Genome programs changed our view of bacteria as cell factories, by making them amenable to systematic rational improvement. As a first step, isolated genes (including those of the metagenome), or small gene clusters are improved and expressed in a variety of hosts. New techniques derived from functional genomics (transcriptome, proteome and metabolome studies) now allow users to shift from this single-gene approach to a more integrated view of the cell, where it is more and more considered as a factory. One can expect in the near future that bacteria will be entirely reprogrammed, and perhaps even created de novo from bits and pieces, to constitute man-made cell factories. This will require exploration of the landscape made of neighbourhoods of all the genes in the cell. Present work is already paving the way for that futuristic view of bacteria in industry. More than 40,000 pages are indexed in the WWW Browser Engine Google for the keyword "cell factory". Early in 1999 the European Union launched a research programme on the cell factory , stating that « The concept of the "bio-product" is as old as the knowledge involved in the making of bread, beer, wine or cheese. However, recent techniques and knowledge in molecular biology and genetics mean that living cells – from bacteria to man – are now becoming real "factories". In vast fermentation vats, engineers can direct and control natural metabolism in order to produce all sorts of substances with a high added value: proteins, amino acids, alcohols, citric acid, solvents and even bio-plastics. This industrial mastery of the mechanisms of life opens up revolutionary perspectives in the development of new kinds of medicines, foodstuffs with specific nutritional properties, and biodegradable biochemical products » [At the date of October 30Taken together these pieces of information show that exploration of the potential of microbes as industrial tools is shifting from its former status of traditional biotechnology assets to new high technology devices, meant to perform highly specific tasks, with the highest possible yields and security, and genomics as the background support. We shall not here review the use of microbes in traditional production (bread, beer, cheese and wine have been invented since the origin of the Neolithic, and perhaps even earlier ) but, ra<name of species>genome sequencing project resulted in the discovery of a number of new genes with potential interest for biotechnological applications ».Genomes are most often viewed as bags of genes. While this is not our personal view – we see genomes as highly organized set of genes, certainly not randomly distributed along the chromosomes , this isEscherichia coli, for example [Photorhabus luminescens [Streptomyces species in particular [Indeed, many biotechnological procedures still rest (and will rest) on the isolation of individual genes, or series of genes involved in the biosynthesis of a specific compound (this is illustrated in the complex case of coenzyme B12 biosynthesis in  example ). Remark example -11. As ainescens , when itrticular -16, and rticular .The genome concept for identifying new genes of biotechnological interest has now been expanded to that of a « metagenome », formed of communities of organisms (often non-cultivatable) in a given environment ,19. ThisHowever interesting, these « single-gene » approaches remain conceptually very limited, they only explore the surface of what could be provided by the knowledge of genomes. Furthermore, they often aim at the preparation of a single enzyme, that is meant to be used in a process that does not make use of the adaptation and maintenance potential of living organisms. In short, the cell is not used for what it is in reality, a factory. This is however dramatically changed with the advent of genomics as we shall now see.Progresses in genome sequencing were followed by attempts to better understand how a cell behaves as a whole. The knowledge of complete genome sequences permitted scientists to set up expression profiling techniques that play an ever increasing role in biotechnology . Indeed Many metabolic engineering strategies now use genome-wide methodologies such as DNA sequencing, transcription profiling and global analysis of metabolites. These techniques allow the identification of genetic differences and provide insight into their cellular effects. Inverse metabolic engineering endeavours to map differences between strains with different degree of a certain desired phenotype and subsequent identification of factors conferring that phenotype. Briefly reviewed, expression profiling can be divided into three major branches that each have a particular outcome, and gives a specific knowledge on the organism.With all genes known from a cell it has been possible to create DNA arrays sampling a subfamily or all genes on a variety of physical supports. These arrays can subsequently been used to monitor the level of expression of each gene in a particular condition. While this transcriptome approach is widely used, its interpretation is still a matter of research ,26 but iThe second level of expression profiling is, of course, that of the direct access to the gene products, the proteins. Two-dimensional gel electrophoresis has been developed for thirty years, with considerable success, but it is still extremely limited by the lack of reproducibility of 2-D gel patterns . Other mFermentation processes often aim at producing a given metabolite. The major problem facing industry in this domain is to improve the production yield, often for products that do not have a very high added-value (as opposed to proteins used in medicine, for example), in a background that has already been improved by generations of mutational improvement. Furthermore, many metabolites have to be as pure as possible, trying to prevent contamination by side-products that may be toxic . It is tCorynebacterium glutamicum [The traditional way for biotechnology to improve its processes was to select mutants having interesting properties (in terms of stability, resistance to foreign agents such as viruses, and of course metabolite or biomass production). This required long and tedious procedures where relevant features were usually gradually improving . Howeverutamicum .Further progress is certainly possible. It is important to try to understand whether genomes are simply random collection of genes, or whether they show rules, that might be exploited for using cells as factories. Remarkably, at least in bacteria, the organisation of the genome reflects some kind of optimisation of gene expression . Genes dWhile this has not yet, to our knowledge, be taken into consideration for improvement of production by industrial strains, it is more than likely that this will be performed in the near future . Regulation of gene expression is also of major interest. It must be understood however that this feature of life is evolving much more rapidly than catalytic or structural components of the cell. One should therefore be cautious in extrapolating knowledge from an organism to another one. Theoretical studies, associated to validation experiments have now begun to decipher the rules that govern regulation of gene expression, and it is certainly already possible to construct subtle regulation systems , that arAmong the recent discoveries that will play a considerable role in genome-mediated control of gene expression is that of riboswitches . This moIn the same way quorum-sensing has much to say for the control of gene expression at high cell density . Until nStreptomyces lividans [Corynebacterium glutamicum [Bacillus subtilis [Escherichia coli [Zymomonas mobilis [3) are now growing Xanthomonas campestris, used as a supplement not only in food, but also in dentrifrice, housekeeping products and even in painting, to prevent it from making drops [Many bacteria have been used as cell factories. In most cases this was to produce small molecules (in particular antibiotics, vitamins and amino acids). These bacteria were usually the result of continuous improvement using standard mutagenesis/screening techniques of bacteria isolated in the wild. Streptomyces species, for example, account for a large number of antibiotics production. lividans , Corynebutamicum , Bacillusubtilis , Escherihia coli , Zymomon mobilis , to giveng drops . In the E. coli as a ubiquitous cell factory. This trend was particularly emphasized as soon as genetic engineering techniques were developed, as early as in the early eighties, with the construction of new vectors for expressing foreign proteins at will . Mid-eiabolites . EscheriB. subtilis, are much more difficult to use, except for biomass production, or secreted proteins, because heterologous protein expression is difficult there. This has been understood after the genome was deciphered, as a consequence of the poorly versatile control of translation initiation , as welrticular .Taken together these observations suggest the rational choice of a new organism that would play the role of a ubiquitous cell factory. This organism should have several properties. It should be non pathogenic, and its envelope should not trigger inflammation reactions in animals (Man included). It should be easily transformable and allow recombination with linear DNA, with as little matches needed for recombination as possible. It should grow fast at temperature compatible with the size of fermenters (metabolic activity heats up the medium), and it should reach high cell density. More specialized views, adapted to specific productions will also be considered at some point, but it will be interesting to witness the choice of new model bacteria in the new era of the cell-factory.E. coli, producing heterologous proteins. As we now sequence a new genome every third day or so, it is clear that we will be able soon to understand the core of bacterial life, and probably be able to choose new models, better suited to the goals of industry. However we must always remember that life is full of surprises, even in the best explored domains: who would have thought that E. coli communicates with its kins using the boron atom? Discovery cannot be planned, and the most surprising observations, that have the most considerable consequences in terms of applications of research, come from studies that are totally academic in nature (who would have thought that the discovery of RNAi would have come from the study of variagation in petunia flowers?). One should not mix up domains: discovery first, and this needs a considerable degree of freedom of choice in the topics explored, and then, naturally, one can think of applications of research. Constructing the best of bacterial cell factory would be such a goal.Bacteria have been used as factories for a long time. A first step to rationalize this approach has been met with the first genetic engineering of GRAS: Generally Recognized As SafeRNAi: RNA interferenceThe author declares that he has no competing interests.


