This adaptability of motility styles to the environment is currently considered to be the main reason for the failure of clinical trials testing protease inhibitors in patients with metastatic cancers. Brabek et al. [ad hoc switch between different motility strategies. The interest of molecular biologists is particularly focussed on this family of GTPases and their regulators as targets for an effective antimetastatic therapy. Indeed, instead of inhibiting a specific motility mechanism, it would be preferable to target the adaptation skills of cancer cells to the tumor microenvironment.Eukaryotic cells move within the surrounding environment essentially for two reasons: the necessity to reach a predetermined site or the hostility of the primitive site. Moving in the direction of an attractive site or factor is typical for embryonic movements and metastatic dissemination of cancer cells and motility strategies are very similar for both categories. Activation of an epigenetic process called epithelial mesenchymal transition (EMT) is indeed characteristic of embryonic development, of fibrotic or regeneration processes, and of the spreading of cancer cells from their primitive origin ,2. The mk et al.  review ik et al.  focus onThis microenvironment is indeed a mandatory element for the regulation of cell motility . Three kThe nervous system also plays an important role in cell motility, for two reasons: the secretion of neurotransmitters which also act as motility factors and the contribution of an alternative escaping way to migrating cells, commonly called perineural invasion. In this special issue Voss and Entschladen review this aspect with a particular focus on the role of cathecolamine and stress mediators on tumoral cell motility .As mentioned at the beginning, a second reason for cells to move is the escape from an hostile ambiente, for example due to the scarcity of growth factors (chemotaxis), due to the presence of improper ECM (aptotaxis and durotaxis), because of the accumulation of toxic or pro-oxidant factors  or to escape oxygen or nutrient deprivation (hypoxia and ischemia). De Donatis et al.  focus thFar from being exhaustive, this special issue focused on cell motility aims to underscore the fertility of the current research efforts in this field, as well as highlighting key questions that still are awaiting definitive answers.


The lung is constantly exposed to the environment and its microbial components. Infections of the respiratory tract are amongst the most common diseases. Several concepts describe how this microbial exposure interacts with allergic airway disease as it is found in patients with asthma. Infections are classical triggers of asthma exacerbations. In contrast, the hygiene hypothesis offers an explanation for the increase in allergic diseases by establishing a connection between microbial exposure during childhood and the risk of developing asthma. This premise states that the microbial environment interacts with the innate immune system and that this interrelation is needed for the fine-tuning of the overall immune response. Based on the observed protective effect of farming environments against asthma, animal models have been developed to determine the effect of specific bacterial stimuli on the development of allergic inflammation. A variety of studies have shown a protective effect of bacterial products in allergen-induced lung inflammation. Conversely, recent studies have also shown that allergic inflammation inhibits antimicrobial host defense and renders animals more susceptible to bacterial infections. This paper focuses on examples of animal models of allergic disease that deal with the complex interactions of the innate and adaptive immune system and microbial stressors. The lung is constantly exposed to the environment and its microbial components. Infections of the respiratory tract are amongst the most common diseases. Several concepts describe how this microbial exposure interacts with allergic airway disease as it is found in patients with asthma. Infections are classical triggers of asthma exacerbations. Infections of the respiratory tract, especially with various viruses, are common causes of exacerbation of asthma ,2.The hygiene hypothesis offers an explanation for rising rates of allergic diseases such as asthma in modern westernized societies. The core of this hypothesis is the complex interaction of the microbial environment and the innate immune system in the childhood of individuals. In modern societies, different factors such as small family size, high antibiotics use, and good sanitation contribute to higher living standards and life expectancy . As a reThe observed protective effect of farming environments in connection with environmental exposure to endotoxin may have a crucial role in the development of tolerance to ubiquitous allergens found in natural environments against asthma . This obLactobacillus reuteri attenuated the influx of eosinophils into the respiratory tract and was accompanied by levels of Th2 cytokines.In the last years, it has become clear that the appropriate bacterial composition of the human microflora is a factor in protection from allergy and asthma and is needed for an adequate Th1 / Th2 balance . InteresThe studies outlined above deal with the impact of bacterial stressors that preferentially promote a Th1 cell mediated response on the development of Th2 mediated allergic disease such as asthma. Conversely, a largely unknown field is the influence of established allergic diseases on infectious diseases that require an appropriate innate or Th1 cell mediated immune response.Pseudomonas aeruginosa. Mice with allergic airway inflammation had more viable bacteria and reduced levels of pro-inflammatory cytokines and antimicrobial peptides in their lung. Furthermore, the influx of neutrophils into the respiratory tract was significantly diminished in asthmatic animals.A recent study investigated the effect of an established allergic inflammation of the lung on the innate host defense during bacterial infection of the respiratory tract . The maiThe suppressive effect of the Th2 milieu was also shown in an in vitro model using differentiated human airway epithelia tissue . The Th2Mycoplasma and Chlamydia species [These results provide evidence that the adaptive immune system closely interacts with the innate immune system and that the adaptive immune response influences the innate host defense Figure . The Th2 species .The development of allergic diseases is a complex process. In recent years, it became clear that the interaction of the microbial environment with the innate and adaptive immune system during childhood is crucial for a well balanced immune system. The combination of animal models of allergic disease with infection models is a useful tool to further study the interactions between these processes and is a starting point for new therapeutic strategies.The authors declare that they have no competing interests.


One hundred resected cases of squamous cell carcinomas of the oesophagus were reviewed and a series of histological criteria related to the survival time. Two histological features were important in the assessment of survival. Good prognostic factors were a marked lymphocytic response to the tumour and a lack of intravenous tumour infiltration. Presence of tumour in the middle third of the oesophagus, infiltration through the muscularis propria, severe tumour necrosis, glandular or small cell tumour differentiation, lymphatic invasion and lack of peritumoural fibrosis were all factors which tended to worsen prognosis. None of these factors reached statistical significance. The degree of squamous differentiation had no effect on survival.


