Landscape attributes influence spatial variations in disease risk or incidence. We present a review of the key findings from eight case studies that we conducted in Europe and West Africa on the impact of land changes on emerging or re-emerging vector-borne diseases and/or zoonoses. The case studies concern West Nile virus transmission in Senegal, tick-borne encephalitis incidence in Latvia, sandfly abundance in the French Pyrenees, Rift Valley Fever in the Ferlo , West Nile Fever and the risk of malaria re-emergence in the Camargue, and rodent-borne Puumala hantavirus and Lyme borreliosis in Belgium.We identified general principles governing landscape epidemiology in these diverse disease systems and geographic regions. We formulated ten propositions that are related to landscape attributes, spatial patterns and habitat connectivity, pathways of pathogen transmission between vectors and hosts, scale issues, land use and ownership, and human behaviour associated with transmission cycles.A static view of the "pathogenecity" of landscapes overlays maps of the spatial distribution of vectors and their habitats, animal hosts carrying specific pathogens and their habitat, and susceptible human hosts and their land use. A more dynamic view emphasizing the spatial and temporal interactions between these agents at multiple scales is more appropriate. We also highlight the complementarity of the modelling approaches used in our case studies. Integrated analyses at the landscape scale allows a better understanding of interactions between changes in ecosystems and climate, land use and human behaviour, and the ecology of vectors and animal hosts of infectious agents. Medical geography was defined as the study of the distribution of manifested and potential diseases over the earth's surface followed by the study of correlations between these and environmental factors [The emergence and re-emergence of vector-borne and zoonotic diseases is controlled by ecosystem changes at the landscape level, in addition to other factors . Spatial factors . The RusFiguratively speaking, the existence of the natural focus of a transmissible disease depends on a continuous interaction of the quintet (five) of its prerequisites associated with a specific geographic landscape [andscape .These five prerequesites were listed as:(1) Animal donors; (2) vectors; (3) animal recipients; (4) the pathogenic agent itself in an infective state, (5) the influence of factors of the external environments contributing to an unhindered transmission of infection from one organism to another (circulation of pathogenic agent) [ipients;  the pathSpatial interactions between these agents in a landscape explain patterns of infection risk and may contribute to disease emergence. Analysing these complex landscape systems of interacting agents requires an interdisciplinary approach. Data from different sources and collected at different scales need to be linked, using innovative analytic methods.As part of a broader project on the impact of environmental changes on vector-borne diseases, we conducted a series of landscape scale studies of different disease systems in Europe and West Africa. These studies allowed better understanding of the influence of landscapes on the transmission of each of these infections. Here we present a review of the key findings from these case studies on the impact of land changes on emerging or re-emerging diseases that are transmitted by arthropod vectors and/or have an animal origin (zoonoses). Through an inductive approach, we identify general principles governing spatial epidemiology, outlining a set of propositions of general validity for different diseases and geographic contexts. All these propositions are related to spatial patterns and processes associated with transmission cycles at the landscape scale. Together, they contribute to advance the theory of spatial epidemiology.We developed various methods to understand interactions between land change, vectors, animal and human hosts. It was crucial to develop tools to link the various components of disease systems across space and to model spatial interactions. These innovations in analytic methods were a key component for developing an integrated approach of disease systems. For each site, we produced detailed land cover maps based on remote sensing data at medium to fine spatial resolutions and extracted landscape metrics. We also mapped land surface brightness, greenness, and wetness based on these data. Various spatial statistical models were used. Habitat suitability models relate the presence or abundance of vectors or animal hosts to landscape predictors that represent aspects of the species' habitat- e.g., vegetation cover, landscape configuration, surface moisture, topography, soil types. The spatial units for these models were small plots for which field observations on vector presence or abundance were collected. A variant models infection prevalence among vectors and/or hosts, as measured by field trapping in different landscapes. Another type of spatial statistical models used human cases, as compiled by public health records. Explanatory variables in these models are demographic and socio-economic variables from census data, land use maps including types of settlements, proxy variables for risk behaviours, climate and land cover. The spatial units of these latter models are administrative units at which census data are aggregated.0) - which quantifies the average number of new infections that will arise from introducing an infective host into a susceptible population [0 is generally estimated at the aggregate level of populations. In estimating R0, the degree of contact between people and vectors is an essential factor for disease dynamics. Factors influencing people-vector contacts include the relative population densities and spatial distributions of both vectors and people [0 have often assumed a constant value across space of the human biting rate, given the difficulty in obtaining spatially-explicit and quantitative estimates of this variable. By coupling R0 models with spatial statistical models, we spatialized R0 and therefore better represented the spatial heterogeneity in the risk of establishment of an infection. Among the various input variables forming R0, the vector-host ratio displays the greatest spatial heterogeneity. By combining fine-scale land cover variables and coarse-scale climatic variables, we predicted the spatial distribution of vectors. This was then integrated with maps of human host distribution to spatialize the vector-host ratio in the R0 formula [0 [0at district level for the veterinary blue tongue disease in the Netherlands.The Basic Reproductive Rate  . An agena priori mathematical description of the main processes determining mosquito population dynamics. It is also deterministic as it represents an average behaviour of the population an approach that is well adapted for large populations, such as mosquito populations.Finally, we developed a spatially-explicit population dynamics model of mosquito populations ,19, inteThe set of propositions described below were generated in an inductive manner, by generalisation from the set of empirical studies that we conducted. For each case study, we extracted the main conclusion(s) on the role of land use and land cover in the transmission cycle. The validity of these conclusions was then evaluated for each of the other case studies. In a synthesis table, we identified all the case studies for which a particular conclusion was empirically supported. We also identified disease systems for which the literature suggests that this conclusion may be valid.We summarize below and in Table Chevalier et al.  conducteVanwambeke et al.  investig0 model was developed for canine leishmaniasis in the French Pyrennées [0.A spatially-explicit Ryrennées . An impoAedes vexans and Culex poicilippes, takes into account the main events of the mosquito life cycle and climatic fluctuations. Simulations of daily spatial and temporal variations in the area of temporary ponds around a village in Senegal relied on the Tropical Rainfall Measuring Mission (TRMM) rainfall product [The impact of landscape variables on the transmission of RVF in small ruminants was investigated in the semi-arid region of Barkedji, Ferlo, Senegal . The rel product ,19. MosqBased on the seasonal distribution of mosquito and bird populations, simulations of introduction, amplification and emergence of WNV under different realistic scenarios were produced and compared with seroprevalence measured in horse and bird populations .The link between environmental features and PUUV prevalence in bank vole population was investigated in Belgium. Linard et al.  exploredThe impact of fine-grained landscape patterns on the exposure of people to LB infection was also investigated in Belgium. A combination of factors linked to the vector and host populations, landscape attributes, and socio-economic factors were included in a negative binomial regression to explain the number of LB cases per municipality .Anopheles hyrcanus, was defined as the probability of observing its larvae in a given site at least once over a year. It was mapped by associating in a statistical model environmental indices that were derived from high spatial resolution imagery and entomological field data  are immobile. The ability of female vectors to spread from their breeding sites to hosts increases host/vector contacts. Landscape features largely control these movements . The stun France . The conn France  found thn France . Habitatn France  observedn France  showed tCx. modestus was identified as the main amplifier of WNV, which is consistent with competence studies [Great numbers of hosts and vectors species are potentially involved in the transmission of WNF, making its epidemiology complex. One should better understand underlying processes accounting for observed patterns of WNF when correlations between land use/cover and disease prevalence have been established . In the  studies . In the  studies . Yet, ot studies ,55,56. TBorrelia spp. and TBE virus. Transmission to ticks related to systemic and non-systemic host infections  has been described for both pathogens. Yet, transmission through co-feeding of ticks in non-systemically infected hosts may be more important to sustain the transmission of TBE [The transmission of vector-borne diseases requires a direct contact - i.e., a bite - between an infectious vector and a susceptible host. By contrast, zoonoses such as PUUV can be transmitted directly, by physical contact between infected and susceptible hosts, or indirectly, with the environment as an intermediate. Actually, the virus can be shed in the environment via rodent excretions, and transmitted to humans in aerosols ,58. The n of TBE ,60. As an of TBE ,62. The n of TBE .The emergence of a disease in a particular region is associated with multiple macro-level changes such as a shift in political and economic regimes that influence people's livelihood strategies and therefore their interaction with natural ecosystems ,65, rapiAe. vexans and Cx. poicilippes. Modelling spatial and temporal variations in water level and surface of temporary ponds around a village in Senegal allowed simulating mosquito population dynamics and host distribution [Culex and Aedes populations and therefore the risk of circulation of RVF virus. Depending on the frequency of rainfall events, high densities of Culex and Aedes may occur simultaneously. This co-occurrence of species leads to a higher risk of transmission, Ae. vexans and Cx. poicilipes acting as, respectively, initiators and amplifiers of RVF virus circulation. Thus, in the Ferlo region, a combination of rainfall frequency and amount identifies years at risk for RVF. Landscape features also influence the spread distance of mosquitoes away from their breeding sites [In the semi-arid region of the Ferlo, Senegal, temporary ponds - i.e., that are flooded after the first rains and remain dry for most of the dry season - constitute a favourable habitat for RVF vectors, ribution ,19. Resung sites . Such evng sites . The flong sites . Meteorong sites .Land cover is defined by the attributes of the earth's land surface and immediate subsurface, including biota, soil, topography, surface and groundwater, and human structures. Land use is defined by the purposes for which humans exploit the land cover. While a focus on land cover helps understanding the presence of vectors and hosts, a