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1.  Collagen reorganization at the tumor-stromal interface facilitates local invasion 
BMC Medicine  2006;4:38.
Background
Stromal-epithelial interactions are of particular significance in breast tissue as misregulation of these interactions can promote tumorigenesis and invasion. Moreover, collagen-dense breast tissue increases the risk of breast carcinoma, although the relationship between collagen density and tumorigenesis is not well understood. As little is known about epithelial-stromal interactions in vivo, it is necessary to visualize the stroma surrounding normal epithelium and mammary tumors in intact tissues to better understand how matrix organization, density, and composition affect tumor formation and progression.
Methods
Epithelial-stromal interactions in normal mammary glands, mammary tumors, and tumor explants in three-dimensional culture were studied with histology, electron microscopy, and nonlinear optical imaging methodologies. Imaging of the tumor-stromal interface in live tumor tissue ex vivo was performed with multiphoton laser-scanning microscopy (MPLSM) to generate multiphoton excitation (MPE) of endogenous fluorophores and second harmonic generation (SHG) to image stromal collagen.
Results
We used both laser-scanning multiphoton and second harmonic generation microscopy to determine the organization of specific collagen structures around ducts and tumors in intact, unfixed and unsectioned mammary glands. Local alterations in collagen density were clearly seen, allowing us to obtain three-dimensional information regarding the organization of the mammary stroma, such as radiating collagen fibers that could not have been obtained using classical histological techniques. Moreover, we observed and defined three tumor-associated collagen signatures (TACS) that provide novel markers to locate and characterize tumors. In particular, local cell invasion was found predominantly to be oriented along certain aligned collagen fibers, suggesting that radial alignment of collagen fibers relative to tumors facilitates invasion. Consistent with this observation, primary tumor explants cultured in a randomly organized collagen matrix realigned the collagen fibers, allowing individual tumor cells to migrate out along radially aligned fibers.
Conclusion
The presentation of these tumor-associated collagen signatures allowed us to identify pre-palpable tumors and see cells at the tumor-stromal boundary invading into the stroma along radially aligned collagen fibers. As such, TACS should provide indications that a tumor is, or could become, invasive, and may serve as part of a strategy to help identify and characterize breast tumors in animal and human tissues.
doi:10.1186/1741-7015-4-38
PMCID: PMC1781458  PMID: 17190588
2.  Macrophage invasion contributes to degeneration of stria vascularis in Pendred syndrome mouse model 
BMC Medicine  2006;4:37.
Background
Pendred syndrome, an autosomal-recessive disorder characterized by deafness and goiter, is caused by a mutation of SLC26A4, which codes for the anion exchanger pendrin. We investigated the relationship between pendrin expression and deafness using mice that have (Slc26a4+/+ or Slc26a4+/-) or lack (Slc26a4-/-) a complete Slc26a4 gene. Previously, we reported that stria vascularis of adult Slc26a4-/- mice is hyperpigmented and that marginal cells appear disorganized. Here we determine the time course of hyperpigmentation and marginal cell disorganization, and test the hypothesis that inflammation contributes to this tissue degeneration.
Methods
Slc26a4-/- and age-matched control (Slc26a4+/+ or Slc26a4+/-) mice were studied at four postnatal (P) developmental stages: before and after the age that marks the onset of hearing (P10 and P15, respectively), after weaning (P28-41) and adult (P74-170). Degeneration and hyperpigmentation stria vascularis was evaluated by confocal microscopy. Gene expression in stria vascularis was analyzed by microarray and quantitative RT-PCR. In addition, the expression of a select group of genes was quantified in spiral ligament, spleen and liver to evaluate whether expression changes seen in stria vascularis are specific for stria vascularis or systemic in nature.
Results
Degeneration of stria vascularis defined as hyperpigmentation and marginal cells disorganization was not seen at P10 or P15, but occurred after weaning and was associated with staining for CD68, a marker for macrophages. Marginal cells in Slc26a4-/-, however, had a larger apical surface area at P10 and P15. No difference in the expression of Lyzs, C3 and Cd45 was found in stria vascularis of P15 Slc26a4+/- and Slc26a4-/- mice. However, differences in expression were found after weaning and in adult mice. No difference in the expression of markers for acute inflammation, including Il1a, Il6, Il12a, Nos2 and Nos3 were found at P15, after weaning or in adults. The expression of macrophage markers including Ptprc (= Cd45), Cd68, Cd83, Lyzs, Lgals3 (= Mac2 antigen), Msr2, Cathepsins B, S, and K (Ctsb, Ctss, Ctsk) and complement components C1r, C3 and C4 was significantly increased in stria vascularis of adult Slc26a4-/- mice compared to Slc26a4+/+ mice. Expression of macrophage markers Cd45 and Cd84 and complement components C1r and C3 was increased in stria vascularis but not in spiral ligament, liver or spleen of Slc26a4-/- compared to Slc26a4+/- mice. The expression of Lyzs was increased in stria vascularis and spiral ligament but not in liver or spleen.
Conclusion
The data demonstrate that hyperpigmentation of stria vascularis and marginal cell reorganization in Slc26a4-/- mice occur after weaning, coinciding with an invasion of macrophages. The data suggest that macrophage invasion contributes to tissue degeneration in stria vascularis, and that macrophage invasion is restricted to stria vascularis and is not systemic in nature. The delayed onset of degeneration of stria vascularis suggests that a window of opportunity exists to restore/preserve hearing in mice and therefore possibly in humans suffering from Pendred syndrome.
doi:10.1186/1741-7015-4-37
PMCID: PMC1796619  PMID: 17187680
3.  CHKA and PCYT1A gene polymorphisms, choline intake and spina bifida risk in a California population 
BMC Medicine  2006;4:36.