The emergence of drug resistance in treated populations and the transmission of drug resistant strains to newly infected individuals are important public health concerns in the prevention and control of infectious diseases such as HIV and influenza. Mathematical modelling may help guide the design of treatment programs and also may help us better understand the potential benefits and limitations of prevention strategies.To explore further the potential synergies between modelling of drug resistance in HIV and in pandemic influenza, the Public Health Agency of Canada and the Mathematics for Information Technology and Complex Systems brought together selected scientists and public health experts for a workshop in Ottawa in January 2007, to discuss the emergence and transmission of HIV antiviral drug resistance, to report on progress in the use of mathematical models to study the emergence and spread of drug resistant influenza viral strains, and to recommend future research priorities.General lectures and round-table discussions were organized around the issues on HIV drug resistance at the population level, HIV drug resistance in Western Canada, HIV drug resistance at the host level , and drug resistance for pandemic influenza planning.Some of the issues related to drug resistance in HIV and pandemic influenza can possibly be addressed using existing mathematical models, with a special focus on linking the existing models to the data obtained through the Canadian HIV Strain and DR Surveillance Program. Preliminary statistical analysis of these data carried out at PHAC, together with the general model framework developed by Dr. Blower and her collaborators, should provide further insights into the mechanisms behind the observed trends and thus could help with the prediction and analysis of future trends in the aforementioned items. Remarkable similarity between dynamic, compartmental models for the evolution of wild and drug resistance strains of both HIV and pandemic influenza may provide sufficient common ground to create synergies between modellers working in these two areas. One of the key contributions of mathematical modeling to the control of infectious diseases is the quantification and design of optimal strategies, combining techniques of operations research with dynamic modeling would enhance the contribution of mathematical modeling to the prevention and control of infectious diseases. The emergence of drug resistance in treated populations and the transmission of drug resistant strains to newly infected individuals are important public health concerns in the prevention and control of infectious diseases such as HIV and influenza. Mathematical modelling may help guide the design of HIV treatment programs to minimize the development and spread of drug resistant strains. Modelling may also help us achieve a better understanding of the optimal use of antiviral drugs as the first line of defence against a new strain of influenza and of the potential benefits and limitations of mitigation strategies using antiviral drugs during an influenza pandemic.While acknowledging the fundamental differences in the evolution of drug resistance between the two diseases, sufficient common ground may be found to create synergies between modellers working in these two areas. To explore this further, the Public Health Agency of Canada (PHAC) and Mathematics for Information Technology and Complex Systems  organized a workshop in Ottawa in January 2007. The workshop brought together selected scientists and public health experts to discuss the emergence and transmission of HIV antiviral drug resistance, to report on progress in the use of mathematical models to study the emergence and spread of drug resistant influenza viral strains, and to recommend future research priorities.Dr. Chris Archibald  indicated that PHAC strongly supports collaboration between modelers and public health policy makers to better understand the evolution of drug resistant strains and that the research priority recommendations coming out of the meeting would be closely examined.In the opening remarks, Dr. Donald Sutherland  spoke about the work of WHO in the area of HIV drug resistance (DR) and the approach to HIVDR within the global goal of universal access to anti-retroviral treatment by 2010. He stressed the importance of addressing the potential problem of drug resistance during the scale-up of anti-retroviral treatment programs. WHO's program of HIVDR monitoring follows individuals who are starting HIV treatment for the first time and makes use of a variety of early warning indicators that may signal a potential problem with drug supply or treatment compliance, and hence a greater likelihood of the development of HIV drug resistance. HIVDR transmission surveillance is done through a threshold survey of a small number of recently infected persons to assess transmitted HIV drug resistance; the percentage of persons that show laboratory evidence of DR is used to decide whether to trigger a set of specific recommended actions (with 5% being the first threshold for considering action). Dr. Sutherland concluded by providing a number of useful WHO web links for HIV treatment and drug resistance information [ormation .Dr. Sally Blower  echoed the concern that the scale-up of anti-retroviral treatment could generate an epidemic of drug resistant HIV. She reviewed her previous modelling work on HIV and anti-retroviral treatment [In a lecture entitled "Predicting the Unpredictable: the Evolution of Drug Resistant HIV Epidemic in Africa", reatment -9 that areatment ,10,11. Hreatment -15.Dr. Sally Blower's lecture also illustrated how mathematical modelling can be used to help determine the optimal use of limited resources. She presented recent work  that useDr. Gayatri Jayaraman  introduced the Canadian HIV Strain and DR Surveillance Program. She described the methods used to collect samples from individuals newly diagnosed with HIV and to analyze pol gene sequences to determine drug resistance mutations according to the International AIDS Society-USA list (2005). She stressed the uniqueness of this surveillance program since it gathers data at the population level rather than from a limited number of clinical sites. Dr. Ping Yan  then presented his exploratory analysis of trends in transmitted drug resistance in western Canada, and Dr. Shenghai Zhang  discussed further stratification of the population and its impact on the trend analysis.In summary, this work modeled trends in the prevalence of transmitted drug resistance using data collected from this surveillance program for the four provinces of western Canada between 1998 and 2004. Generalized linear models were fit to the binary data to examine trends in drug resistance for three drug classes: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). The results showed that while the overall prevalence of transmitted drug resistance has remained constant over time, there were significant differences according to drug class: a decrease in the prevalence of transmitted NRTI resistance, an increase in the prevalence of transmitted NNRTI resistance, and little change in the prevalence of transmitted PI resistance. In addition, there were distinct differences between provinces in these trends. Possible reasons for these differences over time and between provinces include changes in drug prescribing patterns and in risk behaviours. In conclusion, the results highlight the need for continued national surveillance of transmitted drug resistance to fully understand inter-regional differences and the course of the HIV epidemic in Canada .Four lectures dealt with HIV drug resistance and optimal treatment strategies.Dr. John Mittler  described two kinds of regimen-sparing treatment strategies: structured treatment interruptions and induction-maintenance therapies. He then presented his model-based analysis to help determine the optimal length for the induction phase, ways to improve the success of induction-maintenance therapy, and which drugs should be included in the induction and maintenance regimens [regimens ,19.Dr. Robert Smith?  emphasized that mathematical models for HIV treatment should explicitly account for the mechanics and temporal aspects of drug dosing. His analysis suggested that the use of PIs alone may lead to treatment failure, whereas RTIs would lead to treatment success, whether or not they were combined with PIs. He also presented his recent work which shows that to minimize drug resistance, RTI therapy should remain outside a certain (predictable) parameter region [r region ,21.Dr. Beni Sahai  presented several theories for the loss of effectiveness of the anti-HIV immune response, and concluded that anti-HIV cytotoxic T-lymphocytes (CTLs) play an essential role in preventing progression to AIDS and that drug-resistant HIV strains do not cause a surge of viremia or accelerate progression to AIDS in the presence of multivalent anti-HIV CTLs.In his lecture entitled "Emergence and Impact of HIV CTL-Escape Mutants on Progression to AIDS", Dr. Jane Heffernan  noted that viral load and CD4 T-cell counts in patients infected with HIV are commonly used to guide clinical decisions regarding drug therapy or to assess therapeutic outcomes in clinical trials. However, random fluctuations in CD4 T-cell count and viral load, due solely to the stochastic nature of HIV infection, can obscure clinically significant change. She reported her work [her work -24 that Influenza pandemics have historically been devastating to human populations. Considering the extent of morbidity and mortality caused by previous pandemics and the growing threat of an imminent human outbreak of the avian influenza strain H5N1, identification of effective mitigation strategies is a major global public health priority. It has been recognized that pharmaceutical measures  would have the greatest impact in containing a pandemic. However, given the significant challenges involved in the development of an effective vaccine against a newly emerging pandemic strain, it is likely that antiviral drugs will be the sole pharmaceutical defense. Since a critical limitation to their application is the emergence of highly transmissible resistant viral mutants, it is paramount to evaluate the use of these drugs for both treatment and prophylaxis. To do this, mathematical models need to be developed that not only incorporate the population phenomenon of disease transmission, but also integrate viral evolution and disease dynamics at the individual level.Dr. Seyed Moghadas  described a model to evaluate the potential impact of an antiviral drug strategy on the emergence of drug-resistance and containment of an influenza pandemic [pandemic . The modDr. Murray Alexander  compared deterministic models with individual-based network models [k models -29 and sDr. John Glasser  spoke about the evaluation of alternative vaccination and treatment strategies. He presented a standard compartmental model in which infection rates reflected different social activities and networking by age-group [ge-group . The impDrs. Fred Brauer  and Zhilan Feng , Dr. Theresa Tam  suggested that pandemic influenza plans should incorporate other non-medical measures  and she encouraged further work that examines the drug resistance issue for scenarios involving prophylaxis as well as treatment.In a discussion facilitated by Dr. Jianhong Wu . He first invited Dr. Jayaraman to comment on the HIV issues that should be addressed through modeling and Dr. Jayaraman listed some of the areas where she and her colleagues at PHAC thought input from modelers would be most useful:The workshop ended with a group discussion on next steps coordinated by 1. To predict the incidence and prevalence of transmitted (and acquired) drug resistance;2. To model the contribution of transmitted DR to overall DR HIV prevalence;3. To model the contribution of transmitted DR to annual HIV incidence;4. To model which factors contribute the most to transmitted (and acquired) DR and what factors that can minimize the transmission of DR;5. To model the level of increased risk behaviour that would off-set the expected decrease in HIV incidence resulting from widespread anti-retroviral therapy use.The general discussion suggested that some of these issues can possibly be addressed using existing mathematical models, with a special focus on linking the existing models to the data obtained through the Canadian HIV Strain and DR Surveillance Program. Participants noted that the preliminary statistical analysis of these data led by Dr. Yan has already provided some solutions to items #1–4 in terms of historical data. This, together with the general model framework discussed in Dr. Blower's lecture, should provide further insights into the mechanisms behind the observed trends and thus could help with the prediction and analysis of future trends in the aforementioned items. Participants also noted the remarkable similarity between dynamic, compartmental models for the evolution of wild and drug resistance strains of both HIV and pandemic influenza, and so the above remarks also apply to the drug resistance issue for pandemic influenza. It was suggested that proposals should be prepared to apply for funding to develop new models and take advantage of the large amount of high quality surveillance data available at PHAC.The participants felt the urgent need of high quality clinical data for the study of drug resistance and it was believed that future collaboration between modelers and public health policy makers would benefit very much from a centralized clinical data base. Therefore, it was recommended that such a data base should be developed as soon as possible.Finally, participants observed that one of the key contributions of mathematical modeling to the control of infectious diseases is the quantification and design of optimal strategies. This was demonstrated in all the lectures of the workshop and the proposed priority item #5 further reinforced this observation. Combining techniques of operations research with dynamic modeling would enhance the contribution of mathematical modeling to the prevention and control of infectious diseases.Mathematics for Information Technology and Complex Systems (MITACS) provides the funding support to cover the article processing cost. Otherwise, the authors declare that they have no competing interests.JW, PY and CA helped conceive the workshop and participated in its design and coordination. JW summarized the workshop discussion based on the invited lectures and the round-table discussions, JW and PY then converted this summary to a preliminary version of the manuscript. JW, PY and CA all participated in the revision process, and all read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


The human microbiome, especially in the intestinal tract has received increased attention in the past few years due to its importance in numerous biological processes. Recent advances in DNA sequencing technology and analysis now allow us to better determine global differences in the composition of the gut microbial population, and ask questions about its role in health and disease. Thus far, roles of these commensal bacteria on nutrient acquisition, vitamin production, and intestinal development have been identified Despite all the increased attention on the interface between the microbiota and host immune responses, it is still unclear whether these commensal bacteria affect the efficacy of vaccines. Due to its impact in the development of immune function, both in the gut and other organs, it is reasonable to consider that the intestinal microbiota will significantly affect how individuals respond to vaccine antigens Shigella flexneri also showed differential protection on individuals from developing countries. In a study testing Bangladeshi adults and children, no significant immune response to this vaccine was mounted, although the same antigen was reactogenic in North American individuals Clinical trials testing the efficacy of oral vaccines against polio, rotavirus, and cholera have showed a lower immunogenicity of these vaccines in individuals from developing countries when compared to individuals from the developed world SalmonellaHaemophilus influenzae type B, and hepatitis B Salmonella infection Discerning the effects of genetic and environmental factors on vaccine efficacy is a challenging task. Large clinical trials involving individuals from different areas of the world will likely be required to shed light on whether the blunt immune responses to some of the oral vaccines mentioned herein are a consequence of genetic factors or environmental variations, such as the gut microbial community. Studies involving immigrant volunteers could be useful in addressing this issue by providing a clear distinction between the effects of genetics and the environment. Although this is still an open question, data in the literature suggest a more direct link between the intestinal microbiota composition and the development of immune responses to certain vaccine antigens. For instance, the use of antibiotics in chickens has been shown to increase the antibody response following immunization Although some studies indicate that the microbiota may play an important role in vaccine efficacy, this area of research is still in its infancy. For instance, the mechanisms involved in the pro- and prebiotic enhancement of vaccine efficacy mentioned above are largely unknown. Nevertheless, current knowledge of the effect of the intestinal microbiota on the development of not only local but also systemic immune functions provides a direct link between commensal populations in the intestine and immune responses to vaccine antigens


