http://www.biomedcentral.com/bmcmed/ The most accessed research articles published by BMC Medicine 2009-11-16T00:00:00Z 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/ 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: 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: Autism comprises a spectrum of behavioral and cognitive disturbances of childhood development and is known to be highly heritable. Although numerous approaches have been used to identify genes implicated in the development of autism, less than 10% of autism cases have been attributed to single gene disorders. Methods: We describe the use of high-resolution genome-wide tilepath microarrays and comparative genomic hybridization to identify copy number variants within 119 probands from multiplex autism families. We next carried out DNA methylation analysis by bisulfite sequencing in a proband and his family, expanding this analysis to methylation analysis of peripheral blood and temporal cortex DNA of autism cases and matched controls from independent datasets. We also assessed oxytocin receptor (OXTR) gene expression within the temporal cortex tissue by quantitative real-time polymerase chain reaction (PCR). Results: Our analysis revealed a genomic deletion containing the oxytocin receptor gene, OXTR (MIM accession no.: 167055), previously implicated in autism, was present in an autism proband and his mother who exhibits symptoms of obsessive-compulsive disorder. The proband's affected sibling did not harbor this deletion but instead may exhibit epigenetic misregulation of this gene through aberrant gene silencing by DNA methylation. Further DNA methylation analysis of the CpG island known to regulate OXTR expression identified several CpG dinucleotides that show independent statistically significant increases in the DNA methylation status in the peripheral blood cells and temporal cortex in independent datasets of individuals with autism as compared to control samples. Associated with the increase in methylation of these CpG dinucleotides is our finding that OXTR mRNA showed decreased expression in the temporal cortex tissue of autism cases matched for age and sex compared to controls. Conclusion: Together, these data provide further evidence for the role of OXTR and the oxytocin signaling pathway in the etiology of autism and, for the first time, implicate the epigenetic regulation of OXTR in the development of the disorder.See the related commentary by Gurrieri and Neri: http://www.biomedcentral.com/1741-7015/7/63 http://www.biomedcentral.com/1741-7015/7/62 Simon Gregory Jessica Connelly Aaron Towers Jessica Johnson Dhani Biscocho Christina Markunas Carla Lintas Ruth Abramson Harry Wright Peter Ellis Cordelia Langford Gordon Worley G Robert Delong Susan Murphy Michael Cuccaro Antonello Persico Margaret Pericak-Vance BMC Medicine 2009, 7:62 2009-10-22T00:00:00Z doi:10.1186/1741-7015-7-62 BMC Medicine 1741-7015 7 62 2009-10-22T00:00:00Z XML Here we present a review of the literature of influenza modeling studies, and discuss how these models can provide insights into the future of the currently circulating novel strain of influenza A (H1N1), formerly known as swine flu. We discuss how the feasibility of controlling an epidemic critically depends on the value of the Basic Reproduction Number (R0). The R0 for novel influenza A (H1N1) has recently been estimated to be between 1.4 and 1.6. This value is below values of R0 estimated for the 1918–1919 pandemic strain (mean R0~2: range 1.4 to 2.8) and is comparable to R0 values estimated for seasonal strains of influenza (mean R0 1.3: range 0.9 to 2.1). By reviewing results from previous modeling studies we conclude it is theoretically possible that a pandemic of H1N1 could be contained. However it may not be feasible, even in resource-rich countries, to achieve the necessary levels of vaccination and treatment for control. As a recent modeling study has shown, a global cooperative strategy will be essential in order to control a pandemic. This strategy will require resource-rich countries to share their vaccines and antivirals with resource-constrained and resource-poor countries. We conclude our review by discussing the necessity of developing new biologically complex models. We suggest that these models should simultaneously track the transmission dynamics of multiple strains of influenza in bird, pig and human populations. Such models could be critical for identifying effective new interventions, and informing pandemic preparedness planning. Finally, we show that by modeling cross-species transmission it may be possible to predict the emergence of pandemic strains of influenza. http://www.biomedcentral.com/1741-7015/7/30 Brian Coburn Bradley Wagner Sally Blower BMC Medicine 2009, 7:30 2009-06-22T00:00:00Z doi:10.1186/1741-7015-7-30 BMC Medicine 1741-7015 7 30 2009-06-22T00:00:00Z 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: On 11 June the World Health Organization officially raised the phase of pandemic alert (with regard to the new H1N1 influenza strain) to level 6. As of 19 July, 137,232 cases of the H1N1 influenza strain