Very little is known about the correlates of adoption and maintenance of vigorous exercise. The purpose of this study was to understand the sociodemographic correlates of exercise adoption and maintenance in a community sample.917 women and 229 men completed annual surveys as part of a community-based weight gain prevention trial over four years. Multivariate regressions evaluated predictive factors for maintenance of vigorous exercise over time in regular exercisers, and predictors of adoption of exercise in adults who were sedentary at baseline.Exercise maintenance at Years 2 and 3 was associated with ethnicity and exercise level at baseline, while exercise maintenance at Year 4 was associated with television watching, BMI and exercise at baseline. Exercise level at baseline was associated with exercise initiation at Year 2 and Year 3. Income level, marital status, and smoking status predicted exercise initiation at Year 4.Predictors of vigorous exercise maintenance were more consistent than predictors of vigorous exercise initiation. Results suggest that those who adopt vigorous exercise are a heterogeneous group and intervention messages could be more broadly focused. These data also suggest that exercise maintenance interventions should continue to target low-income populations with messages regarding smoking, weight and television. Clearly further research is needed to understand the factors that contribute to exercise initiation and maintenance, and to develop effective interventions to improve levels of physical activity levels. Vigorous exercise is considered one of the key-components of a healthy lifestyle and cardiovascular fitness. Higher levels of exercise are associated with lower risks of hypertension, diabetes, osteoporosis, colon cancer, coronary heart disease, depression, anxiety, and has been shown to enhance weight control -3. WhileNumerous studies have examined predictors of exercise maintenance among participants in organized exercise programs . HoweverAlthough more research is being conducted on correlates of adoption and maintenance of exercise, more longitudinal research is needed among demographically diverse community samples . ConsideThe present study sought to cross-sectionally and prospectively examine the correlates of regular vigorous exercise in a sample of community adults over a four year period. Specifically, this study attempted to expand on the current literature by understanding the relationship between regular vigorous exercise and exercise adoption and maintenance by evaluating three comparisons in a community sample: 1) cross-sectional differences in characteristics of regular vigorous exercisers compared to non-exercisers, 2) predictive factors for maintenance of vigorous exercise over time in people who are already exercising at a high level as compared to those who do not maintain their exercise level, and 3) predictors of adoption of exercise in community adults who were sedentary at baseline as compared to those who do not adopt vigorous exercise. The study sample included 917 women and 229 men who completed baseline surveys as part of a 3-year community-based weight gain prevention trial . Participants were recruited using a variety of methods, including direct mail sent to university employees, and advertisements in community newspapers, health department employee newsletters and radio public service announcements. In addition, recruitment also targeted lower-income women at commercial shopping centers and at community health department clinics. Lower income women were paid $20 to enroll in the study. All participants were informed that they would be randomly assigned to either a mail-based educational program, or a no contact control group and that they would be measured once per year for a total of 4 years. This study was approved by the University of Minnesota Institutional Review Board.Study participants completed questionnaires and were measured for height and weight at baseline and at three annual data collection visits (Years 2, 3 and 4) following baseline. Measures included in the present study are listed below.Planned vigorous exercise behavior was assessed using 5 questions from a self-administered version of the Physical Activity History questionnaire (PAH). The PAH is reliable and valid and has been used in several large epidemiologic studies . For thiTo evaluate competing activities, we evaluated participant's report of time spent watching television. Time spent watching television has been positively correlated with body weight, presumably in part due to its displacement of exercise behaviors . ParticiSocial support from family and friends has been found to be related to exercise in a number of studies . ParticiHeight was measured to the nearest centimeter using a wall-mounted ruler and weight was measured to the nearest half pound using calibrated balance beam scales. Body mass index was calculated using the formula weight (kg)/height (m2). All demographic information was self-reported and included age, educational attainment (highest level completed), gender, employment status, income, ethnicity, smoking status and marital status.2 = 14.14, p = .042) and at Year 4 (X2 = 6.42, p = .011). Initiation of exercise at Year 2 and Year 3 were not significantly associated with treatment status. However, initiation of exercise at Year 4 was marginally positively associated with treatment (X2 = 3.30, p = .069). Due to these associations, treatment assignment (intervention vs control) was controlled in multiple regression analyses.Before performing analyses evaluating the predictors of exercise maintenance and initiation, the possibility of an intervention effect was evaluated. Maintenance of high intensity exercise at Year 2 was not significantly associated with treatment, however, maintenance of high intensity exercise at Years 3 and 4 were associated with treatment status. Intervention participants were more likely to be maintaining exercise behavior at Year 3 (XParticipants were classified as regular vigorous exercisers (> 3 times per week) and non-regular exercisers (< 3 times per week) based on their responses to the five planned high-intensity exercises on the PAH at each of the 4 assessment points. Using these classifications (yes/no vigorous exercise), the participants were classified as maintainers if they exercised more than three times per week at both baseline and at a subsequent annual evaluation (Year 2, 3, or 4), and non-maintainers if they exercised three times per week at baseline and less than three times per week at a subsequent annual evaluation (Year 2, 3, or 4). Similarly, participants were classified as initiators if they reported less than three exercise sessions per week at baseline and more than three exercise sessions per week at subsequent annual evaluation (Year 2, 3, or 4), and non-initiators if they exercised less than three times per week at both baseline and a subsequent annual evaluation (Year 2, 3, or 4).Descriptive analyses using t-tests and chi-square tests were utilized to assess univariate associations between the baseline predictor variables and exercise status. Maintainers were compared with non-maintainers, and consistently sedentary participants were compared with participants who adopted vigorous activity at Years 2, 3 and 4. Logistic regression was used to further assess the statistical significance of associations between the predictor variables and exercise maintenance and adoption. These univariate logistic regression models predicted exercise maintenance (yes/no) and exercise initiation (yes/no) at Years 2, 3 and 4 using the baseline demographic factors as independent variables. Furthermore, the variables that were significant in the univariate analyses were entered into a multivariate logistic regression model to assess the relative weight and statistical significance of associations between the predictor variables and the variables representing exercise maintenance and initiation. These multivariate logistic regression models predicted exercise maintenance (yes/no) and exercise initiation (yes/no) at Years 2, 3 and 4. In these multivariate regressions, we controlled for exercise level at baseline and treatment status. All statistical analyses were conducted using the SAS Version 6.12 .Since other research studies have indicated gender differences in predictors of exercise maintenance and initiation , the genUsing the definition of vigorous exercise described above, 564 participants  vigorously exercised more than 3 times per week and 582 participants  did not vigorously exercise more than 3 times per week at baseline. Sociodemographic characteristics of these participants are described in Table Maintainers and non-maintainers were compared on baseline demographic variables, social support, hours spent watching television and smoking. Similar patterns of associations were found for annual visits at Years 2, 3 and 4. Participants who maintained their exercise level at evaluation Years 2, 3 and 4 weighed less, were employed, Caucasian, of a higher income group, more highly educated, more likely to be non-smokers and watched less television per day at baseline. At evaluation Years 3 and 4, the maintainers were older than the non-maintainers at baseline. The maintainers and non-maintainers did not report differences in marital status or social support. These results are presented in Table Multivariate logistic regression analyses were performed to examine the predictors exercise maintenance at Years 2, 3 and 4. Demographic variables at baseline (BMI, income group, employment status, education, ethnicity, smoking status, hours watched TV/day, age, gender) were entered into logistic regression model along with exercise level at baseline and treatment group. Exercise maintenance at Years 2, 3 and 4 were the dependent variables in the three models. At Year 2, ethnicity (OR = .52, CI = .27–.99), BMI (OR = .93, CI = .89–.96) and exercise at baseline (OR = 1.21, CI = 1.11–1.31) were significant predictors of exercise maintenance. Ethnicity (OR = .463, CI = 0.229–0.933) and exercise at baseline (OR = 1.21, CI = 1.12–1.31) were significant predictors of exercise maintenance at Year 2. Television hours per day (OR = 0.86, CI = .74–.99), BMI (OR = .95, CI = .91–.99) and exercise at baseline (OR = 1.22, CI = 1.13–1.31) were significant predictors of exercise maintenance at Year 4.Results of univariate analyses relating exercise initiation with baseline variables are shown in Table Logistic regression analyses were also performed to examine the predictors of exercise initiation and Years 2, 3 and 4. Similar to the evaluations for exercise maintenance, demographic variables at baseline which were significant in the univariate analyses  were entered into three separate models controlling for exercise level at baseline and treatment group to identify predictors exercise initiation at Years 2, 3 and 4. Four variables were significant predictors of exercise initiation at one or more time points. Exercise level at baseline was positively related to exercise initiation at Year 2 (OR = .23, CI = 1.71–2.90) and at Year 3 (OR = 1.71, CI = 1.23–2.38). Baseline income group (OR = 2.38, CI = 1.08–5.23), marital status (OR = 6.07, CI = 0.39–0.95) and smoking status (OR = 3.53, CI = 0.14–0.91) predicted exercise initiation at Year 4.This study evaluated the demographic predictors of vigorous exercise initiation and maintenance in a community sample. To our knowledge, this is the first study to look at baseline demographic factors as predictors for exercise adoption and maintenance over a four-year period. This study found that demographic predictors were more consistent for exercise maintenance than exercise initiation over the four years evaluated in this study. Results showed that compared to those who did not maintain vigorous exercise, participants who maintained exercise over a 2, 3 and 4 year period were more likely to be employed, Caucasian, have a higher income, have more education, be a nonsmoker, watch less television and have a lower BMI. One of the interesting findings was that correlates of exercise initiation were less consistent than correlates of exercise maintenance over time. There did not appear to be a consistent pattern that described the associations between the predictors included in this study and vigorous exercise initiation. Although certain predictors were associated with exercise initiation at Years 2, 3 or 4, such as gender or BMI, none of the predictors were consistent over the years measured in the study. These results suggest that people in community populations who initiate vigorous exercise are a heterogeneous group, and there may be greater difficulties predicting who will initiate exercise. It could be much simpler to identify the participants who will be more likely to continue exercise, as compared to the participants who will adopt exercise. It is possible that changes in attitudes, life circumstances (such as sickness), new relationships, or variables that were not measured in this study may be better predictors of exercise adoption or maintenance. However, since we did not measure these variables, we can only speculate whether they may disrupt exercise patterns. The processes of vigorous exercise adoption may be better represented by theoretical understandings of exercise behavior, such as the health belief model , transthThese results may have implications for designing and implementing exercise interventions. The results support others studies that suggest targeting exercise maintenance interventions at the lower income participants. However, to achieve the Healthy People 2010 objectives by increasing participation rate in vigorous exercise, interventions need to be designed to promote exercise adoption. Unfortunately, the present study's results only suggest that we can not characterize this group well. This lack of characterization of this group may actually be a benefit for interventions. Ethnic group, gender, and socio-economic status did not predict exercise initiation in this study. This suggests that each group was as likely to begin a vigorous exercise program. This is good news as exercise initiation may not be limited to those who can afford health clubs and trainers, or those who are the member of a specific ethnic group or gender. Although previous studies have stratified participants by gender , no inteStrengths and limitations of the present study should be recognized. This is one of a few studies that evaluate predictors of exercise initiation, and the first to evaluate exercise initiation over a four-year period. In addition, the sample is large, diverse, and includes longitudinal measurements. This study did not evaluate the predictors of moderate exercise initiation or maintenance. Thus, these results can not be directly interpreted for public health interventions targeted at increasing moderate activity in the general population. In addition, this study may also be affected by a selection bias. The participants in this study volunteered for a study on weight gain prevention, for which the participants may have expected to include a message on increasing exercise. Of note, 49% of the sample reported vigorous exercise more than 3 times per week at baseline, which is much higher than the 15–25% reported in national surveillance studies ,2. AlthoConsidering these limitations, this study does add to the knowledge base about who initiates and maintains vigorous exercise. The results suggest that vigorous exercise maintenance interventions should continue to target low-income populations and that interventions could incorporate messages regarding smoking, weight control, and television. We found that those who adopt vigorous exercise are a more heterogeneous group, and that no one group is more likely to adopt exercise than the others. This suggests that vigorous exercise intervention messages could be more broadly based. This study also suggests that further research is needed to identify participants and effective interventions for those who begin exercise programs. None declared. KB conceptualized the study, planned and executed the analyses, interpreted the results, and drafted the manuscript. RJ participated in conceptualization of the study, interpretation of the results and assisted in drafting the manuscript. SF participated in conceptualization of the study, interpretation of the results and assisted in drafting the manuscript. All authors read and approved the final manuscript.