The chemical behavior of these complexes has been studied by means ofspectroscopic techniques both in slightly acidic distilled water and in phosphate bufferedsolution at physiological pH. The influence of biological reductants on the chemicalbehavior is also described. The antitumor properties have been investigated on a numberof experimental tumors. Out of the effects observed, notheworthy appears the capabilityof the tested ruthenates to control the metastatic dissemination of solid metastasizingtumors. The analysis of the antimetastatic action, made in particular on the MCamammary carcinoma of CBA mouse, has demonstrated a therapeutic value for thesecomplexes which are able to significantly prolong the survival time of the treatedanimals. The antimetastatic effect is not attributable to a specific cytotoxicity formetastatic tumor cells although in vitro experiments on pBR322 double stranded DNAhas shown that the test ruthenates bind to the macromolecule, causing breakscorresponding to almost all bases, except than thymine, and are able to cause interstrandbonds, depending on the nature of the complex being tested, some of which results activeas cisplatin itself.In this paper we report a review of the results obtained in the last few years by ourgroup in the development of ruthenium(III) complexes characterized by the presence ofsulfoxide ligands and endowed with antitumor properties. In particular, we will focus onruthenates of general formula Na[


This study compared the histologic characteristics of ulcerative colitis with findings on conventional colonoscopy and on magnification and dye application for 70 sites that underwent biopsy. The primary objective was to study the correspondence between histologic findings and endoscopic findings with respect to glandular restructuring and the resolution of inflammation from the active to the remission phase of ulcerative colitis. Widened grooves, as assessed by the endoscopic staining technique and magnified observation, most closely correlated with histologic evidence of resolution of inflammation, and vascular markings and color tone of the mucosa on general colonoscopy most closely correlated with histologic evidence of glandular restructuring, such as glandular maturity. Magnifying endoscopy after dye application, in addition to conventional endoscopy, is therefore considered essential in the evaluation of ulcerative colitis during the resolving phase.


A case of cholangitis due to the migration of a metal clip used for surgical cholecystectomy 4 yearsearlier, is reported. The diagnostic approach and therapeutic options, either endoscopic or surgical arediscussed. The use of resorbable clips during the performance of laparoscopic cholecystectomy shouldavoid this type of complication.


An unusual anatomic variation of the deltoid muscle was found in a 45-year-old female cadaver during dissection of the right upper extremity. The posterior fibers of the right deltoid muscle were enclosed in a distinct fascial sheet and the deltoid muscle was seen to arise from the middle 1/3 of the medial border of the scapula. There was no accompanying vascular or neural anomaly of the deltoid muscle. To the best of our knowledge, unilateral posterior separation of the deltoid muscle with a distinct fascia has not been described previously. While dissecting deltoid, posterior deltoid, or scapular flaps, the surgeon needs to look out for this variation because it may cause confusion. The deltoid muscle derives from the dorsal muscle mass of the limb bud which is formed by somatic mesoderm during the fifth intrauterine week. VariatioDuring the gross anatomic dissection of the right upper extremity of a 45-year-old female cadaver, we observed an unusual anatomic variation of the deltoid muscle. The posterior fibers of the right deltoid muscle were enclosed in a distinct fascial sheath . In addiThe deltoid muscle arises from the anterior border and upper surface of the lateral third of the clavicle, the lateral margin and upper surface of the acromion, and the lower edge of the posterior border of the spine of the scapula. The insertion is into the deltoid tubercle on the middle of the lateral side of the body of the humerus. It is inThe continuation of the fibers of the deltoid muscle into the trapezius; fusion with the pectoralis major; and the presence of additional slips from the vertebral border of the scapula, infraspinous fascia, and the axillary border of scapula are the commonly reported variations of the deltoid muscle.The myogenic cells coalesce into two muscle masses during the fifth intrauterine week. One is tClinically fasciocutaneus, musculocutaneus or muscular deltoid and posterior deltoid flaps are especially used in; tetraplegia (by a transfer to triceps), radionecrotic defects situated over the glenohumeral joint, reconstruction of extremity, rotator cuff tears, and oral cavity. While elevating musculocutaneus or muscular deltoid and posterior deltoid flaps, the surgeon must be alert to the possibility of this variation's presence because it may cause confusion when dissecting the borders. Similarly, while elevating fasciocutaneus deltoid and posterior deltoid flaps or a scapular flap (either transverse or parascapular), an accessory deltoid may be confused with the teres major muscle because of its location and its distinct fascia and as a result of this the dissection of the pedicle can be much more difficult. To conclude, the variations possible in this region should be kept in mind during any surgery.


Five patients with papillary adenocarcinoma of the common bile duct (CBD) are described.These are rare tumors and make up 5% of all malignant tumors of the biliary tract. Thesymptoms and signs at the time of initial diagnosis resemble benign obstructive lesions of the bileducts. The tumor is soft, less invasive to adjacent tissues and tends to grow into the lumen. Theearly onset of the symptoms results in early intervention, with a better prognosis. Two of ourpatients are doing well after two and four years, where as three others were readmitted withrecurrent disease.


The ovaries of leukaemic children were studied in 31 specimens obtained at autopsy. Twenty-eight ovaries from normal children of the same age who died from misadventure served as control. All ovaries from normal childred showed follicle growth and contained several large antral follicles. Follicle development was inhibited in all ovaries of leukaemic children; 22% showed no follicle growth (quiescent ovaries), and in the ovaries in which there was follicle development, the number and size of antral follicles was significantly smaller than in the control. All children had been treated with cytotoxic drugs, the duration of the treatment being correlated with the stage of ovarian development. The ovaries of children treated for only 1 week were near-normal, while those treated for more than 2 months showed inhibition of follicle growth. It is argued that the disturbance in follicle development is an effect of the cytotoxic drugs, and not an effect of the disease itself.


Several methods of ascertaining and classifying childhood neoplasms for epidemiological study have been evaluated using material from the University of Manchester Children's Tumour Registry (CTR), which includes data from several sources on children with neoplasms first seen in the period 1954-73 who were under 15 years old and living in the Manchester Regional Hospital Board area at the time. Two systems of classification-the International Classification of Diseases (ICD) and the Morphology Section of the Manual of Tumor Nomenclature and Coding -were tested. No major problems arose with the Morphology Section of MOTNAC, and we recommend that the revised version of this section, in the proposed "International Classification of Diseases for Oncology", should be used in epidemiological reports on children's tumours whenever possible. The ICD discriminates less well between the commoner types of childhood neoplasms, but must be retained as a supplementary classification to facilitate international comparisons. A comparison of the completeness of ascertainment achieved in recent years by each source of data showed that more than 98% of the serious cases  could have been identified using a combination of Hospital Activity Analysis (HAA) and cancer registration records, and more than 95% using HAA and death records. But in an analysis of 2 years' HAA returns and 6 years' cancer registrations of serious cases, nearly one quarter of the former and one fifth of the latter were shown to record diagnoses which differed from those finally assigned at the CTR. It is concluded that, in epedimiological studies based on routine records, the diagnoses given should always be checked centrally, by experts, in the light of all the available clinical and pathological material .


We have carried out a case-control study to evaluate the association between Wolfe's mammographic patterns and the risk of breast cancer, and to examine the influence of control selection and the radiologist who read the films upon the results obtained. Mammograms of the non-cancerous breast of 183 women with unilateral breast cancer were compared with mammograms from two age-matched control groups: a group of asymptomatic women attending a screening centre, and a group of symptomatic women referred for the diagnostic evaluation of suspected breast disease. Films were arranged in random sequence and independently classified by 3 radiologists. A strong and statistically significant association was found between mammographic dysplasia and breast cancer when controls from the screening centre were compared to cases, but not when cases were compared to women referred for the diagnostic evaluation of breast disease. This result appears to arise in part because of an association between symptoms of benign breast disease and mammographic dysplasia, and suggests that some previous negative studies of the association of mammographic patterns with breast cancer may have arisen from the inclusion of symptomatic subjects as controls.


