http://www.biomedcentral.com/bmcmed/ The latest research articles published by BMC Medicine 2009-12-02T00:00:00Z 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/ Background: With the rise of the second pandemic wave of the novel influenza A (H1N1) virus in the current season in the Northern Hemisphere, pandemic plans are being carefully re-evaluated, particularly for the strategic use of antiviral drugs. The recent emergence of oseltamivir-resistant in treated H1N1 patients has raised concerns about the prudent use of neuraminidase inhibitors for both treatment of ill individuals and post-exposure prophylaxis of close contacts. Methods: We extended an established population dynamical model of pandemic influenza with treatment to include post-exposure prophylaxis of close contacts. Using parameter estimates published in the literature, we simulated the model to evaluate the combined effect of treatment and prophylaxis in minimizing morbidity and mortality of pandemic infections in the context of transmissible drug resistance. Results: We demonstrated that, when transmissible resistant strains are present, post-exposure prophylaxis can promote the spread of resistance, especially when combined with aggressive treatment. For a given treatment level, there is an optimal coverage of prophylaxis that minimizes the total number of infections (final size) and this coverage decreases as a higher proportion of infected individuals are treated. We found that, when treatment is maintained at intermediate levels, limited post-exposure prophylaxis provides an optimal strategy for reducing the final size of the pandemic while minimizing the total number of deaths. We tested our results by performing a sensitivity analysis over a range of key model parameters and observed that the incidence of infection depends strongly on the transmission fitness of resistant strains. Conclusions: Our findings suggest that, in the presence of transmissible drug resistance, strategies that prioritize the treatment of only ill individuals, rather than the prophylaxis of those suspected of being exposed, are most effective in reducing the morbidity and mortality of the pandemic. The impact of post-exposure prophylaxis depends critically on the treatment level and the transmissibility of resistant strains and, therefore, enhanced surveillance and clinical monitoring for resistant mutants constitutes a key component of any comprehensive plan for antiviral drug use during an influenza pandemic. http://www.biomedcentral.com/1741-7015/7/73 Seyed Moghadas Christopher Bowman Gergely Rost David Fisman Jianhong Wu BMC Medicine 2009, 7:73 2009-12-02T00:00:00Z doi:10.1186/1741-7015-7-73 BMC Medicine 1741-7015 7 73 2009-12-02T00:00:00Z PDF Atrial fibrillation affects at least 1% of the population and causes marked society-wide morbidity and mortality. Current management of atrial fibrillation including antithrombotic therapy and management of concomitant conditions in all patients, rate control therapy in most patients, and rhythm control therapy in patients with severe atrial fibrillation-related symptoms can alleviate atrial fibrillation-related symptoms but can neither effectively prevent recurrent atrial fibrillation nor suppress atrial fibrillation-related complications. Hence, there is a need for better therapy of atrial fibrillation.The etiology of atrial fibrillation is complex. Most of the causes of atrial fibrillation which are known at present perpetuate themselves in vicious circles, and presence of the arrhythmia by itself causes marked damage of atrial myocardium. These pathophysiological insights suggest that early diagnosis and comprehensive therapy of atrial fibrillation, including adequate therapy of all atrial fibrillation-causing conditions, rate control, and rhythm control therapy, could help to prevent progression of atrial fibrillation and reduce atrial fibrillation-related complications. Such a therapy should make use of safe and effective therapeutic modalities, some of which have become available recently or will become available in the near future. The hypothesis that early diagnosis and early, comprehensive therapy of atrial fibrillation can improve outcomes requires formal testing in controlled trials. http://www.biomedcentral.com/1741-7015/7/72 Paulus Kirchhof BMC Medicine 2009, 7:72 2009-11-26T00:00:00Z doi:10.1186/1741-7015-7-72 BMC Medicine 