Carcinoma of the esophagus is an aggressive malignancy with an increasing incidence. Its virulence, in terms of symptoms and mortality, justifies a continued search for optimal therapy. The large and growing number of patients affected, the high mortality rates, the worldwide geographic variation in practice, and the large body of good quality research warrants a systematic review with meta-analysis.A systematic review and meta-analysis investigating the impact of neoadjuvant or adjuvant therapy on resectable thoracic esophageal cancer to inform evidence-based practice was produced.MEDLINE, CANCERLIT, Cochrane Library, EMBASE, and abstracts from the American Society of Clinical Oncology and the American Society for Therapeutic Radiology and Oncology were searched for trial reports.Included were randomized trials or meta-analyses of neoadjuvant or adjuvant treatments compared with surgery alone or other treatments in patients with resectable thoracic esophageal cancer. Outcomes of interest were survival, adverse effects, and quality of life. Either one- or three-year mortality data were pooled and reported as relative risk ratios.Thirty-four randomized controlled trials and six meta-analyses were obtained and grouped into 13 basic treatment approaches.Single randomized controlled trials detected no differences in mortality between treatments for the following comparisons:- Preoperative radiotherapy versus postoperative radiotherapy.- Preoperative and postoperative radiotherapy versus postoperative radiotherapy. Preoperative and postoperative radiotherapy was associated with a significantly higher mortality rate.- Postoperative chemotherapy versus postoperative radiotherapy.- Postoperative radiotherapy versus postoperative radiotherapy plus protein-bound polysaccharide versus chemoradiation versus chemoradiation plus protein-bound polysaccharide.Pooling one-year mortality detected no statistically significant differences in mortality between treatments for the following comparisons:- Preoperative radiotherapy compared with surgery alone .- Postoperative radiotherapy compared with surgery alone .- Preoperative chemotherapy versus surgery alone .- Preoperative and postoperative chemotherapy versus surgery alone .- Preoperative chemoradiation therapy versus surgery alone .Single randomized controlled trials detected differences in mortality between treatments for the following comparison:- Preoperative hyperthermia and chemoradiotherapy versus preoperative chemoradiotherapy in favour of hyperthermia.Pooling three-year mortality detected no statistically significant difference in mortality between treatments for the following comparison:- Postoperative chemotherapy compared with surgery alone .Pooling three-year mortality detected statistically significant differences between treatments for the following comparisons:- Preoperative chemoradiation therapy versus surgery alone  in favour of preoperative chemoradiation with surgery.- Preoperative chemotherapy compared with preoperative radiotherapy  in favour of preoperative radiotherapy.For adult patients with resectable thoracic esophageal cancer for whom surgery is considered appropriate, surgery alone (i.e., without neoadjuvant or adjuvant therapy) is recommended as the standard practice. Carcinoma of the esophagus is an aggressive malignancy that continues to kill more than 90% of people with the disease within five years . The inc2 = 0.02, p = 0.9) and a 52% relative increase in the risk of death at three years with radiotherapy compared with surgery alone .Surgical esophagectomy remains the preferred treatment for clinically localized thoracic esophageal carcinoma ,4-6. TwoThe failure of surgery alone is attributed to the systemic nature of the disease at the time of presentation ,8. EarlyThe large and growing number of patients affected, the high mortality rates, the geographic variation in practice, and the large body of good quality research evidence warrants a systematic review with meta-analysis.This systematic review was developed by the Practice Guidelines Initiative (PGI) of Cancer Care Ontario's Program in Evidence-based Care (PEBC). Evidence was selected and reviewed by two members of the PGI's Gastrointestinal Cancer Disease Site Group (DSG) and two methodologists. Members of the Gastrointestinal Cancer DSG disclosed potential conflict of interest information.This systematic review is a convenient and up-to-date source of the best available evidence on neoadjuvant or adjuvant therapy for resectable esophageal cancer. The body of evidence in this systematic review is primarily comprised of mature randomized controlled trial data; it forms the basis of a clinical practice guideline developed by the Gastrointestinal Cancer DSG published elsewhere (18). This systematic review and companion practice guideline are intended to promote evidence-based practice in Ontario, Canada. The PGI is editorially independent of Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.The MEDLINE (1966 through October (week 2) 2003), CANCERLIT (1983 to October 2001), Cochrane Library (2003, Issue 3), and EMBASE (to week 40, 2003) databases were searched with no language restrictions. "Esophageal neoplasms" ) was combined with "chemotherapy, adjuvant" (MeSH), "radiotherapy, adjuvant" (MeSH), "immunotherapy, adjuvant" (MeSH), and each of the following phrases used as text words: "preoperative", "neoadjuvant", "chemotherapy", "radiotherapy", "radiation therapy", "irradiation", "immunotherapy", "chemoradiotherapy", "chemoradiation", and "hyperthermia". These terms were then combined with the search terms for the following study designs or publication types: practice guidelines, meta-analyses, and randomized controlled trials. Additionally, the conference proceedings of the 1997 to 2003 annual meetings of the American Society of Clinical Oncology (ASCO) and the 1999 to 2002 annual meetings of the American Society for Therapeutic Radiology and Oncology (ASTRO) were searched for reports of new or ongoing trials. Relevant articles and abstracts were reviewed, and the reference lists from these sources were searched for additional trials. This formal search was supplemented with published abstracts from thoracic surgery and oncology conferences, conversations with colleagues and experts in the field, and a review of textbooks related to esophageal oncology.Articles were included in this systematic review if they were fully published reports, abstracts, or meta-analyses of randomized controlled trials (RCT) of neoadjuvant or adjuvant treatments compared with surgery alone or surgery plus another treatment in patients with resectable and operable thoracic esophageal cancer. Data on survival had to be reported. Other outcomes of interest were adverse effects and quality of life. Reports of carcinomas located in the cervical esophagus were excluded.Because diverse treatment strategies were evaluated, the eligible studies were grouped into 13 basic treatment approaches (Table 2 (Chi-square) statistic using a planned cut-off for significance of p < 0.05. Potential sources of heterogeneity were postulated a priori and included study quality assessed with the Jadad scale [Heterogeneity of study results was assessed using a visual plot of the outcomes and by calculating the Xad scale  .Six randomized trials of preoperative radiotherapy and surgery versus surgery alone are presented in Table A published meta-analysis  using upFive randomized trials of surgery and postoperative radiotherapy compared with surgery alone are presented in Table Only Zieren et al. assessed quality of life. The results indicated more rapid recovery of quality of life with surgery alone compared with postoperative radiotherapy. Three trials ,29,47 de2 = 7.53, p = 0.11). The rate of local recurrence with radiotherapy was lower in three of the trials [The Gastrointestinal Cancer DSG pooled the five trials that reported one-year mortality data ,27-29,47e trials ,47, but e trials  noted thOne randomized trial evaluated preoperative radiotherapy versus postoperative radiotherapy with curative esophagectomy as part of a four-arm study . PatientIizuka et al.  reportedSeven randomized trials of preoperative chemotherapy and surgery versus surgery alone are presented in Table 2 = 8.26, p = 0.14).The Gastrointestinal Cancer DSG pooled the available data on preoperative chemotherapy with surgery versus surgery alone -34,37,48The first meta-analysis, by Bhansali et al. , pooled The second meta-analysis, by Urschel et al. , pooled The third meta-analysis  was a Co2 = 0.65, p = 0.42).Two randomized trials of preoperative and postoperative chemotherapy and surgery versus surgery alone ,36 Tabl were exaThree randomized trials of postoperative chemotherapy and surgery compared with surgery alone are presented in Table 2 = 0.08, p = 0.77).The Gastrointestinal Cancer DSG pooled the three-year mortality data for two trials ,40 Figu. The triEight randomized trials of combined modality neoadjuvant chemotherapy and radiotherapy are presented in Table 2 = 1.67, p = 0.89).The Gastrointestinal Cancer DSG pooled the one-year mortality data for the six trials with data available at one year ,42-46 .To compare the results between the two published meta-analyses ,55 with No randomized trials have evaluated postoperative chemotherapy combined with radiation versus surgery alone.One randomized trial evaluated postoperative chemotherapy versus postoperative radiotherapy following curative esophagectomy . PatientTwo randomized trials evaluating preoperative chemotherapy compared with preoperative radiotherapy were reviewed ,57. KelsOne randomized trial evaluated the role of preoperative bleomycin in addition to radiotherapy . SeventyOne Japanese trial evaluated protein-bound polysaccharide (PSK) as an adjunct to postoperative radiotherapy or chemoradiation in resected esophageal cancer . This trOne Japanese randomized trial, reported by Kitamura et al. , evaluatAdverse effects were inconsistently reported Tables ,4,5,6,7.Most trials excluded patients with cancers located in the cervical esophagus, and therefore the interpretation of this review is limited to tumours in the more distal two thirds.The options for neoadjuvant or adjuvant therapy for resectable thoracic esophageal cancer are many. On reviewing the results of randomized trials and meta-analyses, the Gastrointestinal Cancer DSG did not recommend neoadjuvant or adjuvant therapy based on the following:Preoperative radiotherapy does not improve survival compared with surgery alone. Postoperative radiotherapy may, in fact, be harmful .Preoperative chemoradiation does not appear to improve survival compared to surgery alone. Although the pooled analysis shows that all six studies are in the direction favouring preoperative chemoradiation at one year, the pooled estimate did not achieve statistical significance. When examining the individual trial results, only the trial by Walsh et al.  detectedPreoperative cisplatin-based chemotherapy does not appear to improve survival. Four of the seven trials ,32-34 deThe available evidence from three randomized trials does not support the use of postoperative chemotherapy over surgery alone -41.Two novel approaches, immunotherapy and hyperthermia, were studied by two groups in Japan ,60. OgosExamination of the results of randomized trials, including the pooled analyses, fails to support the use of preoperative or postoperative adjuvant treatment of any type at this time for patients with resectable carcinoma of the thoracic esophagus. Overall, the evidence does not support the use of neoadjuvant or adjuvant therapy for patients with resectable cancer of the lower two-thirds of the esophagus. Surgical resection alone should remain the standard for localized thoracic esophageal cancer. Patient staging information can be found in Appendix 1  dose; PSK, protein-bound polysaccharide; MRC, Medical Research Council; PGCC, Practice Guidelines Coordinating Committee.Gy, Gray; OR, odds ratio; DSG, Disease Site Group; RR, (relative) risk ratio; PGI, Practice Guidelines Initiative; PEBC, Program in Evidence-based Care; MeSH, Medical subject heading; ASCO, American Society of Clinical Oncologists; ASTRO, American Society for Therapeutic Radiology and Oncology; RCT, randomized controlled trial; CI, confidence interval; XThe author(s) declare that they have no competing interests.RM, RW and LZ performed the initial literature search and created the initial drafts of the systematic review with input from other members of the Gastrointestinal Cancer DSG. RM, RW and BR created the final draft of this systematic review. All statistical analysis was performed by BR in consultation with RM and RW. Creation of the submitted manuscript was performed by BR and RM.The pre-publication history for this paper can be accessed here:Click here for file