Background
Neural tube defects (NTDs) are among the most common of all human congenital defects. Over the last two decades, accumulating evidence has made it clear that periconceptional intake of folic acid can significantly reduce the risk of NTD affected pregnancies. This beneficial effect may be related to the ability of folates to donate methyl groups for critical physiological reactions. Choline is an essential nutrient and it is also a methyl donor critical for the maintenance of cell membrane integrity and methyl metabolism. Perturbations in choline metabolism in vitro have been shown to induce NTDs in mouse embryos.
Methods
This study investigated whether single nucleotide polymorphisms (SNPs) in human choline kinase A (CHKA) gene and CTP:phosphocholine cytidylytransferase (PCYT1A) gene were risk factors for spina bifida. Fluorescence-based allelic discrimination analysis was performed for the two CHKA intronic SNPs hCV1562388 (rs7928739) and hCV1562393, and PCYT1A SNP rs939883 and rs3772109. The study population consisted of 103 infants with spina bifida and 338 non-malformed control infants who were born in selected California counties in the period 1989–1991.
Results
The CHKA SNP hCV1562388 genotypes with at least one C allele were associated with a reduced risk of spina bifida (odds ratio = 0.60, 95%CI = 0.38–0.94). The PCYT1A SNP rs939883 genotype AA was associated with a twofold increased risk of spina bifida (odds ratio = 1.89, 95% CI = 0.97–3.67). These gene-only effects were not substantially modified by analytic consideration to maternal periconceptional choline intake.
Conclusion
Our analyses showed genotype effects of CHKA and PCYT1A genes on spina bifida risk, but did not show evidence of gene-nutrient interactions. The underlying mechanisms are yet to be resolved.
doi:10.1186/1741-7015-4-36
PMCID: PMC1770928  PMID: 17184542
4.  Communicating population health statistics through graphs: a randomised controlled trial of graph design interventions 
BMC Medicine  2006;4:33.
Background
Australian epidemiologists have recognised that lay readers have difficulty understanding statistical graphs in reports on population health. This study aimed to provide evidence for graph design improvements that increase comprehension by non-experts.
Methods
This was a double-blind, randomised, controlled trial of graph-design interventions, conducted as a postal survey. Control and intervention participants were randomly selected from telephone directories of health system employees. Eligible participants were on duty at the listed location during the study period. Controls received a booklet of 12 graphs from original publications, and intervention participants received a booklet of the same graphs with design modifications. A questionnaire with 39 interpretation tasks was included with the booklet. Interventions were assessed using the ratio of the prevalence of correct responses given by the intervention group to those given by the control group for each task.
Results
The response rate from 543 eligible participants (261 intervention and 282 control) was 67%. The prevalence of correct answers in the control group ranged from 13% for a task requiring knowledge of an acronym to 97% for a task identifying the largest category in a pie chart. Interventions producing the greatest improvement in comprehension were: changing a pie chart to a bar graph (3.6-fold increase in correct point reading), changing the y axis of a graph so that the upward direction represented an increase (2.9-fold increase in correct judgement of trend direction), a footnote to explain an acronym (2.5-fold increase in knowledge of the acronym), and matching the y axis range of two adjacent graphs (two-fold increase in correct comparison of the relative difference in prevalence between two population subgroups).
Conclusion
Profound population health messages can be lost through use of overly technical language and unfamiliar statistical measures. In our study, most participants did not understand age standardisation and confidence intervals. Inventive approaches are required to address this problem.
doi:10.1186/1741-7015-4-33
PMCID: PMC1766925  PMID: 17178006
5.  Prioritising between direct observation of therapy and case-finding interventions for tuberculosis: use of population impact measures 
BMC Medicine  2006;4:35.
Background
Population impact measures (PIMs) have been developed as tools to help policy-makers with locally relevant decisions over health risks and benefits. This involves estimating and prioritising potential benefits of interventions in specific populations. Using tuberculosis (TB) in India as an example, we examined the population impact of two interventions: direct observation of therapy and increasing case-finding.
Methods
PIMs were calculated using published literature and national data for India, and applied to a notional population of 100 000 people. Data included the incidence or prevalence of smear-positive TB and the relative risk reduction from increasing case finding and the use of direct observation of therapy (applied to the baseline risks over the next year), and the incremental proportion of the population eligible for the proposed interventions.
Results
In a population of 100 000 people in India, the directly observed component of the Directly Observed Treatment, Short-course (DOTS) programme may prevent 0.188 deaths from TB in the next year compared with 1.79 deaths by increasing TB case finding. The costs of direct observation are (in international dollars) I$5960 and of case finding are I$4839 or I$31702 and I$2703 per life saved respectively.
Conclusion
Increasing case-finding for TB will save nearly 10 times more lives than will the use of the directly observed component of DOTS in India, at a smaller cost per life saved. The demonstration of the population impact, using simple and explicit numbers, may be of value to policy-makers as they prioritise interventions for their populations.
doi:10.1186/1741-7015-4-35
PMCID: PMC1764027  PMID: 17181867
6.  Effects of the diabetes linked TCF7L2 polymorphism in a representative older population 
BMC Medicine  2006;4:34.
Background
A polymorphism in the transcription factor 7-like 2 (TCF7L2) gene has been found to be associated with type 2 diabetes in case-control studies. We aimed to estimate associations of the marker rs7903146 (C/T) polymorphism with fasting glucose, lipids, diabetes prevalence and complications in an older general population.
Methods
In total, 944 subjects aged ≥ 65 years from the population representative InCHIANTI study were enrolled in this study. Those with fasting blood glucose of ≥ 7 mmol/l or physician diagnosis were considered diabetic. Cut-off points for impaired fasting glucose (IFG) were ≥ 5.6 mmol/l to < 7 mmol/l.
Results
In the general population sample, minor (T) allele carriers of rs7903146 had higher fasting blood glucose (FBG) (p = 0.028) but lower fasting insulin (p = 0.030) and HOMA2b scores (p = 0.001), suggesting poorer beta-cell function. T allele carriers also had smaller waist circumference (p = 0.009), lower triglyceride levels (p = 0.006), and higher high-density lipoprotein cholesterol (p = 0.008).