In spite of a decrease in the metabolic capacity of microsomes to induce lipid peroxidation during inflammation, the endogenous lipid peroxidation remained unchanged and unrelated with the hepatic activities measured. The continuous increase in hepatic cAMP observed during acute and chronic phases could be related to adenylate cyclase stimulation by mediators, and could be an initial step in the hepatocyte adaptation leading to the increased level of hepatic caeruloplasmin, to the reduction of cytochrome P-450 level and to the modifications of Ca


In adults with congenital heart disease coronary arterial anatomy, normal as well as anomalous, may have implications in surgical reconstruction of an underlying cardiac structure. In addition to the diagnostic imaging, necessary in surgery for adult congenital heart disease, additional information with regard to the spatial relation between the relevant cardiac structure and the coronary arterial system may be required for planning the operation and providing a good outcome.The congenital cardiac surgeon should have the necessary skills in coronary artery bypass techniques.With lack of adequate data, the estimation of mortality due to complications as a result of coronary damage in surgery for adult congenital cardiac disease of below 1% seems fair. In adults with congenital heart disease, the origin and course of the coronary arteries, both normal as well as anomalous, may have implications in surgical reconstruction of an underlying cardiac structure. In isolated congenital coronary arterial anomalies, a wide variety in anatomy as well as pathophysiology and clinical presentation is found ,2. RecenIn addition to the diagnostic imaging, necessary in surgery for adult congenital heart disease, additional information with regard to the spatial relation between the relevant cardiac structure and the coronary arterial system may be required for planning the operation and providing a good outcome.The goal of this presentation is to increase the awareness for the spatial relationship between the coronary arterial system, either normal or anomalous, and underlying structural congenital heart disease and the possible consequences for surgery and outcome in this regard.Embryological studies have shown the crucial role of the pro-epicardial organ (PEO) in the development the coronary arterial system . Epicardtantly also to the coronary vasculature . It has With regard to the results of the embryological studies, it is not surprising that the vast majority of coronary arterial anomalies are found in the area of the three rings.Among the anomalies associated with myocardial ischemia are coronary fistula’s, the abnormal right or left coronary artery connected to the pulmonary artery (ARCAPA or ALCAPA), congenital coronary stenosis or atresia, anomalous origin from the contralateral sinus  and a siAnomalies coronary arteries usually not associated with myocardial ischemia are a left circumflex coronary artery originating from the right sinus and the coronary arteries originating from one sinus with separate orifices -3.The incidence, clinical characteristics and possible therapeutical interventions for these coronary arterial anomalies are well described. Nevertheless, attempts at further classification of coronary anomalies are being produced, a recent contribution being made with regard to the anomalous origin of a coronary artery from the opposite sinus .All of these can be regarded as isolated anomalies ,2. ExactNot all cases of isolated congenital anomalies of the coronary arteries warrant treatment ,3. For iSurgical options should depend on the local anatomy and the surgical expertise and may consist of reimplantion of the ectopic coronary arterial orifice, unroofing of the intramural coronary segment or creating of an additional aortic orifice at the end of the intramural course of the coronary artery ,3In adults with congenital heart disease, the origin and course of coronary arteries have implications in surgical reconstruction of an underlying cardiac structure, The spatial relation between the relevant cardiac structure and the coronary arterial system is essential for planning the operation and providing a good outcome. Three-dimensional representation of the diagnostic data plays an increasingly important role in this regard.It is important to realize that not only the coronary anomalies pose a risk in cardiac surgery in adults with congenital heart disease, but also injury of the normal coronary artery system.The diagnostic sequence may therefore start with the usual echocardiography . This wiThe proximal parts of both normal and abnormal coronary arteries are at risk in surgery near the proximal coronary arteries. In any aortotomy the surgeon should be aware of the position of the coronary orifices and the course of the proximal segment of the coronary arteries. Harvesting the pulmonary root in an autograft procedure may damage the left main coronary artery or the first septal branch. In any primary or redo surgical procedure of the right ventricular outflow tract  a coronary arterial branch may also be at risk for injury. This may include a left anterior descending coronary artery (LAD) from the right coronary sinus, a single right coronary artery (RCA) with an LAD anterior to the pulmonary trunk, a single left coronary artery with an RCA anterior to the pulmonary trunk or a large infundibular branch from the RCA. In pulmonary root surgery  the left main coronary artery at the posterior annular level of the pulmonary orifice may also be at risk. In most of these patients atherosclerotic coronary disease does not play a role, probably because of the younger age at operation No hard data are available on actual damage, but it seems reasonable to estimate mortality due to complications as a result of coronary arterial damage up to 1%.Also the coronary arterial orifices themselves may be at risk for damage in aortic root surgery. Particularly when coronary orifices are replanted in root replacement surgery as in the autograft procedure or during prosthetic valve composite graft root replacement. Especially when the coronary buttons have to be re-excised and re-implanted again, scar tissue and local fibrosis and calcification may pose an additional challenge in the pursuit of successful surgery. In case of surgery in common arterial trunk, the increased variability of the position of the coronary arterial orifices should be adequately appreciated . DespiteAlthough no firm data are available, again it seems fair to estimate mortality due to complications as a result of coronary damage in this regard at up to 1%.In all surgical procedures that involve opening of the aortic root, the coronary orifices are at risk of damage due to manipulation. The risk is small, but direct application of cardioplegia into the orifices may be traumatic. In addition there is the risk of coronary embolism by gas (air or carbon dioxide) or debris after completion of the root surgery.Not only abnormal, but also normal coronary arterial anatomy may have implications in surgery for adult congenital heart disease.Three-dimensional diagnostic tools demonstrating the spatial relation between coronary arteries and the cardiac region of interest are essential.The congenital cardiac surgeon should have the necessary skills in coronary artery bypass techniques.With lack of adequate data, the estimation of mortality due to complications as a result of coronary damage in surgery for adult congenital cardiac disease of below 1% seems fair.So far, clinical atherosclerotic coronary disease in adults with congenital cardiac disease is infrequent.


Dear Editor,The geographical distribution of publications as an indicator of the research productivity of individual countries, regions or Institutions has become a field of interest. A few studies on geographical distribution of articles in peer reviewed indexed journals have been conducted to identify the countries that are making maximum contributions to the development of medical science. Ever sin


The incidence of lung cancer has markedly increased in the past few decades and is still increasing in many countries worldwide. Lung cancer is a leading cause of death in many developed countries, and approximately 140 000 new cases are identified each year in the US alone . The majProgress in palliative care for lung cancer has been slow; however, advances have been made due to better utilisation of drugs , choice of drugs for first-line therapy and subsequent regimens, and optimal combination and timing with radiation therapy . ChemothHowever, chemotherapy benefits can be at the expense of adverse effects in different organ systems, including the lung . SeveralGefitinib (‘Iressa’) is a new type of targeted treatment for NSCLC. It is an inhibitor of the epidermal growth factor receptor (EGFR) signalling pathway that acts intracellularly at the level of the EGFR tyrosine kinase. Two phase II monotherapy trials  have reported unprecedented antitumour activity and symptom relief in pretreated patients with advanced metastatic NSCLC (vs placebo-exposed patients with NSCLC (Although gefitinib is not associated with many of the general adverse effects of broadly acting cytotoxic chemotherapeutic agents, recent reports from Japan have indicated that a proportion of patients treated with gefitinib experienced severe ILD (This experience of ILD in patients with NSCLC has posed a number of important questions relating to definition, diagnosis, management and mechanisms. A group of experts in the field of NSCLC and lung disease discussed these issues at a symposium held in Seattle in May 2003. The content of the presentations is discussed within this supplement. Hopefully, the knowledge of gefitinib may provide new insights into the field of ILD and chemotherapy-associated lung disease in the way it has in the treatment of cancer.