Surprisingly little information on symptoms of paroxysmal atrial fibrillation is available in scientific literature. Using questionnaires, we have analyzed the symptoms associated with arrhythmia attacks.One hundred randomly-selected patients with idiopathic paroxysmal atrial fibrillation filled in a structured questionnaire.Psychic stress was the most common factor triggering arrhythmia (54%), followed by physical exertion (42%), tiredness (41%) coffee (25%) and infections (22%). Thirty-four patients cited alcohol, 26 in the form of red wine, 16 as white wine and 26 as spirits. Among these 34, red wine and spirits produced significantly more episodes of arrhythmia than white wine (p = 0.01 and 0.005 respectively).Symptoms during arrhythmia were palpitations while exerting (88%), reduced physical ability (87%), palpitations at rest (86%), shortage of breath during exertion (70%) and anxiety (59%). Significant differences between sexes were noted regarding swollen legs (women 21%, men 6%, p = 0.027), nausea (women 36%, men 13%, p = 0.012) and anxiety .Psychic stress was the commonest triggering factor in hospitalized patients with paroxysmal atrial fibrillation. Red wine and spirits were more proarrhythmic than white wine. Symptoms in women in connection with attacks of arrhythmia vary somewhat from those in men. Atrial fibrillation (AF) is nowadays divided into three different forms; paroxysmal, persistent and permanent . Even ifA group of one hundred patients suffering ECG-verified PAF and whose symptoms prompted hospital care were asked to fill in a structured questionnaire with 58 questions covering arrhythmia-triggering factors, time at which the attack starts and symptoms during attack. All patients completed the data by personal interviews by one of the authors. The vast majority of all patients were recruited during two periods of totally 14 months. In some questions, extra information could be supplied by the patients in their own words.  age of the entire group was 59.9 (22.4–79.2) years. Patients with previous histories of hypertension were significantly older than those without 65.0 (46.6–78.6) years as against 58.6 (22.4–79.2) years respectively. The women in the group were significantly older than the men 67.9 54.1–78.6) years and 58.2 (22.4–79.2) years respectively, p = 0.02 , attacks typically lasted less than one day, while a further 17% gave 1–7 days. No attack lasted more than one week.Thirty-five percent of the entire group woke up with episodes of fibrillation, 34% stated that attacks began with psychic stress, as defined by the patients. Thirty one percent of the episodes started during rest and 22% of the attacks followed physical exertion. Twenty-five percent could not think of any special factor initiating attacks. No differences in the onset of attacks between men and women could be established. Eighty-five percent of the group succeeded in identifying some sort of triggering-factor . There were no significant differences in the arrhythmia-provoking effects of spirits and red wine nor between men and women (Table Foodstuffs such as onion, nuts, chocolate and ice-cream were cited as agents producing fibrillation by a few patients Table .Seventy-four percent considered that the episodes of AF they experienced affected their lifestyles, while 26% thought this was not the case. Among answers in their own words, a common reply was that they did not dare to exercise as much as they would have liked (13 patients). Eight patients did not dare to travel. Sixty-six percent stated that their episodes of AF affected their relatives, while 32% answered this question in the negative. In their own words, they remarked that the main problem was their relatives' uneasiness.During attacks of AF, the most common symptoms were palpitations in connection with strain, reduced physical performance, palpitations when at rest, breathlessness during exertion and anxiety Table . FemalesAlthough PAF is one of the most common heart-disturbances causing patients to get in touch with medical care centres, surprisingly little information is available about the factors which trigger it and the symptoms associated with the onset of arrhythmia in larger groups of patients. This study has therefore been undertaken to determine which factors patients consider responsible for triggering arrhythmia and the symptoms that occur in connection with episodes of arrhythmia.From observations of heart-rate in sinus rhythm shortly before its onset, a separation of PAF into sympathetically-mediated and vagal forms has been suggested . EarlierIn our study, the 72 patients who thought that their attacks of arrhythmia usually occurred at about the same time of day gave this as the evening or at night. Hence a large fraction of those investigated should have vagal PAF since this often starts at night . DespiteAlcohol has long been considered to play an etiological role in PAF, a correlation underlined in the expression "holiday heart" . Since tIt is now generally accepted that most attacks of PAF are induced by ectopic impulses originating in the pulmonary veins ,20. BothAlthough a number of patients with PAF are without any symptoms , in geneThe limited amount of literature on the symptomology of PAF includes Quality of Life investigations, Case Reports and quantification of a few symptoms . InvestiThe most frequent symptoms in periods of AF reported by our group of patients included palpitations, reduced physical performance, palpitations when at rest, breathlessness when exerting oneself and anxiety. In an earlier report, the most pronounced symptoms were palpitations and anxiety as well as giddiness . That feSwollen legs can also be accounted for due to right-sided cardiac failure in some patients. That most patients experience definite symptoms following acute but transient attacks of AF can possibly depend on the increased activity of the sympathetic nervous system triggered by an attack of AF . It is pThis material was taken at a hospital and is thus not representative of all patients with PAF. The symptoms of our patients are so far advanced that hospitalization or a visit to a hospital was required. Ongoing treatment can have modified patients' recollections of anamnestic factors. The material was not taken consecutively, but randomness was favoured by lack of a systemic inclusion mechanism.Patients with hypertension are not excluded, even if subtle diastolic changes in the left ventricle and hence the left atrial performance could be caused by hypertension .Although symptoms associated with the onset of PAF may be age related, the present material is too limited to allow exploration of this relation.Most of the patients in a group being treated at a hospital for PAF consider psychic stress to be the factor triggering their arrhythmia.Red wine and spirits seems more prone to trigger attacks of AF than white wine.The symptoms of PAF are many and occur frequently.In women, PAF leads to significantly higher frequencies of swollen legs, indisposition and anxiety than in men.None.Author AH designed the investigation, collected all patient data, performed the statistical analysis and interpretation of the results, as well as the preparation of the manuscript.Author BMH assisted with the statistical analysis and the preparation of the manuscript.Author SBO supervised and designed the investigation as well as participated in the preparation of the manuscript.All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:The complete questionnaire. The structured questionnaire with 58 questions covering arrhythmia-triggering factors, time at which the attack starts and symptoms during attack.Click here for file


Arabidopsis core promoters.Core promoters are the gene regulatory regions most proximal to the transcription start site (TSS), central to the formation of pre-initiation complexes and for combinatorial gene regulation. The DNA elements required for core promoter function in plants are poorly understood. To establish the sequence motifs that characterize plant core promoters and to compare them to the corresponding sequences in animals, we took advantage of available full-length cDNAs (FL-cDNAs) and predicted upstream regulatory sequences to carry out the analysis of 12,749 Arabidopsis core promoters. One of them corresponded to the TATA element, for which an in-depth analysis resulted in the generation of robust TATA Nucleotide Frequency Matrices (NFMs) capable of predicting Arabidopsis TATA elements with a high degree of confidence. We established that approximately 29% of all Arabidopsis promoters contain TATA motifs, clustered around position -32 with respect to the TSS. The presence of TATA elements was associated with genes represented more frequently in EST collections and with shorter 5' UTRs. No cis-elements were found over-represented in TATA-less, compared to TATA-containing promoters.Using a combination of expectation maximization and Gibbs sampling methods, we identified several motifs overrepresented in Arabidopsis promoters. The percentage of TATA-containing promoters is much lower than commonly recognized, yet comparable to the number of Drosophila promoters containing a TATA element. Although several other DNA elements were identified as over-represented in Arabidopsis promoters, they are present in only a small fraction of the genes and they represent elements not previously described in animals, suggesting a distinct architecture of the core promoters of plant and animal genes.Our studies provide a first genome-wide illustration of the composition and structure of core  Initiation of transcription by RNA polymerase II requires the assembly of the basal transcription apparatus at the core promoter, a region of about 70 bp flanking the transcription start site (TSS) . Interacromoters . Class Iromoters . Recruitromoters ,5. In adromoters . The funArabidopsis cDNAs [Arabidopsis genome [In spite of the availability of a large number of computational programs that predict the presence of plant genes and their architecture (reviewed in ), accurais cDNAs ,9. Theses genome , providica. 