have been officially confirmed in 142 different countries, and the pandemic unfolding in the Southern hemisphere is now under scrutiny to gain insights about the next winter wave in the Northern hemisphere. A major challenge is pre-empted by the need to estimate the transmission potential of the virus and to assess its dependence on seasonality aspects in order to be able to use numerical models capable of projecting the spatiotemporal pattern of the pandemic. Methods: In the present work, we use a global structured metapopulation model integrating mobility and transportation data worldwide. The model considers data on 3,362 subpopulations in 220 different countries and individual mobility across them. The model generates stochastic realizations of the epidemic evolution worldwide considering 6 billion individuals, from which we can gather information such as prevalence, morbidity, number of secondary cases and number and date of imported cases for each subpopulation, all with a time resolution of 1 day. In order to estimate the transmission potential and the relevant model parameters we used the data on the chronology of the 2009 novel influenza A(H1N1). The method is based on the maximum likelihood analysis of the arrival time distribution generated by the model in 12 countries seeded by Mexico by using 1 million computationally simulated epidemics. An extended chronology including 93 countries worldwide seeded before 18 June was used to ascertain the seasonality effects. Results: We found the best estimate R0 = 1.75 (95% confidence interval (CI) 1.64 to 1.88) for the basic reproductive number. Correlation analysis allows the selection of the most probable seasonal behavior based on the observed pattern, leading to the identification of plausible scenarios for the future unfolding of the pandemic and the estimate of pandemic activity peaks in the different hemispheres. We provide estimates for the number of hospitalizations and the attack rate for the next wave as well as an extensive sensitivity analysis on the disease parameter values. We also studied the effect of systematic therapeutic use of antiviral drugs on the epidemic timeline. Conclusion: The analysis shows the potential for an early epidemic peak occurring in October/November in the Northern hemisphere, likely before large-scale vaccination campaigns could be carried out. The baseline results refer to a worst-case scenario in which additional mitigation policies are not considered. We suggest that the planning of additional mitigation policies such as systematic antiviral treatments might be the key to delay the activity peak in order to restore the effectiveness of the vaccination programs. http://www.biomedcentral.com/1741-7015/7/45 Duygu Balcan Hao Hu Bruno Goncalves Paolo Bajardi Chiara Poletto Jose Ramasco Daniela Paolotti Nicola Perra Michele Tizzoni Wouter Van den Broeck Vittoria Colizza Alessandro Vespignani BMC Medicine 2009, 7:45 2009-09-10T00:00:00Z doi:10.1186/1741-7015-7-45 BMC Medicine 1741-7015 7 45 2009-09-10T00:00:00Z 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 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 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 The autism spectrum disorders are a group of conditions with neurobehavioral impairment affecting approximately 0.6% of children. The clinical presentation is complex and the etiology is largely unknown, although a major role of genetic factors is widely accepted. A number of genetic studies led to the identification of genes and/or copy number variants whose alterations are associated with autism, but no specific factor has been found so far to be responsible for a substantial proportion of cases. Epigenetic modifications may also play a role, as demonstrated by the occurrence of autism in genetic conditions caused by mutations in imprinted genes or regions.The article by Gregory et al. published this month in BMC Medicine, reports on genomic and epigenetic alterations of OXTR, the gene encoding the receptor for oxytocin. The involvement of this gene was suggested by its deletion in an autistic patient. The subsequent analysis of a group of unrelated autistic subjects did not show an OXTR deletion, but rather hypermethylation of the gene promoter, with a reduced mRNA expression.These findings address two major points of the current debate on the etiology and pathogenesis of autism: the role of oxytocin, known to be involved in modeling human behavior, and the possible involvement of epigenetic mechanisms. The nature of this epigenetic dysregulation is unknown but, if proved to be true, might explain the failure to identify sequence alterations in a host of candidate genes. Practical implications of these findings may be forthcoming, however not before extension and validation on a larger scale have confirmed their value.See the associated research paper by Gregory et al: http://www.biomedcentral.com/1741-7015/7/62 http://www.biomedcentral.com/1741-7015/7/63 Fiorella Gurrieri Giovanni Neri BMC Medicine 2009, 7:63 2009-10-22T00:00:00Z doi:10.1186/1741-7015-7-63 BMC Medicine 1741-7015 7 63 2009-10-22T00:00:00Z XML