focus on land use identifies which places people visit for specific activities, at what time of the day and of the year, and at what frequency. The attractivity of various places for a given activity depends on their attributes such as accessibility and value for that activity - e.g., presence of recreational features, easily accessible forests with amenities such as good trails. Our studies on human cases of PUUV and LB in Belgium showed that the spatial distributions of the two diseases were very dissimilar . PUUV waLand ownership and access rules determine whether distributions of ticks and human activities overlap in space and time. In most countries, State forests are more accessible to the public than privately-owned forests. In the statistical analysis of TBE incidence in rural parishes of Latvia , land owAedes, the mosquito vector, and by risk and protective behaviours [Humans can adopt a range of preventive measures to decrease the risk of contact with vectors or pathogens. The rate of adoption of these measures depends on the availability of such preventive measures, the nuisance of the vector, the risk of infection and its level of perception by susceptible agents. For transmission to occur, one needs a combination of a conducive environment, which is created by an ecosystem favourable to interactions between pathogens, vectors and their animal hosts, and risk behaviours by human hosts that lead to a greater incidence among a human population. For example, the emergence of TBE in the Baltics was associated with a complex combination of abiotic, biotic and human factors ,75. Simihaviours ,80. One The above propositions have the status of hypotheses requiring further testing in different geographic and biological contexts. Yet, they further our understanding of the impact of land-use and land-cover change on the transmission cycle of vector-borne diseases. A practical implication of this enhanced knowledge is to identify indicators of "pathogenic landscapes", to provide early warning signals of an increased likelihood of disease transmission. A static view of the "pathogenicity" of landscapes overlays maps of the spatial distribution of: (i) vectors and their habitats, (ii) animal hosts carrying specific pathogens and their habitat, (iii) susceptible human hosts and their land use. A more dynamic view would represent the spatial and temporal dynamics of these agents at multiple scales. Potential indicators of a higher transmission risks would be derived from any combination of social and ecological processes that are associated with spatial boundaries and temporal transitions that increase - or create new - interactions between disease transmission agents. Spatial indicators of infection risks would be associated with ecotones; margins of the geographic distributions of vectors, hosts or pathogens; and highly connected places, being at the crossroad of circulating vectors, hosts or pathogens. Temporal indicators of infection risks would be associated with biological mutation of pathogens, invasion of vectors, change in composition of animal host population, migration of naïve human hosts, abrupt land use/cover changes , political and economic changes, rapid climatic changes... Importantly, it is synergistic interactions between several of these indicators that are most likely to be associated with high infection risks.The above findings have implications for the design of public health surveillance systems. For example, georeferencing of serological data collected on hosts is essential. For human cases, recording the place of infection in addition to the place of residence of patients is also necessary. Systematic trapping of vectors and/or animal hosts for serological surveys should be spatially targeted on areas with a high risk of transmission. This could be achieved through spatially stratified sampling schemes defined based on the relevant landscape attributes. Budgeting should allow for rapidly increasing the intensity of serological surveys on hosts in periods of unexpected socio-economic, ecological or climatic transitions that have the potential to affect transmission of infections. Data on land cover, land use, and socio-economic factors associated with risk behaviours should be systematically integrated in surveillance systems. Finally, the ability of public health analysts to integrate data from different sources, at multiple scales, and representing various components of disease systems should be enhanced.0 models allow investigation of establishment potential in the absence of a disease. They are based on a representation of biological processes of transmission. Yet, the spatial heterogeneity of environmental attributes is not explicitly included in these models. The development of multi-agent simulations necessitates a considerable amount of data and a good preliminary knowledge of the disease system. MAS represent the dynamics of people-vector contacts in space and time and are therefore ideal to explore scenarios associated with conditions that have not been observed previously. Coupling R0 models with MAS could therefore better represent the influence of spatial and temporal heterogeneity in people-vector contacts on the risk of establishment of an infection. There is a logical sequence in the use of the various methods, from the land cover description by remote sensing to the spatially-explicit multi-agent simulation, transiting through exploratory statistical analyses to better understand the key components of disease transmission and their associations.The different modelling approaches used in the case studies were highly complementary. A detailed and accurate land cover mapping by remote sensing was at the basis of the methods used. Spatial statistical models were used to explore empirical relationships between disease systems and landscape patterns, as a preliminary approach of disease systems for the development of more integrated models. The finding of statistically significant associations does not establish causal relationships. Moreover, regression models cannot be used for extrapolation beyond the region of the variable space corresponding to the original data. RWe conclude as we started, with a quote by E.N. Pavlovsky (1966):"The epidemiological significance of a locality is determined by the following factors: (a) the landscape of an area with natural foci of diseases in newly-settled and reclaimed regions (...); (b) the extent and nature of contact between man and his natural environment."All our case studies show that spatial variations in infection risk are controlled by three sets of factors: (i) the pathogenic cycle and the biology of vectors, hosts and pathogens; (ii) ecosystem processes at the landscape scale, as influenced by ecosystem structure and composition, landscape connectivity and configuration, climate, species interactions; and (iii) land use, human behaviour and mobility, knowledge and perception of disease risk, and socio-economic conditions. In general, previous studies in spatial epidemiology have ignored or given less emphasis to the latter set of factors . The challenge in landscape epidemiology is to integrate dynamically these different factors, with an emphasis on their interactions and not just on their spatial overlay. By identifying a set of propositions on factors controlling these interactions, this review contributes to a general understanding of spatial variations in disease risk.The authors declare that they have no competing interests.EFL designed and coordinated the synthesis study. AT, SV, CL, VS contributed to the synthesis study and analyzed the data for individual case studies. All authors wrote, read and approved the final manuscript.


Chronic obstructive pulmonary disease (COPD) represents a significant burden for healthcare systems that is expected to grow further in the future. Inhaled long-acting bronchodilators, including tiotropium, represent the cornerstone of management of COPD patients. Economic studies evaluating the cost-effectiveness ratio of inhaled bronchodilators have to take into account several parameters, including the reduction of COPD exacerbations and related hospitalizations, as well as disease modification and improvement in quality of life and mortality. At an era when the healthcare resources are unlikely to grow as quickly as demand, economic analyses remain the cornerstone for the justification of the broad use of medication with an acceptable cost-effectiveness ratio. The greatest importance of such studies in COPD is the identification of subgroups of patients that will have the most benefit with an acceptable cost-effectiveness ratio for the healthcare providers. The development of models that will incorporate a global evaluation of the different aspects of this multi-component disease, in order to provide the best available care to each individual patient is urgently needed. Chronic obstructive pulmonary disease (COPD) represents a major cause of morbidity and mortality worldwide, with a significant economic burden for health systems and individual patients, both in high and in low income countries. According to the WHO Global Burden of Disease Project, COPD was the fifth leading cause of disease in 2001 and is expected to become the third leading cause by 2020 . SeveralInhaled long-acting bronchodilators represent the cornerstone of current management of COPD ,8, provi1 in patients with GOLD Stage II COPD [Differences in study design and definitions along with differences between healthcare systems may account for the observed differences between the study of Neyt et al. and previous ones, yet several factors have to be taken into account. COPD exacerbations represent a significant outcome in all major COPD therapeutic trials ,17 and h II COPD , therefo II COPD , and suc II COPD .Disease severity represents another important parameter that needs to be considered in the evaluation of efficacy of inhaled medication. The cost-effectiveness of tiotropium has been previously shown to be more favorable in more severe disease and in patients with previous hospitalizations . In the Besides the fact that Neyt and colleagues evaluated only a single outcome  in their cost-effectiveness analysis and they did not provide data according to disease severity, their study presents further limitations. The short-term horizon of one year chosen by the authors may not be enough for the appropriate evaluation of adverse events, given the low rate of COPD exacerbations per year reported in all the large trials ,17, that1. In that time-course, we have learned that inhaled corticosteroids may reduce exacerbations [In the last decade our understanding of COPD pathogenesis, natural history and treatment has improved significantly. A major part of this improvement is due to the fact that we have evaluated the effectiveness of treatments on patient-centered outcomes beyond the cornerstone measure of FEVrbations , and everbations . We haverbations , yet thorbations . Pulmonarbations , in contrbations . Yet, alrbations . The maiIn a multi-component disease, such as COPD, many parameters have to be addressed in order to evaluate globally the individual patients and recognize possible therapeutic phenotypes . DespiteKK has received speaking fees and reimbursements for participation in congresses from Boehringer-Ingelheim and Pfizer, AstraZeneca, Nykomed, Novartis, GlaxoSmithKline and UCB Pharma and has participated in advisory boards held by Nycomed.DB has received speaking fees and reimbursements for participation in congresses from Boehringer-Ingelheim and Pfizer, AstraZeneca, Novartis, GlaxoSmithKline and UCB Pharma and has participated in advisory boards held by Nycomed and Actelion.KK and DB have equally contributed to the conception and preparation of this commentary and they have both read and approved the final version of this manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2466/10/48/prepub