12,750 Arabidopsis genes, using publicly available FL-cDNA sequences. Our objectives for this study were to i) identify motifs characteristic of Arabidopsis core promoters; ii) determine how often Arabidopsis core promoters contain a TATA box, and iii) compare the architecture of Arabidopsis core promoters with those of Drosophila, the only higher eukaryote for which such a genome-wide analysis has been performed. We examined the presence, distribution and consensus sequence of conserved motifs proximal to the TSS. In addition to TATA elements, we identified several other motifs, primarily representing microsatellite elements, some of them overrepresented in particular regions of core promoters. Using Nucleotide Frequency Matrices (NFM), we carried out a genome-wide analysis for the presence and position of TATA-box elements. Our studies show that only about 29% of all Arabidopsis genes contain a recognizable TATA element. The position of the TATA motif with respect to the TSS and correlations between the presence of a TATA with EST abundance and 5' UTR lengths are discussed.Here, we describe the analysis of core promoters of Arabidopsis promoters, we queried TAIR's Gene Search with the condition of a FL-cDNA entry. We retrieved a total of 13,964 non-redundant hits, derived from over 28,000 total FL-cDNAs deposited at TAIR. The locus Ids for these 13,964 FL-cDNAs was used to retrieve the 5' UTR corresponding to 12,749 genes. The remaining 1,215 genes for which a 5' UTR was not retrieved corresponded to FL-cDNAs that differed between the annotations at TAIR and TIGR, sequences for which no 5'UTR was annotated or sequences with 5' UTR regions corresponding to alternative gene models.As a first step towards identifying core The [-500, -1] and [-50, -1] regions of all 12,749 genes was directly retrieved from the TAIR 500 bp upstream dataset. To obtain the [+1, +50] regions, we first checked the length of the 5' UTRs, which was shorter than 50 bp for 2,649 genes and which was interrupted by introns in 2,179 genes. To include into our analyses these cases, three different strategies were followed. If the 5' UTR was longer than 50 bp, and no introns were present in the corresponding [-50, -1] region (10,100 genes), a direct retrieval of the [+1, +50] region was performed from the TAIR 5' UTR dataset. If the 5' UTR was shorter than 50 bp and no intron interrupted this region (2,617 genes), we extended the 5' UTR to 50 nt with a fragment of the immediately adjacent downstream coding sequence using the TIGR cDNA dataset. Finally, if the 5' UTR was shorter than 50 nt and an intron interrupted this region (32 genes), we manually retrieved the [+1, +50] region from the genomic sequence using TAIR's SeqViewer. After these analyzes, we were able to generate datasets corresponding to the [-500, -1], [-50, -1] and [+1, +50] regions from a total of 12,749 genes. These datasets were used for all the subsequent analyzes in this study.Arabidopsis core promoters, we first searched for DNA elements conserved in the [-50, -1] and [+1, +50] regions of the 12,749 Arabidopsis genes. The search was carried using both MEME and AlignACE (see Methods). Motifs correspond to short sequences (6–10 bp), often recognized by a DNA-binding protein, and which can be represented by a consensus sequence. While the total number of motifs retrieved per region with these algorithms was 16 and 32 respectively, only motifs detected in at least 50 sequences with either MEME or AlignACE are shown  for each one of these motifs from the results of the MEME search (see Methods). The NFMs for each of these motifs, provided as Arabidopsis genes [Arabidopsis this motif is associated with dark-induced genes and is over-represented in genes under circadian regulation [Motifs 3 and Motifs 7 showed a clear Overrepresentation in the -50, -1] interval. Motif 3 has all the characteristics of a TATA box n microsatellites have been extensively researched in humans [Arabidopsis.Three motifs were also found to be overrepresented in the +1, +50] region. Motif 10 resembles the (GAA), +50 regn humans , but notMotif 13, with the consensus T/A CCGGCGA , was found to be only slightly overrepresented in the [-50, -1] region, compared to the [-500, -450] background model  [Arabidopsis, only 23 showed the presence of a TATA, representing a frequency of 36.5%, comparable to our own results. Previous studies also suggested that plant TATA-less promoter were the exception [Arabidopsis is the exception among the plants, a possibility to be considered given the much lower percentage of TATA-containing promoters in Arabidopsis compared to other plants [According to our analysis for conserved core promoter elements, Motif 3 Figure  is likelTATA NFM . With th28–34%) , but sti(28–34%) . Interes–34% , buxception . Our resr plants . More liThe sequences from all these putative TATA-containing promoters were retrieved and the NFMs were retrained with this new information. The new matrix obtained from 1,899 sequences gathered using our MEME NFM Figure . These NArabidopsis is more similar to what is typically the case in animal promoters, usually 25–30 nt from the TSS [The new NFMs were used to scan the [-500, -1] region and establish where each of them localized a TATA with the highest probability. As shown in Figure Arabidopsis genes is 129 nt , the 12,749 sequences utilized here are represented in average by 13.02 ESTs, suggesting that the available FL-cDNAs are likely to correspond to genes expressed at a higher level than the average Arabidopsis gene. Interestingly, however, TATA-containing genes were represented in average by 17.6 ESTs  were manually parsed out independent of the number of occurrences or positional preferences. The obtained motifs were plotted according to their positions within the regions and their consensus sequences were graphed using WebLogo version 2.7 [To characterize core promoters, we first investigated features represented by conserved regions or motifs. From several algorithms available , we chossion 2.7 .Drosophila core promoters [To find pre-defined motifs in the [-50, -1] and [+1, +50] regions, we used the higher order probabilistic model MotifScanner from MotifSampler version 3.0 . The searomoters . For theArabidopsis [-50, -1] and [+1, +50] regions are ~65% A/T to ~35% C/G and ~61% A/T to ~39% C/G, respectively, a pseudo-random set of 50 bp sequences was generated for each region to be tested with the matrices as a way of determining the chances of finding the motifs candidates in a stochastic environment. This information was then used together with the search results obtained from the real data to support the confidence of the findings.After establishing that the distribution of nucleotides in the For the analysis of the TATA motif, the TATA NFM previously described  was usedArabidopsis genes with the ones found in the motif clusters. Under the assumption that the contribution of a gene to transcription activity is related to the number of its detected ESTs, we downloaded a dataset from TAIR that accounts for the number of ESTs submissions per locus [To determine whether the occurrences of the discovered motifs were associated with specific gene functions or products we retrieved the Arabidopsis Gene Ontology Database  (last uper locus  (last upbp, base pair; EST, expressed sequence tag; FL-cDNA, full-length cDNA; Inr, Initiator element; NFM, nucleotide frequency matrix; nt, nucleotide; PIC, pre-initiation complex; TBP, TATA-binding protein; TSS, translations start site 5' UTR, 5' untranslated regionC.M. carried out all the analyses and interpreted the results. E.G. was involved in the design and supervision of the project. C.M. and E.G. jointly wrote the manuscript. Both authors read and approved the final manuscript.Arabidopsis genes. The analysis was carried out as described for the results shown in Figure Complete list of the motifs present in the -50, -1] and [+1, +50] regions of 12,749  and [+1,Click here for fileNucleotide Frequency Matrices for all the motifs shown in Figure Click here for file


Africa in the twenty-first century is faced with a heavy burden of disease, combined with ill-equipped medical systems and underdeveloped technological capacity. A major challenge for the international community is to bring scientific and technological advances like genomics to bear on the health priorities of poorer countries. The New Partnership for Africa's Development has identified science and technology as a key platform for Africa's renewal. Recognizing the timeliness of this issue, the African Centre for Technology Studies and the University of Toronto Joint Centre for Bioethics co-organized a course on Genomics and Public Health Policy in Nairobi, Kenya, the first of a series of similar courses to take place in the developing world. This article presents the findings and recommendations that emerged from this process, recommendations which suggest that a regional approach to developing sound science and technology policies is the key to harnessing genome-related biotechnology to improve health and contribute to human development in Africa.The objectives of the course were to familiarize participants with the current status and implications of genomics for health in Africa; to provide frameworks for analyzing and debating the policy and ethical questions; and to begin developing a network across different sectors by sharing perspectives and building relationships. To achieve these goals the course brought together a diverse group of stakeholders from academic research centres, the media, non-governmental, voluntary and legal organizations to stimulate multi-sectoral debate around issues of policy. Topics included scientific advances in genomics innovation systems and business models, international regulatory frameworks, as well as ethical and legal issues.Seven main recommendations emerged: establish a network for sustained dialogue among participants; identify champions among politicians; use the New Plan for African Development (NEPAD) as entry point onto political agenda; commission an African capacity survey in genomics-related R&D to determine areas of strength; undertake a detailed study of R&D models with demonstrated success in the developing world, i.e. China, India, Cuba, Brazil; establish seven regional research centres of excellence; and, create sustainable financing mechanisms. A concrete outcome of this intensive five-day course was the establishment of the African Genome Policy Forum, a multi-stakeholder forum to foster further discussion on policy.With African leaders engaged in the New Partnership for Africa's Development, science and technology is well poised to play a valuable role in Africa's renewal, by contributing to economic development and to improved health. Africa's first course on Genomics and Public Health Policy aspired to contribute to the effort to bring this issue to the forefront of the policy debate, focusing on genomics through the lens of public health. The process that has led to this course has served as a model for three subsequent courses (in India, Venezuela and Oman), and the establishment of similar regional networks on genomics and policy, which could form the basis for inter-regional dialogue in the future. Inequities in global health continue to be among the major challenges facing the international community . Despite, and the Institute for Molecular and Cell Biology-Africa (IMCB-A), founded in 1999 to study the molecular