Alveolar volume measured according to the American Thoracic Society-European Respiratory Society (ATS-ERS) guidelines during the single breath diffusion test can be underestimated when there is maldistribution of ventilation. Therefore, the alveolar volume calculated by taking into account the ATS-ERS guidelines was compared to the alveolar volume measured from sequentiallly collected samples of the expired volume in two groups of individuals: COPD patients and healthy individuals. The aim of this study was to investigate the effects of the maldistribution of ventilation on the real estimate of alveolar volume and to evaluate some indicators suggestive of the presence of maldistribution of ventilation.Thirty healthy individuals and fifty patients with moderate-severe COPD were studied. The alveolar volume was measured either according to the ATS-ERS guidelines or considering the whole expired volume subdivided into five quintiles. An index reflecting the non-uniformity of the distribution of ventilation was then derived (DeltaVA/VE).Significant differences were found when comparing the two measurements and the alveolar volume by quintiles appeared to have increased progressively towards residual volume in healthy individuals and much more in COPD patients. Therefore, DeltaVA/VE resulted in an abnormal increase in COPD.The results of our study suggest that the alveolar volume during the single breath diffusion test should be measured through the collection of a sample of expired volume which could be more representative of the overall gas composition, especially in the presence of uneven distribution of ventilation. Further studies aimed at clarifying the final effects of this way of calculating the alveolar volume on the measure of DLCO are needed. DeltaVA/VE is an index that can help assess the severity of inhomogeneity in COPD patients. There is evidence that the gases inspired into the alveolar regions are not well mixed and that the alveolar units fill and empty sequentially -4. ImporIt is well recognized that the single breath diffusion test -16 requiWe hypothesize that the alveolar volume measured according to the ATS-ERS method is very different from that calculated considering subsequent phases of the expired volume in those areas where the gas composition is different owing to the fact that the slow-emptying units predominate. In the course of the single breath diffusion test, with the aid of rapid response analyzers it is now possible to follow exhalation to the residual volume after breath-hold and to measure in selected points of the exhalation process the instantaneous expired inert gas fractions which could enter into the calculations of the alveolar volume. In this way, we compared the measurements of the standard alveolar volume obtained following the ATS-ERS recommendations (VAst) to those derived by considering the whole expirate of the same single breath diffusion test, minus the dead spaces, divided into five quintiles and considering the related expired inert gas fractions (VAq) in each quintile. This procedure allowed us to evaluate whether there existed any large discrepancy between the two measurements of the alveolar volume in those cases like COPD, where the process of sequential emptying of different alveolar regions may be excessive. This comparison was made both in healthy individuals and in COPD patients.1 and FEV1/VC respectively below 70% and 88% of the normal value predicted after inhalation of a bronchodilator. Bronchodilator reversibility was defined as an increase of 12% of the baseline value and 200 mL respectively for either FEV1 or FVC above the prebronchodilator baseline, 30 minutes after inhalation of 400 μg of salbutamol [The study included 30 healthy individuals and 50 patients affected by COPD. The healthy subjects had no history of smoking, nor respiratory symptoms consistent with the diagnosis of COPD nor other pulmonary disease. The healthy subjects were receiving no respiratory medication nor any other medication which could affect the respiratory function. The patients with COPD fulfilled the diagnostic criteria of the Global Initiative for Chronic Obstructive Lung Disease guidelines . All patlbutamol . All vallbutamol . In ordelbutamol . The sinlbutamol -18. EachIn accordance with the purpose of this study the effective alveolar volume was calculated by two different methods. The first method directly measures tracer gas reduction during breath-holding time according to the ATS-ERS guidelines and was defined VAst  obtained following the ERS-ATS recommendations according to the following formula:where FICH4 = methane concentration in the inspired gas, and FACH4 (750 mL) = methane concentration in the alveolar sample collected for 750 mL after having discarded the instrumental and anatomical dead spaces; Vinsp = inhaled volume; VD = instrumental dead space and VD anat = anatomical dead space. Sampling of the tracer gas CH4 was executed at the mouth level of the patient in real time and in correspondence of the measurement of the inspiratory and mean expiratory volumes.The second method, which allowed us to derive the alveolar volume subdividing the whole expirate into quintiles (VAq), uses measurements made during the same manoeuver. The difference is that the total expired space is divided into quintiles. In these quintiles the mean concentrations of CH4 were promptly read and retained for the calculations during exhalation from TLC to RV, according to the following formula:FACH4 (quintile) = the methane concentration in the expired volume of that quintile; Vinsp = inhaled volume. Two examples of the different ways of deriving the alveolar volume from the single breath CO manoeuver have been reported in Figure Group data are expressed as mean and standard deviation. The groups and functional parameters in Table Demographic characteristics and parameters of lung function in healthy subjects and COPD patients have been reported in Table The ideal approach would be to compute automatically, point by point, as a continuum, the FICH4/FECH4 ratio during the whole expiration in the course of the single-breath CO test. In order to evaluate whether the sampling of five quintiles was sufficient, we subdivided the whole expired volume into a series of four, five, six and ten exact portions. The alveolar volume calculated using four portions was significantly different when compared to that obtained using five, six or ten portions in both healthy individuals and in COPD patients. At the same time, no differences were observed when the calculated alveolar volumes, obtained subdividing the whole expirate into six portions, were compared to five or ten exact portions both in healthy individuals and in COPD patients. As a result of this prior analysis, the method of sampling five quintiles appeared sufficiently good, more precise than the use of four portions, not different from the use of six or ten portions. Therefore, the method was considered suitable for the purpose of our study and was ultimately chosen and compared to the ERS-ATS method of measuring the alveolar volume.The repeatability of VAst  and of VAq  was tested both in healthy individuals and in patients with COPD and has been reported in Table It is evident that variation in the calculated alveolar volume between two tests appeared statistically significant for the VAst of COPD patients. In the healthy individuals it resulted approximately close to the level of significance. On the contrary, for the alveolar volume calculated by the quintile method, the variation was only statistically significant for the 2nd quintile of the COPD patients. No other significant variations were observed in the healthy individuals nor in the other quintiles of the COPD patients. In addition, the healthy individuals and COPD patients were not different in repeatability  at different lung volumes was compared between healthy individuals and COPD patients in the box-plot graph of Figure The main findings of this study are as follows: 1. the measure of the alveolar volume is different depending on the point where sampling for evaluation of the alveolar concentration of inert tracer gas methane is done in the course of exhalation of the single breath diffusion test; 2. the alveolar volume measured by the quintile method shows a progressive increase from total lung capacity to residual volume and appears significantly different when compared with that measured according to the ATS-ERS guidelines; 3. its size increases much more in COPD patients than in healthy individuals from the beginning to the end of the exhalation; 4. changes of the mean alveolar volume per litre of the expired volume exhaled, expressed as DeltaVA/VE, are significantly and remarkably greater in COPD patients with severe airflow obstruction than in healthy individuals; 5. DeltaVA/VE represents a parameter that is influenced by the effect of non-uniform distribution of convective ventilation as well as by the increased time-constants of the emptying of lung units in diseased lungs.It is well documented that the single breath diffusion test may markedly increase or slightly change upon the effect of variation in lung volume ,15,25-29Although this study did not provide any conclusive information on how the final DLCO can be affected by the changes of lung volume as well as by size and precise estimate of the alveolar volume, in our COPD patients it seems to increase on the average by 1 mmol/min/mmHg for a total increase of 2.5 litres of alveolar volume, as reported in Figure The purpose of our study was to indicate the weakness of the ATS-ERS method to measure the alveolar volume, which collects the alveolar inert gas concentration at the beginning of exhalation, especially in diseased lungs. In fact at this exact point (on the average a volume of 750 ml) the concentration of the tracer gas is not representative of the mean alveolar gas concentration and thus of the real alveolar volume, since it represents only the behaviour of the faster lung units ,17. ThisLiterature well documents the extent to which the distribution of ventilation becomes progressively more inhomogeneous at high lung volume  or underThe exaggerated asymmetry of lung units caused by the obstructive airway diseases may ultimately be responsible for the inequality of gas concentration within alveolar gas and, therefore, for the very inhomogeneous dilution of the concentration of the tracer gas methane in the course of the single breath CO inhalation test.et al.[In 1978 Ferris et al. comparedet al.,35.et al.[Some explanations for the remarkable differences in the values of the alveolar volume when measured at the different intervals of exhalation are well reported in the paper by Yuh T Huang et al.. These aIt follows that the true mean alveolar volume should be that derived from the average of each alveolar volume exhaled in each quintile Figures , 3.In summary, our study provides additional information on the real estimate of the alveolar volume when different sampling points are used in the course of the single breath diffusion test for the assessment of diffusing capacity. A model was developed which subdivided into 5 parts the total volume of air exhaled after the breath-hold manoeuver was developed. The instantaneous concentration of tracer gas methane was considered in each quintile; the calculation of the alveolar volume was consequently derived and compared with that derived from the traditional method according to the ATS-ERS recommendations. A significant difference was found between these two ways of measuring the alveolar volume, and the results showed significant differences in COPD patients. The conclusion drawn is that sampling at the beginning of exhalation of the single breath-test is not representative of the real mean alveolar gas concentration, especially when an important ventilation/perfusion mismatch is present. A non-uniform distribution of ventilation, coupled with an exaggerated time constant of emptying of lung units, seems ultimately to be the mechanism responsible for the differences in the size of the alveolar volume when measured differently in the course of expiration. An index reflecting this process was identified which appeared useful to assess the degree of non-uniformity of the ventilation distribution. These analyses provide a basis for further study in order to test the effects on DLCO of this way of measuring the alveolar volume from the sampling of the instantaneous tracer gas concentrations at different intervals of exhalation, but also to observe the behaviour of the diffusivity of carbon monoxide at different intervals of exhalation, as a direct consequence of the complex emptying process of lung units in different diseased states.1 = forced expiratory volume in one second; FEV1/VC: ratio of forced expiratory volume in one second to vital capacity or Tiffeneau index; FVC = forced vital capacity; TLC = total lung capacity; RV = residual volume; FRC = functional residual capacity; RV/TLC = ratio of residual volume to total lung capacity; BMI = body mass index expressed in Kg/m2; VD anat = anatomical dead space; VD instrumental = instrumental dead space; VI = inspiratory volume; Hb= concentration of hemoglobin expressed as g/dl of blood; FICH4 = inspiratory fraction of tracer gas methane; FACH4= alveolar fraction of tracer gas methane; DeltaVA/VE = changes in percentage of the alveolar volume for each litre of expired volume exhaled; ATS = American Thoracic Society; ERS = European Respiratory Society; SD = standard deviation.DLCO = single breath diffusion capacity for carbon monoxide; VA = alveolar volume; VAst = alveolar volume measured according to the ERS-ATS guidelines; VAq = alveolar volume measured according to the method of subdividing the whole expirate into quintiles and considering the instantaneous expired tracer gas fraction in each quintile; FEVThe author(s) declare that they have no competing interests.RP participated in the design of the study and drafted the manuscript, EF and GC participated in the design of the study and helped to perform it, CC participated in the design of the study and performed the functional tests. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Sir,Drs Mason, Johnson and Rudd suggest that criticism of the guidance issued by the National Institute for Clinical Excellence (NICE) regarding the use of irinotecan and oxaliplatin in the treatment of patients with advanced colorectal cancer may have implications for the FOCUS trial . Howevervs monotherapy), the crucial point is that all patients should have access to these three drugs.While recognising there may be merit in fine-tuning the sequence of use of these three agents (combinations