Health technology assessments (HTAs) by the National Institute for Health and Clinical Excellence (NICE) enjoy high levels of international attention. The present analysis addresses NICE's appraisal of methylphenidate, atomoxetine and dexamphetamine for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents, published in March 2006.A qualitative study of NICE Technology Appraisal No. 98 was done focusing on the >600-page technology assessment report, which aimed at evaluating ADHD treatment strategies by a clinical effectiveness review and an economic analysis using meta-analytical techniques and a cost-effectiveness model.The technology assessment was unable to differentiate between the various drugs in terms of efficacy, and its economic model was ultimately driven by cost differences. While the assessment concluded that the economic model "clearly identified an optimal treatment strategy" with first-line dexamphetamine, the NICE appraisal committee subsequently found it impossible to distinguish between the different strategies on grounds of cost-effectiveness. Analyzing the assessment reveals gaps and inconsistencies concerning data selection , data synthesis , and economic model structure .Many conclusions of the NICE technology assessment rest on shaky grounds. There remains a need for a new, state-of-the-art systematic review of ADHD treatment strategies including economic evaluation, which ideally should address outcomes beyond children's health-related quality of life, such as long-term sequelae of the disorder and caregiver burden. Health care policy makers and clinicians increasingly seek evidence-based guidance on how to provide mental health services effectively and efficiently. Systematic reviews have come to be accepted to produce the best estimates of clinical efficacy and effectiveness, thus constituting a cornerstone of policy analysis and cost-effectiveness evaluation . FoundedIn March 2006, NICE published guidance on the use of methylphenidate, atomoxetine and dexamphetamine for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents . This gIn the United States, NICE guidelines are routinely referenced by the National Guideline Clearinghouse, an initiative of the Agency for Healthcare Research and Quality (AHRQ). NICE technology assessments and appraisals are easily accessible through its website, which receives more than one million hits per month from the United States alone . The NICA qualitative study was done of NICE Technology Appraisal No. 98, "Methylphenidate, atomoxetine and dexamfetamine for attention deficit hyperactivity disorder (ADHD) in children and adolescents "  model tends to be driven by drug cost, which differ considerably" . More specifically, it was asserted that "for a decision taken now, with current available data, the results of the economic model clearly identify an optimal treatment strategy"  and that "this analysis showed that a treatment strategy of 1st line dexamphetamine, followed by 2nd line methylphenidate immediate-release for treatment failures, followed by 3rd line atomoxetine for repeat treatment failures was optimal" .The Technology Assessment Report (TAR), comprising 605 pages with 13 appendices, included a systematic review of the evidence and a statistical data synthesis using mixed treatment comparison (MTC) techniques, a review of submissions by manufacturers, and an economic evaluation model. Main conclusions of the TAR were that "(i) drug therapy seems to be superior to no drug therapy; (ii) no significant differences between the various drugs in terms of efficacy or side effects were found – mainly due to Remarkably the NICE Appraisal Committee did not uphold these "clear conclusions", issuing guidance that was based on the assumption that it was "not possible to distinguish between the different [treatment] strategies on the grounds of cost-effectiveness" .Analysis of the TAR reveals a number of methodological issues, which collectively leave the assessment open to critique concerning all four essential components of a review question , namely Departing from the assessment protocol , literattreatment duration of three weeks. However, a minimum study duration of three weeks was applied as inclusion criterion. As a consequence, more than one third of the 64 trials included in the clinical effectiveness review were very-short-term crossover studies with treatment periods of one week or less, some of which had been conducted without washout phases between treatment periods   analysis on trials that are more similar in terms of how they measure the outcome of interest" , in fact internally consistent model results were achieved after this pooling only, and there is no indication that potential confounding effects between treatment strategies and effect measures were assessed.Can the intervention work?"), economic evaluations to be meaningful require a pragmatic orientation ("Does the intervention work?")  adequately captures the effect of compliance on response to treatment" . As a consequence, data from highly controlled double-blind RCTs and from randomized pragmatic open-label studies were pooled, necessarily concealing any differentiation on grounds of treatment compliance. Nevertheless it was claimed "the effect of compliance on response rates [...] is reflected in the model" .The economic model cf. Fig.  relied oNone of the studies selected for the primary model exceeded an observation period of eight weeks per treatment arm , and also the secondary model extensions  were informed by trials with observations periods of 12 weeks or less, except for the data extracted from three out of four parallel arms of the MTA study . On this basis, costs and benefits were extrapolated over a time horizon of 12 years. Although the assessment includes a discussion of sensitivity of findings to time horizon , this did not include a review of long-term sequelae associated with ADHD. No attempt was made to address the impact of the disorder on educational outcomes, injuries and accidents, or other problems such as encounters with the criminal justice system and the burden of caregivers.The technology assessment purports to have "clearly identified an optimal treatment strategy" . The caveats offered essentially relate to a paucity of evidence and poor reporting of studies , which were blamed for the inability to discriminate between drugs in efficacy or between patients in terms of ADHD subtype, age, gender or previous treatment .The NICE ADHD health technology assessment does not provide a complete account of the problem addressed. From an economic perspective, the omission from analysis of psychosocial interventions, representing a mainstay of ADHD therapy, is especially disturbing, as estimates of allocative efficiency require all possible options to be considered.Furthermore the literature search was incomplete, existing evidence was used in an overly restrictive manner, and neither long-term sequelae nor caregiver burden were addressed. These shortcomings were confounded by outright technical errors, including but not limited to  the appaAlthough the assessment may have its uses in listing existing literature and presenting condensed summaries, it leaves substantial room for improvement. Its main conclusions rest on shaky grounds and are potentially misleading. NICE itself, in its final appraisal determination and its guidance issued in March 2006, wisely moderated the putatively "clear conclusions" of the technology assessment report . UnderstRegarding the technology assessment process, the broad range of observed anomalies can be interpreted as symptoms, which may be indicative of specific underlying problems. In the present case, such underlying issues appear likely to have included an insufficient integration of clinical and economic perspectives, the extraordinarily high level of standardization of NICE technology appraisals, enforcing the computation of clinical outcomes as quality-adjusted life years and hereby requiring the clinical problem definition to fit to a preconceived solution, and the apparent absence of effective quality assurance systems . Beyond While there remains a need for more research into the long-term effectiveness and cost-effectiveness of ADHD treatment strategies , at the There was no third-party or industry involvement in the present study, which was funded by the Institute for Innovation & Valuation in Health Care . InnoVal-HC is a not-for-profit organization accepting support under a policy of unrestricted educational grants only. Potential competing interests: The Institute and/or its staff report having received public speaking and conference attendance as well as project support from payers', physicians', and pharmacists' associations, and served on advisory boards for companies including E. Lilly, Johnson & Johnson, Novartis, Pfizer, and Shire.


A rare case of thoracic malignant schwannomma, in an adult, is presented here. This case shows an aggressive, rapid progression, which is characteristic of the disease. In spite of the best surgical and chemotherapy treatment, the patient died within four months of diagnosis. Schwannomas (or neurilemommas) and neurofibromas are the most common mediastinal tumors. They are benign, slow-growing neoplasms that frequently arise from a spinal nerve root but may involve any thoracic nerve. Malignan32-year-old male presented with chest pain and mild dyspnea of 20 days duration. He was a laborer and non-smoker with no history of exposure to any occupational or inorganic dust. Chest pain was retrosternal and pricking in character with no radiation and not related to the meals. Examination revealed averagely built person with BMI of 22, and no clubbing and lymphadenopathy. Respiratory system examination revealed diminished movements on the left hemi-thorax. There was stony dullness on the left hemi-thorax, and breath sounds were absent. No adventitious sounds were heard. Chest radiograph revealed a uniform density homogenous opacity in the left hemi-thorax occupying the full hemi-thorax except at the left apex. The mediastinum was shifted to the right side .Routine blood investigations were within normal limits. A Computed tomography (CT) of the thorax revealed a large well defined heterogenous mediastinal mass in the left hemi-thorax. There were some areas of necrosis and calcification within the mass. The mass was extending up to the pleural surface, and infiltrating into the subcutaneous tissues in the chest wall . The diaAs the diagnosis was inconclusive, the patient was taken up for thoracotomy with excision of the tumor. Intra-operatively it was observed that there was a large firm mass in the mediastinum on the left side with invasion of the great vessels and involvement of mediastinal lymph nodes. The lymph nodes involved were: left hilar group, subcarinal group, aorto-pulmonary window group, right hilar group and left interlobar group of lymph nodes. The mass was seen infiltrating the great vessels, pericardium and the chest wall. Hence, de-bulking of the tumor was done to the extent possible. Complete excision of the tumor could not be done as it was infiltrating the great vessels and the pericardium. Histologically, the specimen revealed sheets of pleomorphic spindle shaped cells, with enlarged hyperchromatic twisted nuclei and amphophilic moderate eosinophilic cytoplasm. The neoplastic cells were arranged in fascicles that closely resembled the architecture of leiomyosarcomas . They haNeurogenic tumor is the most common cause of a mass lesion in the thoracic para-vertebral region in the general adult population. Schwannomas are rare in people less than 20 years of age and are largely asymptomatic. SchwannoMalignant schwannomas typically arise from a simple or plexiform neurofibroma, but rareApproximately half of the cases occur in individuals with neurofibromatosis and the incidence of sarcomatous degeneration is seen in five per cent cases. Malignant schwannomas may occur sporadically or be induced by radiation exposure. Most of Differential diagnosis of the dense homogenous density lesion in the left hemithorax, similar to the present case, includes bronchogenic carcinoma, lymphomas (Hodgkins or non-Hodgkins disease), pleural mesothelioma, thymic tumours, teratomas, and tumours arising from sympathetic ganglia like ganglioneuroma, ganglioneuroblastoma and neuroblastomas, and encysted pleural effusion. Radiologically, schwannomas appear as a well circumscribed, round masses which are homogenous, soft-tissue density on plain CT images, with clear preservation of surrounding fat planes. OccasionIn this case, diagnosis could not be reached following routine procedures, and hence exploratory thoracotomy was performed. It confirmed malignant schwannomma. In this case, wide excision of the tumor was done. Complete excision was not possible due to the invasion of the great vessels and chest wall. He was also given adjunct radiation therapy and chemotherapy. However, due to rapid progression of the tumor, the patient succumbed to the disease within four months of diagnosis.