mechanisms of tropical infections. A further example is the new Biosciences Facility for Eastern and Central Africa that was recently launched as part of a NEPAD initiative [Africa in the twenty-first century is faced with a heavy burden of disease, combined with ill-equipped medical systems and underdeveloped technological capacity . The criitiative . Its strIn March 2002, the African Centre for Technology Studies (ACTS) and the University of Toronto Joint Centre for Bioethics (JCB) co-organized an intensive five-day Course on Genomics and Public Health Policy in Nairobi, Kenya, bringing together scientists, policy makers, journalists, lawyers and NGOs from ten African countries to discuss, collectively, the question of "How best to harness genomics to improve health in Africa?" This course was sponsored by Genome Canada, the International Development Research Centre, and the African Centre for Technology Studies, through the Norwegian Agency for Development Co-operation. The primary goal of the course was to familiarize participants with the potential of genomics and related biotechnologies to address health needs in Africa. This article presents the findings and recommendations that emerged from this process, and suggests how such courses might be more broadly employed as a method for bringing together opinion leaders to share ideas and work collectively to develop practical policy solutions.The programme was planned collaboratively by the African Centre for Technology Studies and the Joint Centre for Bioethics. The basic layout of the sessions and their topics was modelled on a prior course held in Toronto, Canada in May 2002. The programme was organized in line with the objectives outlined in Table Because of the diversity of the participants, no background in science was presupposed. The sessions were organized so that participants were first introduced to the subject of the "new science" of genomics, and were then instructed in areas including national innovation systems, business models, intellectual property rights, international conventions and regulatory structures, ethics, and the role of networks in facilitating dialogue, advocacy and policy making. A detailed time-table of the programme is shown in Table Early in the course, participants were divided into small Study Teams consisting of persons with diverse backgrounds, in order to maximize complementary skills. These Study Teams were an integral part of the learning process of the programme. Sessions were intended primarily to provide input for participant Study Teams, which assembled several times during the week. Their primary task was to draw upon the course material and their own experiences to propose recommendations for policy relating to genomics and biotechnology in Africa. Presentations were made on the last day of the course, and the final sessions focused on how to take forward the ideas and proposals generated during the course.This was the first course of its kind in Africa, as well as the first of a series of planned courses on genomics policy to be held in developing countries; evaluation was therefore a key component of the programme. At the end of each day, participants were given a questionnaire to complete, in which they had an opportunity to evaluate the day's sessions. At the end of the course, participants were asked to complete a more detailed questionnaire, asking for their feedback on the overall aims and organization of the course.The course opened with an Introduction, where Prof. Abdallah Daar and Dr John Mugabe welcomed the participants, explained the course's objectives, and then invited each of the participants to introduce him- or herself to the rest of the group. The opening session was led by Dr Stephen Scherer, and was intended to provide a comprehensive overview of the science of genomics and its relevance to health. Several of the participants had a limited scientific background; the presentation therefore include very basic descriptions of the science involved, as well as images and a brief video, and gradually progressed to a discussion of its applications in health research and medicine, both now and in the future. This session was followed by an introduction by Prof. Onesmo ole-MoiYoi, a pioneering Kenyan scientist, to advances in genomics and molecular biology within the African context – including cutting-edge research at his institute and others on the continent, as well as the broader relevance of genomics and molecular approaches to the health of Africa's people, animals and the environment. The first day closed with a session led by Dr Peter Singer who described a five-point strategy to systematically capture the benefits of genomics for the health of citizens in developing countries, through research, capacity-strengthening, consensus-building, public engagement, and an investment fund. Examples of ongoing work by the University of Toronto's Canadian Program on Genomics and Global Health in these areas were discussed, including the results of its 2002 study to identify the most promising biotechnologies to improve health in developing countries .Prof. Joseph D'Cruz opened the second day with a discussion introducing participants to new approaches to forming and expressing opinions about emerging issues using the internet. Leaders in any area are required to develop their own views about new developments in their fields, and the process of forming these views is facilitated by peer discussions. Though traditionally these processes have taken place face-to-face, the internet offers an alternative medium that allows individuals to interact with their peers in other locations at a time and pace suited to each individual's commitments, without forcing the group to reach early consensus. Prof. Norman Clark followed with a session aimed at introducing participants to the concept of 'National Systems of Innovation', a conceptual framework for analysing country-specific factors that influence innovation across sectors. Innovation is understood as processes of generating new ideas, products and production processes, as well as to processes of institutional change and development. Such frameworks can be useful in identifying and analyzing key factors affecting African countries' ability to engage effectively in biotechnology and genomics for human development. The last session of the day focused on the business life cycle of a genomic product, tracing its development from the laboratory bench to a patented invention that is exploited commercially. The session addressed the strategic issues and choices that firms face at each point in this life cycle, and used a case-study based approach to frame the issues. The last one-and-a-half-hour session of the day was devoted to group work among members of Study Teams, whose members were selected to bring diverse views and experiences to bear on their deliberations.The third day of the course was devoted primarily to the issue of intellectual property rights (IPRs). The two sessions on IPRs were led by Dr Patricia Kameri-Mbote, Kenyan lawyer and scholar. During the first of these, Dr Kameri-Mbote explained the nature and different kinds of IPR protection, and explored how these impact on biotechnology development and technology transfer. She also considered the relationship between IP protection and public health in developing countries, using specific cases that have arisen under the World Trade Organization's Agreement on Trade Related Aspects of Intellectual Property Rights (TRIPS). Positions held by different countries and scholars on IP and biotechnology transfer in health were examined, and international, regional and national intellectual property regimes were reviewed. The second session focused on the link between IP, public health and transfer of biotechnology, in addition to the ethical, social and policy implications of the "Doha Declaration" on health by WTO ministers intellectual property rights in the area of health under TRIPS. At the end of the third and fourth days, participants again met for 1.5 hours in their Study Teams to prepare their proposals.Day four of the course had a heavy focus on ethical dimensions of emerging technologies like genomics. The first session provided an overview of ethical issues related to genomics and public health policy. Prof. Abdallah Daar led this and the second session on ethics. He described the World Health Organization's draft Guiding Principles on Medical Genetics and Biotechnology document, which he co-authored and which provides a broad overview of the ethical principles in this field. During the second session, Prof. Daar and Dr. Singer led the group through a case involving benefit sharing, and introduced the Human Genome Organization's principles and statement on benefit sharing. Dr. Singer then described an ethical framework and approach to priority-setting for genomics technologies in health care institutions. The last hour of this session was devoted to providing a forum for participants to share their expertise and experiences in areas related to policy. The final session of the day was led by Dr John Mugabe, then-Director of the African Centre for Technology Studies in Nairobi, Kenya. This session introduced participants to international conventions and protocols that emerged out of the United Nations Conference on Environment and Development (UNCED), and focused on science and innovation issues covered by the Conventions on Biological Diversity and its Cartagena Protocol on Biosafety, and the International Treaty on Plant Genetic Resources for Food and Agriculture. Specific lessons were drawn for international rule-making for health equity, and emphasis was given to biotechnology, risks assessment, technology transfer, sharing benefits of global scientific and technological advances, and technical cooperation.On the last day, each of the four Study Teams presented their proposals, which addressed the overarching question of the course: "How to harness genomics and related biotechnology to improve health in Africa?" Study Teams presented one at a time; after each presentation, there was a period for questions and discussion, and afterward an opportunity to consider all proposals together in light of the host of issues raised during the course of the week. The presentations, though prepared independently by each group, demonstrated a number of common themes that tended to be organized in terms of long-term foundational issues of sustainability, and more concrete short-term issues relating to garnering political involvement. Table The following is a synthesis of the participants' efforts, summarizing and describing key issues that emerged from their presentations and throughout the weeks' deliberations. It includes several concrete action-steps recommended by the participants, which flow from these considerations.African Genome Policy Forum (AGPF), to allow the continued exchange of ideas and the building of consensus on issues related to genomics and public health policy. The group, composed of participants from areas of government, academia, civil society and the media, was created to bring to the table the views of their respective constituencies, and inform their peers of insights gained from the course and through the network. The network may also play an advocacy role in promoting the responsible use of genomics as a tool to improve health and promote development in Africa.The course generated a great deal of enthusiasm