1741-7015 7 72 2009-11-26T00:00:00Z XML Migraine is a largely inherited disorder of the brain characterized by a complex, but stereotypical, dysfunction of sensory processing. Often the most obvious clinical symptom is head pain, but non-headache symptoms such as photophobia, phonophobia and nausea are clearly part of the typical presentation. This review discusses the current pathophysiological concepts of migraine and migraine aura, such as a possible brainstem dysfunction and cortical spreading depression. Acute and preventive migraine treatment approaches are briefly covered with a focus on shortcomings of the currently available treatment options. A number of different receptors, such as calcitonin gene-related peptide (CGRP), TRPV1 and glutamate receptors, are currently being targeted by potential novel migraine therapeutics. The prospects of this research are exciting and are likely to improve patient care. http://www.biomedcentral.com/1741-7015/7/71 Peter Goadsby Till Sprenger BMC Medicine 2009, 7:71 2009-11-16T00:00:00Z doi:10.1186/1741-7015-7-71 BMC Medicine 1741-7015 7 71 2009-11-16T00:00:00Z XML Background: High dose oral ascorbic acid substantially improved myelination and locomotor function in a Charcot-Marie-Tooth type 1A mouse model. A phase II study was warranted to investigate whether high dose ascorbic acid also has such a substantial effect on myelination in Charcot-Marie-Tooth type 1A patients and whether this treatment is safe. Methods: Patients below age 25 years were randomly assigned to receive placebo or ascorbic acid (one gram twice daily) in a double-blind fashion during one year. The primary outcome measure was the change over time in motor nerve conduction velocity of the median nerve. Secondary outcome measures included changes in minimal F response latencies, compound muscle action potential amplitude, muscle strength, sensory function, Charcot-Marie-Tooth neuropathy score, and disability. Results: There were no significant differences between the six placebo-treated (median age 16 years, range 13 to 24) and the five ascorbic acid-treated (19, 14 to 24) patients in change in motor nerve conduction velocity of the median nerve (mean difference ascorbic acid as opposed to placebo treatment of 1.3 m/s, confidence interval -0.3 to 3.0 m/s, P = 0.11) or in change of any of the secondary outcome measures over time. One patient in the ascorbic acid group developed a skin rash, which led to discontinuation of the study medication. Conclusion: Oral high dose ascorbic acid for one year did not improve myelination of the median nerve in young Charcot-Marie-Tooth type 1A patients. Treatment was relatively safe.Trial registrationCurrent Controlled Trials ISRCTN56968278, ClinicalTrials.gov NCT00271635. http://www.biomedcentral.com/1741-7015/7/70 Camiel Verhamme Rob de Haan Marinus Vermeulen Frank Baas Marianne de Visser Ivo van Schaik BMC Medicine 2009, 7:70 2009-11-12T00:00:00Z doi:10.1186/1741-7015-7-70 BMC Medicine 1741-7015 7 70 2009-11-12T00:00:00Z XML Background: Recently published results from a large randomized trial (Canadian Cervical Cancer Screening Trial study group) suggest that human papillomavirus testing followed by Pap smear-based triage for human papillomavirus positive women may be an effective way to screen women for cervical cancer. We determined the potential cost-effectiveness of including human papillomavirus tests for cervical cancer screening for Canada and three provinces: Alberta, Newfoundland and Ontario. Methods: We developed four Markov decision models using data from relevant Canadian and provincial studies and databases. The models were used to determine the number of false positive test results, cancers, lifetime costs and life-expectancy for 27 different screening strategies that varied by age to begin screening (18 or 25 years), screening interval (one, two, three, or five years) and whether the currently recommended strategy (screening every year from age 18 until 21 and then every three years afterwards with conventional Paps) was conducted prior to age 25. Strategies were compared using incremental cost-effectiveness ratios. Results: Screening strategies beginning at age 18 were associated with a substantial increase in the number of false-positive test results but only small differences in the number of cancers compared to the same strategy conducted beginning at age 