bluuebunny/crossref_metadata_2025 huggingface dataset:
Vascular Endothelial Growth Factor Regulates Reendothelialization and Neointima Formation in a Mouse Model of Arterial Injury
Authors: Hutter Randolph , Carrick Francine E. , Valdiviezo Carolina , Wolinsky Claire , Rudge John S. , Wiegand Stanley J. , Fuster Valentin , Badimon Juan J. , Sauter Bernhard V.
Published: October 2004

Background—

The rate of reendothelialization is critical in neointima formation after arterial injury. Vascular endothelial growth factor (VEGF), a potent endothelial mitogen, has been advocated for accelerating endothelial repair and preventing intimal hyperplasia after percutaneous coronary interventions. However, the precise mechanism of action of VEGF treatment and the physiologic role of endogenous VEGF after arterial injury are not well described. To better understand the role of VEGF in arterial repair, we overexpressed both VEGF and a soluble, chimeric VEGF receptor (VEGF-trap), which binds free VEGF with high affinity, in a mouse model of arterial injury.

Methods and Results—

Four groups of C57BL/6 mice underwent denuding endothelial injury 1 day after systemic injection of recombinant adenovirus expressing (1) VEGF, (2) VEGF-trap, (3) VEGF plus VEGF-trap, or (4) control adenovirus. Circulating levels of adenovirus-encoded proteins were significantly elevated after gene transfer. VEGF overexpression accelerated reendothelialization and increased luminal endothelial cell proliferation 2 weeks after arterial injury (
P
<0.05), resulting in decreased neointima formation at 4 weeks compared with control (
P
<0.01). Cotreatment with VEGF-trap completely sequestered free VEGF and abrogated the beneficial effect of VEGF overexpression. Interestingly, sequestration of endogenous VEGF by VEGF-trap overexpression alone also led to delayed reendothelialization at 2 weeks (
P
<0.01) and increased neointima formation at 4 weeks (
P
<0.01).

Conclusions—

VEGF overexpression accelerated endothelial repair and inhibited neointima formation after arterial injury. Conversely, sequestration of exogenous and/or endogenous VEGF by VEGF-trap delayed reendothelialization and significantly increased neointima size. This demonstrates the therapeutic potential of VEGF but also emphasizes the important physiologic role of endogenous VEGF in vascular repair.
Broad-Spectrum CC-Chemokine Blockade by Gene Transfer Inhibits Macrophage Recruitment and Atherosclerotic Plaque Formation in Apolipoprotein E–Knockout Mice
Authors: Bursill Christina A. , Choudhury Robin P. , Ali Ziad , Greaves David R. , Channon Keith M.
Published: October 2004

Background—

The CC-chemokines (CKs) recruit monocytes/macrophages to sites of inflammation; several different CC-CKs play a role in the pathogenesis of atherosclerosis. The vaccinia virus expresses a 35-kDa soluble protein (35K) that binds to and inactivates nearly all of the CC-CKs, providing a potentially useful therapeutic strategy for broad-spectrum CC-CK inhibition in atherosclerosis. A recombinant adenovirus encoding soluble 35K (Ad35K) was generated to investigate the effect of 35K gene transfer on atherosclerosis in Western diet–fed apolipoprotein E–knockout (ApoE KO) mice.

Methods and Results—

ApoE KO mice received tail-vein injections of phosphate-buffered saline, Ad35K, or control adenovirus AdGFP encoding green fluorescence protein. Two weeks after Ad35K gene transfer, atherosclerotic lesion area was significantly reduced in aortic roots by 55% compared with PBS or AdGFP control mice (
P
<0.05). Furthermore, 35K gene transfer strikingly reduced the macrophage content in aortic root lesions by 85% (
P
<0.01) and reduced lipid deposition in descending aortas by more than half (
P
<0.05). By an in vitro chemotaxis assay, plasma and aortic homogenates from 35K gene transfer mice promoted significantly less CC-CK–induced cell migration than did PBS or AdGFP controls.

Conclusions—

These findings show that a single intravenous injection of a recombinant adenovirus encoding the broad-spectrum CC-CK inhibitor 35K can reduce atherosclerosis by inhibiting CC-CK–induced macrophage recruitment in atherosclerotic ApoE KO mice. These experiments suggest that CC-CKs play an important role in atherogenesis and are a rational target for therapeutic intervention.
Angiogenesis-Dependent and Independent Phases of Intimal Hyperplasia
Authors: Khurana Rohit , Zhuang Zhenwu , Bhardwaj Shalini , Murakami Masahiro , De Muinck Ebo , Yla-Herttuala Seppo , Ferrara Napoleone , Martin John F. , Zachary Ian , Simons Michael
Published: October 2004

Background—

Neointimal vascular smooth muscle cell (VSMC) proliferation is a primary cause of occlusive vascular disease, including atherosclerosis, restenosis after percutaneous interventions, and bypass graft stenosis. Angiogenesis is implicated in the progression of early atheromatous lesions in animal models, but its role in neointimal VSMC proliferation is undefined. Because percutaneous coronary interventions result in induction of periadventitial angiogenesis, we analyzed the role of this process in neointima formation.

