene Transfer to Vascular Smooth Muscle Cells
Authors: Zhang Zhongming , Dickerson Ian M. , Russo Andrew F.
Published: December 2005

The neuropeptide calcitonin gene-related peptide (CGRP) is a potent vasodilator that plays a protective role in the cardiovascular system. The receptor for CGRP is an unusual complex of the G protein-coupled calcitonin-like receptor and an obligate receptor activity modifying protein-1 (RAMP1). In this report we provide the first evidence that RAMP1 is rate limiting in vascular smooth muscle cells. Although cultured rat aorta smooth muscle cells express calcitonin like-receptor and RAMP1, we found that CGRP is not a potent activator of the receptor. After overexpression of RAMP1 by adenoviral gene transfer, there was a striking increase in CGRP-induced production of cAMP, with a 75-fold decrease in the EC50 and a 1.5-fold increase in the maximal response. The biological consequence of this increased receptor activity was observed in three different paradigms. First, RAMP1 gene transfer caused a CGRP-dependent decrease in cell proliferation. Second, RAMP1 and CGRP treatment led to a 3-fold greater free radical-induced reduction in cell number. Finally, RAMP1 gene transfer resulted in a 5-fold CGRP-dependent increase in terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling-positive apoptotic cells upon serum withdrawal. The mechanisms underlying these effects involved cAMP-dependent pathways. We propose that RAMP1 gene transfer may be an effective strategy for increasing the effectiveness of CGRP-induced decrease in restenosis after aortic angioplasty.
Minireview: The Neuroendocrine Regulation of Puberty: Is the Time Ripe for a Systems Biology Approach?
Authors: Ojeda Sergio R. , Lomniczi Alejandro , Mastronardi Claudio , Heger Sabine , Roth Christian , Parent Anne-Simone , Matagne Valérie , Mungenast Alison E.
Published: December 2005

The initiation of mammalian puberty requires an increase in pulsatile release of GnRH from the hypothalamus. This increase is brought about by coordinated changes in transsynaptic and glial-neuronal communication. As the neuronal and glial excitatory inputs to the GnRH neuronal network increase, the transsynaptic inhibitory tone decreases, leading to the pubertal activation of GnRH secretion. The excitatory neuronal systems most prevalently involved in this process use glutamate and the peptide kisspeptin for neurotransmission/neuromodulation, whereas the most important inhibitory inputs are provided by γ-aminobutyric acid (GABA)ergic and opiatergic neurons. Glial cells, on the other hand, facilitate GnRH secretion via growth factor-dependent cell-cell signaling. Coordination of this regulatory neuronal-glial network may require a hierarchical arrangement. One level of coordination appears to be provided by a host of unrelated genes encoding proteins required for cell-cell communication. A second, but overlapping, level might be provided by a second tier of genes engaged in specific cell functions required for productive cell-cell interaction. A third and higher level of control involves the transcriptional regulation of these subordinate genes by a handful of upper echelon genes that, operating within the different neuronal and glial subsets required for the initiation of the pubertal process, sustain the functional integration of the network. The existence of functionally connected genes controlling the pubertal process is consistent with the concept that puberty is under genetic control and that the genetic underpinnings of both normal and deranged puberty are polygenic rather than specified by a single gene. The availability of improved high-throughput techniques and computational methods for global analysis of mRNAs and proteins will allow us to not only initiate the systematic identification of the different components of this neuroendocrine network but also to define their functional interactions.