The prevalence of diabetes or IFG was 32.4% in TT carriers and 23.3% in CC carriers; adjusted OR = 1.67 (95% confidence interval 1.05 to 2.65, p = 0.031). Within the diabetic and IFG groups, fewer T allele carriers had metabolic syndrome features (p = 0.047) or had experienced a myocardial infarction (p = 0.037). Conversely, T allele carriers with diabetes had poorer renal function (reduced 24-hour creatinine clearance, p = 0.013), and possibly more retinopathy (p = 0.067). Physician-diagnosed dementia was more common in the T carriers (in diabetes p = 0.05, with IFG p = 0.024).
Conclusion
The TCF7L2 rs7903146 polymorphism is associated with lower insulin levels, smaller waist circumference, and lower risk lipid profiles in the general elderly population. Patients with diabetes who are carriers of the minor allele are less likely to have metabolic-syndrome features, but may experience more microvascular complications, although the number of cases was small. If replicated, these findings may have implications for developing treatment approaches tailored by genotype.
doi:10.1186/1741-7015-4-34
PMCID: PMC1769391  PMID: 17181866
7.  The effect of travel restrictions on the spread of a moderately contagious disease 
BMC Medicine  2006;4:32.
Background
Much research in epidemiology has been focused on evaluating conventional methods of control strategies in the event of an epidemic or pandemic. Travel restrictions are often suggested as an efficient way to reduce the spread of a contagious disease that threatens public health, but few papers have studied in depth the effects of travel restrictions. In this study, we investigated what effect different levels of travel restrictions might have on the speed and geographical spread of an outbreak of a disease similar to severe acute respiratory syndrome (SARS).
Methods
We used a stochastic simulation model incorporating survey data of travel patterns between municipalities in Sweden collected over 3 years. We tested scenarios of travel restrictions in which travel over distances >50 km and 20 km would be banned, taking into account different levels of compliance.
Results
We found that a ban on journeys >50 km would drastically reduce the speed and geographical spread of outbreaks, even when compliance is < 100%. The result was found to be robust for different rates of intermunicipality transmission intensities.
Conclusion
This study supports travel restrictions as an effective way to mitigate the effect of a future disease outbreak.
doi:10.1186/1741-7015-4-32
PMCID: PMC1764026  PMID: 17166291
8.  A population-based study of human immunodeficiency virus in south India reveals major differences from sentinel surveillance-based estimates 
BMC Medicine  2006;4:31.
Background
The human immunodeficiency virus (HIV) burden among adults in India is estimated officially by direct extrapolation of annual sentinel surveillance data from public-sector antenatal and sexually transmitted infection (STI) clinics and some high-risk groups. The validity of these extrapolations has not been systematically examined with a large sample population-based study.
Methods
We sampled 13838 people, 15–49 years old, from 66 rural and urban clusters using a stratified random method to represent adults in Guntur district in the south Indian state of Andhra Pradesh. We interviewed the sampled participants and obtained dried blood spots from them, and tested blood for HIV antibody, antigen and nucleic acid. We calculated the number of people with HIV in Guntur district based on these data, compared it with the estimate using the sentinel surveillance data and method, and analysed health services use data to understand the differences.
Results
In total, 12617 people (91.2% of the sampled group) gave a blood sample. Adjusted HIV prevalence was 1.72% (95% confidence interval 1.35–2.09%); men 1.74% (1.27–2.21%), women 1.70% (1.36–2.04%); rural 1.64% (1.10–2.18%), urban 1.89% (1.39–2.39%). HIV prevalence was 2.58% and 1.20% in people in the lower and upper halves of a standard of living index (SLI). Of women who had become pregnant during the past 2 years, 21.1% had used antenatal care in large public-sector hospitals participating in sentinel surveillance. There was an over-representation of the lowest SLI quartile (44.7%) in this group, and 3.61% HIV prevalence versus 1.08% in the remaining pregnant women. HIV prevalence was higher in that group even when women were matched for the same SLI half (lower half 4.39%, upper 2.63%) than in the latter (lower 1.06%, upper 1.05%), due to referral of HIV-positive/suspected women by private practitioners to public hospitals. The sentinel surveillance method (HIV prevalence: antenatal clinic 3%, STI clinic 22.8%, female sex workers 12.8%) led to an estimate of 112635 (4.38%) people with HIV, 15–49 years old, in Guntur district, which was 2.5 times the 45942 (1.79%) estimate based on our population-based study.
Conclusion
The official method in India leads to a gross overestimation of the HIV burden in this district due to addition of substantial extra HIV estimates from STI clinics, the common practice of referral of HIV-positive/suspected people to public hospitals, and a preferential use of public hospitals by people in lower socioeconomic strata. India may be overestimating its HIV burden with the currently used official estimation method.
doi:10.1186/1741-7015-4-31
PMCID: PMC1764025  PMID: 17166257
9.  Chronic kidney disease care delivered by US family medicine and internal medicine trainees: results from an online survey 
BMC Medicine  2006;4:30.
Background
Complications of chronic kidney disease (CKD) contribute to morbidity and mortality. Consequently, treatment guidelines have been developed to facilitate early detection and treatment. However, given the high prevalence of CKD, many patients with early CKD are seen by non-nephrologists, who need to be aware of CKD complications, screening methods and treatment goals in order to initiate timely therapy and referral.
Methods
We performed a web-based survey to assess perceptions and practice patterns in CKD care among 376 family medicine and internal medicine trainees in the United States. Questions were focused on the identification of CKD risk factors, screening for CKD and associated co-morbidities, as well as management of anemia and secondary hyperparathyroidism in patients with CKD.
Results
Our data show that CKD risk factors are not universally recognized, screening for CKD complications is not generally taken into consideration, and that the management of anemia and secondary hyperparathyroidism poses major diagnostic and therapeutic difficulties for trainees.