Methods and Results—

Local injury to the arterial wall in 2 different animal models induced periadventitial angiogenesis and neointima formation. Application of angiogenesis stimulators vascular endothelial growth factor (VEGF-A
165
) or a proline/arginine-rich peptide (PR39) to the adventitia of the injured artery induced a marked increase in neointimal thickening beyond that seen with injury alone in both in vivo models. Inhibition of either VEGF (with soluble VEGF receptor 1 [sFlt1]) or fibroblast growth factor (FGF) (with a dominant=negative form of FGF receptor 1 [FGF-R1DN]), respectively, signaling reduced adventitial thickening induced by VEGF and PR39 to the level seen with mechanical arterial injury alone. However, neither inhibitor was effective in preventing neointimal thickening after mechanical injury when administered in the absence of angiogenic growth factor.

Conclusions—

Our findings indicate that adventitial angiogenesis stimulates intimal thickening but does not initiate it.
Adenoviral Gene Transfer With Soluble Vascular Endothelial Growth Factor Receptors Impairs Angiogenesis and Perfusion in a Murine Model of Hindlimb Ischemia
Authors: Jacobi Johannes , Tam Betty Y.Y. , Wu Grace , Hoffman Jana , Cooke John P. , Kuo Calvin J.
Published: October 2004

Background—

The purpose of the current study was to examine the contribution of endogenous vascular endothelial growth factor (VEGF) to ischemia-induced angiogenesis and perfusion.

Methods and Results—

C57BL/6J mice (n=28) were subjected to unilateral hindlimb ischemia after intravenous injection of recombinant adenoviruses (10
9
plaque-forming units) encoding the ligand-binding ectodomain of VEGF receptor 1 (VEGFR1/Ad Flt1), VEGF receptor 2 (VEGFR2/Ad Flk1-Fc), a control murine IgG2α Fc fragment (Ad Fc), or vehicle (phosphate-buffered saline). Hindlimb perfusion was assessed by both laser Doppler and fluorescent microsphere injection 10 days after surgery. The role of endogenous VEGF in ischemia-induced angiogenesis and arteriogenesis was measured by capillary density and microangiography, respectively. Adenoviral gene transfer with soluble VEGFRs significantly attenuated hindlimb perfusion as assessed by laser Doppler and microsphere analysis (
P
<0.05). Furthermore, soluble VEGFRs significantly reduced ischemia-induced angiogenesis and collateral growth and inhibited histological recovery of muscle tissue. Adverse events consistent with ongoing vascular insufficiency such as limb necrosis or gangrene were observed only in animals expressing soluble VEGFRs and not in control animals.

Conclusions—

Systemic, soluble receptor–mediated VEGF inhibition indicates an essential role for endogenous VEGF during postischemic angiogenesis and hindlimb perfusion.
Prognostic Significance of the Long Pentraxin PTX3 in Acute Myocardial Infarction
Authors: Latini Roberto , Maggioni Aldo P. , Peri Giuseppe , Gonzini Lucio , Lucci Donata , Mocarelli Paolo , Vago Luca , Pasqualini Fabio , Signorini Stefano , Soldateschi Dario , Tarli Lorenzo , Schweiger Carlo , Fresco Claudio , Cecere Rossana , Tognoni Gianni , Mantovani Alberto
Published: October 2004

Background—

Inflammation has a pathogenetic role in acute myocardial infarction (MI). Pentraxin-3 (PTX3), a long pentraxin produced in response to inflammatory stimuli and highly expressed in the heart, was shown to peak in plasma ≈7 hours after MI. The aim of this study was to assess the prognostic value of PTX3 in MI compared with the best-known and clinically relevant biological markers.

Methods and Results—

In 724 patients with MI and ST elevation, PTX3, C-reactive protein (CRP), creatine kinase (CK), troponin T (TnT), and N-terminal pro-brain natriuretic peptide (NT-proBNP) were assayed at entry, a median of 3 hours, and the following morning, a median of 22 hours from symptom onset. With respect to outcome events occurring over 3 months after the index event, median PTX3 values were 7.08 ng/mL in event-free patients, 16.12 ng/mL in patients who died, 9.12 ng/mL in patients with nonfatal heart failure, and 6.88 ng/mL in patients with nonfatal residual ischemia (overall
P
<0.0001). Multivariate analysis including CRP, CK, TnT, and NT-proBNP showed that only age ≥70 years (OR, 2.11; 95% CI, 1.04 to 4.31), Killip class >1 at entry (OR, 2.20; 95% CI, 1.14 to 4.25), and PTX3 (>10.73 ng/mL) (OR, 3.55; 95% CI, 1.43 to 8.83) independently predicted 3-month mortality. Biomarkers predicting the combined end point of death and heart failure in survivors were the highest tertile of PTX3 and of NT-proBNP and a CK ratio >6.

Conclusions—

In a representative contemporary sample of patients with MI with ST elevation, the acute-phase protein PTX3 but not the liver-derived short pentraxin CRP or other cardiac biomarkers (NT-proBNP, TnT, CK) predicted 3-month mortality after adjustment for major risk factors and other acute-phase prognostic markers.
Left Ventricular Pacing Minimizes Diastolic Ventricular Interaction, Allowing Improved Preload-Dependent Systolic Performance
Authors: Bleasdale R.A. , Turner M.S. , Mumford C.E. , Steendijk P. , Paul V. , Tyberg J.V. , Morris-Thurgood J.A. , Frenneaux M.P.
Published: October 2004

Background—

Left ventricular (LV) pacing improves hemodynamics in patients with heart failure. We hypothesized that at least part of this benefit occurs by minimization of external constraint to LV filling from ventricular interaction.