and vigorous discussion, and there was consensus among the participants on the need to create a mechanism for capitalizing on this momentum. Course participants and faculty therefore established an e-mail-based network, the On the final day of the course, it was decided that a regional network, the "African Genome Policy Forum", be established comprising all participants and session leaders; it was further agreed that the Joint Centre for Bioethics would set up a web-site, discussion board, and e-mail based platform to facilitate ongoing discussion and inter-sectoral debate on the issues and proposals raised during the course.e.g. [The success of any major initiative requires sustained dialogue with politicians. It is important to take the time to address their legitimate concerns, by clarifying the specific relevance of genomics and its applicability within the context of their communities. A point of particular relevance is the link between technologies like genomics and Africa's development, which has been well described in a number of recent reports e.g. ,10]. Par. Pare.g.e.g. . GenomicThe most efficient means of garnering political support is often to go directly to the politicians themselves – those who have been supportive or outspoken of the issues in question – to put the subject before their colleagues. The course itself represented an important step in this direction, as it brought together a spectrum of stakeholders, including academics, civil society, and government officials. The course, and the subsequently established network, therefore furnished an opportunity for direct communication and dialogue among individuals with a shared vision, including policymakers in a position to "champion" the issues and proposals that emerged from the course to their colleagues and others.NEPAD offers a possible forum to bring the subject of genomics-related biotechnology onto the political agenda, and provides a means of informing African leaders of genomics and its relevance to improving health and development in Africa. In particular, the AGPF recommends the establishment by NEPAD of an 'African Genomics Committee', which would provide a plan for utilizing genomics and other new technologies to enhance health in Africa, advocate for increased investment in S & T, target other relevant stakeholders in individual countries, educate policy makers about the need for a strong R&D base established through partnerships across Africa, and organize steering committees to identify gaps and implement strategies for improvement.Participants agreed on the need to consider emerging technologies like genomics in light of Africa's specific health challenges, and consequently on the importance of prioritizing these and identifying strategic entry points. Infectious  diseases, genetic and other non-communicable disorders, sanitation, nutrition, environmental pollution and loss of biodiversity were all proposed as areas requiring concerted attention, with a special emphasis on the potential for using genomics-related biotechnology to target the three biggest killers in Africa: malaria, HIV/AIDS and tuberculosis. There are already well-known African-led initiatives to apply scientific innovation to combat important health concerns, such as the Multilateral Initiative on Malaria, and the African Malaria Vaccine Testing Network (AMVTN). It will be important to build on existing success stories, and to identify gaps in terms of priority health areas receiving inadequate attention. This will help to focus efforts and to more efficiently channel limited resource, both financial and human. A regional approach, which has since been adopted by NEPAD, was proposed as a promising mechanism for harnessing existing competence to address local needs.This survey would identify strategic areas of strength, such as existing centres of excellence, potential areas of improvement, and health priorities receive inadequate attention. It would also serve to identify local and national innovators, and to inform the structuring of Regional Centres of Excellence described below.For several years, genomics has been linked with a number of high-profile, intensely controversial issues like human cloning and genetically modified organisms. While emerging technologies like genomics raise a number of important ethical and social issues that deserve careful consideration , a nuancPublic engagement was seen to form part of a long-term strategy for capacity building, and raising the overall profile of science and technology in Africa. The discussions reflected a conception of capacity strengthening as intimately linked with quality education – at all levels, and across disciplines. Core to this debate among course participants was the belief that endogenous capacity must be developed in order that Africa can begin to be self-sufficient, and itself become an innovator. Participants identified the following categories as needing attention:There is a need to introduce innovative techniques to teach science and technology in the classroom, in order to generate interest and aptitude in the subject matter from an early stage in the educational process. Besides contemporary scientific approaches, indigenous knowledge and its applications to health could also be a relevant component to include in the curriculum.Those in a position to shape policy should be familiarized with codes of ethics pertaining to their field; moreover, they should be educated about how best to capitalize on international frameworks  in order to ensure that their countries benefit from such arrangements, and are not exploited. Policy makers should develop strategies for negotiating their interests collectively in international forums, when appropriate, given shared needs and values.There is a general need to strengthen capacity in the area of communication, in particular on increasing the level of science literacy among the media. This might include integrating journalism and science programs at the college and university levels. There is a corresponding need to improve the ability of scientists to communicate the relevance of their work to the public, and to policy-makers.There is a great need to build capacity in Africa with regard to the ethical, legal and social issues (ELSI) which inevitably accompany the emergence of new technologies. Strategies would in many cases involve sensitizing the public to issues of relevance, such as their rights as patients and participants in research , encouraging dialogue about the social consequences of introducing new technologies into traditional settings, and putting frameworks in place (e.g. ethics review boards) to ensure that ethical, quality and safety standards before research is undertaken.Networks provide a means of generating new ideas, pooling the creative energies of individuals, and exchanging advice and expertise around a particular area of focus, in this case genomics and health policy. Such networks could play an advocacy role, combining the voices and the influence of key players from diverse disciplines and sectors, to advance a common aim. Collaborations, at the level of institutions – both within and between countries and regions – would facilitate the transfer of both knowledge and technology. During the course, it was pointed out that there is a particular need to encourage linkages between universities and industry to, among other things, facilitate the move from research and development to product generation and commercialization. This could include mechanisms to facilitate relationships between universities undertaking research in biotechnology and local industries. Institutional partnerships and collaborations at all levels, including internationally, can mean the channelling of resources to common areas of focus, and pooling the relative strengths and resources of partner institutions [Along with the need to strengthen the R&D base in science and technology, participants of the course identified a related need to increase the emphasis on commercialization – not only as a tool for sparking innovation but also to permit the generation of capital necessary to sustain the industry. An important step in the process of moving toward commercialization is the forming of alliances within countries, between universities and industry, sometimes known as "cross-linking". The fruitfulness of the Africa course, where people from across sectors and sub-regions came together with a common mission, re-enforced the value and the importance of establishing cross-sectoral networks and collaborations. itutions . Such coEnsuring that the benefits of science and technology, including emerging fields like genomics, requires a long-term strategy for sustained investment.Three models were suggestedThe establishment of an African Science and Technology Fund, dedicated to supporting research and development in the area of health-related biotechnology, would rely upon the contribution of African governments.The establishment of an Investment Fund for genome-related biotechnologies for improving health would represent an innovative approach to obtaining capital, providing a further incentive for investors to put money into development by creating a fund that provides a return on investment, as well as furnishing funds for advancement. Such a fund might be dedicated to providing capital for the development of mature, or future, health-related technologies.Capitalizing on existing funds allocated for research related to diseases afflicting Africa, such as the WHO's Global Fund to Fight   AIDS, Tuberculosis and Malaria. Genomics and biotechnology represents a powerful set of tools for health improvement, and the World Health Organization through its Genomics and World Health (2002) report has raised it as an important issue deserving international attention. It is important to use this positive emphasis to give weight to the case for the relevance of biotechnology to health in developing countries, particularly for policy makers.With respect to R&D, there are already areas of strength on the continent; it is crucial to identify localized expertise, and to establish linkages with centres elsewhere in the region, as well as abroad, to ensure the transfer of knowledge and of technology, and to facilitate human resource development. Infrastructure must be developed to attract qualified African researchers to remain in or to return to Africa – both to support them, technically, intellectually, and socially and to provide them with similar opportunities for creativity and growth as may be found in other locales. The Biosciences Facility, established in 2003 by NEPAD, takes up this challenge, promoting "scientific excellence by bringing together a critical mass of scientists drawn from national, regional and international institutions in state-of-the-art facilities where they can undertake cutting-edge research to help solve the most important development constraints faced by the poor in Africa" . While tDeveloping countries in various parts of the world have proven that they too can have strong technology sectors, and make important contributions in terms of science and innovation. Their successes represent an opportunity to bring to the attention of politicians that there are countries succeeding in genomics. A detailed study of these models can provide important insights into how Africa can capitalize on the promise of genomics and biotechnology, particularly as it relates to health. In 