The objective of this work is to obtain the correct relative DNA contents of chromosomes in the normal male and female human diploid genomes for the use at FISH analysis of radiation-induced chromosome aberrations.The relative DNA contents of chromosomes in the male and female human diploid genomes have been calculated from the publicly available international Human Genome Project data. New sequence-based data on the relative DNA contents of human chromosomes were compared with the data recommended by the International Atomic Energy Agency in 2001. The differences in the values of the relative DNA contents of chromosomes obtained by using different approaches for 15 human chromosomes, mainly for large chromosomes, were below 2%. For the chromosomes 13, 17, 20 and 22 the differences were above 5%.New sequence-based data on the relative DNA contents of chromosomes in the normal male and female human diploid genomes were obtained. This approach, based on the genome sequence, can be recommended for the use in radiation molecular cytogenetics. FISH echnique .Several questions of radiation cytogenetics are connected with the comparison of results obtained by FISH analysis and those by conventional dicentric analysis -10 and wIt is necessary to know the fractions of the genome covered by FISH probes at the translocation analysis in order to obtain the whole genome equivalent genomic frequencies of chromosome aberrations . In mostThe relative human DNA contents given in  are recoWith the increasing accuracy of chromosome aberration analysis , the impIn the post-genomic era, with the completion of the international Human Genome Project , new morThe total sizes of the normal male and female diploid human genomes and the relative DNA contents of chromosomes in the diploid genomes were calculated by using the Human Genome Project data on the chromosome lengths presented in the Ensembl database . The resThe DNA contents of all chromosomes, except chromosome 13, were overestimated in the work of Morton  when comThe comparison of the data from Table However, noticeable differences (larger than 5%) were found in the relative DNA contents of chromosomes 13, 17, 20 and 22 in the human diploid genomes obtained by different approaches Figure . This reThe coefficient 2.05 in the formula of Lucas et al.  was re-cMany radiobiological investigations were carried out with the use of DNA probes specific for large chromosomes because the probabilities of their damages by ionizing radiations and the levels of aberrations are highest and the translocation analysis is more effective. It should be noted that taking into account small differences in the values of the relative DNA contents of large chromosomes from work  and TablIn spite of the high-quality sequencing data there are still some uncertainties about the gaps in the genome sequence and human genetic variations . RecentlNevertheless, new values of the relative DNA contents of chromosomes in the normal human diploid genome based on the international Human Genome Project sequence data could be considered as the best data to date.At present we have the unique opportunity to use precise sequence-based parameters of the reference human genome including the relative DNA contents of chromosomes in the human genome instead of the approximate estimates that have been done by indirect methods at the initial stage of the Human Genome Project. New sequence-based data on the relative DNA contents of chromosomes in the normal male and female human diploid genomes were obtained. The approach, based on the DNA sequence data, can be recommended for the use in radiation molecular cytogenetics., release 52 – December 2008 [The data on the lengths of each human chromosome were taken from the public Ensembl database ber 2008 . The seqFor each pair of the autosomes the relative DNA contents were calculated as a ratio of the doubled DNA size to the size of diploid female and male genomes, correspondingly. Similarly the relative DNA content of the sex chromosome X in the female genome was calculated. The single DNA contents in the genome were used to obtain the relative DNA content of the sex chromosomes in the diploid male human genome.Fp = 2.05 fp(1 - fp)FG, relating the translocation frequency, Fp, measured using FISH to the genomic translocation frequency, FG, where fp is the fraction of the genome covered by the composite probe, the coefficient 2.05 was recalculated separately for the human female and male genomes by using the sequence-based relative DNA contents of the chromosomes from Table In the formula derived by Lucas et al. Fp = 2.05= 2.05 fp - fpFG, Ci is a fraction of the DNA content of the i-chromosome in the male or female human diploid genome.where The authors declare that they have no competing interests.MVR wrote the manuscript and PIG and LAR contributed significant editorial input and original ideas. All authors read and approved the final manuscript.


Malignant fibrous histiocytoma (MFH) is one of the most common types of soft tissue sarcomas in adults. The most common location of MFH are the extremities and the trunk, with the most common site for distant metastases being the lung. We describe a case with multiple synchronous sites of myxoid MFH but no lung metastases and presence of abnormalities of 19p13.


The usefulness of pharmacokinetically guided individualisation of drug therapy will depend, among other things, on the quality of the analytical and pharmacokinetic methods used. We surveyed the quality of analytical and pharmacokinetics methodology and reporting in a literature search of the oncology literature from 1987 to 1992, using the Medline database. Thirty articles that examined relationships between normal tissue toxicity and area under the plasma concentration-time curve (AUC) formed the study sample. Analytical procedures were adequately described in 77% of the articles, but details of validation of the assay were seriously deficient in the great majority of articles. Methods for calculation of AUC were also deficient in over half of the articles. The findings suggest that greater attention needs to be paid to the quality of pharmacokinetic investigation in oncology, otherwise progress in the use of pharmacokinetically guided individualisation of dosage may be hindered.


The synthetic models for the structures, spectroscopic properties and catalytic activities of metalloproteinactive sites have been reviewed. Calixarenes were used as new biomimetic catalysts because of theiradvantage of providing preorganiiation of the catalytic group, which can bind the substrate dynamically thatresults in fast turnover and fast release of the products. Functional and structural models based on calixarenesare presented and in addition importance of molecular recognition and non-covalent interactions e.g. hydrogen bonding and their role in biological systems are discussed with the help of synthetic systems.


Mothers of a population-based series of 86 children with osteosarcoma or chondrosarcoma were traced and their health status or cause of death ascertained. There were 6 cases of breast cancer among these mothers and 6 other cancers. Risk of breast cancer was approximately three times that expected, and appeared to be highest in mothers of boys and in mothers of children under the median age at diagnosis. The mothers who developed breast cancer were relatively young at diagnosis compared with population data. Risk of other malignancies in the mothers was not in excess of expectation. These findings are in line with those reported for breast cancer risk in mothers of children with soft tissue sarcomas, and provide further indications of a genetic component in the aetiology of these cancers.


A redundant publication is a manuscript which fundamentally presents results from the same study in more than one original paper. This term is synonymous with a "dual" or "duplicate" publication of identical data  and with the disaggregated presentation of identical data in multiple publications derived from the same study , published by the same author or group. Hereby, the content of redundant papers may overlap in part or completely, such that the main findings of an original study are published in multiple papers in different electronic or print journals.Redundant publications in biomedical journals are considered unethical for the following reasons -3:• "Inflation" of the available peer-reviewed literature.• Skewing of evidence-based medicine when readers erroneously assume to be confronted with reports from independent studies.• Distortion of available scientific data by unjustified overestimation of a therapeutic effect in systematic meta-analyses.• Increased, unnecessary workload for editors and peer reviewers, leading to a backlog of "true" original articles in the publication process.• Cost-ineffective use of resources, waste of journal space, and waste of readers' time by reading republished material considered to be original work.• Distortion of the purpose of biomedical journals as being the source of new information.• Potential infringement of international copyright law.The Journal of Bone and Joint Surgery (British and American volumes), which is considered the most prestigious journal in the field of orthopedics, revealed that one in 13 original articles were either duplicate or fragmented publications . Permission for such secondary publication should be free of charge".5. "The footnote on the title page of the secondary version informs readers, peers, and documenting agencies that the paper has been published in whole or in part and states the primary reference. A suitable footnote might read: 6. "The title of the secondary publication should indicate that it is a secondary publication  of a primary publication".Surgical Journals Editors Group [According to the official consensus statement by the rs Group , the fol• Prior publication in meeting program abstract booklets and proceedings from scientific meetings. These must be acknowledged and referenced in the final manuscript.• Expansion of the original database, published in the primary source, by 50% or more. Previous manuscripts reporting the original database must be referenced in the secondary publication.Ethical standards in publishing place a high level of self responsibility upon publishers, editors, authors and readers. The scientific/medical community at every level should safeguard the medical literature upon which so many of our therapeutic concepts are based and so many of our patients are treated. The "slippery slope" of self rationalization that leads a physician or scientist to justify unauthorized duplicate publication is the same deceptive impulse that results in false data and unjustified conclusions. Ultimately, what we publish and read may end up impacting the care and outcome of individuals who present to us for relief of disease and suffering. There is no line on any academic curriculum vitae worth a human life. On behalf of our patients, we must remain vigilant and educate ourselves, our colleagues, and our students on the high ethical standards of scientific publishing.The author(s) declare that they have no competing interests.All authors contributed equally to the design and writing of this editorial. All authors read and approved the final manuscript.


There was an error in the penultimate sentence of the Abstract. The correct sentence is: Native North Americans have received ancestry from a source closely related to modern North-East Asians (Mongolians and Oroquen) that is distinct from the sources for native South Americans, implying multiple waves of migration into the Americas.


The post-natal development of “natural” resistance of Balb/c mice to the challenge of syngeneic tumours was studied using injections of various doses of live neoplastic cells into untreated animals of increasing age, from neonatal to 12 weeks.The minimum quantity of neoplastic cells capable of inducing tumours increased in parallel with the age of the animals. Immunodepression with whole body irradiation with X-rays reduced the resistance offered by adult mice to tumour challenge to that of the neonate. The relationship of the increase in resistance to tumour challenge with the development of the animals' own immune response during the course of post-natal growth is discussed.


The production of graft-versus-host (GVH) reactions in (PVGc X Wistar) F1 hybrids by the transfer of PVGc spleen cells resulted in significant resistance of these recipients to a subsequent challenge with the PVGc leukaemia. Protection was markedly dependent on dose and timing of allogeneic cell transfer and was abrogated by irradiation of the cells prior to transfer. GVH activity was shown to be a prerequisite for induction of the protective effect but was equally effective when produced by the transfer of Wistar spleen cells in place of PVGc cells. These points, plus the fact that invitro investigations of possible immune mechanisms failed to demonstrate cytotoxic immunity in treated rats, suggested a nonspecific "bystander" effect as the mechanism of protection. The implications of such a mechanism are discussed.