Methods and Results—

We present median values (interquartile ranges) for 13 heart failure patients with LV pacing systems implanted for New York Heart Association class III/IV limitation. We used the conductance catheter method to measure LV pressure and volume simultaneously. External constraint was measured from the end-diastolic pressure-volume relation recorded during inferior vena caval occlusion, during LV pacing, and while pacing was suspended. External constraint to LV filling was reduced by 3.0 (4.6 to 0.6) mm Hg from 4.8 (0.6 to 7.5) mm Hg (
P
<0.01) in response to LV pacing; effective filling pressure (LV end-diastolic pressure minus external constraint) increased by 4.0 (2.2 to 5.8) mm Hg from 17.7 (13.3 to 22.6;
P
<0.01). LV end-diastolic volume increased by 10 (3 to 11) mL from 238 (169 to 295) mL (
P
=0.01), whereas LV end-systolic volume did not change significantly (−1 [−2 to 3] mL from 180 [124 to 236] mL,
P
=0.97), which resulted in an increase in stroke volume of 11 (5 to 13) mL from 49 (38 to 59) mL (
P
<0.01). LV stroke work increased by 720 (550 to 1180) mL · mm Hg from 3400 (2110 to 4480) mL · mm Hg (
P
=0.01), and maximum dP/dt increased by 120 (2 to 161) mm Hg/s from 635 (521 to 767) mm Hg/s (
P
=0.03).

Conclusions—

This study suggests a potentially important mechanism by which LV pacing may produce hemodynamic benefit. LV pacing minimizes external constraint to LV filling, resulting in an increase in effective filling pressure; the consequent increase in LV end-diastolic volume increases stroke volume via the Starling mechanism.
Blood Pressure and the Cystic Fibrosis Gene
Authors: Super Maurice , Irtiza-Ali Ayesha , Roberts Stephen A. , Schwarz Martin , Young Michele , Smith Alison , Roberts Theresa , Hinks Joanna , Heagerty Anthony
Published: October 2004

Individuals homozygous for the autosomal recessive disorder CF are known to have low blood pressure, thought to be caused by greatly increased sweat salt loss. We examined whether carriers of the CF gene also have low blood pressure. Our pilot studies had suggested an effect limited to females, leading to 2 further studies in white females. In the first, blood pressure was measured in 232 known CF mutation carriers and compared with 246 mutation-negative control subjects. The carriers showed a significantly lower rate of increase in systolic blood pressure with age than the controls, especially after age 50 (3.5% per decade compared with 5.4% per decade,
P
=0.010). In a small substudy, sweat sodium and chloride levels were highest in those CF carriers with the lowest blood pressures. In the second study, CF carrier status was investigated in 563 normotensive females and in 607 women with essential hypertension diagnosed to test whether a lower incidence of carriers in the hypertensives suggested a protective effect. Twenty-five of the normotensives (4.4%) were carriers compared with 21 (3.5%) of the hypertensive group (
P
=0.45). Older CF carrier females had lower systolic and diastolic pressures than matched control subjects, with a tendency for blood pressure to increase less with age. This could result in significant reduction in stroke and heart disease. The effect on blood pressure is insufficient to prevent hypertension, though it remains conceivable that the severity might be ameliorated in carriers.
State of the union
Authors: Gall Gregor
Published: October 2004

Gall examines the resurgence of the National Union of Journalists as a power in the media industries and concludes that despite progress having been made on behalf of members, there is still a long way to go: "Successes against trenchant opposition should not preclude cognisance that in many companies the NUJ has either not regained recognition or has not, to date, even tried to do so. In the provinces, most of Northcliffe's operations have yet to witness NUJ activity and in Newquest's Warrington centre, a chapel has only just reformed. It is also worth recalling that following the termination of the Newspaper Society/NUJ provincial industry-wide agreement in 1987, only 120 out of 249 chapels gained "house agreements" by the following year. The next year the number of chapels that maintained such agreements dropped further. Thus, even if the NUJ regained all the recognition agreements it lost in the 1990s, the provincial sector would still remain only partial unionised."
This star of England
Authors: Rostron Bryan
Published: October 2004

A former colleague of the late Journalist of the Decade, Robson writes: "Re-reading Paul Foot, only days after his death, what instantly struck me was how his words roar off the page, energising and fresh but above all as ferociously passionate and spot on as the day he wrote them. In that wonderfully direct style, full of wit and brio, one can hear Paul's own spirited voice. It never wavered. It was not a specially tailored public performance; the man, his life, his work, his titanic integrity and generosity were one. This probably explains how Paul Foot sustained - often against the odds - such an epic and courageous journalistic output. It also explains, I think, why so many fellow journalists and readers loved him."
Identitag, a relational database for SAGE tag identification and interspecies comparison of SAGE libraries
Authors: Keime Céline , Damiola Francesca , Mouchiroud Dominique , Duret Laurent , Gandrillon Olivier
Published: October 2004

Background

Serial Analysis of Gene Expression (SAGE) is a method of large-scale gene expression analysis that has the potential to generate the full list of mRNAs present within a cell population at a given time and their frequency. An essential step in SAGE library analysis is the unambiguous assignment of each 14 bp tag to the transcript from which it was derived. This process, called tag-to-gene mapping, represents a step that has to be improved in the analysis of SAGE libraries. Indeed, the existing web sites providing correspondence between tags and transcripts do not concern all species for which numerous EST and cDNA have already been sequenced.