Conclusion
Educational efforts are needed to raise awareness of clinical practice guidelines and recommendations for patients with CKD among future practitioners.
doi:10.1186/1741-7015-4-30
PMCID: PMC1713248  PMID: 17164005
10.  Grey matter changes can improve the prediction of schizophrenia in subjects at high risk 
BMC Medicine  2006;4:29.
Background
We hypothesised that subjects at familial high risk of developing schizophrenia would have a reduction over time in grey matter, particularly in the temporal lobes, and that this reduction may predict schizophrenia better than clinical measurements.
Methods
We analysed magnetic resonance images of 65 high-risk subjects from the Edinburgh High Risk Study sample who had two scans a mean of 1.52 years apart. Eight of these 65 subjects went on to develop schizophrenia an average of 2.3 years after their first scan.
Results
Changes over time in the inferior temporal gyrus gave a 60% positive predictive value (likelihood ratio >10) of developing schizophrenia compared to the overall 13% risk in the cohort as a whole.
Conclusion
Changes in grey matter could be used as part of a predictive test for schizophrenia in people at enhanced risk for familial reasons, particularly for positive predictive power, in combination with other clinical and cognitive predictive measures, several of which are strong negative predictors. However, because of the limited number of subjects, this test requires independent replication to confirm its validity.
doi:10.1186/1741-7015-4-29
PMCID: PMC1698489  PMID: 17156415
11.  The effects of tea extracts on proinflammatory signaling 
BMC Medicine  2006;4:28.
Background
Skin toxicity is a common side effect of radiotherapy for solid tumors. Its management can cause treatment gaps and thus can impair cancer treatment. At present, in many countries no standard recommendation for treatment of skin during radiotherapy exists. In this study, we explored the effect of topically-applied tea extracts on the duration of radiation-induced skin toxicity. We investigated the underlying molecular mechanisms and compared effects of tea extracts with the effects of epigallocatechin-gallate, the proposed most-active moiety of green tea.
Methods
Data from 60 patients with cancer of the head and neck or pelvic region topically treated with green or black tea extracts were analyzed retrospectively. Tea extracts were compared for their ability to modulate IL-1β, IL-6, IL-8, TNFα and PGE2 release from human monocytes. Effects of tea extracts on 26S proteasome function were assessed. NF-κB activity was monitored by EMSAs. Viability and radiation response of macrophages after exposure to tea extracts was measured by MTT assays.
Results
Tea extracts supported the restitution of skin integrity. Tea extracts inhibited proteasome function and suppressed cytokine release. NF-κB activity was altered by tea extracts in a complex, caspase-dependent manner, which differed from the effects of epigallocatechin-gallate. Additionally, both tea extracts, as well as epigallocatechin-gallate, slightly protected macrophages from ionizing radiation
Conclusion
Tea extracts are an efficient, broadly available treatment option for patients suffering from acute radiation-induced skin toxicity. The molecular mechanisms underlying the beneficial effects are complex, and most likely not exclusively dependent on effects of tea polyphenols such as epigallocatechin-gallate.
doi:10.1186/1741-7015-4-28
PMCID: PMC1698929  PMID: 17140430
12.  Neurologic adverse events associated with smallpox vaccination in the United States – response and comment on reporting of headaches as adverse events after smallpox vaccination among military and civilian personnel 
BMC Medicine  2006;4:27.
Background
Accurate reporting of adverse events occurring after vaccination is an important component of determining risk-benefit ratios for vaccinations. Controversy has developed over alleged underreporting of adverse events within U.S. military samples. This report examines the accuracy of adverse event rates recently published for headaches, and examines the issue of underreporting of headaches as a function of civilian or military sources and as a function of passive versus active surveillance.
Methods
A report by Sejvar et al was examined closely for accuracy with respect to the reporting of neurologic adverse events associated with smallpox vaccination in the United States. Rates for headaches were reported by several scholarly sources, in addition to Sejvar et al, permitting a comparison of reporting rates as a function of source and type of surveillance.
Results
Several major errors or omissions were identified in Sejvar et al. The count of civilian subjects vaccinated and the totals of both civilians and military personnel vaccinated were reported incorrectly by Sejvar et al. Counts of headaches reported in VAERS were lower (n = 95) for Sejvar et al than for Casey et al (n = 111) even though the former allegedly used 665,000 subjects while the latter used fewer than 40,000 subjects, with both using approximately the same civilian sources. Consequently, rates of nearly 20 neurologic adverse events reported by Sejvar et al were also incorrectly calculated. Underreporting of headaches after smallpox vaccination appears to increase for military samples and for passive adverse event reporting systems.
Conclusion
Until revised or corrected, the rates of neurologic adverse events after smallpox vaccinated reported by Sejvar et al must be deemed invalid. The concept of determining overall rates of adverse events by combining small civilian samples with large military samples appears to be invalid. Reports of headaches as adverse events after smallpox vaccination appear to be have occurred much less frequently using passive surveillance systems and by members of the U.S. military compared to civilians, especially those employed in healthcare occupations. Such concerns impact risk-benefit ratios associated with vaccines and weigh against making vaccinations mandatory, without informed consent, even among military members. Because of the issues raised here, adverse event rates derived solely or primarily from U.S. Department of Defense reporting systems, especially passive surveillance systems, should not be used, given better alternatives, for making public health policy decisions.
doi:10.1186/1741-7015-4-27
PMCID: PMC1647285  PMID: 17096855
13.  A 'small-world-like' model for comparing interventions aimed at preventing and controlling influenza pandemics 
BMC Medicine  2006;4:26.
Background
With an influenza pandemic seemingly imminent, we constructed a model simulating the spread of influenza within the community, in order to test the impact of various interventions.
Methods
The model includes an individual level, in which the risk of influenza virus infection and the dynamics of viral shedding are simulated according to age, treatment, and vaccination status; and a community level, in which meetings between individuals are simulated on randomly generated graphs. We used data on real pandemics to calibrate some parameters of the model. The reference scenario assumes no vaccination, no use of antiviral drugs, and no preexisting herd immunity. We explored the impact of interventions such as vaccination, treatment/prophylaxis with neuraminidase inhibitors, quarantine, and closure of schools or workplaces.