We report on a new methodology which allows the direct analysis ex vivo of tumour cells and host cells  from a metastasised organ (liver or spleen) at any time point during the metastatic process and without any further in vitro culture. First, we used a tumour cell line transduced with the bacterial gene lacZ, which permits the detection of the procaryotic enzyme beta-galactosidase in eukaryotic cells at the single cell level thus allowing flow adhesion cell sorting (FACS) analysis of tumour cells from metastasised target organs. Second, we established a method for the separation and enrichment of tumour and host cells from target organs of metastasis with a high viability and reproducibility. As exemplified with the murine lymphoma ESb, this new methodology permits the study of molecules of importance for metastasis or anti-tumour immunity  at the RNA or protein level in tumour and host cells during the whole process of metastasis. This novel approach may open new possibilities of developing strategies for intervention in tumour progression, since it allows the determination of the optimal window in time for successful treatments. The possibility of direct analysis of tumour and host cell properties also provides a new method for the evaluation of the effects of immunisation with tumour vaccines or of gene therapy.


Malawi is reassessing its HIV prevention strategy in the light of a limited reduction in the epidemic. No community based incidence studies have been carried out in Malawi, so estimates of where new infections are occurring require the use of mathematical models and knowledge of the size and sexual behaviour of different groups. The results can help to choose where HIV prevention interventions are most needed.The UNAIDS Mode of Transmission model was populated with Malawi data and estimates of incident cases calculated for each exposure group. Scenarios of single and multiple interventions of varying success were used to identify those interventions most likely to reduce incident cases.The groups accounting for most new infections were the low-risk heterosexual group - the discordant couples (37%) and those who had casual sex and their partners (a further 16% and 27% respectively) of new cases.Circumcision, condoms with casual sex and bar girls and improved STI treatment had limited effect in reducing incident cases, while condom use with discordant couples, abstinence and a zero-grazing campaign had major effects. The combination of a successful strategy to eliminate multiple concurrent partners and a successful strategy to eliminate all infections between discordant couples would reduce incident cases by 99%.concurrency and discordancy.A revitalised HIV prevention strategy will need to include interventions which tackle the two modes of transmission now found to be so important in Malawi -  HIV infection prevention has been largely unsuccessful in many sub-Saharan countries including Malawi, where HIV prevalence remains high despite prevention activities ,2. In MaThree things make it timely to review national HIV prevention strategies. Firstly, epidemiologists have belatedly come to realise the importance of concurrent sex partners in the spread of HIV infection. Until recently transmission models, while taking the importance of multiple partnerships into account, failed to include the magnitude of the spread within concurrent partnerships in the early stages of infection. An example of this failure is in a paper written in 1989 which wrongly anticipated a heterosexually spread epidemic in the UK because the difference between serial monogamous multiple partnerships and concurrent partnerships was not realised [Secondly, the very high transmission risk in the early infection period was not fully realised until the paper from Rakai in 2005 . The stuThirdly, the belief that deep seated cultural practice of polygamy and concurrent sexual partnerships in Africa could not be changed was disproved . The proThe Mode of Transmission spreadsheet provides a simple means of assessing the impact of HIV prevention measures singly and in combination. This paper assesses the impact using a set of input variables to accurately reflect what is likely to be happening in Malawi. For this exercise absolute numbers are not as important as relative ones because the exercise is looking at the relative not the absolute value of different interventions.The mode of transmission model uses categories of those at risk of exposure: low risk are single partner couples; the casual sex group are either those having pre-marital sex or those having multiple partners; no risk are those not having sex. The mode of transmission model was populated with best estimate Malawi data for 56 of the 62 input variables required, with default estimates for Africa being used for the other six  was halved in response to improved syndromic treatment services. The use of condoms with all STIs was assessed by reducing the cofactor (4 in the model) to zero. Uniform use of condoms by bar girls was assessed by increasing condom use to 100% for bar girls (from 92%) and their clients (from 64%). The circumcision rate was doubled and trebled to assess the effect on incidence in males. A 100% successful zero-grazing campaign was assessed by converting all casual and commercial sex risk to low risk adults. Doubling condom use was assessed to identify the value of this increased protection. The effect of abstinence for one year was calculated by converting 20% of the 15-24 year olds from high and low risk to no-risk.The overall national HIV incidence per year was estimated using the Estimation and Projection Package (EPP)  in the lNo participants were involved in the study and hence ethics committee approval was not required.New cases in the year were estimated to be 94,454, which is an annual national incidence of 1.6% Table .The number of cases in each exposure group depended on its size Figure . The larThe results of model manipulation to assess the effect of possible HIV prevention interventions were found to produce limited effect for some - condom use with bar girls, circumcision, abstinence and reducing STIs. Major effect was found with others - condom use with discordant couples, a zero-grazing campaign, condom use with a sexually transmitted infection (STI) and in high risk sex Table . The sizThe mode of transmission model is easy to use and adapt to the local situation. Sufficient local data were found to populate 90% of necessary model variables. The use of such data and a simple model gave national planners confidence to base a new HIV prevention strategy on the results. The results were sufficiently different from preconceived notions of which population groups had the most new infections to make a big shift in strategic emphasis. It appears that while originally developed for low level epidemics the mode of transmission model can be used in generalised epidemics if sufficient local data are available as found in this study. The UNAID Estimation and Projection Package (EPP) provides estimates of overall levels of HIV transmission. The mode of transmission model provides estimates of the relative contribution of the different risk groups.The predominant data set was from the most recent DHS. This has significant problems of interpretation in relation to recall of sexual activity, on which the model relies. In this DHS which had an HIV test refusal rate of 22%, the recall of sexual activity about coital frequency and multiple partners are particular causes of uncertainty. Fortunately Malawi has some detailed sexual activity data collected by the Malawi Diffusion and Ideation Project over a number of years -19. ThisHowever the main limitation of the study is the sensitivity of the choice of risk of infection in the different risk groups. Until evidence is available to be confident about the proportion of concurrent partners and new infections that make up the casual risk group, any analysis relies on the assumptions used in the model. The model can be re-run with revised assumptions as this evidence becomes available. An advantage of the model over more sophisticated ones is that public health practitioners can test quite easily the sensitivity of the model to changes in input variables about which they are unsure. Indeed the model is simple enough to be used in planning meetings where participants can suggest alternative estimates of input variables and alternative mixes of possible interventions.The choice of intervention depends on the relative importance of the mode of transmission with which it interferes, its effectiveness and its cost. The cost-effectiveness of HIV/AIDS interventions is known . While cconcurrency and discordancy.But which HIV prevention interventions are effective in the Malawian setting? The choice of appropriate interventions requires knowledge and experience of ways which are likely to change sexual behaviour in the Malawi population. Clearly interventions used to date have been inadequate, insufficient or inappropriate. A revitalised strategy will need to include more of those existing strategies that have worked and new ones such as a "zero grazing campaign" and couple HCT which tackle the two modes of transmission now found to be so important in Malawi - In conclusion the mode of transmission model offers a practical means of identifying in countries such as Malawi with a generalised HIV epidemic those groups within the community for which HIV prevention programmes can be targeted.The authors declare that they have no competing interests.KM undertook the compilation of data sources for input variables and populated the model. CB modified the model, undertook the analysis of possible interventions and wrote the first draft of the manuscript for publication. Both authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6963/10/243/prepubData sources used to populate the Mode of Transmission model - Malawi 2007. Data sources referenced which were used to populate the Mode of Transmission model demonstrating the availability of most data items from local data sources and the limited number variables for which regional estimates were used.-30Data sClick here for fileSensitivity analysis of Mode of Transmission results. Sensitivity analysis assessing the effect on HIV incidence using Mode of Transmission model by varying estimates of risk of transmission variable and size of selected risk groups - Malawi 2008.Click here for file


In spite of the reasonable size of the numbers forming the basis for the analysis, no statistically significant differences were found between smokers and non-smokers. However, it was found that the frequency of epithelial dysplasia is not higher among smokers than among non-smokers.The smoking habits of 345 Danish and 184 Hungarian leukoplakia patients were analysed against the histopathology of the leukoplakias,


We report observations on the spread by metastasis and infiltration of a transplantable tumour in rats treated by 60Co gamma-irradiation of the primary, irradiation plus parenteral cyclophosphamide, or parenteral cyclophosphamide alone. The proportion of animals with overt disseminated disease and the extent of spread were measured with respect to the time elapsed after implantation and treatment of the primary tumour. The incidence of metastatic disease was broadly similar for all treatment groups, but the extent of dissemination was greater in rats whose treatment included cyclophosphamide.


The toxicity mechanisms of mercury and tin organic derivatives are still under debate. Generally thepresence of organic moieties in their molecules makes these compounds lipophilic and membrane activespecies. The recent results suggest that Hg and Sn compounds deplete HS-groups in proteins, glutathione andglutathione-dependent enzymatic systems; this process also results in the production of reactive oxygenspecies (ROS), the enhancement of membrane lipids peroxidation and damage of the antioxidative defencesystem. The goal of this review is to present recent results in the studies oriented towards the role oforganomercury and organotin compounds in the xenobiotic-mediated enhancement of radical production andhence in the promotion of cell damage as a result of enhanced lipids peroxidation. Moreover the conceptionof the carbon to metal bond cleavage that leads to the generation of reactive organic radicals is discussed asone of the mechanisms of mercury and tin organic derivatives toxicity. The possible use of natural andsynthetic antioxidants as detoxification agents is described. The data collected recently and presented hereare fundamentally important to recognizing the difference between the role of metal center and of organicfragments in the biochemical behavior of organomercury and organotin compounds in their interaction withprimary biological targets when entering a living organism.