2003, the Joint Centre for Bioethics completed a qualitative study of R&D in biotechnology in South Africa; similar studies are underway in Cuba, Egypt and China. Research of this kind could feed into more systematic efforts in the region to better understand how some developing countries, including those in Africa, have managed to develop S&T research and manufacturing capacity in the health sector.Africa. These regional centres of excellence need not preclude the existence of national centres of excellence. The Biosciences Facility is modelled on such an approach.The proposed centres would be distributed across Northern, Southern, Eastern, Western and Central African sub-regions. Each centre would have its own area of focus, in terms of targeted health problems, depending on regional expertise. The Centres would not be the sole preserve of each region, but would in fact use the strengths and specializations of each region to achieve the goal of harnessing genomics to improve health in The course on Genomics and Public Health Policy in Africa was carefully designed, with inputs from both its Canadian and African co-organizers, to have a programme and participant profile reflecting the inter-disciplinarity of the issue being considered. Genomics cuts across S&T, environmental, development, industrial, education and health policy and generates important ethical, legal and social issues. It therefore requires a genuinely participatory and multi-stakeholder approach, as well as frank discussions about both the potential promise and perils of a relatively new science.The strength of the course, as reflected in the evaluations submitted by participants, was the rare opportunity for discussion and networking among opinion leaders from different sectors. Both during and between sessions, participants exchanged perspectives and experiences with others from different regions of the content, and from different disciplines. Senior political officials, journalists, academics, and civil society representatives worked together in Study Teams to create proposals. Discussions were lively and open, with broad participation from those in attendance. However, a weakness of the course was the absence of industry representatives, who would certainly have contributed an important and valuable point of view. The small number of women participants was also a notable disadvantage. Later courses modelled on the Nairobi offering (i.e. those in Latin America, the Eastern Mediterranean, and India) had greater success in drawing participants from industry and obtaining a better gender balance. Notably, however, the recommendations that emerged from these courses, while reflecting differences due to regional priorities and context, did not vary considerably despite the broader contribution, particularly from the private sector ., as well as a web-based discussion board. While there was some initial activity on the discussion board, this eventually subsided, and was soon evident that this approach had failed. In an effort to revive the momentum and to solicit ideas from AGPF members about how to best move forward with the network, a short survey was sent to members asking what their needs were, both in terms of the network as well as in terms of the technical facilities at their disposal. The response rate was extremely low; however, those who provided feedback confirmed what the participation level suggested: namely, that information technology facilities in Africa are such that very few individuals, outside of some well-equipped academic or private institutions, have regular access to the internet. The web-based discussion board was, therefore, in practice a highly unsustainable option for the majority of participants. The point was also raised that it was not enough to be connected electronically; there was also a need to share a more tangible goal or project, and to have a more visible leader from within the group, to galvanize efforts and motivate continued interaction. One respondent explained that finding the time to contribute to such networks is extraordinarily difficult for many Africans, who often "wear many hats". As a result, a general interest was insufficient to justify diverting time from other tasks; a concrete, realizable goal was essential for engaging individuals who already feel over-stretched. As a consequence of these inputs, an email-based forum was established, since most AGPF members have better access to email than to the internet, and a moderator was temporarily appointed over the group. Activity on the forum improved and continues today, more than two years later, though interventions are irregular and generally extend to the sharing of information or material of interest, rather than discussions about issues.A major outcome of the Nairobi course, and one which had strong support from participants, was the creation of a virtual network to facilitate ongoing interaction and discussion. Within two weeks of its completion, a website was created for the course The India course on Genomics and Public Health Policy was held in January 2003, less than one year after the inaugural Nairobi effort. Based on feedback from the previous course, the questionnaire requesting feedback about participants' technical and substantive needs in relation to the creation of a network was distributed during the course, to permit the creation of a network that was much more responsive to the needs of the participants. Moderators from among the participants were nominated before the course' end and their roles clarified, to facilitate the sustainability and autonomy of the network.Later in 2003, two further courses were held in Oman and in Venezuela, both of which added a further element demonstrating the learning from the first two courses. On both occasions, the Joint Centre for Bioethics collaborated with the Regional Offices of the World Health Organization; in the first instance, with the Eastern Mediterranean office (EMRO) and in the second, with the Pan-American Health Organization (PAHO). This collaboration ensured that the recommendations of each course had an institutional structure through which they could be channelled, to reach the ear of decision-makers. EMRO and PAHO have extensive links with ministries of health within their regions, as well as with representatives from civil society and industry. This provided an opportunity for the results of the course to have a much wider impact. By contract, the impact of the Nairobi course is very much linked to the efforts of individual participants to engage with their constituencies and with the NEPAD initiative, of which one of their members is now a senior actor. The Forum developed following the Nairobi course has not provided a framework to drive action the way it was initially intended; however, it continues to provide a portal for information-sharing and dialogue.The executive course on Genomics and Public Health Policy in Africa was the first of its kind to be held on the continent. The response of participants indicated a tremendous enthusiasm for and interest in discussing the emerging technology of genomics and its applications for addressing the health woes of Africans. The sessions covered a spectrum of topics, from basic science, to ethics, business models and international frameworks – exemplifying the range of intersecting issues relevant to informed discussions about genomics and related policy. The course also was a demonstration of the fruitfulness of a multi-stakeholder approach. An important aim of the course was to encourage network-building and the development of meaningful interactions, as a foundation for sustained dialogue among opinion leaders. Participants were encouraged to develop independent proposals in a collaborative environment, rather than to be passive recipients of "expertise" from the session leaders. The result was a series of concrete proposals for action, and the establishment of an e-network to provide a forum for ongoing communication, discussion and elaboration of the issues and proposals raised during the course. Several participants agreed to raise the proposals and themes articulated to their colleagues; the course also generated some publicity, as journalists invited to attend and to participate actively in the meeting reported on the key issues in various media ,17; see ; see 17;across regions in the developing world. Each of the three executive course held to-date has addressed similar themes in relation to genomics and health; but each has also been adapted to the particular context and interests of the host country or region. This has partly been achieved through active collaboration between the Joint Centre for Bioethics and the host institutions. The electronic networks provide a means of generating a long-term impact, driven by participants who are empowered, in their particular capacities, to take forward the ideas shared and the proposals developed through their interaction. The Nairobi course also highlighted the importance of being proactive in soliciting suggestions from participants about creative means of virtual networking that realistically address the poor information technology infrastructure in most parts of Africa. It also was instructive in demonstrating that a network is not itself self-sustaining; it must be driven by a clear, shared vision among participants, and possibly even a concrete and realizable project. Moreover, ideally a moderator from within the group should take leadership in feeding the forum, and motivating ongoing participation.Since the completion of this course, three more offerings have taken place, one in India in collaboration with the Indian Council for Medical Research (ICMR) in January 2003, another in Oman in August 2003, and a third in Venezuela in 2004. A fourth course is being planned for a venue in South-east Asia. The Nairobi offering demonstrated clearly the receptiveness of African researchers and policy makers to such an initiative, and captured the vision of a cross-section of stakeholders around how to ensure that the new wave of scientific promise does not pass them by, or crush them in its wake, but instead is harnessed for better health and to further economic development in their region . The couconcrete proposals to inform policymaking.The New Partnership for Africa's Development (NEPAD) has made science and technology (including genomics and biotechnology) a key platform in its plan for economic renewal ,9. IndeeThe author(s) declare that they have no competing interests.All authors participated in and contributed to the course. ACS drafted the manuscript. PAS and ASD conceived of the course, refined the manuscript for critical content and approved final version; and with JM, participated the course design and its coordination. AGFP members provided intellectual input, through their lively discussions and proposals during the Course on Genomics & Public Health Policy in Africa, held 4–8 March 2002.. This course was funded primarily by Genome Canada and the International Development Research Centre (Canada). PAS holds a Distinguished Investigator Award from the Canadian Institutes for Health Research. ASD is supported by the McLaughlin Centre for Molecular Medicine. The African Centre for Technology Studies, which hosted the course, was supported by the Norwegian Agency for Development Co-operation.The Canadian Program from Genomics and Global Health is funded by several sources listed at