Results
In the reference scenario, 57% of realizations lead to an explosive outbreak, lasting a mean of 82 days (standard deviation (SD) 12 days) and affecting 46.8% of the population on average. Interventions aimed at reducing the number of meetings, combined with measures reducing individual transmissibility, would be partly effective: coverage of 70% of affected households, with treatment of the index patient, prophylaxis of household contacts, and confinement to home of all household members, would reduce the probability of an outbreak by 52%, and the remaining outbreaks would be limited to 17% of the population (range 0.8%–25%). Reactive vaccination of 70% of the susceptible population would significantly reduce the frequency, size, and mean duration of outbreaks, but the benefit would depend markedly on the interval between identification of the first case and the beginning of mass vaccination. The epidemic would affect 4% of the population if vaccination started immediately, 17% if there was a 14-day delay, and 36% if there was a 28-day delay. Closing schools when the number of infections in the community exceeded 50 would be very effective, limiting the size of outbreaks to 10% of the population (range 0.9%–22%).
Conclusion
This flexible tool can help to determine the interventions most likely to contain an influenza pandemic. These results support the stockpiling of antiviral drugs and accelerated vaccine development.
doi:10.1186/1741-7015-4-26
PMCID: PMC1626479  PMID: 17059593
14.  Acute ischemic heart disease and interventional cardiology: a time for pause 
BMC Medicine  2006;4:25.
Background
A major change has occurred in the last few years in the therapeutic approach to patients presenting with all forms of acute coronary syndromes. Whether or not these patients present initially to tertiary cardiac care centers, they are now routinely referred for early coronary angiography and increasingly undergo percutaneous revascularization. This practice is driven primarily by the angiographic image and technical feasibility. Concomitantly, there has been a decline in expectant or ischemia-guided medical management based on specific clinical presentation, response to initial treatment, and results of noninvasive stratification. This 'tertiarization' of acute coronary care has been fuelled by the increasing sophistication of the cardiac armamentarium, the peer-reviewed publication of clinical studies purporting to show the superiority of invasive cardiac interventions, and predominantly supporting (non-peer-reviewed) editorials, newsletters, and opinion pieces.
Discussion
This review presents another perspective, based on a critical reexamination of the evidence. The topics addressed are: reperfusion treatment of ST-elevation myocardial infarction; the indications for invasive intervention following thrombolysis; the role of invasive management in non-ST-elevation myocardial infarction and unstable angina; and cost-effectiveness and real world considerations. A few cases encountered in recent practice in community and tertiary hospitals are presented for illustrative purposes The numerous and far-reaching scientific, economic, and philosophical implications that are a consequence of this marked change in clinical practice as well as healthcare, decisional and conflict of interest issues are explored.
Summary
The weight of evidence does not support the contemporary unfocused broad use of invasive interventional procedures across the spectrum of acute coronary clinical presentations. Excessive and unselective recourse to these procedures has deleterious implications for the organization of cardiac health care and undesirable economic, scientific and intellectual consequences. It is suggested that there is need for a new equilibrium based on more refined clinical risk stratification in the treatment of patients who present with acute coronary syndromes.
doi:10.1186/1741-7015-4-25
PMCID: PMC1617111  PMID: 17034632
15.  Timing and risk factors for clinical fractures among postmenopausal women: a 5-year prospective study 
BMC Medicine  2006;4:24.
Background
Many risk factors for fractures have been documented, including low bone-mineral density (BMD) and a history of fractures. However, little is known about the short-term absolute risk (AR) of fractures and the timing of clinical fractures. Therefore, we assessed the risk and timing of incident clinical fractures, expressed as 5-year AR, in postmenopausal women.
Methods
In total, 10 general practice centres participated in this population-based prospective study. Five years after a baseline assessment, which included clinical risk factor evaluation and BMD measurement, 759 postmenopausal women aged between 50 and 80 years, were re-examined, including undergoing an evaluation of clinical fractures after menopause. Risk factors for incident fractures at baseline that were significant in univariate analyses were included in a multivariate Cox survival regression analysis. The significant determinants were used to construct algorithms.
Results
In the total group, 12.5% (95% confidence interval (CI) 10.1–14.9) of the women experienced a new clinical fracture. A previous clinical fracture after menopause and a low BMD (T-score <-1.0) were retained as significant predictors with significant interaction. Women with a recent previous fracture (during the past 5 years) had an AR of 50.1% (95% CI 42.0–58.1) versus 21.2% (95% CI 20.7–21.6) if the previous fracture had occurred earlier. In women without a fracture history, the AR was 13.8% (95% CI 10.9–16.6) if BMD was low and 7.0% (95% CI 5.5–8.5) if BMD was normal.
Conclusion
In postmenopausal women, clinical fractures cluster in time. One in two women with a recent clinical fracture had a new clinical fracture within 5 years, regardless of BMD. The 5-year AR for a first clinical fracture was much lower and depended on BMD.
doi:10.1186/1741-7015-4-24
PMCID: PMC1609173  PMID: 17029622
16.  Hyper-IgG4 disease: report and characterisation of a new disease 
BMC Medicine  2006;4:23.
Background
We highlight a chronic inflammatory disease we call 'hyper-IgG4 disease', which has many synonyms depending on the organ involved, the country of origin and the year of the report. It is characterized histologically by a lymphoplasmacytic inflammation with IgG4-positive cells and exuberant fibrosis, which leaves dense fibrosis on resolution. A typical example is idiopathic retroperitoneal fibrosis, but the initial report in 2001 was of sclerosing pancreatitis.
