This is an RSS newsfeed from BioMed Central It is intended to be used with an RSS reader. For more information about RSS newsfeeds from BioMed Central, visit http://www.biomedcentral.com/info/about/rss/ http://www.biomedcentral.com/bmcmed/ The latest articles from BMC Medicine (ISSN 1741-7015) published by BioMed Central Exacerbations are a major cause of morbidity and mortality in COPD. Exacerbations can be of bacterial, viral or mixed etiology, with bacteria involved in 50% of exacerbations. Consequently, current management of exacerbations frequently involves the use of antibiotics. The paper by Puhan et al , published this month in BMC Medicine examines the benefit of antibiotics in placebo controlled trials in mild to moderate outpatient exacerbations. The authors use a meta-analytic approach and rightly conclude that more trials are needed in this area. However, the heterogeneity of COPD patients and exacerbations and the limited end-points in past trials does not let firm conclusions to be drawn about antibiotic use in outpatient exacerbations based on this meta-analysis. Future trials need to take in to account this heterogeneity as well as incorporate novel end-points to address this important issue. http://www.biomedcentral.com/1741-7015/6/29 Sanjay Sethi BMC Medicine 2008, 6:29 2008-10-10 doi:10.1186/1741-7015-6-29 BMC Medicine 1741-7015 6 29 2008-10-10 Background: Randomised trials comparing different drugs head-to-head are extremely valuable for clinical decision-making. However, it is scientifically and ethically sensible to demand strong evidence that a drug is effective by showing superiority over a placebo before embarking on head-to-head comparisons of potentially ineffective drugs. Our aim was to study the evolvement of evidence from placebo-controlled and head-to-head trials on the effects of antibiotics for the treatment of mild to moderate exacerbations of chronic obstructive pulmonary disease. Methods: We conducted a historical systematic review. Through electronic databases and hand-searches, we identified placebo-controlled and head-to-head antibiotic trials for the treatment of mild to moderate chronic obstructive pulmonary disease exacerbations. We compared the numbers of patients recruited in placebo-controlled and head-to-head trials between 1957 and 2005. Using cumulative meta-analysis of placebo-controlled trials, we determined when, if ever, placebo-controlled trials had shown convincing evidence that antibiotics are effective in preventing treatment failure in patients with mild to moderate chronic obstructive pulmonary disease exacerbations. Results: The first head-to-head trial was published in 1963. It was followed by another 100 trials comparing different antibiotics in a total of 34,029 patients with mild to moderate chronic obstructive pulmonary disease exacerbations. Over time, the cumulative odds ratio in placebo-controlled trials remained inconclusive throughout with odds ratios ranging from 0.39 (95% confidence intervals 0.04-4.22) to the most recent estimate (1995) of 0.81 (95% confidence intervals 0.52-1.28, P=0.37). Conclusions: Placebo-controlled trials do not support the use of antibiotics in chronic obstructive pulmonary disease patients with mild to moderate exacerbations. Conducting head-to-head trials is, therefore, scientifically and ethically questionable. This underscores the requirement to perform or study systematic reviews of placebo-controlled trials before conducting head-to-head trials. http://www.biomedcentral.com/1741-7015/6/28 Milo A Puhan, Daniela Vollenweider, Johann Steurer, Patrick M Bossuyt and Gerben ter Riet BMC Medicine 2008, 6:28 2008-10-10 doi:10.1186/1741-7015-6-28 BMC Medicine 1741-7015 6 28 2008-10-10 Identifying the complete repertoire of genes and genetic variants that regulate the pathogenesis and progression of human disease is a central goal of post-genomic biomedical research. In cancer, recent studies have shown that genome-wide association studies can be successfully used to identify germline polymorphisms associated with an individual's susceptibility to malignancy. In parallel to these reports, substantial work has also shown that patterns of somatic alterations in human tumors can be successfully employed to predict disease prognosis and treatment response. A paper by Van Ness et al. published this month in BMC Medicine reports the initial results of a multi-institutional consortium for multiple myeloma designed to evaluate the role of germline polymorphisms in influencing multiple myeloma clinical outcome. Applying a custom-designed single nucleotide polymorphism microarray to two separate patient cohorts, the investigators successfully identified specific combinations of germline polymorphisms significantly associated with early clinical relapse. These results raise the exciting possibility that besides somatically acquired alterations, germline genetic background may also exert an important influence on cancer