Results

This is the reason why we designed and implemented a freely available tool called Identitag for tag identification that can be used in any species for which transcript sequences are available. Identitag is based on a relational database structure in order to allow rapid and easy storage and updating of data and, most importantly, in order to be able to precisely define identification parameters. This structure can be seen like three interconnected modules : the first one stores virtual tags extracted from a given list of transcript sequences, the second stores experimental tags observed in SAGE experiments, and the third allows the annotation of the transcript sequences used for virtual tag extraction. It therefore connects an observed tag to a virtual tag and to the sequence it comes from, and then to its functional annotation when available. Databases made from different species can be connected according to orthology relationship thus allowing the comparison of SAGE libraries between species. We successfully used Identitag to identify tags from our chicken SAGE libraries and for chicken to human SAGE tags interspecies comparison. Identitag sources are freely available on http://pbil.univ-lyon1.fr/software/identitag/ web site.

Conclusions

Identitag is a flexible and powerful tool for tag identification in any single species and for interspecies comparison of SAGE libraries. It opens the way to comparative transcriptomic analysis, an emerging branch of biology.
Tools for loading MEDLINE into a local relational database
Authors: Oliver Diane E , Bhalotia Gaurav , Schwartz Ariel S , Altman Russ B , Hearst Marti A
Published: October 2004

Background

Researchers who use MEDLINE for text mining, information extraction, or natural language processing may benefit from having a copy of MEDLINE that they can manage locally. The National Library of Medicine (NLM) distributes MEDLINE in eXtensible Markup Language (XML)-formatted text files, but it is difficult to query MEDLINE in that format. We have developed software tools to parse the MEDLINE data files and load their contents into a relational database. Although the task is conceptually straightforward, the size and scope of MEDLINE make the task nontrivial. Given the increasing importance of text analysis in biology and medicine, we believe a local installation of MEDLINE will provide helpful computing infrastructure for researchers.

Results

We developed three software packages that parse and load MEDLINE, and ran each package to install separate instances of the MEDLINE database. For each installation, we collected data on loading time and disk-space utilization to provide examples of the process in different settings. Settings differed in terms of commercial database-management system (IBM DB2 or Oracle 9i), processor (Intel or Sun), programming language of installation software (Java or Perl), and methods employed in different versions of the software. The loading times for the three installations were 76 hours, 196 hours, and 132 hours, and disk-space utilization was 46.3 GB, 37.7 GB, and 31.6 GB, respectively. Loading times varied due to a variety of differences among the systems. Loading time also depended on whether data were written to intermediate files or not, and on whether input files were processed in sequence or in parallel. Disk-space utilization depended on the number of MEDLINE files processed, amount of indexing, and whether abstracts were stored as character large objects or truncated.

Conclusions

Relational database (RDBMS) technology supports indexing and querying of very large datasets, and can accommodate a locally stored version of MEDLINE. RDBMS systems support a wide range of queries and facilitate certain tasks that are not directly supported by the application programming interface to PubMed. Because there is variation in hardware, software, and network infrastructures across sites, we cannot predict the exact time required for a user to load MEDLINE, but our results suggest that performance of the software is reasonable. Our database schemas and conversion software are publicly available at http://biotext.berkeley.edu.
Extreme conservation of noncoding DNA near HoxD complex of vertebrates
Authors: Sabarinadh Chilaka , Subramanian Subbaya , Tripathi Anshuman , Mishra Rakesh K
Published: October 2004

Background

Homeotic gene complexes determine the anterior-posterior body axis in animals. The expression pattern and function of hox genes along this axis is colinear with the order in which they are organized in the complex. This 'chromosomal organization and functional correspondence' is conserved in all bilaterians investigated. Genomic sequences covering the HoxD complex from several vertebrate species are now available. This offers a comparative genomics approach to identify conserved regions linked to this complex. Although the molecular basis of 'colinearity' of Hox complexes is not yet understood, it is possible that there are control elements within or in the proximity of these complexes that establish and maintain the expression patterns of hox genes in a coordinated fashion.

Results

We have compared DNA sequence flanking the HoxD complex of several primate, rodent and fish species. This analysis revealed an unprecedented conservation of non-coding DNA sequences adjacent to the HoxD complex from fish to human. Stretches of hundreds of base pairs in a 7 kb region, upstream of HoxD complex, show 100% conservation across the vertebrate species. Using PCR primers from the human sequence, these conserved regions could be amplified from other vertebrate species, including other mammals, birds, reptiles, amphibians and fish. Our analysis of these sequences also indicates that starting from the conserved core regions, more sequences have been added on and maintained during evolution from fish to human.