Harmful algal blooms (HABs) are one focus of the national research initiatives on Oceans and Human Health (OHH) at NIEHS, NOAA and NSF. All of the OHH Centers, from the east coast to Hawaii, include one or more research projects devoted to studying HAB problems and their relationship to human health. The research shares common goals for understanding, monitoring and predicting HAB events to protect and improve human health: understanding the basic biology of the organisms; identifying how chemistry, hydrography and genetic diversity influence blooms; developing analytical methods and sensors for cells and toxins; understanding health effects of toxin exposure; and developing conceptual, empirical and numerical models of bloom dynamics.Pseudo-nitzschia and Microcystis, and a biosensor for domoic acid. There have been advances in predictive models of blooms, most notably for the toxic dinoflagellates Alexandrium and Karenia. Other work is focused on the future, studying the ways in which climate change may affect HAB incidence, and assessing the threat from emerging HABs and toxins, such as the cyanobacterial neurotoxin β-N-methylamino-L-alanine.In the past several years, there has been significant progress toward all of the common goals. Several studies have elucidated the effects of environmental conditions and genetic heterogeneity on bloom dynamics. New methods have been developed or implemented for the detection of HAB cells and toxins, including genetic assays for Along the way, many challenges have been encountered that are common to the OHH Centers and also echo those of the wider HAB community. Long-term field data and basic biological information are needed to develop accurate models. Sensor development is hindered by the lack of simple and rapid assays for algal cells and especially toxins. It is also critical to adequately understand the human health effects of HAB toxins. Currently, we understand best the effects of acute toxicity, but almost nothing is known about the effects of chronic, subacute toxin exposure. The OHH initiatives have brought scientists together to work collectively on HAB issues, within and across regions. The successes that have been achieved highlight the value of collaboration and cooperation across disciplines, if we are to continue to advance our understanding of HABs and their relationship to human health. For residents of marine and freshwater coastal regions, perhaps one of the most visible manifestations of the interdependence of human and ocean health are the episodic harmful algal blooms (HABs) that affect almost every part of the U.S. coastline. HABs are natural phenomena caused by the proliferation of algae, resulting in damage to the environment and/or risk to the health of humans and aquatic life. Many HAB species produce toxins that are accumulated and passed up the food chain, causing illness or death in humans and other organisms that consume them. Nontoxic organisms can also cause blooms. These so-called "noxious" or "nuisance" bloom species grow to high biomass and cause oxygen depletion, reduction in biodiversity, physical damage, and shading of the benthos. The frequency and severity of HAB events appears to be increasing globally -3, whichAlexandrium tamarense, Gambierdiscus spp., Karenia brevis, Microcystis spp., and Pseudo-nitzschia spp.  at NSF/NIEHS and NOAA. All of the OHH Centers, spread from the east coast to Hawaii, include one or more research projects devoted to understanding HAB problems. Collectively, the Centers are engaged in intense study of a variety of major recurrent toxic HAB species in the U.S.: . Figure . EmerginAlexandrium can cause outbreaks of paralytic shellfish poisoning (PSP), the most widespread of the HAB-related shellfish poisoning syndromes. PSP is caused by saxitoxins, a family of toxins that bind to sodium channels in nerve and muscle cells, and results from ingestion of shellfish that accumulate toxins from feeding on Alexandrium cells. The economic, public health, and ecosystem impacts of PSP outbreaks take a variety of forms and include human intoxications and death from contaminated shellfish or fish, loss of natural and cultured seafood resources, impairment of tourism and recreational activities, alterations of marine trophic structure, and death of marine mammals, fish, and seabirds. The economic impact of Alexandrium blooms is substantial; for example, economists estimated that a large bloom in the northeastern U.S. in 2005 cost the seafood industry alone $2.7 million per week in lost revenues, with some estimates suggesting double that amount [Alexandrium species are found worldwide in temperate coastal and estuarine waters. Thousands of miles of U.S. coastline are affected, with recurrent blooms affecting both the northeastern and western coasts of the U.S.Blooms of neurotoxic dinoflagellates of the genus t amount . Toxic AGambierdiscus spp. is the primary source of ciguatoxin, the poison that causes ciguatera fish poisoning (CFP). Humans acquire ciguatoxin (CTX) by eating reef fish that have accumulated the toxin via the marine food web. Gambierdiscus dinoflagellates are found in association with various macroalgae in coral reef ecosystems. These dinoflagellates are consumed by herbivorous fish, beginning a process of bioaccumulation, biomagnification, and biomodification in the reef food web, as the herbivores are consumed by carnivores, and, ultimately, by humans. Gambierdiscus is found in tropical and subtropical coral reef regions worldwide; in the U.S. it has been reported from Hawaii [The toxic dinoflagellate m Hawaii ,8, the Fm Hawaii ), and thm Hawaii . CFP prom Hawaii -13, and Karenia brevis, can be found in low concentrations throughout much of the Gulf of Mexico, but episodically forms large blooms [K. brevis has become more abundant during this time [K. brevis occur within five kilometers of the shoreline [K. brevis produces a suite of neurotoxins called brevetoxins, which can cause neurotoxic shellfish poisoning (NSP), in which nerve cell paralysis results in gastroenteritis, muscle cramps, seizures, paralysis, and other neurological symptoms after the consumption of toxic shellfish [K. brevis blooms is the release of brevetoxins from the cells, which then form a toxic aerosol that can cause respiratory problems in humans, especially those with asthma [K. brevis blooms [The toxic dinoflagellate, e blooms -16. These blooms ,16. The his time , though horeline , where thellfish ,19. Due h asthma -22. Thiss blooms ,24. The Anabaena, Aphanizomenon and Microcystis) occurred during summer when the water column was thermally stratified [Microcystis. Large persistent Microcystis blooms in the relatively warm and shallow regions of the Great Lakes  have been present during most summers. Microcystis produces the hepatotoxin microcystin that is responsible for mortality in livestock, wildlife and birds. Human health effects of exposure to microcystins in drinking water include gastrointestinal illness for acute exposure and increased liver disease and damage and possible tumor promotion for chronic exposure [Microcystis cells tend to accumulate at the water surface, particularly in calm conditions, resulting in dense surface scums in embayments, against structures such as docks and piers, and in nearshore regions where humans are most likely to come in contact with the water, further increasing the potential impacts on human health.Cyanobacterial HABs have been observed in the Great Lakes for decades. In the 1960s and 1970s massive blooms of diverse cyanobacteria  [Pseudo-nitzschia is a cosmopolitan genus found in both coastal and open ocean regions from tropical to arctic latitudes. In the U.S., toxic Pseudo-nitzschia species have been documented along the west coast [Pseudo-nitzschia are prevalent along the west coast of the United States where they have been responsible for closures of shellfish harvests, sometimes for over a year, resulting in the loss of millions of dollars in revenue for the coastal economy. During toxic events, recreational, commercial and tribal subsistence harvest of clams, valued at over $20 million annually [The diatom genus cid (DA) . The toxcid (DA) -33. Conscid (DA) ,35. The cid (DA) . Sublethcid (DA) ,37. Pseust coast , in the st coast , the Gulst coast , and thest coast . Blooms annually , is prohWhile the organisms and environments may be diverse, all of the seven Centers employ a similar strategy for the study of HABs. This approach shares a set of five common goals for understanding, monitoring and predicting HAB events in order to protect and improve human health. These goals are: 1) understanding the basic biology of the organisms; 2) understanding how chemistry, hydrography and genetic diversity influence blooms; 3) developing analytical methods and sensors for cells and toxins; 4) understanding health effects of toxin exposure; and 5) developing and validating conceptual, empirical and numerical models of bloom dynamics for predictive purposes. For all of the Centers, the ultimate goal is to develop better methods and technologies for monitoring and predicting HAB events. The ability to detect cells and toxins at high spatial and temporal resolution and to project that information into the future using predictive models will provide the greatest protection to public health. However, we also need to have a better understanding of the organisms and their ecology if we are to build effective sensors and predictive models.HAB research at the Oceans and Human Health Centers is part of a large and active research community that includes scientists from around the world. Center activities build upon and complement years of research on all aspects of HAB problems. A strength of the OHH Centers is that they bring together scientists from diverse fields, greatly facilitating collaboration and cooperation across scientific disciplines. The ability to tap the combined expertise within and between Centers has made it easy to approach HAB problems "from all angles," and the successes that have been achieved highlight the value of this interdisciplinary approach to the study of HABs.Amphidinium [Karenia brevis and Alexandrium tamarense [Aureococcus anophagefferens and the toxic diatom Pseudo-nitzschia multiseries. These sequencing efforts should greatly advance overall knowledge of the biology of HAB species.In comparison to many other organisms, especially model systems, relatively little is known about the basic biology of HAB species. One of the biggest gaps is the lack of information about the biochemical pathways for toxin synthesis, especially in eukaryotic HAB species. Several genera of cyanobacteria produce different toxins, and researchers have completely described the multi-gene systems for the synthesis of microcystins  and cylihidinium ; knowledamarense ,48 and uamarense . HABs haPseudo-nitzschia species produce domoic acid [Pseudo-nitzschia [Pseudo-nitzschia in the presence of bacteria [Pseudo-nitzschia cell [Pseudo-nitzschia has focused on several strains of one species, Pseudo-nitzschia multiseries.While we lack in-depth genetic information for many HAB species, we do have relatively good information on their physiology, due to laboratory studies that have investigated the response of cultured isolates to environmental conditions. However, we are just beginning to investigate how these organisms function as part of the complex communities that exist in natural waters. This can include multiple species or strains of the same organism, or multi-species assemblages. For example, researchers are beginning to unravel the complex relationship between toxic diatoms and their associated bacteria. Previous studies have shown that not all oic acid -52, and oic acid , nutrienoic acid ,55, growitzschia ,57. Othebacteria , with grhia cell -60. LitePseudo-nitzschia strains, representing 6 species, using a DNA fingerprinting technique called ARISA . ARISA amplifies the intergenic spacer region located between 16S and 23S ribosomal RNA (rRNA) genes in bacteria [Pseudo-nitzschia species host significantly different bacterial assemblages. Furthermore, bacterial assemblages associated with species capable of high toxin production differed significantly from those associated with species with low toxin production.Center researchers have built upon this work by examining bacterial assemblages associated with 18 bacteria . This mebacteria , seasonabacteria , and