Methods
We report an index case with fever and severe systemic disease. We have also reviewed the histology of 11 further patients with idiopathic retroperitoneal fibrosis for evidence of IgG4-expressing plasma cells, and examined a wide range of other inflammatory conditions and fibrotic diseases as organ-specific controls. We have reviewed the published literature for disease associations with idiopathic, systemic fibrosing conditions and the synonyms: pseudotumour, myofibroblastic tumour, plasma cell granuloma, systemic fibrosis, xanthofibrogranulomatosis, and multifocal fibrosclerosis.
Results
Histology from all 12 patients showed, to varying degrees, fibrosis, intense inflammatory cell infiltration with lymphocytes, plasma cells, scattered neutrophils, and sometimes eosinophilic aggregates, with venulitis and obliterative arteritis. The majority of lymphocytes were T cells that expressed CD8 and CD4, with scattered B-cell-rich small lymphoid follicles. In all cases, there was a significant increase in IgG4-positive plasma cells compared with controls. In two cases, biopsies before and after steroid treatment were available, and only scattered plasma cells were seen after treatment, none of them expressing IgG4. Review of the literature shows that although pathology commonly appears confined to one organ, patients can have systemic symptoms and fever. In the active period, there is an acute phase response with a high serum concentration of IgG, and during this phase, there is a rapid clinical response to glucocorticoid steroid treatment.
Conclusion
We believe that hyper-IgG4 disease is an important condition to recognise, as the diagnosis can be readily verified and the outcome with treatment is very good.
doi:10.1186/1741-7015-4-23
PMCID: PMC1618394  PMID: 17026742
17.  Cardioprotective aspirin users and their excess risk of upper gastrointestinal complications 
BMC Medicine  2006;4:22.
Background
To balance the cardiovascular benefits from low-dose aspirin against the gastrointestinal harm caused, studies have considered the coronary heart disease risk for each individual but not their gastrointestinal risk profile. We characterized the gastrointestinal risk profile of low-dose aspirin users in real clinical practice, and estimated the excess risk of upper gastrointestinal complications attributable to aspirin among patients with different gastrointestinal risk profiles.
Methods
To characterize aspirin users in terms of major gastrointestinal risk factors (i.e., advanced age, male sex, prior ulcer history and use of non-steroidal anti-inflammatory drugs), we used The General Practice Research Database in the United Kingdom and the Base de Datos para la Investigación Farmacoepidemiológica en Atención Primaria in Spain. To estimate the baseline risk of upper gastrointestinal complications according to major gastrointestinal risk factors and the excess risk attributable to aspirin within levels of these factors, we used previously published meta-analyses on both absolute and relative risks of upper gastrointestinal complications.
Results
Over 60% of aspirin users are above 60 years of age, 4 to 6% have a recent history of peptic ulcers and over 13% use other non-steroidal anti-inflammatory drugs. The estimated average excess risk of upper gastrointestinal complications attributable to aspirin is around 5 extra cases per 1,000 aspirin users per year. However, the excess risk varies in parallel to the underlying gastrointestinal risk and might be above 10 extra cases per 1,000 person-years in over 10% of aspirin users.
Conclusion
In addition to the cardiovascular risk, the underlying gastrointestinal risk factors have to be considered when balancing harms and benefits of aspirin use for an individual patient. The gastrointestinal harms may offset the cardiovascular benefits in certain groups of patients where the gastrointestinal risk is high and the cardiovascular risk is low.
doi:10.1186/1741-7015-4-22
PMCID: PMC1590044  PMID: 16987411
18.  Mental health and resiliency following 44 months of terrorism: a survey of an Israeli national representative sample 
BMC Medicine  2006;4:21.
Background
Israeli citizens have been exposed to intense and ongoing terrorism since September 2000. We previously studied the mental health impact of terrorism on the Israeli population (Bleich et al., 2002), however the long-term impact of ongoing terrorism has not yet been examined. The present study evaluated the psychological sequelae of 44 months of terrorism in Israel, and sought to identify factors that may contribute to vulnerability and resilience.
Methods
This was a telephone survey using strata sampling of 828 households, which reached a representative sample of 702 adult Israeli residents (84.8% contact rate). In total, 501 people (60.5%) agreed to participate. The methodology was similar to that of our previous study. Exposure to terrorism and other traumatic events, number of traumatic stress-related symptoms (TSRS), percentage of respondents with symptom criteria for post-traumatic stress disorder (PTSD), traumatic stress (TS) resiliency and feelings of depression, anxiety, optimism, sense of safety, and help-seeking were the main outcome measures.
Results
In total, 56 participants (11.2%) were directly exposed to a terrorist incident, and 101 (20.2%) had family members or friends exposed. Respondents reported a mean ± SD of 5.0 ± 4.5 TSRS; 45 (9%) met symptom criteria for PTSD; and 72 (14.4%) were TS-resilient. There were 147 participants (29.5%) who felt depressed, 50 (10.4%) felt anxious, and almost half (235; 47%) felt life-threatening danger; 48 (9.7%) felt the need for professional help. Women and people of Arab ethnicity had more TSRS, more PTSD, and less TS resiliency. Injury following a life-threatening experience, a major stressful life event, and a major loss of income were associated with PTSD. Immigrant status, lower education, low sense of safety, low sense of social support, high societal distress, and injury following life-threatening experiences were associated with TSRS. TSRS did not increase with exposure severity. This study revealed less depression and functional impairment, similar rates of PTSD, increased help-seeking and poorer TSRS and TS resiliency than our initial study, 2 years previously.
Discussion
The response of people in Israel to 4 years of terrorism is heterogeneous. Vulnerability factors change over time; Arab ethnicity, immigrant status and less education, not found to be risk factors in our previous study, were found in the present study to contribute to trauma-related distress. Prior experience of highly stressful events increases vulnerability to adverse psychological effects of terror.
doi:10.1186/1741-7015-4-21
PMCID: PMC1560155  PMID: 16934160
19.  Gender perspective in medicine: a vital part of medical scientific rationality. A useful model for comprehending structures and hierarchies within medical science 
BMC Medicine  2006;4:20.