Conclusion

Such a high degree of conservation in the core regions of this 7 kb DNA, where no variation occurred during ~500 million years of evolution, suggests critical function for these sequences. We suggest that such sequences are likely to provide molecular handle to gain insight into the evolution and mechanism of regulation of associated gene complexes.
Branched-chain amino acid aminotransferase and methionine formation in Mycobacterium tuberculosis
Authors: Venos Erik S , Knodel Marvin H , Radford Cynthia L , Berger Bradley J
Published: October 2004

Background

Tuberculosis remains a major world-wide health threat which demands the discovery and characterisation of new drug targets in order to develop future antimycobacterials. The regeneration of methionine consumed during polyamine biosynthesis is an important pathway present in many microorganisms. The final step of this pathway, the conversion of ketomethiobutyrate to methionine, can be performed by aspartate, tyrosine, or branched-chain amino acid aminotransferases depending on the particular species examined.

Results

The gene encoding for branched-chain amino acid aminotransferase in Mycobacterium tuberculosis H37Rv has been cloned, expressed, and characterised. The enzyme was found to be a member of the aminotransferase IIIa subfamily, and closely related to the corresponding aminotransferase in Bacillus subtilis, but not to that found in B. anthracis or B. cereus. The amino donor preference for the formation of methionine from ketomethiobutyrate was for isoleucine, leucine, valine, glutamate, and phenylalanine. The enzyme catalysed branched-chain amino acid and ketomethiobutyrate transamination with a Km of 1.77 – 7.44 mM and a Vmax of 2.17 – 5.70 μmol/min/mg protein, and transamination of ketoglutarate with a Km of 5.79 – 6.95 mM and a Vmax of 11.82 – 14.35 μmol/min/mg protein. Aminooxy compounds were examined as potential enzyme inhibitors, with O-benzylhydroxylamine, O-t-butylhydroxylamine, carboxymethoxylamine, and O-allylhydroxylamine yielding mixed-type inhibition with Ki values of 8.20 – 21.61 μM. These same compounds were examined as antimycobacterial agents against M. tuberculosis and a lower biohazard M. marinum model system, and were found to completely prevent cell growth. O-Allylhydroxylamine was the most effective growth inhibitor with an MIC of 78 μM against M. marinum and one of 156 μM against M. tuberculosis.

Conclusion

Methionine formation from ketomethiobutyrate is catalysed by a branched-chain amino acid aminotransferase in M. tuberculosis. This enzyme can be inhibited by selected aminooxy compounds, which also have effectiveness in preventing cell growth in culture. These compounds represent a starting point for the synthesis of branched-chain aminotransferase inhibitors with higher activity and lower toxicity.
In vitro evaluation of the potential role of sulfite radical in morphine-associated histamine release
Authors: Gordon Emma M , Myers Carolyn , Blumer Jeffrey
Published: October 2004

Background

Intravenous morphine use is associated with elevated histamine release leading to bronchoconstriction, edema and hemodynamic instability in some patients. This study evaluated the possibility that sulfite, which is present as a preservative in many morphine preparations, might contribute to histamine release in vitro.

Results

The human mast cell line, HMC-1, was exposed to various morphine concentrations, in the absence of sulfite, under cell culture conditions. Clinically attained concentrations of morphine (0.018μg/ml and 0.45μg/ml) did not cause increased histamine release from mast cells. There was a significant increase in histamine release when the morphine concentration was increased by 1184-fold (668μg/ml morphine). Histamine release from mast cells exposed to morphine and/or sulfite required the presence of prostaglandin H synthetase. Histamine release in experiments using sulfite-containing morphine solutions was not statistically different from that observed in morphine-only solutions.

Conclusion

Sulfite in sulfite-containing morphine solutions, at concentrations seen clinically, is not responsible for histamine release in in vitro experiments of the human mast cell line, HMC-1. This does not preclude the fact that sulfite may lead to elevation of histamine levels in vivo.
The fallacy of enrolling only high-risk subjects in cancer prevention trials: Is there a "free lunch"?
Authors: Baker Stuart G , Kramer Barnett S , Corle Donald
Published: October 2004

Background

There is a common belief that most cancer prevention trials should be restricted to high-risk subjects in order to increase statistical power. This strategy is appropriate if the ultimate target population is subjects at the same high-risk. However if the target population is the general population, three assumptions may underlie the decision to enroll high-risk subject instead of average-risk subjects from the general population: higher statistical power for the same sample size, lower costs for the same power and type I error, and a correct ratio of benefits to harms. We critically investigate the plausibility of these assumptions.

Methods

We considered each assumption in the context of a simple example. We investigated statistical power for fixed sample size when the investigators assume that relative risk is invariant over risk group, but when, in reality, risk difference is invariant over risk groups. We investigated possible costs when a trial of high-risk subjects has the same power and type I error as a larger trial of average-risk subjects from the general population. We investigated the ratios of benefit to harms when extrapolating from high-risk to average-risk subjects.