phybacteria . Using tPseudo-nitzschia has recently been selected for whole genome sequencing, genetic characterization of toxic dinoflagellates such as Karenia and Alexandrium has been limited to the sequencing of EST libraries. This is primarily because the genome sizes of dinoflagellates are often prohibitively large for full genome sequencing. Estimates of dinoflagellate DNA content range from 3 to 250 pg·cell-1 [Symbiodinium has a relatively small genome, ca. 2 pg, and investigatory genome sequencing of this organism is currently underway . Although this genus is not toxic, the genome sequences from this dinoflagellate, along with the development of new, ultra-high throughput sequencing technologies, are encouraging advances that make the prospect of a full genome sequence for a toxic dinoflagellate more likely.Studies of HAB organisms can be complicated by unusual aspects of their biology and life cycles. For example, while the toxic diatom g·cell-1 , correspPseudo-nitzschia cultures eventually die out if they are not mated with larger cells of the same species. The toxic dinoflagellate Gambierdiscus has also proved difficult to maintain in culture; it grows slowly and does not attain high biomass [For some HAB species, even controlled laboratory experiments can be a challenge because organisms are often difficult to culture. Many HAB species have complex life cycles that include a sexual phase. For example, clonal  biomass -68. EstaA necessary step in understanding the formation of HABs is taking what we have learned from laboratory studies of clonal culture isolates and translating that into field populations. In the laboratory, conditions can be controlled so that only one factor varies at a time, whereas natural blooms involve a complex interplay of changing chemical, physical and biological conditions, which vary both in time and space. A common goal of the HAB research at the OHH Centers is to understand the effects of nutrient availability, hydrography, and genetic diversity on HAB formation and development.Microcystis blooms is determined both by environmental factors and the genetic composition of the bloom. Nutrients, light, trace metals and temperature are some of the factors that change bloom toxicity either through direct stimulation of toxin production or through coupling to cell growth and division [Microcystis based on sequence analysis of one of the microcystin synthetase genes (mcyB), further supporting the role of community composition in bloom toxicity.In the Great Lakes, the toxicity of division -71. Statdivision . Though division ,74. In wPseudo-nitzschia, genetic diversity is reflected in inter- and intraspecific variability in toxin production, which has complicated the implementation of early warning systems for blooms, largely because Pseudo-nitzschia are notoriously difficult to identify. Center research has led to the development of a DNA-based Pseudo-nitzschia-specific ARISA for species identification, which is used in tandem with environmental clone libraries for strain identification and to assess the diversity of Pseudo-nitzschia communities [Pseudo-nitzschia blooms are common. However, global distributions of Pseudo-nitzschia types are also being investigated to better evaluate the extent of genetic diversity in this genus. Thus far, the Center project has identified more than 14 putative species of Pseudo-nitzschia in Pacific Northwest waters using ARISA, compared to ~7 described by past studies [P. delicatissima was detected in Portugal, Denmark, and throughout the Pacific Northwest [P. pungens detected in the Pacific Northwest exhibit distinct distribution patterns and high divergence levels in comparison to other species, suggestive of distinct populations or cryptic species that might co-exist in Pacific Northwest waters.In munities . Both te studies . Some oforthwest . PrelimiAlexandrium fundyense in the northeastern U.S. Center scientists are using microsatellite markers to analyze the diversity and population structure of Alexandrium blooms over consecutive bloom years. Results show that blooms are not genetically "static" – that populations present at the end of a bloom can be distinct from those at the start of a bloom. However, results also show that the starting bloom populations in consecutive years are not significantly different from one another. This apparent paradox challenges our assumptions about the homogeneity of blooms, and about the sources of cells for bloom initiation and propagation. It also highlights the potential of genetic markers; they not only provide information about population structure, but can also help us to understand the sources of toxic cells and to identify mixing of populations.The presence of multiple populations, strains or species during HAB events is turning out to be the rule, rather than the exception, for many HAB organisms. In addition to the cyanobacteria and diatoms described above, high genetic diversity has also been observed in blooms of the toxic dinoflagellate A. fundyense bloom populations in the northeast and measured their growth rates and toxicity under varying conditions of light and temperature. The heterogeneity observed is remarkable – growth rates vary up to three-fold, and toxicity varies as much as four-fold among isolates grown under the same conditions. These differences may lead to the selection of specific genotypes in natural waters, with a resulting variability in population abundance and toxicity from year to year. The effects of this growth and toxin variability on regional blooms are currently being explored using the Gulf of Maine Alexandrium numerical model, also as a Center activity [Center research has also been devoted to understanding the effects of changing conditions  on cell growth and toxicity. For example, Center scientists have established dozens of isolates from activity .in situ analysis of cell physiology, and the collection of long-term field data sets. If we could determine the status of cells in the field, we could use that knowledge to predict the behavior of blooms. For example, fluorescent, precipitable substrates of alkaline phosphatase have been used to demonstrate phosphorus limitation of cells in the ocean [One of the biggest challenges to understanding toxic blooms is that chemical, biological, and physical conditions can all be changing simultaneously, and not necessarily in concert with one another. It is therefore extremely difficult to determine the proximate cause of changes in a natural bloom. Did the bloom die off because it ran out of nutrients? Because of a parasite? Because the winds changed and forced the bloom offshore? Some combination of these factors? This issue could be addressed through the development of methods for the he ocean . To dateLong-term data sets of field measurements of bloom (and non-bloom) events have the potential to greatly increase our understanding of bloom dynamics. Data from many years or bloom events enable us to assess the factors that change from year to year, or bloom-to-bloom, and correlate those with changes in bloom events. Do blooms only occur in years with above average rainfall? Warm summers? Northeast winds? Unfortunately, long-term synoptic data sets are very difficult to obtain, because a single grant proposal often only allows for a few years of monitoring, and it is challenging to keep a field program funded for the period of time necessary to accumulate a substantial time series. The five-year term of the Centers has provided a great boost to field efforts in many regions. Maintaining these programs will be a challenge, but they provide critical information not just for our conceptual understanding of bloom dynamics, but also for the development and testing of mechanistic models of blooms.Methods for detection of marine algal cells and toxins are one of the primary goals of HAB research at the OHH Centers, but the work presents many challenges. Methods must be sensitive enough for detection well below regulatory limits, while being fast enough to allow for detection of toxicity before human exposure. Current methods for detecting many toxins are based on the exposure of laboratory animals to the suspect toxin, a procedure that is slow and costly, or liquid chromatographic purification of the toxin that lacks sensitivity and requires time-consuming sample preparation. Current research is directed towards developing automated portable algal cell detectors capable of distinguishing toxin-producing strains from innocuous strains and toxin sensors capable of real-time detection with high sensitivity during field operation.In general, the methods that have been developed for the detection and enumeration of HAB cells are more numerous and diverse than those for HAB toxins. HAB researchers have developed a variety of molecular technologies for cell detection including fluorescent in-situ hybridization (e.g. ), sandwiPseudo-nitzschia species in Puget Sound and Washington coastal waters can be achieved using the ARISA technique described above. Once the sensitivity of both assays is improved, ARISA and SPR biosensor detection could be combined to enable field characterization of HABs  biosensor. Center scientists raised antibodies raised against domoic acid, which were used to develop competition-based assays for a portable 6-channel SPR system designed by another Center . The curs Figure .Microcystis cells and their toxigenicity. Other researchers have previously identified the genetic pathway for microcystin synthesis, which includes a cluster of 10 genes encoding polyketide synthases and peptide synthetases [mcyA, mcyB, mcyD or mcyE genes [Microcystis in environmental samples [Microcystis in the western basin of Lake Erie and Saginaw Bay, the degree of genetic diversity of Microcystis populations and the proportion of toxic vs. nontoxic Microcystis strains. In other systems dominated by Microcystis, strains with and without the genetic potential for microcystin production generally are present [Molecular methods are also being used to detect and quantify thetases . Of the yE genes -85. In a samples ,87. Such present ,89. Resuin situ, real-time, observing systems capable of detecting specific HAB species and associated toxins.Most of the techniques and sensors developed for HAB detection still require a human operator, in a laboratory, which increases the time between sample collection and measurement. Along with cell and toxin data, we need to understand how blooms are driven by and/or respond to chemical and physical properties of the water column, and how toxins produced by some of these organisms propagate through the food web. For these reasons, the study and management of HABs would benefit tremendously from the development of remote, Direct optical measurements can provide a tractable means of detecting high biomass blooms. HAB scientists are studying toxic red tides that occur in the Gulf of Mexico using an optical sensor fitted onto an inexpensive, unmanned underwater glider that can collect continuous profiles of the water column and its characteristics . HoweverTo date, only a few of the emerging observing systems in marine and freshwater environments include HAB-specific instrumentation, since much of it is still under development. The automated real-time bloom or toxin detection systems emerging now are therefore being operated in parallel with more traditional cell and toxin detection methods to better characterize the robustness of these systems as well as the reliability and accuracy of the data. Despite the challenges that lie ahead, the development of sensors based on molecular, biological and optical techniques is progressing rapidly and holds great promise for application on autonomous platforms for future HAB management and mitigation.K. brevis can become aerosolized, which results in respiratory irritation and associated illness. Microcystins can be ingested through drinking water [Understanding the health effects of toxin exposure on humans and other animals is necessary if we are to improve prevention efforts and reduce the health risks from HAB events. In the U.S., there are few reported cases of illness from the consumption of shellfish contaminated with known HAB toxins. This is because states have effective monitoring programs that test for toxins in shellfish and, in some cases, the presence of harmful species in coastal waters. However, shellfish consumption is not the