25. Strategies of human papillomavirus testing first, followed by triage with Pap smears were associated with lower costs and greater increases in life-expectancy than the currently recommended screening strategy in Canada. Conclusion: A strategy of human papillomavirus testing beginning at age 25, with Pap triage for women with positive human papillomavirus results may be more effective at reducing cervical cancer at a lower cost than the current recommended strategy for screening in Canada. http://www.biomedcentral.com/1741-7015/7/69 Shalini Kulasingam Raghu Rajan Yvan St.Pierre C. Victoria Atwood Evan Myers Eduardo Franco BMC Medicine 2009, 7:69 2009-11-09T00:00:00Z doi:10.1186/1741-7015-7-69 BMC Medicine 1741-7015 7 69 2009-11-09T00:00:00Z XML Background: The Signal Transducer and Activator of Transcription 1 (STAT1) has traditionally been regarded as a transmitter of interferon signaling and a pro-apoptotic tumour suppressor. Recent data have identified new functions of STAT1 associated with tumourigenesis and resistance to genotoxic stress, including ionizing radiation (IR) and chemotherapy. To investigate the mechanisms contributing to the tumourigenic functions of STAT1, we performed a combined transcriptomic-proteomic expressional analysis and found that STAT1 is associated with regulation of energy metabolism with potential implication in the Warburg effect. Methods: We generated a stable knockdown of STAT1 in the SCC61 human squamous cell carcinoma cell line, established tumour xenografts in athymic mice, and compared transcriptomic and proteomic profiles of STAT1 wild-type (WT) and knockdown (KD) untreated or irradiated (IR) tumours. Transcriptional profiling was based on Affymetrix Human GeneChip® Gene 1.0 ST microarrays. Proteomes were determined from the tandem mass spectrometry (MS/MS) data by searching against the human subset of the UniProt database. Data were analysed using Significance Analysis of Microarrays for ribonucleic acid and Visualize software for proteins. Functional analysis was performed with Ingenuity Pathway Analysis with statistical significance measured by Fisher's exact test. Results: Knockdown of STAT1 led to significant growth suppression in untreated tumours and radio sensitization of irradiated tumours. These changes were accompanied by alterations in the expression of genes and proteins of glycolysis/gluconeogenesis (GG), the citrate cycle (CC) and oxidative phosphorylation (OP). Of these pathways, GG had the most concordant changes in gene and protein expression and demonstrated a STAT1-dependent expression of genes and proteins consistent with tumour-specific glycolysis. In addition, IR drastically suppressed the GG pathway in STAT1 KD tumours without significant change in STAT1 WT tumours. Conclusion: Our results identify a previously uncharacterized function of STAT1 in tumours: expressional regulation of genes encoding proteins involved in glycolysis, the citrate cycle and mitochondrial oxidative phosphorylation, with predominant regulation of glycolytic genes. STAT1-dependent expressional regulation of glycolysis suggests a potential role for STAT1 as a transcriptional modulator of genes responsible for the Warburg effect. http://www.biomedcentral.com/1741-7015/7/68 Sean Pitroda Bassam Wakim Ravi Sood Mara Beveridge Michael Beckett Dhara MacDermed Ralph Weichselbaum Nikolai Khodarev BMC Medicine 2009, 7:68 2009-11-05T00:00:00Z doi:10.1186/1741-7015-7-68 BMC Medicine 1741-7015 7 68 2009-11-05T00:00:00Z XML Background: Tuberculosis contributes significantly to morbidity and mortality among HIV-infected children in sub-Saharan Africa. Isoniazid prophylaxis can reduce tuberculosis incidence in this population. However, for the treatment to be effective, adherence to the medication must be optimized. We investigated adherence to isoniazid prophylaxis administered daily, compared to three times a week, and predictors of adherence amongst HIV-infected children. Methods: We investigated adherence to study medication in a two centre, randomized trial comparing daily to three times a week dosing of isoniazid. The study was conducted at two tertiary paediatric care centres in Cape Town, South Africa. Over a 5 year period, we followed 324 HIV-infected children aged ≥ 8 weeks. Adherence information based on pill counts was available for 276 children. Percentage adherence was calculated by counting