Results

Appearances here are misleading. First, the increase in statistical power with a trial of high-risk subjects rather than the same number of average-risk subjects from the general population assumes that the relative risk is the same for high-risk and average-risk subjects. However, if the absolute risk difference rather than the relative risk were the same, the power can be less with the high-risk subjects. In the analysis of data from a cancer prevention trial, we found that invariance of absolute risk difference over risk groups was nearly as plausible as invariance of relative risk over risk groups. Therefore a priori assumptions of constant relative risk across risk groups are not robust, limiting extrapolation of estimates of benefit to the general population. Second, a trial of high-risk subjects may cost more than a larger trial of average risk subjects with the same power and type I error because of additional recruitment and diagnostic testing to identify high-risk subjects. Third, the ratio of benefits to harms may be more favorable in high-risk persons than in average-risk persons in the general population, which means that extrapolating this ratio to the general population would be misleading. Thus there is no free lunch when using a trial of high-risk subjects to extrapolate results to the general population.

Conclusion

Unless the intervention is targeted to only high-risk subjects, cancer prevention trials should be implemented in the general population.
Identification of hip fracture patients from radiographs using Fourier analysis of the trabecular structure: a cross-sectional study
Authors: Gregory Jennifer S , Stewart Alison , Undrill Peter E , Reid David M , Aspden Richard M
Published: October 2004

Background

This study presents an analysis of trabecular bone structure in standard radiographs using Fourier transforms and principal components analysis (PCA) to identify contributions to hip fracture risk.

Methods

Radiographs were obtained from 26 hip fracture patients and 24 controls. They were digitised and five regions of interest (ROI) were identified from the femoral head and neck for analysis. The power spectrum was obtained from the Fourier transform of each region and three profiles were produced; a circular profile and profiles parallel and perpendicular to the preferred orientation of the trabeculae. PCA was used to generate a score from each profile, which we hypothesised could be used to discriminate between the fracture and control groups. The fractal dimension was also calculated for comparison. The area under the receiver operating characteristic curve (A
z
) discriminating the hip fracture cases from controls was calculated for each analysis.

Results

Texture analysis of standard radiographs using the fast Fourier transform yielded variables that were significantly associated with fracture and not significantly correlated with age, body mass index or femoral neck bone mineral density. The anisotropy of the trabecular structure was important; both the perpendicular and circular profiles were significantly better than the parallel-profile (P < 0.05). No significant differences resulted from using the various ROI within the proximal femur. For the best three groupings of profile (circular, parallel or perpendicular), method (PCA or fractal) and ROI (A
z
= 0.84 – 0.93), there were no significant correlations with femoral neck bone mineral density, age, or body mass index. PCA analysis was found to perform better than fractal analysis (P = 0.019).

Conclusions

Both PCA and fractal analysis of the FFT data could discriminate successfully between the fracture and control groups, although PCA was significantly stronger than fractal dimension. This method appears to provide a powerful tool for the assessment of bone structure in vivo with advantages over standard fractal methods.
The validity of the SF-36 in an Australian National Household Survey: demonstrating the applicability of the Household Income and Labour Dynamics in Australia (HILDA) Survey to examination of health inequalities
Authors: Butterworth Peter , Crosier Timothy
Published: October 2004

Background

The SF-36 is one of the most widely used self-completion measures of health status. The inclusion of the SF-36 in the first Australian national household panel survey, the Household, Income and Labour Dynamics in Australia (HILDA) Survey, provides an opportunity to investigate health inequalities. In this analysis we establish the psychometric properties and criterion validity of the SF-36 HILDA Survey data and examine scale profiles across a range of measures of socio-economic circumstance.

Methods

Data from 13,055 respondents who completed the first wave of the HILDA Survey were analysed to determine the psychometric properties of the SF-36 and the relationship of the SF-36 scales to other measures of health, disability, social functioning and demographic characteristics.

Results

Results of principle components analysis were similar to previous Australian and international reports. Survey scales demonstrated convergent and divergent validity, and different markers of social status demonstrated unique patterns of outcomes across the scales.

Conclusion

Results demonstrated the validity of the SF-36 data collected during the first wave of the HILDA Survey and support its use in research examining health inequalities and population health characteristics in Australia.
Effectiveness of behavioural graded activity compared with physiotherapy treatment in chronic neck pain: design of a randomised clinical trial [ISRCTN88733332]
Authors: Vonk Frieke , Verhagen Arianne P , Geilen Mario , Vos Cees J , Koes Bart W
Published: October 2004

Background

Chronic neck pain is a common complaint in the Netherlands with a point prevalence of 14.3%. Patients with chronic neck pain are often referred to a physiotherapist and, although many treatments are available, it remains unclear which type of treatment is to be preferred.

The objective of this article is to present the design of a randomised clinical trial, Ephysion, which examines the clinical and cost effectiveness of behavioural graded activity compared with a physiotherapy treatment for patients with chronic non-specific neck pain.

Methods

Eligible patients with non-specific neck pain persisting longer than 3 months will be randomly allocated to either the behavioural graded activity programme or to the physiotherapy treatment. The graded activity programme is based on an operant approach, which uses a time-contingent method to increase the patient's activity level. This treatment is compared with physiotherapy treatment using a pain-contingent method.