We illustrate the principle of conformal radiotherapy by discussing the case of a patient with a primitive neuroectodermaltumour of the chest wall. Recent advances in radiotherapy planning enable precise localization of the planning target volume(PTV) and normal organs at risk of irradiation. Customized blocks are subsequently designed to produce a treatment fieldthat ‘conforms’ to the PTV. The use of conformal radiotherapy (CRT) in this case facilitated the delivery of concurrentchemotherapy and radiotherapy by significantly reducing the volume of red marrow irradiated.The lack of acute and latetoxicities was attributed to optimal exclusion of normal tissues from the treatment field, made possible by CRT.


British Journal of Cancer (2002) 87, 28–30. doi:10.1038/sj.bjc.6600427www.bjcancer.comCancer Research UK© 2002  This is a salutary lesson that highlights the need for restraint in propounding the immediate benefits of the human genome sequence to the elucidation of disease processes and the development of new treatments. Nevertheless EBV has come a long way and this slender volume edited by Kenzo Takada nicely highlights the current state of the field and sets the scene for the challenges ahead.The study of virus-associated human malignancy has provided many important insights into the pathogenesis of cancer as well as facilitating the development and testing of novel therapeutic strategies relevant to the treatment of common cancers. Epstein-Barr virus or EBV, as the first oncogenic human virus to be identified, has been at the vanguard of these studies and even 40 years after its discovery the virus continues to fascinate and surprise as it yields up its secrets. The study of EBV intersects many disciplines including cell biology, immunology, molecular biology and pathology and this provides an important advantage in tackling the complexity of the tumorigenic process. The virus also provides a useful paradigm for the benefits and challenges associated with the impact of having a complete DNA sequence on our understanding of human disease. The full DNA sequence of the EBV genome, some 172 kilobases, was published in 1984 thus we are almost 20 years into the post-genomic era but the ‘big questions’ relating to such areas as the nature of virus persistence and replication myc expression, a central player in the pathogenesis of BL, is reviewed by Ruf et al. Another important contribution from Takada's group has been the use of recombinant drug-resistant forms of EBV to infect epithelial cells and thus Imai et al provide a superb review of this area highlighting the association of the virus with NPC and other carcinomas and examining over 20 years' worth of in vitro studies attempting to elucidate the nature of the virus-epithelial cell interaction.‘Epstein-Barr Virus and Human Disease’ is a selective collection of reviews from experts in Japan and the United States covering a range of topics. While considering detailed aspects of EBV biology such as virus replication and the function of EBV-encoded glycoproteins, some key fundamental features of the virus like the function of the latent membrane proteins (LMP1 and LMP2) or the latest theories on the nature and site of EBV persistence are not covered. This reflects the interests of the various authors and with nine of the 14 chapters being provided by Japanese researchers the volume is naturally biased towards certain topics at the expense of others. This is best exemplified in Section II which covers EBV-associated malignancies and provides two chapters on those tumours which are of particularly interest and importance in Japan  but relatively rare in the West. The other review on AIDS lymphoma in relation to both EBV and HHV8 seems a little out of place and some consideration of the evidence and recent work implicating EBV in the aetiology of Hodgkin's disease or nasopharyngeal carcinoma (NPC) may have been more appropriate. These minor deficiencies are more than compensated by the editor's own contribution and that of Jeff Sample's group describing their studies using the Burkitt lymphoma (BL) cell line, Akata, to examine the role of EBV in the pathogenesis of BL. Takada was the first to describe the ability of EBV-positive Akata BL cells to lose the virus in culture with consequent loss of the transformed phenotype and his chapter summarises these studies. This system provides a valuable tool for dissecting the role of individual EBV-encoded latent genes in the oncogenic process and for generating recombinant forms of the virus. The use of this approach to examine the impact of EBV infection on cell growth and on c-oriP, is described and the possible role of cellular licensing factors in controlling replication of the EBV episome is considered. Two chapters cover the other aspect of virus replication, that is the activation of the EBV lytic cycle which results in the production of progeny virus. Tsurimi examines the role of various viral proteins in this complex process and provides a model for the EBV replication fork whereas Fujiwara describes his work on the possible influence of the EBNA2 protein on lytic cycle induction. Lindsey Hutt-Fletcher's chapter on the two major EBV glycoprotein complexes is an important reminder of the critical functions of these membrane proteins in relation to EBV replication and tropism and how these might impact on EBV pathogenesis. The final section of the book deals with animal models and therapeutic approaches. Fred Wang reviews the EBV-like herpesviruses infecting Old World primates and describes the similarities, at both the molecular and biological level, of these so-called lymphocryptoviruses (LCVs). Rhesus LCV is a particularly good model for EBV in terms of tumour association, in vitro B cell transformation and the natural history of infection and thus provides a valuable experimental model to study key aspects of EBV pathogenesis such as the role of latent genes in acute and persistent infection, virus immune evasion strategies and virus-associated tumorigenesis. Finally, Clio Rooney and co-workers consider the use of EBV-specific cytotoxic T lymphocytes for the treatment of virus-associated tumours. This group has pioneered this form of adoptive immunotherapy for the treatment of EBV-induced lymphoproliferative disease and the chapter reviews their experience with a comprehensive assessment of the ‘pros and cons’ of this therapy. The possibility of using this approach for the treatment of other EBV-associated tumours such as Hodgkin's disease is also discussed.The volume also contains a section on the molecular mechanisms of maintenance and disruption of virus latency. Two reviews deal with the factors governing the extrachromosomal maintenance and replication of the circular  EBV genome. Here the interaction of the EBNA1 protein with the latent viral replication origin, ‘Things are seldom what they seem’ when it comes to studying virus-associated human tumours. There are many challenges and paradoxes. For instance, EBV is probably one of the most common viral infections throughout the world but only a small proportion of infected individuals develop tumours and these differ dependent on where you reside. This highlights the complexity of oncogenesis and the fact that whilst EBV may be essential in this process other factors working in concert with virus infection are required to fully transform a normal cell. For many years EBV-induced transformation of B lymphocytes in culture was considered to be a model for virus-associated cancers until it was discovered that EBV adopts distinct patterns of latent gene expression in different tumours and that in certain situations such as BL the virus-encoded proteins considered to have oncogenic activity are not expressed! These are important points for post-graduate students and post-doctoral research fellows to appreciate which may not be clear from a reading of this volume. However, the book provides a useful but selective snap shot of the current state of play contrasting our detailed knowledge of certain molecular aspects of EBV biology with almost complete ignorance of fundamentally important processes such as the role of EBV in the pathogenesis of NPC or the contribution of epithelial cell infection to virus persistence and replication. The book also highlights the value of new approaches, particularly the ability to generate EBV recombinants, as well as illustrating how new treatments can be developed without a full understanding of the disease process. There's much still to do and, with an increasing number of viruses being implicated in the development of human cancer, EBV stands as a paradigm for both tumour virology and for the challenges of the post-genomic era.


We studied 273 premenopausal women recruited from mammography units who had different degrees of density of the breast parenchyma on mammography, in whom we measured height, weight and skinfold thicknesses. Mammograms were digitized to high spatial resolution by a scanning densitometer and images analysed to measure the area of dense tissue and the total area of the breast. Per cent density and the area of non-dense tissue were calculated from these measurements. We found that the mammographic measures had different associations with body size. Weight and the Quetelet index of obesity were strongly and positively associated with the area of non-dense tissue and with the total area of the breast, but less strongly and negatively correlated with the area of dense tissue. We also found a strong inverse relationship between the areas of radiologically dense and non-dense breast tissue. Statistical models containing anthropometric variables explained up to 8% of the variance in dense area, but explained up to 49% of the variance in non-dense area and 43% of variance in total area. These results suggest that aetiological studies in breast cancer that use mammographic density should consider dense and non-dense tissues separately. In addition to per cent density, methods should be examined that combine information from these two tissues.


An electrolytic reduction system has been developed to model the cytotoxic action of a range of nitroimidazole drugs against DNA hypoxic cells or anaerobic microorganisms. THe degree of damage induced by these drugs (measured as the release of [14C]-dT from DNA) and their relative rates of reduction have been correlated with their redox potentials. The results show that the correlation of drug-induced damage and electron affinity is related to the amount of drug reduced, and supports the hypothesis that at the molecular level the cytotoxic mechanism of reduced nitroimidazoles is identical in hypoxic mammalian cells, bacteria and protozoa.


Objective: Numerous published reports have linked various disease states and pregnancy-related conditions with meteorologic factors such as weather, humidity, and temperature. The purpose of this study was to determine if temperature and dew point affect the incidence of pyelonephritis during pregnancy.Methods: A retrospective chart review of a 4-year period from 1989 to 1992 was performed. The records of women who were diagnosed with pyelonephritis during pregnancy were abstracted for the dates of admission. The climatic records of the Tampa Bay area of Florida were obtained from the National Weather Service.Results: The average, minimum, or maximum daily temperature or average daily dew point during the month of admission had no significant effect on the rate of pyelonephritis during pregnancy in the Tampa Bay area.Conclusions: The rate of pyelonephritis during pregnancy per number of deliveries in the Tampa Bay area was not affected by the average, minimum, or maximum daily temperature or average daily dew point.