only route through which HABs impact human health. The toxins of ng water . We undeKarenia blooms. Center research has shown that average Karenia cell concentrations along the west coast of Florida have been increasing over the last 50 years, along with increases in the geographic extent and duration of the blooms [Human and animal studies are being conducted to understand the health effects of brevetoxin exposure. Studies of brevetoxin exposure are complicated by the fact that brevetoxin can enter human beings by two major pathways: ingestion of seafood contaminated with the toxins and breathing the aerosol that contains the toxins. Brevetoxin is a lipid-soluble cyclic polyether that is not easily metabolized by organisms and can be passed up the food chain . Becausee blooms .K. brevis is a relatively delicate unarmored dinoflagellate, the cells can be disrupted by surface wave action, leading to the release of brevetoxin-laden aerosols [Karenia bloom events [Because aerosols ,98. The aerosols . Inhalataerosols ,99. Peopm events . While nm events , the posCenter researchers are also examining the effects of sub-acute domoic acid (DA) exposure on gene expression in the vertebrate central nervous system using the zebrafish model system. Zebrafish are currently recognized as one of the most important vertebrate model organisms for gene function and toxicogenomics studies . In addiThe primary route of human exposure to microcystins in the Great Lakes is thought to be through drinking water and recreation. In particular, microcystin concentrations in the source waters of Saginaw Bay (Lake Huron), western Lake Erie, Bay of Quinte and Hamilton Harbor (Lake Ontario) have exceeded the recommended threshold of 1 μg/L of microcystin established for finished drinking water. Microcystin concentrations in surface scums have been measured as high as 400 μg/L , well exin utero or during early childhood, are also unknown. Our understanding of the health risks of HAB toxins, and therefore our ability to mitigate those risks, is incomplete until we know the human health effects associated with both chronic and acute toxin exposures.It is sometimes easy to lose sight of the risks that HABs pose to human health, because effective monitoring efforts prevent almost all shellfish poisoning events. The value of HAB research and monitoring is enormous in terms of risk avoidance and mitigation, but it makes epidemiological study of these phenomena extremely difficult. Almost nothing is known about the effects of toxins below these regulatory limits, yet regular consumption of drinking water and seafood may result in chronic low-level toxin exposure. This risk can be particularly pronounced in certain sub-populations, for instance the elderly, or those whose diets rely heavily on seafoods for cultural or subsistence reasons. The risks of low-level toxin exposure during development, either As mentioned above, one of the common goals of all of the OHH Centers is the development of predictive models that will help us to understand and avoid human health risks from HABs. Dyble et al. 2008   is available for people to report any effects they have felt or to ask questions about Florida's red tide. In the future, poison information center and other human health surveillance data as well as real-time monitoring by lifeguards on beaches will be incorporated into the system [Scientists use the satellite data, along with cell counts, meteorological data and oceanographic buoys to monitor bloom movement, for the purpose of predicting future developments. This information is distributed to researchers and other interested partners weekly. Information about e system .Alexandrium model benefited enormously from years of accumulated experimental data on the physiology of the dinoflagellate. This provided information on the behavior of the cysts and cells in response to light, nutrients, and temperature. Numerous research cruises collected data on cell numbers and oceanographic conditions, during bloom and non-bloom years, and on the distribution and abundance of resting cysts in the sediments. All of this information was then coupled with an existing physical model of the region. For many organisms, these basic building blocks for a model are just not available. This underscores the need for long-term observational field programs, and for basic physiological data on the organisms themselves. Our ability to understand and eventually predict HABs depends critically on this type of science.The situations in Florida and the northeastern U.S. are not typical – for most HAB organisms, no conceptual or mechanistic models are currently available. One reason for this is the lack of long-term observations and detailed laboratory studies to provide the data to parameterize and constrain the models. Development of the The establishment of the OHH Centers has greatly facilitated cooperation between researchers from different scientific disciplines and geographic regions. While Center research addresses the current challenges that HABs present, Center scientists are also cognizant of new, potentially unknown, problems in the future. Two areas that are likely to become more prominent in the near future are emerging HAB species and events, and the effects of global environmental change on HABs  and colleagues. In April 2005, they reported that the neurotoxic glutamate agonist, β-N-methylamino-L-alanine (BMAA), is produced by all known groups of cyanobacteria, including cyanobacterial symbionts and free-living freshwater, marine and terrestrial cyanobacteria ; Figure Gambierdiscus has been reported in the United States only from Hawaii, the Florida Keys, and Puerto Rico, but it has recently been reported in the Gulf of Mexico [G. toxicus in areas that are otherwise inhospitable due to unsuitable bottom conditions. The Gulf of Mexico has over 4000 of these producing sites, which provide a nexus for fisherman and potentially toxic fish. Multiple CFP cases have been reported from fish caught near oil platforms [In addition to previously unknown HAB organisms or toxins, an additional threat comes from the expansion or emergence of known HABs in areas where they have not previously occurred. Historically, f Mexico . In the latforms . The steGambierdiscus occurs primarily between the 35°N and 35°S latitudes. It is believed that any latitudinal extension of warmer water to the north where human populations are greater will similarly increase the incidence of CFP [The consequences of projected global change for HABs are generally poorly understood. They are likely to vary for tropical and temperate ecosystems because of differing regional expressions of global change in environmental forcing parameters of HAB dynamics. In the Pacific Northwest, HAB species proliferate primarily during warmer seasons , and thee of CFP . Such imAlexandrium blooms. However, considerable challenges remain for all of the HAB problems being studied. Long-term field data and basic knowledge of the effects of nutrient availability, hydrography, and genetic diversity on HAB formation and development are necessary if we are to develop accurate conceptual, empirical and numerical models. Sensor development calls for simple and rapid assays for algal cells and especially toxins. It is also critical for us to adequately understand the human health effects of HAB toxins; we best understand the acute toxicity effects, but almost nothing is known about the effects of chronic, subacute toxin exposure. At the same time that we are working towards filling the current gaps in our knowledge of HABs, we must also be aware of future challenges that we may face. Changing climate conditions may affect the range, frequency and severity of HAB events. New HABs are likely to emerge, as in the case of the cyanobacterial neurotoxin BMAA. The OHH initiatives have brought scientists together to work collectively on a number of HAB problems, both within and across regions. The successes that have been achieved highlight the value of collaboration and cooperation across disciplines to the study of HABs.HAB research at each of the OHH Centers shares a common set of goals that encompasses many of the primary needs and issues for understanding the links between HABs and human health. For all of the Centers, the ultimate goal is the development of better methods and technologies for monitoring and predicting HAB events, so that we can mitigate or eliminate their adverse human health effects. There has been notable progress towards this goal for several HAB organisms, for example the development of toxin sensors for domoic acid and the forecasting and hindcasting of The authors declare that they have no competing interests.All authors contributed to drafting the manuscript and revising it critically for intellectual content. All authors read and approved the final manuscript.


Malignant tumours contain normal cells, descendants of transformed cells, and conceivably also initiated cells which have taken some but not all of the steps toward malignancy, and hybrid cells. Tumours are propagated by multiplication of clonogenic cells, which are a subclass of the descendants of transformed cells. The clonogenic cells of a tumour may differ in respect of morphology, karyotype, metastatic capacity, sensitivity to cytotoxic drugs, expression of cell surface antigens and hormone receptors, immunogenicity, sensitivity to the immune reaction of the host, and other properties. Evidence (disputed by some) suggests that selection of particular subpopulations plays a role in tumour metastasis and recurrence. Heterogeneity may be due to pleoclonal origin, generation of phenotypic diversity within a clone, or spontaneous hybridization and chromosome loss. The possibility of interaction between different subpopulations must be taken into account in discussing tumour cell population kinetics. Heterogeneity also has important therapeutic implications and may help to explain the failure of some therapeutic regimes and the success of others.


Saturnalia suggests also that Saurischia had already diverged into Theropoda and Sauropodomorpha. Knowledge of Carnian sauropodomorphs has been restricted to this single species.The earliest dinosaurs are from the early Late Triassic (Carnian) of South America. By the Carnian the main clades Saurischia and Ornithischia were already established, and the presence of the most primitive known sauropodomorph Panphagia protos gen. et sp. nov., on the basis of a partial skeleton. The genus and species are characterized by an anteroposteriorly elongated fossa on the base of the anteroventral process of the nasal; wide lateral flange on the quadrate with a large foramen; deep groove on the lateral surface of the lower jaw surrounded by prominent dorsal and ventral ridges; bifurcated posteroventral process of the dentary; long retroarticular process transversally wider than the articular area for the quadrate; oval scars on the lateral surface of the posterior border of the centra of cervical vertebrae; distinct prominences on the neural arc of the anterior cervical vertebra; distal end of the scapular blade nearly three times wider than the neck; scapular blade with an expanded posterodistal corner; and medial lamina of brevis fossa twice as wide as the iliac spine.We describe a new small sauropodomorph dinosaur from the Ischigualsto Formation (Carnian) in northwest Argentina, Panphagia as the most basal sauropodomorph, which shares the following apomorphies with Saturnalia and more derived sauropodomorphs: basally constricted crowns; lanceolate crowns; teeth of the anterior quarter of the dentary higher than the others; and short posterolateral flange of distal tibia. The presence of Panphagia at the base of the early Carnian Ischigualasto Formation suggests an earlier origin of Sauropodomorpha during the Middle Triassic.We regard  Marasuchus lilloensisPseudolagosuchus talampayensisDromomeron romeriSilesaurus opolensisThe early evolution of the Dinosauria, including the split between its two main clades Saurischia and Ornithischia, remains poorly understood because of the scarcity of fossiliferous terrestrial beds covering the late Middle Triassic (Ladinian) and early Late Triassic (Carnian). The best preserved record of Ladinian continental tetrapod assemblages comes from the Chañares Formation in Northwestern Argentina. The representative fauna includes the best known sister taxa of Dinosauria, the