Primary treatment outcome is the patient's global perceived effect concerning recovery from the complaint. Global perceived effect on daily functioning is also explored as primary outcome to establish the impact of treatment on daily activity. Direct and indirect costs will also be assessed. Secondary outcomes include the patient's main complaints, pain intensity, medical consumption, functional status, quality of life, and psychological variables. Recruitment of patients will take place up to the end of the year 2004 and follow-up measurement will continue until end 2005.
Perceived personal, social and environmental barriers to weight maintenance among young women: A community survey
Authors: Andajani-Sutjahjo Sari , Ball Kylie , Warren Narelle , Inglis Victoria , Crawford David
Published: October 2004

Background

Young women are a group at high risk of weight gain. This study examined a range of perceived personal, social and environmental barriers to physical activity and healthy eating for weight maintenance among young women, and how these varied by socioeconomic status (SES), overweight status and domestic situation.

Methods

In October-December 2001, a total of 445 women aged 18–32 years, selected randomly from the Australian electoral roll, completed a mailed self-report survey that included questions on 11 barriers to physical activity and 11 barriers to healthy eating (relating to personal, social and environmental factors). Height, weight and socio-demographic details were also obtained. Statistical analyses were conducted mid-2003.

Results

The most common perceived barriers to physical activity and healthy eating encountered by young women were related to motivation, time and cost. Women with children were particularly likely to report a lack of social support as an important barrier to physical activity, and lack of social support and time as important barriers to healthy eating. Perceived barriers did not differ by SES or overweight status.

Conclusions

Health promotion strategies aimed at preventing weight gain should take into account the specific perceived barriers to physical activity and healthy eating faced by women in this age group, particularly lack of motivation, lack of time, and cost. Strategies targeting perceived lack of time and lack of social support are particularly required for young women with children.
Emerging Themes in Epidemiology: Form and function
Authors: Lopman Ben A
Published: October 2004

Emerging Themes in Epidemiology is a new, online Open Access journal. This editorial – which coincides with the Journal's launch – describes its unique review and publication model. The editorial board and review process of ETE will be managed by research degree students and will therefore be a training ground for students (though final editorial control rests with senior faculty Associate Editors). With our mix of Open Access publishing and the strong involvement of students in editing and reviewing, we believe that Emerging Themes in Epidemiology will be a progressive medium for promoting new ideas in epidemiology.
WWW design code – a new tool for colour estimation in animal studies
Authors: Berggren Åsa , Merilä Juha
Published: October 2004

Background

The colour of animals' skin, fur, feathers or cuticula has been estimated in a large number of studies. The methods used to do so are diverse, with some being costly and not available to all researchers. In a study to measure plumage colour in a bird species, a new method of creating a colour chart was developed. While colour-charts have their own limitations, these can be minimised when they have the following properties: 1) being readily available to the majority of biologists, 2) containing a large array of colours to allow accurate recording and differentiation of subtle colour differences, 3) low cost, 4) adhering to a world-wide standard, and 5) being available in both hard-copy and digital formats to allow for various analytical methods. The method described below satisfies all of these requirements.

Results

Colour charts estimated to fit the range of the species' plumage colours were created on the computer screen using web software that allowed for HTML-coding (in this case Dreamweaver™). The charts were adjusted using feathers from dead specimens until a satisfying range of darker and lighter colours were found. The resulting chart was printed out and was successfully used in the field to determine the plumage colour of hand-held birds.

Conclusion

Access to a computer and printer, and the software to enable the creation of a chart, is within the reach of the vast majority of biologists. The numbers of colours that can be generated should suit most studies, with the advantage of the method being that the chart can be individually tailored to the species under study. HTML colour coding is a worldwide standard, thus the colours used in studies can be described in the methods section of journal articles using the six-digit alphanumeric code. We believe this method is very useful as a low-tech method for future estimation of individual colour.
Resistant starch consumption promotes lipid oxidation
Authors: Higgins Janine A , Higbee Dana R , Donahoo William T , Brown Ian L , Bell Melanie L , Bessesen Daniel H
Published: October 2004

Background

Although the effects of resistant starch (RS) on postprandial glycemia and insulinemia have been extensively studied, little is known about the impact of RS on fat metabolism. This study examines the relationship between the RS content of a meal and postprandial/post-absorbative fat oxidation.

Results

12 subjects consumed meals containing 0%, 2.7%, 5.4%, and 10.7% RS (as a percentage of total carbohydrate). Blood samples were taken and analyzed for glucose, insulin, triacylglycerol (TAG) and free fatty acid (FFA) concentrations. Respiratory quotient was measured hourly. The 0%, 5.4%, and 10.7% meals contained 50 μCi [1-14C]-triolein with breath samples collected hourly following the meal, and gluteal fat biopsies obtained at 0 and 24 h. RS, regardless of dose, had no effect on fasting or postprandial insulin, glucose, FFA or TAG concentration, nor on meal fat storage. However, data from indirect calorimetry and oxidation of [1-14C]-triolein to 14CO2 showed that addition of 5.4% RS to the diet significantly increased fat oxidation. In fact, postprandial oxidation of [1-14C]-triolein was 23% greater with the 5.4% RS meal than the 0% meal (p = 0.0062).