the number of pills returned. Adherence ≥ 90% was considered to be optimal. Analysis was done using summary and repeated measures, comparing adherence to the two dosing schedules. Mean percentage adherence (per child during follow-up time) was used to compare the mean of each group as well as the proportion of children achieving an adherence of ≥ 90% in each group. For repeated measures, percentage adherence (per child per visit) was dichotomized at 90%. A logistic regression model with generalized estimating equations, to account for within-individual correlation, was used to evaluate the impact of the dosing schedule. Adjustments were made for potential confounders and we assessed potential baseline and time-varying adherence determinants. Results: The overall adherence to isoniazid was excellent, with a mean adherence of 94.7% (95% confidence interval [CI] 93.5-95.9); similar mean adherence was achieved by the group taking daily medication (93.8%; 95% CI 92.1-95.6) and by the three times a week group (95.5%; 95% CI 93.8-97.2). Two-hundred and seventeen (78.6%) children achieved a mean adherence of ≥ 90%. Adherence was similar for daily and three times a week dosing schedules in univariate (odds ratio [OR] 0.88; 95% CI 0.66-1.17; P = 0.38) and multivariate (adjusted OR 0.85; 95% CI 0.64-1.11; P = 0.23) models. Children from overcrowded homes were less adherent (adjusted OR 0.71; 95% CI 0.54-0.95; P = 0.02). Age at study visit was predictive of adherence, with better adherence achieved in children older than 4 years (adjusted OR 1.96; 95% CI 1.16-3.32; P = 0.01). Conclusion: Adherence to isoniazid was excellent regardless of the dosing schedule used. Intermittent dosing of isoniazid prophylaxis can be considered as an alternative to daily dosing, without compromising adherence or efficacy.Trial registrationClinical Trials NCT00330304 http://www.biomedcentral.com/1741-7015/7/67 Stanzi le Roux Mark Cotton Jonathan Golub David le Roux Lesley Workman Heather Zar BMC Medicine 2009, 7:67 2009-11-03T00:00:00Z doi:10.1186/1741-7015-7-67 BMC Medicine 1741-7015 7 67 2009-11-03T00:00:00Z XML Background: Alzheimer's disease is the most common progressive neurodegenerative disease. In recent years, numerous progresses in the discovery of novel Alzheimer's disease molecular biomarkers in brain as well as in biological fluids have been made. Among them, those involving lipid metabolism are emerging as potential candidates. In particular, an accumulation of neutral lipids was recently found by us in skin fibroblasts from Alzheimer's disease patients. Therefore, with the aim to assess whether peripheral alterations in cholesterol homeostasis might be relevant in Alzheimer's disease development and progression, in the present study we analyzed lipid metabolism in plasma and peripheral blood mononuclear cells from Alzheimer's disease patients and from their first-degree relatives. Methods: Blood samples were obtained from 93 patients with probable Alzheimer's disease and from 91 of their first-degree relatives. As controls we utilized 57, cognitively normal, over-65 year-old volunteers and 113 blood donors aged 21-66 years, respectively. Data are reported as mean ± standard error. Statistical calculations were performed using the statistical analysis software Origin 8.0 version. Data analysis was done using the Student t-test and the Pearson test. Results: Data reported here show high neutral lipid levels and increased ACAT-1 protein in about 85% of peripheral blood mononuclear cells freshly isolated (ex vivo) from patients with probable sporadic Alzheimer's disease compared to about 7% of cognitively normal age-matched controls. A significant reduction in high density lipoprotein-cholesterol levels in plasma from Alzheimer's disease blood samples was also observed. Additionally, correlation analyses reveal a negative correlation between high density lipoprotein-cholesterol and cognitive capacity, as determined by Mini Mental State Examination, as well as between high density lipoprotein-cholesterol and neutral lipid accumulation. We observed great variability in the neutral lipid-peripheral blood mononuclear cells data and in plasma lipid analysis of the subjects enrolled as Alzheimer's disease-first-degree relatives. However, about 30% of them tend to display a peripheral metabolic cholesterol pattern similar to that exhibited by Alzheimer's