patient prognosis and outcome. Future 'personalized medicine' strategies for cancer may thus require incorporating genomic information from both tumor cells and the non-malignant patient genome. http://www.biomedcentral.com/1741-7015/6/27 Patrick Tan BMC Medicine 2008, 6:27 2008-09-08 doi:10.1186/1741-7015-6-27 BMC Medicine 1741-7015 6 27 2008-09-08 Background: We have engaged in an international program designated the Bank On A Cure, which has established DNA banks from multiple cooperative and institutional clinical trials, and a platform for examining the association of genetic variations with disease risk and outcomes in multiple myeloma.We describe the development and content of a novel custom SNP panel that contains 3404 SNPs in 983 genes, representing cellular functions and pathways that may influence disease severity at diagnosis, toxicity, progression or other treatment outcomes. A systematic search of national databases was used to identify non-synonymous coding SNPs and SNPs within transcriptional regulatory regions. To explore SNP associations with PFS we compared SNP profiles of short term (less than 1 year, n = 70) versus long term progression-free survivors (greater than 3 years, n = 73) in two phase III clinical trials. Results: Quality controls were established, demonstrating an accurate and robust screening panel for genetic variations, and some initial racial comparisons of allelic variation were done. A variety of analytical approaches, including machine learning tools for data mining and recursive partitioning analyses, demonstrated predictive value of the SNP panel in survival. While the entire SNP panel showed genotype predictive association with PFS, some SNP subsets were identified within drug response, cellular signaling and cell cycle genes. Conclusion: A targeted gene approach was undertaken to develop an SNP panel that can test for associations with clinical outcomes in myeloma. The initial analysis provided some predictive power, demonstrating that genetic variations in the myeloma patient population may influence PFS. http://www.biomedcentral.com/1741-7015/6/26 Brian Van Ness, Christine Ramos, Majda Haznadar, Antje Hoering, Jeff Haessler, John Crowley, Susanna Jacobus, Martin Oken, Vincent Rajkumar, Philip Greipp, Bart Barlogie, Brian Durie, Michael Katz, Gowtham Atluri, Gang Fang, Rohit Gupta, Michael Steinbach, Vipin Kumar, Richard Mushlin, David Johnson and Gareth Morgan BMC Medicine 2008, 6:26 2008-09-08 doi:10.1186/1741-7015-6-26 BMC Medicine 1741-7015 6 26 2008-09-08 Background: Animal data show that decreased activity of placental 11-beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which potently inactivates glucocorticoids (e.g. cortisol) to inert forms (cortisone), allows increased access of maternal glucocorticoids to the fetus and 'programs' hypertension. Data in humans are limited. We examined in humans the association between venous umbilical cord blood glucocorticoids, a potential marker for placental 11β-HSD2 enzyme activity, and blood pressure at age 3 years. Methods: Among 286 newborns in Project Viva, a prospective pre-birth cohort study based in eastern Massachusetts, we measured cortisol (F) and cortisone (E) in venous cord blood and used the ratio of F/E as a marker for placental 11β-HSD2 activity. We measured blood pressure (BP) when the offspring reached age 3 years. Using mixed effects regression models to control for BP measurement conditions, maternal and child characteristics, we examined the association between the F/E ratio and child BP. Results: At age 3 years, each unit increase in the F/E ratio was associated with a 1.6 mm Hg increase in systolic BP (95% CI 0.0 to 3.1). The F/E ratio was not associated with diastolic blood pressure or birth weight for gestational age z-score. Conclusion: A higher F/E ratio in umbilical venous cord blood, likely reflecting reduced placental 11β-HSD2 activity, was associated with higher systolic blood pressure at age 3 years. Our data suggest that increased fetal exposure to active maternal glucocorticoids may program later systolic blood pressure. http://www.biomedcentral.com/1741-7015/6/25 Susanna Y Huh, Ruth Andrew, Janet W Rich-Edwards, Ken P Kleinman, Jonathan R Seckl and Matthew W Gillman BMC Medicine 2008, 6:25 2008-08-28 doi:10.1186/1741-7015-6-25 BMC Medicine 1741-7015 6 25 2008-08-28 Malarial anaemia is an enormous public health problem in endemic areas and occurs predominantly in children in the first 3 years of life. Anaemia is due to both a great increase in clearance of uninfected cells and a failure of an adequate bone marrow response. Odhiambo, Stoute and colleagues show how the age distribution of malarial anaemia and the haemolysis of red blood cells may be linked by an age-dependent increase in the capacity of red blood cells to inactivate complement components absorbed or deposited directly on to the surface of the red blood cell. In this commentary, we discuss what has been