dinosauriforms Alwalkeria maleriensisHerrerasaurus ischigualastensis , Eoraptor lunensisStaurikosaurus priceiSaturnalia tupiniquimSaturnalia presents apomorphies that confirm that it is a sauropodomorph  Carnian basal saurischian dinosaurs are scarce and frequently fragmentary. Most are from South America, except the fragmentary We report here a new primitive sauropodomorph dinosaur from the lower levels of the Ischigualasto Formation (Carnian) in San Juan Province, Argentina. The remains consist of one incomplete, partially disarticulated skeleton unearthed during the 2006 field season of the Museo de Ciencias Naturales of San Juan in Ischigualasto Provincial Park.The holotype was prepared using pneumatic air scribe, pin vice and water immersion. The red-brown-colored bones were embedded in a grey-green fine-grained sandstone matrix with calcareous cement. Several pieces were encased in light-grey calcareous concretions.We employ traditional, or “Romerian,” anatomical and directional terms over veterinarian alternatives Saltasaurus loricatus but not Passer domesticus, nor Triceratops horridus.”We used the phylogenetic definitions for basal taxa within Dinosauria proposed by Sereno BRMSG Bristol City Museum and Art Galleries, Bristol, United Kingdom.PVSJ Instituto y Museo de Ciencias Naturales, San Juan 5400, Argentina.YPM Peabody Museum of Natural History, Yale University, New Haven, United States of America.Dinosauria Owen, 1842Saurischia Seeley, 1887Sauropodomorpha Huene, 1932Panphagia gen. nov.pan, all (Greek); phagein, to eat (Greek); ia, pertaining to (Greek). In reference to the inferred omnivorous diet of the new taxon, which appears to be transitional between carnivory and herbivory.Panphagia protos.protos, first (Greek). In reference to the basal position of the new taxon within Sauropodomorpha.2. The specimen is an immature individual that has open neurocranial, neurocentral and scapulocoracoid sutures and an estimated body length of approximately 1.30 m.PVSJ 874; partial skull including the right nasal and prefrontal, left frontal, both parietals, both quadrates, right prootic, supraoccipital, anterior half of the left lower jaw, and right lower jaw lacking the anterior tip of the dentary; axial remains includes one anterior and two posterior cervical vertebrae, four posterior dorsal neural arches, one dorsal centrum, first primordial sacral vertebra, two proximal, one proximo-medial, and 15 distal caudal vertebrae; appendicular elements include the left scapula, left ilium, left pubic apron, left ischium, right tibia and astragalus, right metatarsal 3, proximal half of probable left metatarsal 4, and four pedal phalanges of uncertain position, one of which is an ungual. The bones were found disarticulated but in close association over an area of 1 mValle Pintado, Hollada de Ischigualasto, Ischigualasto Provincial Park, San Juan Province, Argentina .40 m above the base of the Ischigualasto Formation, Carnian (ca. 228.3 Mya) Dinosaur characterized by an anteroposteriorly elongated fossa on the base of the anteroventral process of the nasal; wide lateral flange on the quadrate with a large foramen located far from the shaft; deep groove on the lateral surface of the lower jaw surrounded by prominent dorsal and ventral ridges, extending from the position of ninth tooth to the surangular foramen; posteroventral process of the dentary bifurcated in two slender rami that overlap the lateral surface of the angular; long retroarticular process of the articular transversally wider than the articular area for the quadrate; oval scars on the lateral surface of the posterior border of the centra of cervical vertebrae; distinct prominences located posterodorsally to the diapophyses on the neural arc of the anterior cervical vertebra; distal end of the scapula blade nearly three times wider than the neck; scapula blade with an expanded posterodistal corner limited by a wedged posterior border; and medial lamina of brevis fossa twice wider than the iliac spine.Panphagia protos from known basal sauropodomorphs such as Saturnalia tupiniquim and other basal saurischians as Eoraptor lunensis.These features distinguish Eoraptor, Herrerasaurus, the basal sauropodomorph BRMSG Ca7456 Eoraptor. Nevertheless, Panphagia is slightly larger, axially more elongated, and has relatively shorter hindlimb bones than Eoraptor  and PlateosaurusThe shaft of the quadrate is dorsoventrally bowed as in oid wing . This foHerrerasaurus and basal sauropodomorphs such as PantydracoEfraasiaEoraptor, it presents a prominent nuchal crest on the posterior surface, above the dorsal border of the foramen magnum. The foramina for the vena capitis dorsalis form deep notches on the posterior surface near the laterodorsal border  that delimit deep infradiapophyseal fossae  dorsal rib has a long, robust capitulum and a short, more gracile tuberculum. The capitular articular surface is larger than the tubercular surface. A small lamina spans the distance between both articular facets. The rib curves slightly distal to the union of the capitulum and tuberculum and is straight in anterior view. The posteriorly-bowed shaft has a longitudinal sulcus on its posterodorsal side that vanishes distally.Eoraptor, Saturnalia, EfraasiaPlateosaurusHerrerasaurus and neotheropods The only one sacral vertebra preserved, the first primordial sacral. The anteriorly offset, distally expanding rib is C-shaped in lateral view . The posPanphagia are proportionally longer and lower than in Eoraptor. The anterior transverse processes are distally expanded as in Eoraptor, but are posterolaterally oriented, instead of laterally as in Eoraptor. The prezygapophyses of the distal caudals are short , tooth size differentiation along the tooth row, sublanceolate crowns that have a slight basal constriction and oblique, coarse serrations, imbricate arrangement of posterior dentary teeth, separation between the iliac blade and the posterior part of the transverse process of the first sacral vertebra, and a fibular facet on the astragalus that is transversally narrow in dorsal view. In addition, Panphagia presents some other ambiguous features that strengthen a sauropodomorph affinity.Although Panphagia is of similar length to that of Eoraptor, although all other bones are longer. Considering that the femoral length is correlated with the body mass Panphagia is relatively longer than in Eoraptor and that the femur/tibia ratio of Panphagia would have been greater than in Eoraptor. This also suggests a closer affinity affinity with Sauropodomorpha than with other basal dinosaur clades. Nevertheless it is possible than the entire hindlimb of Panphagia was relatively short compared with Eoraptor.These include reduction of the external mandibular fenestra, rudimentary lateral ridge below the tooth row on the lateral surface of the dentary, lengthening of cervical vertebrae, pubic apron blade-shaped with subparallel lateral and medial margins, and distal end of the tibia subrectangular with a transverse width slightly greater than the anteroposterior length. Furthermore, the tibia of Saturnalia, such as the anteroventral inclination of the distal border of the scapular blade, dorsally expanded distal end of the ischium, lateral border of the astragalus anteroposteriorly wider than the medial border, acute posteromedial angle of the astragalus in proximal view, and ascending process of the astragalus subrectangular with long axis anteroposterior and broader laterally than medially. However, the lack of knowledge of cranial and axial elements of Saturnalia precludes further comparisons.The new specimen shares some features with Panphagia represents the primitive condition when compared with the reduced skull length in other sauropodomorphs. Although the femur is unknown, we infer a skull/femur length ratio of approximately 0.7 based on Eoraptor. This ratio is greater than that inferred for SaturnaliaThe relatively long skull of Panphagia and Eoraptor, such as the extremely hollow bones, similar structure and proportions, internarial process arched above the margin of the skull in lateral view, sublanceolate teeth with lateral prominences on the crowns, dorsoventral compression of the anterior part of the external mandibular fenestra; transverse process of the first primordial sacral vertebra not reaching the ilium, pubic apron blade-shaped with a subparallel lateral and medial margins; distal end of the tibia subrectangular with transverse width slightly greater than the anteroposterior length, medial tip of the posterolateral process of the tibia not distally projected, fibular facet of the astragalus transversally narrow; and ascending process of the astragalus subrectangular with the longer axis anteroposteriorly oriented and laterally wider than medially, among others.Several features are shared between Saturnalia are not surprising, because Saturnalia is currently recognized as a sauropodomorph, but the resemblance with Eoraptor is noticeable, especially if it is considered as a theropod Eoraptor exceeds the purpose of this study, as was noted before, Eoraptor exhibit some features that resemble sauropodomorphs. Those characters are: lanceolate teeth; enlarged external nares; and mandibular joint well below the tooth row Eoraptor, such as the extremely hollow limb bones are also present in basal sauropodomorphs . The new analysis resulted in three most-parsimonious trees of 187 steps . An implPanphagia within Sauropodomorpha as the most basal sauropodomorph and sister group to Saturnalia and other sauropodomorphs. These trees differ from those of Langer and Benton Silesaurus and Guaibasaurus ; lanceolate crowns in most dentary teeth (char. 26); tooth crowns of the anterior quarter of the dentary series higher than the others (character 28); and short posterolateral flange of distal tibia (character 90). The characters that place Panphagia as less derived than Saturnalia are: posteriorly curved crowns (character 25); roughly semicircular distal outline of ischium (character 81); and lateral condyle of tibia posteriorly located (character 85). The aforementioned discussion suggests that Panphagia represents a new distinctive sauropodomorph, representing the most primitive known taxon of Sauropodomorpha.Four synapomorphies unite Eoraptor, Saturnalia and Guaibasaurus. Panphagia and two new but unpublished basal saurischians from the Carnian Ischigualasto Formation Eoraptor, Panphagia and the new basal theropod PVSJ 560 The early evolution of saurischians dinosaurs from a small cursorial ancestor Saturnalia was discovered in the rhynchosaur biozone of the Carnian Santa María Formation in Brazil, strata widely regarded as contemporary to the Ischigualasto Formation in Argentina based on faunal similarities Panphagia near the base of the Ischigualasto Formation suggests that the origin of Sauropodomorpha occurred during the Ladinian or earlier during the Middle Triassic. Panphagia lived with at least other five different basal dinosaurs (Eoraptor, Herrerasaurus, PVSJ 605 The basal sauropodomorph


The novel antifolate lometrexol  inhibits de novo purine biosynthesis, and co-incubation with hypoxanthine abolishes its cytotoxicity. The prevention of hypoxanthine rescue from an antipurine antifolate by the nucleoside transport inhibitor dipyridamole was investigated for the first time in nine human and rodent cell lines from seven different tissues of origin. In A549, HeLa and CHO cells, dipyridamole prevented hypoxanthine rescue and so growth was inhibited by the combination of lometrexol, dipyridamole and hypoxanthine, but in HT29, HCT116, KK47, MDA231, CCRF CEM and L1210 cells dipyridamole had no effect and the combination did not inhibit growth. Dipyridamole inhibited hypoxanthine uptake in A549 but not in CCRF CEM cells. Dipyridamole prevented the hypoxanthine-induced repletion of dGTP pools, depleted by lometrexol, in A549 but not in CCRF CEM cells. Thus, the selective growth-inhibitory effect of the combination of lometrexol, dipyridamole and hypoxanthine is apparently due to the dipyridamole sensitivity (ds) or insensitivity (di) of hypoxanthine transport. Both the human and murine leukaemic cells are of the di phenotype. If this reflects the transport phenotype of normal bone marrow it would suggest that the combination of lometrexol, dipyridamole and hypoxanthine might be selectively toxic to certain tumour types and have reduced toxicity to the bone marrow.