Conclusions

These data indicate that replacement of 5.4% of total dietary carbohydrate with RS significantly increased post-prandial lipid oxidation and therefore could decrease fat accumulation in the long-term.
The rules of the game: interprofessional collaboration on the intensive care unit team
Authors: Lingard Lorelei , Espin Sherry , Evans Cathy , Hawryluck Laura
Published: October 2004

Background

The intensive care unit (ICU) is a nexus for interspecialty and interdisciplinary tensions because of its pivotal role in the care of the hospital's most critically ill patients and in the management of critical care resources. In an environment charged with temporal, financial and professional tensions, learning how to get results collaboratively is a critical aspect of professional competence. This study explored how team members in the ICU interact to achieve daily clinical goals, delineate professional boundaries and negotiate complex systems issues.

Methods

Seven 1-hour focus groups were conducted with ICU team members in two hospitals. Participants consisted of four nursing groups (n = 27), two resident groups (n = 6) and one intensivist group (n = 4). Interviews were audio-recorded, anonymized and transcribed. With the use of a standard qualitative approach, transcripts were analyzed iteratively for recurrent themes by four researchers.

Results

Team members articulated their perceptions of the mechanisms by which team collaboration was achieved or undermined in a complex and high-pressure context. Two mechanisms were recurrently described: the perception of 'ownership' and the process of 'trade'. Analysis of these mechanisms reveals how power is commodified, possessed and exchanged as team members negotiate their daily needs and goals with one another.

Conclusion

Our data provide a non-idealized depiction of how health care professionals function on a team so as to meet both individual and collective goals. We contend that the concept of 'team' must move beyond the rhetoric of 'cooperation' and towards a more authentic depiction of the skills and strategies required to function in the competitive setting of the interprofessional health care team.
Celebrating Ned
Authors: Leijonhufvud Axel
Published: October 2004

This is a review article of the book Knowledge, Information, and Expectations in Modern Macroeconomics: In Honor of Edmund S. Phelps, edited by Philippe Aghion, Roman Frydman, Joseph Stiglitz and Michael Woodford, and published in 2004.
Prostaglandin Deficiency Promotes Sensitization of Adenylyl Cyclase
Authors: Weber S. , Lemoine H. , Wasner H.K.
Published: October 2004

Inhibition of prostaglandin synthesis by the drug indomethacin suppresses the synthesis of the cyclic AMP antagonist, prostaglandylinositol cyclic phosphate (cyclic PIP), and leads to a metabolic state comparable to type II diabetes. It was of interest whether prostaglandindeficiency likewise causes sensitization of adenylyl cyclase, as this has been reported for the diabetic state. In liver plasma membranes of indomethacintreated male rats, basal and forskolinstimulated cyclic AMP synthesis remained unchanged when compared to untreated control rats. In control rats, stimulation of cyclic AMP synthesis by fluoride (2.2-fold) or glucagon (3.5-fold) was much lower than stimulation by forskolin (6.6-fold). In contrast, in indomethacin treated rats, stimulation of cAMP synthesis by fluoride (4.6-fold) or glucagon (5.2-fold) nearly matched the stimulation by forskolin (6.4-fold). The level of α[1]adrenergic receptors was slightly reduced, from 450 to 320 fmol/mg protein, by the indomethacin treatment. Independent of the treatment by indomethacin, stimulation of cyclic AMP synthesis by adrenaline failed, in agreement with the low density of adrenergic βreceptors. In conclusion, PGE deficiency sensitizes adenylyl cyclase in rat liver for G proteincoupled receptors (glucagon) and also for fluoride.
The Eukaryotic Gene Transcription Machinery
Authors: Kornberg Roger D.
Published: October 2004

Seven purified proteins may be combined to reconstitute regulated, promoterdependent RNA polymerase II transcription: five general transcription factors, Mediator, and RNA polymerase II. The entire system has been conserved across species from yeast to humans. The structure of RNA polymerase II, consisting of 10 polypeptides with a mass of about 500 kDa, has been determined at atomic resolution. On the basis of this structure, that of an actively transcribing RNA polymerase II complex has been determined as well.
Binding of IRE-BP to Its Cognate RNA Sequence: SFM Studies on a Universal RNA Backbone for the Analysis of RNA-Protein Interaction
Authors: Bonin Michael , Oberstrass Jürgen , Vogt Ulrike , Wassenegger Michael , Nellen Wolfgang
Published: October 2004

We have used an RNA consisting of the potato spindle
tuber viroid (PSTVd) and 240 bp of doublestranded RNA derived from the GUS gene
as a backbone for scanning force microscope (SFM) studies on RNA binding
proteins. The in vitro transcribed RNA forms a rodlike structure of apparent
130 nm in length with a completely base paired central part flanked by the
incompletely paired viroid helix with bulges on both sides. The termini of the
molecule consist of loops such that no blunt or staggered RNA ends are exposed.
Suitable, asymmetrical restriction sites in the construct allow for the
insertion of sequences of interest, e. g. protein binding sites. We have
inserted the IRE (iron responsive element) sequence into the construct and have
used in vitro transcripts to study binding of IREBP. Relative binding
frequencies show that 70% of the protein binds to the expected site in the
molecule while only a slightly enhanced binding is observed at the termini. In
the GUSPSTVdIRE backbone, the orientation of the molecule is easily determined
by IREBP binding. It thus provides a versatile tool to study specific as well
as preferential interaction of other proteins with sequences or structures
inserted into a different part of the molecule.