established about the role of complement deposition on the surface of red blood cells in the pathology of malarial anaemia, how genetic polymorphisms of the complement control proteins influence the outcome of malaria infection and how the findings of Odhiambo, Stoute and colleagues and others shed light on the puzzling age distribution of different syndromes of severe malaria. http://www.biomedcentral.com/1741-7015/6/24 Oscar K Kai and David J Roberts BMC Medicine 2008, 6:24 2008-08-21 doi:10.1186/1741-7015-6-24 BMC Medicine 1741-7015 6 24 2008-08-21 Background: Severe anemia due to Plasmodium falciparum malaria is a major cause of mortality among young children in western Kenya. The factors that lead to the age-specific incidence of this anemia are unknown. Previous studies have shown an age-related expression of red cell complement regulatory proteins, which protect erythrocytes from autologous complement attack and destruction. Our primary objective was to determine whether in a malaria-endemic area red cells with low levels of complement regulatory proteins are at increased risk for complement (C3b) deposition in vivo. Secondarily, we studied the relationship between red cell complement regulatory protein levels and hemoglobin levels. Methods: Three hundred and forty-two life-long residents of a malaria-holoendemic region of western Kenya were enrolled in a cross-sectional study and stratified by age. We measured red cell C3b, CR1, CD55, and immune complex binding capacity by flow cytometry. Individuals who were positive for malaria were treated and blood was collected when they were free of parasitemia. Analysis of variance was used to identify independent variables associated with the %C3b-positive red cells and the hemoglobin level. Results: Individuals between the ages of 6 and 36 months had the lowest red cell CR1, highest %C3b-positive red cells, and highest parasite density. Malaria prevalence also reached its peak within this age group. Among children ≤ 24 months of age the %C3b-positive red cells was usually higher in individuals who were treated for malaria than in uninfected individuals with similarly low red cell CR1 and CD55. The variables that most strongly influenced the %C3b-positive red cells were age, malaria status, and red cell CD55 level. Although it did not reach statistical significance, red cell CR1 was more important than red cell CD55 among individuals treated for malaria. The variables that most strongly influenced the hemoglobin level were age, the %C3b-positive red cells, red cell CR1, and red cell CD55. Conclusion: Increasing malaria prevalence among children >6 to ≤ 36 months of age in western Kenya, together with low red cell CR1 and CD55 levels, results in increased C3b deposition on red cells and low hemoglobin. The strong contribution of age to C3b deposition suggests that there are still additional unidentified age-related factors that increase the susceptibility of red cells to C3b deposition and destruction. http://www.biomedcentral.com/1741-7015/6/23 Collins O Odhiambo, Walter Otieno, Christine Adhiambo, Michael M Odera and José A Stoute BMC Medicine 2008, 6:23 2008-08-21 doi:10.1186/1741-7015-6-23 BMC Medicine 1741-7015 6 23 2008-08-21 Neurofibromatosis type 1 (NF1) is a dominantly inherited multi-system disorder. Major features include pigmentary abnormalities, benign tumors of the nerve sheath (neurofibromas), malignant tumors, learning disabilities, and skeletal dysplasia. The NF1 gene functions as a tumor suppressor, but haploinsuffiency probably accounts for some aspects of the non-tumor phenotype. The protein product, neurofibromin, is a Ras GTPase-activating protein, and various Ras pathway inhibitors are being tested in preclinical models and clinical trials for effectiveness in treating NF1 complications. This month in BMC Medicine, a paper by Kolanczyk et al describes a preclinical mouse model for tibial dysplasia and provides evidence that the drug lovastatin – in use to treat cardiovascular disease – may be beneficial, opening the door to clinical trials in humans. http://www.biomedcentral.com/1741-7015/6/22 Bruce R Korf BMC Medicine 2008, 6:22 2008-07-31 doi:10.1186/1741-7015-6-22 BMC Medicine 1741-7015 6 22 2008-07-31 Background: Bowing and/or pseudarthrosis of the tibia is a known severe complication of neurofibromatosis type 1 (NF1). Mice with conditionally inactivated neurofibromin (Nf1) in the developing limbs and cranium (Nf1Prx1) show bowing of the tibia caused by decreased bone mineralisation and increased bone vascularisation. However, in contrast to NF1 patients, spontaneous fractures do not occur in Nf1Prx1 mice probably due to the relatively low mechanical load. We studied bone healing in a cortical bone injury model in Nf1Prx1 mice as a model for NF1-associated bone disease. Taking advantage of this experimental model we explore effects of systemically applied lovastatin, a cholesterol-lowering drug, on the Nf1 deficient bone