Background
During the past few decades, research has reported gender bias in various areas of clinical and academic medicine. To prevent such bias, a gender perspective in medicine has been requested, but difficulties and resistance have been reported from implementation attempts. Our study aimed at analysing this resistance in relation to what is considered good medical research.
Method
We used a theoretical model, based on scientific competition, to understand the structures of scientific medicine and how they might influence the resistance to a gender perspective in medicine. The model was originally introduced to discuss how pluralism improves rationality in the social sciences.
Results
The model provided a way to conceptualise different fields of research in medicine: basic research, applied research, medical philosophy, and 'empowering' research. It clarified how various research approaches within medicine relate to each other, and how they differ and compete. It also indicated why there might be conflicts between them: basic and applied research performed within the biomedical framework have higher status than gender research and other research approaches that are performed within divergent research paradigms.
Conclusion
This hierarchy within medical research contributes to the resistance to a gender perspective, causing gender bias and making medical scientific rationality suboptimal. We recommend that the theoretical model can be applied in a wider medical context when different and hierarchically arranged research traditions are in conflict. In this way, the model might contribute to shape a medical community where scientific pluralism is acknowledged to enlarge, not to disturb, the scientific rationality of medicine.
doi:10.1186/1741-7015-4-20
PMCID: PMC1560154  PMID: 16928283
20.  Increase in sickness absence with psychiatric diagnosis in Norway: a general population-based epidemiologic study of age, gender and regional distribution 
BMC Medicine  2006;4:19.
Background
The aim of this study was to assess the incidence of sickness absence with psychiatric diagnoses from 1994–2000, and the distribution across gender, age groups, diagnostic groups and regions in a general population.
Methods
The population at risk was defined as all individuals aged 16–66 years who were entitled to sickness benefits in 1994, 1996, 1998 and 2000 (n = 2,282,761 in 2000). All individuals with a full-time disability pension were excluded. The study included approximately 77% of the Norwegian population aged 16–66 years. For each year, the study base started on 1 January and ended on 31 December. Individuals that were sick-listed for more than 14/16 consecutive days with a psychiatric diagnosis on their medical certificate were selected as cases. Included in this study were data for Norway, the capital city Oslo and five regions in the southeast of the country.
Results
Sickness absence with psychiatric diagnoses increased in all age groups, in women and men, and in all regions. At the national level, the cumulative incidence increased in women from 1.7% in 1994 to 4.6% in 2000, and in men from 0.8% in 1994 to 2.2% in 2000. The highest cumulative incidence was found in middle-aged women and men (30–59 years). Women had a higher incidence than men in all stratification groups. The cumulative incidences in 2000 varied between 4.6% to 5.6% in women in the different regions, and for men the corresponding figures were 2.1% to 3.2%. Throughout the four years studied, women in Oslo had more than twice as high incidence levels of sickness absence with alcohol and drug diagnoses as the country as a whole. There were some differences between regions in sickness absence with specific psychiatric diagnoses, but they were small and most comparisons were non-significant.
Conclusion
Sickness absence with psychiatric diagnoses increased between 1994 and 2000 in Norway. The increase was highest in the middle-aged, and in women. Few regional differences were found. That the increase pervaded all stratification groups supports general explanations of the increase, such as changes in attitudes to psychiatric disorders in both patients and doctors, and increased mental distress probably associated with societal changes at a more structural level.
doi:10.1186/1741-7015-4-19
PMCID: PMC1601961  PMID: 16923198
21.  Use of email in a family practice setting: opportunities and challenges in patient- and physician-initiated communication 
BMC Medicine  2006;4:18.
Background
Electronic mail (email) has the potential to improve communication between physicians and patients.
Methods
We conducted two research studies in a family practice setting: 1) a brief, anonymous patient survey of a convenience sample to determine the number of clinic patients receptive to communicating with their physician via email, and 2) a randomized, controlled pilot study to assess the feasibility of providing health education via email to family practice patients.
Results
Sixty-eight percent of patients used email, and the majority of those (80%) were interested in using email to communicate with the clinic. The majority also reported that their email address changed less frequently than their home address (65%, n = 173) or telephone number (68%, n = 181). Forty-two percent were willing to pay an out-of-pocket fee to have email access to their physicians. When evaluating email initiated by the clinic, 26% of otherwise eligible patients could not participate because they lacked email access; those people were more likely to be black and to be insured through Medicaid. Twenty-four subjects agreed to participate, but one-third failed to return the required consent form by mail. All participants who received the intervention emails said they would like to receive health education emails in the future.
Conclusion
Our survey results show that patients are interested in email communication with the family practice clinic. Our feasibility study also illustrates important challenges in physician-initiated electronic communication. The 'digital divide' – decreased access to electronic technologies in lower income groups – is an ethical concern in the use of email for patient-physician communication.
doi:10.1186/1741-7015-4-18
PMCID: PMC1563473  PMID: 16911780
22.  The effect of giving influenza vaccination to general practitioners: a controlled trial [NCT00221676] 
BMC Medicine  2006;4:17.
Background
No efficacy studies of influenza vaccination given to GPs have yet been published. Therefore, our purpose was to assess the effect of an inactivated influenza vaccine given to GPs on the rate of clinical respiratory tract infections (RTIs) and proven influenza cases (influenza positive nose and throat swabs and a 4-fold titre rise), while adjusting for important covariates.
Methods
In a controlled trial during two consecutive winter periods (2002–2003 and 2003–2004) we compared (77 and 100) vaccinated with (45 and 40) unvaccinated GPs working in Flanders, Belgium. Influenza antibodies were measured immediately prior to and 3–5 weeks after vaccination, as well as after the influenza epidemic. During the influenza epidemic, GPs had to record their contact with influenza cases and their own RTI symptoms every day. If they became ill, the GPs had to take nose and throat swabs during the first 4 days. We performed a multivariate regression analysis for covariates using Generalized Estimating Equations.