Previous studies have shown that in certain tissues, including colonic carcinomas, cell proliferation may be promoted by serotonin, and indirect evidence suggests that the effects of this amine on colonic tumours involves a cellular-uptake mechanism. In the present study, two specific inhibitors of serotonin uptake, Citalopram and Fluoxetine, are examined for their effects on cell proliferation and tumour growth. Each of the agents was found to suppress cell division in dimethylhydrazine-induced colonic tumours in rats, and to retard the growth of 2 out of 3 lines of human colonic tumours propagated as xenografts in immune-deprived mice.


Mucositis, also referred to as mucosal barrier injury, is one of the most debilitating side effects of radiotherapy and chemotherapy treatment. Clinically, mucositis is associated with pain, bacteremia, and malnutrition. Furthermore, mucositis is a frequent reason to postpone chemotherapy treatment, ultimately leading towards a higher mortality in cancer patients. According to the model introduced by Sonis, both inflammation and apoptosis of the mucosal barrier result in its discontinuity, thereby promoting bacterial translocation. According to this five-phase model, the intestinal microbiota plays no role in the pathophysiology of mucositis. However, research has implicated a prominent role for the commensal intestinal microbiota in the development of several inflammatory diseases like inflammatory bowel disease, pouchitis, and radiotherapy-induced diarrhea. Furthermore, chemotherapeutics have a detrimental effect on the intestinal microbial composition (strongly decreasing the numbers of anaerobic bacteria), coinciding in time with the development of chemotherapy-induced mucositis. We hypothesize that the commensal intestinal microbiota might play a pivotal role in chemotherapy-induced mucositis. In this review, we propose and discuss five pathways in the development of mucositis that are potentially influenced by the commensal intestinal microbiota: 1) the inflammatory process and oxidative stress, 2) intestinal permeability, 3) the composition of the mucus layer, 4) the resistance to harmful stimuli and epithelial repair mechanisms, and 5) the activation and release of immune effector molecules. Via these pathways, the commensal intestinal microbiota might influence all phases in the Sonis model of the pathogenesis of mucositis. Further research is needed to show the clinical relevance of restoring dysbiosis, thereby possibly decreasing the degree of intestinal mucositis. Mucositis, also referred to as mucosal barrier injury, is one of the most debilitating side effects of radiotherapy and chemotherapy treatment Historically, research has focused on oral mucositis. More recently, attention has been drawn towards the pathophysiology and clinical symptoms of intestinal mucositis, which is characterized by symptoms like nausea, bloating, vomiting, abdominal pain, and severe diarrhea According to the model introduced by Sonis, five phases are important in the pathophysiology of mucositis: (1) the formation of reactive oxygen species leading to the activation of nuclear factor kappa B (NFκB) during the initiation phase, 2) the induction of messenger molecules such as tumor necrosis factor alpha (TNFα), resulting in treatment-related tissue inflammation and apoptosis during the upregulation/message generation phase, (3) the amplification of messenger molecules in the amplification/signaling phase, leading to more inflammation and apoptosis, (4) discontinuity of the epithelial barrier resulting from apoptosis during the ulcerative phase, thereby promoting bacterial translocation, and (5) a spontaneous healing phase, characterized by cell proliferation  the induA detailed review of the communication pathways between the intestinal microbiota and the human host is beyond the scope of this article and this communication is therefore only shortly reviewed.The epithelial barrier lining the gastrointestinal tract is composed of a single layer of epithelial cells intertwined by tight junctions An important aspect of these two functions of the epithelial cells is the dual mucus layer at the apical side of the epithelial cells With respect to the communication between microbes and the gut, two groups of receptors are thought to be important in the communication between the human body and the resident microbiota: the Toll-like receptor (TLR) family and the nucleotide oligomerisation domain (NOD) receptor family Not only epithelial cells, but also local dendritic cells are thought to play a role in the initiation and/or modulation of intestinal inflammation and, in addition, in the induction of tolerance Bacteroides thetaiotaomicron and Bifidobacterium infantis both decrease NFκB activation Clostridium XIVa group has been proposed to attenuate intestinal inflammation by exerting an effect on polyamine secretion, which in turn regulates the expression of TLR-2 The healthy human intestine is characterized by a state of low-grade inflammation. The resident microbiota guarantees a constant exposure to TLR ligands such as peptidoglycan, LPS, and bacterial DNA. This ensures a continuous basal activation of downstream signaling pathways, resulting in low-grade physiological inflammation Faecalibacterium prausnitzii secretes a substance capable of decreasing NFκB activation. This so far unidentified substance induces the production of the anti-inflammatory IL-10, thereby attenuating inflammation. B. infantis also secretes an unidentified product that attenuates colitis in mice F. prausnitzii and Clostridium XIVa and has been shown to have profound anti-inflammatory effects Bacteria or bacterial parts, as well as their secreted products, relieve inflammatory symptoms. For example, In short, multiple intestinal bacteria are capable of decreasing NFκB activation, resulting in a diminished production of inflammatory cytokines. The exact nature and relevance of the relationship between chemotherapy-induced mucositis, inflammation, and intestinal microbiota is subject to ongoing research.Intestinal permeability increases after chemotherapy treatment, and has been shown to be one of the hallmarks of the third and fourth phases of mucositis as reported by Sonis Another factor contributing to attenuating intestinal permeability is the bacterial induction of heat shock proteins (HSPs). These HSPs are thought to preserve the viability of epithelial cells in stress conditions Finally, the bacterial production of SCFAs is associated with a reduction in intestinal permeability. This effect of SCFAs is also proposed to be mediated by an increase in epithelial cell viability Epithelial cell loss is a hallmark of the third phase of the five-phase mucositis model, eventually resulting in an increased permeability. The commensal intestinal microbiota attenuates cellular atrophy and increases tight junction strength. Therefore, we propose that changes in the commensal intestinal microbiota influence the third phase of mucositis. This way, the commensal intestinal microbiota might influence the eventual severity of mucositis encountered in the ulcerative phase.As mentioned before, the mucus layer covering the intestinal epithelium strengthens the mechanical epithelial barrier. The protective mucus layer is comprised of glycoproteins, trefoil factors, and mucins. These mucins are produced by goblet cells, which are specialized epithelial cells The commensal intestinal microbiota is proposed to play a role in the maintenance of the mucus layer. Indeed, the absence of these intestinal microbiota is associated with a decrease in goblet cells, which are also smaller in size Lactobacillus rhamnosus Gorbach and Goldin (GG) and Lactobacillus plantarum increase the expression of MUC-2 and MUC-3 genes, and Lactobacillus acidophilus upregulates MUC-2 gene expression The genes encoding mucins are directly regulated by bacteria and their products MUC genes, but also interferes with the expression and/or activity of cell glycosyltransferases. These enzymes induce changes in the carbohydrate repertoire of mucins, which might change their efficacy in bacterial defense The commensal resident microbiota not only interferes with the expression of Thus, the intestinal microbiota influences the composition of the mucus layer covering the epithelium, thereby increasing the strength of the epithelial barrier. A strengthened barrier decreases the risk of bacterial translocation, thereby possibly attenuating inflammation present in the ulcerative phase of the Sonis mucositis model.The commensal intestinal microbiota contributes to epithelial repair. In germ-free animals, the mitotic index and cell turnover of epithelial cells are lower as compared to normally colonized animals Bacterial induction of NFκB not only controls the physiological state of low-grade inflammation in the intestine, it also stimulates the repair of, for example, mechanical-induced epithelial damage L. rhamnosus GG, have been shown to inhibit cytokine-induced apoptosis and promote cell growth, thereby also enhancing mucosal repair Bacteria acting as TLR ligands are not the only ones that play an important role in increasing the resistance towards harmful stimuli and enhancing epithelial repair. Again, butyrate plays an important role. Butyrate stimulates the migration of epithelial cells, thereby enhancing mucosal healing Therefore, we again propose that the commensal intestinal microbiota might attenuate the epithelial damage in the third phase of mucositis. As the commensal intestinal microbiota stimulates epithelial repair mechanisms, it can be hypothesized that the microbiota also attenuates mucositis by influencing the healing phase of mucositis.The commensal intestinal microbiota regulates the expression and release of immune effector molecules. These molecules are pivotal for maintaining intestinal homeostasis Another immune effector molecule influenced by the resident microbiota is immunoglobulin A (IgA). IgA is produced by mucosa-associated immune effector cells Both live bacteria and their products are capable of upregulating immune effector molecules. For example, SCFAs such as butyrate regulate the production of cathelicidins, which exhibit broad-spectrum anti-bacterial activity against potential pathogens By influencing the expression and release of immune effector molecules, the commensal intestinal microbiota regulates itself and maintains homeostasis in the intestinal tract. In the end, this will positively influence all five phases described in Sonis's mucositis model.Although the protective role of commensal intestinal bacteria in human disease is increasingly being appreciated, research concerning the relationship between intestinal bacteria and chemotherapy-induced mucositis is still scarce. Most studies that investigate the role of bacteria in human disease have focused on inflammatory bowel disease, which is caused by a chronic inflammatory process instead of the acute damage induced by chemotherapeutics.In the model introduced by Sonis to explain the pathogenesis of radiotherapy-induced and chemotherapy-induced mucositis, the resident intestinal microbiota played no role Further research will also have to show the clinical relevance of restoring dysbiosis, thereby possibly decreasing the degree of intestinal mucositis. This would not only increase the quality of life of patients, but could also positively influence treatment intensity, probably decreasing the morbidity and mortality of cancer patients. Completely restoring dysbiosis might be a clinical problem, since whole live bacteria used as probiotics have already been described as causing invasive infections in immunocompromised patients and were associated with increased mortality in patients with severe pancreatitis