repair. Methods: Cortical injury was induced bilaterally in the tuberositas tibiae in Nf1Prx1 mutant mice and littermate controls according to a method described previously. Paraffin as well as methacrylate sections were analysed from each animal. We divided 24 sex-matched mutant mice into a lovastatin-treated and an untreated group. The lovastatin-treated mice received 0.15 mg activated lovastatin by daily gavage. The bone repair process was analysed at three consecutive time points post injury, using histological methods, micro computed tomography measurements and in situ hybridisation. At each experimental time point, three lovastatin-treated mutant mice, three untreated mutant mice and three untreated control mice were analysed. The animal group humanely killed on day 14 post injury was expanded to six treated and six untreated mutant mice as well as six control mice. Results: Bone injury repair is a complex process, which requires the concerted effort of numerous cell types. It is initiated by an inflammatory response, which stimulates fibroblasts from the surrounding connective tissue to proliferate and fill in the injury site with a provisional extracellular matrix. In parallel, mesenchymal progenitor cells from the periost are recruited into the injury site to become osteoblasts. In Nf1Prx1 mice bone repair is delayed and characterised by the excessive formation and the persistence of fibro-cartilaginous tissue and impaired extracellular matrix mineralisation. Correspondingly, expression of Runx2 is downregulated. High-dose systemic lovastatin treatment restores Runx2 expression and accelerates new bone formation, thus improving cortical bone repair in Nf1Prx1 tibia. The bone anabolic effects correlate with a reduction of the mitogen activated protein kinase pathway hyper-activation in Nf1-deficient cells. Conclusion: Our data suggest the potential usefulness of lovastatin, a drug approved by the US Food and Drug Administration in 1987 for the treatment of hypercholesteraemia, in the treatment of Nf1-related fracture healing abnormalities. The experimental model presented here constitutes a valuable tool for the pre-clinical stage testing of candidate drugs, targeting Nf1-associated bone dysplasia. http://www.biomedcentral.com/1741-7015/6/21 Mateusz Kolanczyk, Jirko Kühnisch, Nadine Kossler, Monika Osswald, Sabine Stumpp, Boris Thurisch, Uwe Kornak and Stefan Mundlos BMC Medicine 2008, 6:21 2008-07-31 doi:10.1186/1741-7015-6-21 BMC Medicine 1741-7015 6 21 2008-07-31 Background: The modulation of gap junctional communication between tumor cells and between tumor and vascular endothelial cells during tumorigenesis and metastasis is complex. The notion of a role for loss of gap junctional intercellular communication in tumorigenesis and metastasis has been controversial. While some of the stages of tumorigenesis and metastasis, such as uncontrolled cell division and cellular detachment, would necessitate the loss of intercellular junctions, other stages, such as intravasation, endothelial attachment, and vascularization, likely require increased cell-cell contact. We hypothesized that, in this multi-stage scheme, connexin-43 is centrally involved as a cell adhesion molecule mediating metastatic tumor attachment to the pulmonary endothelium. Methods: Tumor cell attachment to pulmonary vasculature, tumor growth, and connexin-43 expression was studied in metastatic lung tumor sections obtained after tail-vein injection into nude mice of syngeneic breast cancer cell lines, overexpressing wild type connexin-43 or dominant-negatively mutated connexin-43 proteins. High-resolution immunofluorescence microscopy and Western blot analysis was performed using a connexin-43 monoclonal antibody. Calcein Orange Red AM dye transfer by fluorescence imaging was used to evaluate the gap junction function. Results: Adhesion of breast cancer cells to the pulmonary endothelium increased with cancer cells overexpressing connexin-43 and markedly decreased with cells expressing dominant-negative connexin-43. Upregulation of connexin-43 was observed in tumor cell-endothelial cell contact areas in vitro and in vivo, and in areas of intratumor blood vessels and in micrometastatic foci. Conclusion: Connexin-43 facilitates metastatic 'homing' by increasing adhesion of cancer cells to the lung endothelial cells. The marked upregulation of connexin-43 in tumor cell-endothelial cell contact areas, whether in preexisting 'homing' vessels or in newly formed tumor vessels, suggests that connexin-43 can serve as a potential marker of micrometastases and tumor vasculature and that it may play a role in the early incorporation of endothelial cells into small tumors as seeds for vasculogenesis. http://www.biomedcentral.com/1741-7015/6/20 M Khair Elzarrad, Abu Haroon, Klaus Willecke, Radoslaw Dobrowolski, Mark N Gillespie and Abu-Bakr Al-Mehdi BMC Medicine 2008, 6:20 2008-07-22 doi:10.1186/1741-7015-6-20 BMC Medicine 1741-7015 6 20 2008-07-22