disease patients. Conclusion: We suggest that neutral lipid-peripheral blood mononuclear cells and plasma high density lipoprotein-cholesterol determinations might be of interest to outline a distinctive metabolic profile applying to both Alzheimer's disease patients and asymptomatic subjects at higher risk of disease. http://www.biomedcentral.com/1741-7015/7/66 Alessandra Pani Antonella Mandas Giacomo Diaz Claudia Abete Pier Luigi Cocco Fabrizio Angius Annalisa Brundu Nico Mucaka Maria Elena Pais Antonio Saba Luigi Barberini Cristina Zaru Manuela Palmas Paolo Putzu Alessandra Mocali Francesco Paoletti Paolo La Colla Sandra Dessi BMC Medicine 2009, 7:66 2009-11-02T00:00:00Z doi:10.1186/1741-7015-7-66 BMC Medicine 1741-7015 7 66 2009-11-02T00:00:00Z XML Background: The decreasing range of joint motion caused by insufficient muscle length is a common problem in children with cerebral palsy (CP), often worsening with age. In 1994 a CP register and health care programme for children with CP was initiated in southern Sweden. The aim of this study was to analyse the development of the passive range of motion (ROM) in the lower limbs during all the growth periods in relation to gross motor function and CP subtype in the total population of children with CP. Methods: In total, 359 children with CP born during 1990-1999, living in the southernmost part of Sweden in the year during which they reached their third birthday and still living in the area in the year of their seventh birthday were analysed. The programme includes a continuous standardized follow-up with goniometric measurements of ROM in the lower limbs. The assessments are made by each child's local physiotherapist twice a year until 6 years of age, then once a year. In total, 5075 assessments from the CPUP database from 1994 to 1 January 2007 were analysed. Results: The study showed a decreasing mean range of motion over the period 2-14 years of age in all joints or muscles measured. The development of ROM varied according to GMFCS level and CP subtype. Conclusion: We found a decreasing ROM in children with CP from 2-14 years of age. This information is important for both the treatment and follow-up planning of the individual child as well as for the planning of health care programmes for all children with CP. http://www.biomedcentral.com/1741-7015/7/65 Eva Nordmark Gunnar Hagglund Henrik Lauge-Pedersen Philippe Wagner Lena Westbom BMC Medicine 2009, 7:65 2009-10-28T00:00:00Z doi:10.1186/1741-7015-7-65 BMC Medicine 1741-7015 7 65 2009-10-28T00:00:00Z XML Background: The professional organization of medical work no longer reflects the changing health needs caused by the growing number of complex and chronically ill patients. Key stakeholders enforce coordination and remove power from the medical professions in order allow for these changes. However, it may also be necessary to initiate basic changes to way in which the medical professionals work in order to adapt to the changing health needs.DiscussionMedical leaders, supported by health policy makers, can consciously activate the self-regulatory capacity of medical professionalism in order to transform the medical profession and the related professional processes of care so that it can adapt to the changing health needs. In doing so, they would open up additional routes to the improvement of the health services system and to health improvement. This involves three consecutive steps: (1) defining and categorizing the health needs of the population; (2) reorganizing the specialty domains around the needs of population groups; (3) reorganizing the specialty domains by eliminating work that could be done by less educated personnel or by the patients themselves. We suggest seven strategies that are required in order to achieve this transformation.SummaryChanging medical professionalism to fit the changing health needs will not be easy. It will need strong leadership. But, if the medical world does not embark on this endeavour, good doctoring will become merely a bureaucratic and/or marketing exercise that obscures the ultimate goal of medicine which is to optimize the health of both individuals and the entire population. http://www.biomedcentral.com/1741-7015/7/64 Thomas Plochg Niek Klazinga Barbara Starfield BMC Medicine 2009, 7:64 2009-10-26T00:00:00Z doi:10.1186/1741-7015-7-64 BMC Medicine 1741-7015 7 64 2009-10-26T00:00:00Z XML