Results
One half of the GPs (vaccinated or not) developed an RTI during the 2 influenza epidemics. During the two influenza periods, 8.6% of the vaccinated and 14.7% of the unvaccinated GPs had positive swabs for influenza (RR: 0.59; 95%CI: 0.28 – 1.24). Multivariate analysis revealed that influenza vaccination prevented RTIs and swab-positive influenza only among young GPs (ORadj: 0.35; 95%CI: 0.13 – 0.96 and 0.1; 0.01 – 0.75 respectively for 30-year-old GPs). Independent of vaccination, a low basic antibody titre against influenza (ORadj 0.57; 95%CI: 0.37 – 0.89) and the presence of influenza cases in the family (ORadj 9.24; 95%CI: 2.91 – 29) were highly predictive of an episode of swab-positive influenza.
Conclusion
Influenza vaccination was shown to protect against proven influenza among young GPs. GPs, vaccinated or not, who are very vulnerable to influenza are those who have a low basic immunity against influenza and, in particular, those who have family members who develop influenza.
doi:10.1186/1741-7015-4-17
PMCID: PMC1538610  PMID: 16831228
23.  Hormone-replacement therapy influences gene expression profiles and is associated with breast-cancer prognosis: a cohort study 
BMC Medicine  2006;4:16.
Background
Postmenopausal hormone-replacement therapy (HRT) increases breast-cancer risk. The influence of HRT on the biology of the primary tumor, however, is not well understood.
Methods
We obtained breast-cancer gene expression profiles using Affymetrix human genome U133A arrays. We examined the relationship between HRT-regulated gene profiles, tumor characteristics, and recurrence-free survival in 72 postmenopausal women.
Results
HRT use in patients with estrogen receptor (ER) protein positive tumors (n = 72) was associated with an altered regulation of 276 genes. Expression profiles based on these genes clustered ER-positive tumors into two molecular subclasses, one of which was associated with HRT use and had significantly better recurrence free survival despite lower ER levels. A comparison with external data suggested that gene regulation in tumors associated with HRT was negatively correlated with gene regulation induced by short-term estrogen exposure, but positively correlated with the effect of tamoxifen.
Conclusion
Our findings suggest that post-menopausal HRT use is associated with a distinct gene expression profile related to better recurrence-free survival and lower ER protein levels. Tentatively, HRT-associated gene expression in tumors resembles the effect of tamoxifen exposure on MCF-7 cells.
doi:10.1186/1741-7015-4-16
PMCID: PMC1555602  PMID: 16813654
24.  Superior efficacy of St John's wort extract WS® 5570 compared to placebo in patients with major depression: a randomized, double-blind, placebo-controlled, multi-center trial [ISRCTN77277298] 
BMC Medicine  2006;4:14.
Background
The aim of the current study was to assess the antidepressant efficacy and safety of Hypericum perforatum (St. John's wort) extract WS® 5570 at doses of 600 mg/day in a single dose and 1200 mg/day in two doses.
Methods
The participants in this double-blind, randomized, placebo-controlled, multi-center clinical trial were male and female adult out-patients with an episode of mild or moderate major depressive episode (single or recurrent episode, DSM-IV criteria). As specified by the relevant guideline, the study was preceded by a medication-free run-in phase. For the 6-week treatment, 332 patients were randomized: 123 to WS® 5570 600 mg/day, 127 to WS® 5570 1200 mg/day, and 82 to placebo. The primary outcome measure was the change in total score on the Hamilton Rating Scale for Depression (HAM-D, 17-item version) between baseline and endpoint. Additional measures included the number of responders, the number of patients in remission, and several other standard rating scales. Efficacy and safety were assessed after 2 and 6 weeks. The design included an interim analysis performed after randomization with the option of early termination.
Results
After 6 weeks of treatment, mean ± standard deviation decreases in HAM-D total scores of 11.6 ± 6.4, 10.8 ± 7.3, and 6.0 ± 8.1 points were observed for the WS® 5570 600 mg/day, 1200 mg/day and placebo groups, respectively (endpoint analysis). Secondary measures of treatment efficacy also showed that both WS® 5570 groups were statistically superior to placebo. Significantly more patients in the WS® 5570 treatment groups than in the placebo group showed treatment response and remission. WS® 5570 was consistently more effective than placebo in patients with either less severe or more severe baseline impairment. The number of patients who experienced remission was higher in the WS® 5570 1200 mg/day group than the WS® 5570 600 mg/day group. The incidence of adverse events was low in all groups. The adverse event profile was consistent with the known profile for Hypericum extract preparations.
Conclusion
Hypericum perforatum extract WS® 5570 at doses of 600 mg/day (once daily) and 1200 mg/day (600 mg twice daily) were found to be safe and more effective than placebo, with comparable efficacy of the WS® 5570 groups for the treatment of mild to moderate major depression.
doi:10.1186/1741-7015-4-14
PMCID: PMC1538611  PMID: 16796730
25.  Prevalence and outcomes of delirium in community and non-acute care settings in people without dementia: a report from the Canadian Study of Health and Aging 
BMC Medicine  2006;4:15.
Background
While delirium is common among older adults in acute care hospitals, its prevalence in other settings has been less well studied. We examined delirium prevalence and outcomes in a large cohort of older Canadians living outside of acute care.
Methods
In this secondary analysis of the Canadian Study of Health and Aging, the prevalence of clinically diagnosed delirium was estimated and five-year survival was compared with that of individuals with dementia of graded severity.
Results
Delirium was very uncommon (prevalence <0.5%) and was associated with reduced survival, similar to that of moderate-to-severe dementia.
Conclusion
In this cohort of older Canadians, delirium in non-demented people was associated with very low 5-year survival, at levels comparable with advanced dementia. Although it is common in hospital, delirium is uncommon among older adults in their usual place of residence, suggesting that it is a potent stimulus to seek medical care.
doi:10.1186/1741-7015-4-15
PMCID: PMC1574341  PMID: 16796755

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