An enzyme activity with the characteristics of reverse transcriptase was detected in marrow from patients with leukaemia in relapse and in firm haematological remission. The endogenous enzyme activities increased following culture, and in remission patients the enzyme activities reached levels equal to or exceeding those found in relapse.


A method of comparing differences in growth rates of tumours in small groups of animals is described. A common slope can be fitted to the growth curves of a given tumour in a group of isogeneic animals. Differences between growth potentials can be demonstrated by comparing the common slope for a given tumour against that of another tumour (or the same tumour at a later stage of development).A highly significant difference is shown between the growth potential of an A-strain mammary carcinoma after 7 or after 28 days' growth in isogeneic animals. Since this increase in autonomy is reflected in the tumour's subsequent growth rate in secondary hosts, it is suggested that it involves adaptation of the tumour rather than progressive immunodepression of the primary host.


Comparison of the growth of normal bone marrow cells in CDCs and in ADCs suggests that cell proliferation in diffusion chambers may result from the same precursor cell as detected by colony formation in agar culture in vitro. This proposal is supported by the suicide of approximately 46% of the ADC colony precursor cells following incubation with 3H-labelled thymidine.The conventional diffusion chamber (CDC) as described by Benestad (1970) had been modified to assay the colony forming capacity of RFM bone marrow and spleen cells in agar diffusion chambers (ADCs). The colonies are morphologically identical to those formed by the CFUc in agar culture Colony formation by haemopoietic cells taken from leukaemic mice appears to be due to the proliferation of a remaining normal cell population alone, while the leukaemic cells in the inoculum form a background of uniformly distributed blast cells. In the case of leukaemic cell culture, there are differences in the results from CDCs and ADCs, and data from colonies in leukaemic ADC cultures are similar to those from normal ADC colonies. These comparisons imply that the ADC technique may be used to monitor the functional capacity of normal bone marrow, by its ability to form colonies, during the development of leukaemia. A humoral effect of a leukaemic environment on the growth of normal bone marrow cells in ADCs has also been detected.


We tested the hypothesis that Cache Valley Virus (CVV), an endemic North American bunyavirus, may be involved in the pathogenesis of human neural tube defects. This investigation followed a 1990 and 1991 south Texas outbreak of neural tube defects with a high prevalence of anencephaly and the demonstration in 1987 that in utero infection by CVV was the cause of outbreaks of central nervous system and musculoskeletal defects in North American ruminants. Sera from 74 women who gave birth to infants with neural tube defects in south Texas from 1993 through early 1995 were tested for CVV neutralizing antibody. All tested sera did not neutralize CVV. These data suggest that CVV is not involved in the induction of human neural tube defects during nonepidemic periods but do not preclude CVV involvement during epidemics. Other endemic bunyaviruses may still be involved in the pathogenesis of neural tube defects or other congenital central nervous system or musculoskeletal malformations.


Histological sections of the primary tumour from 496 women with operable breast cancer have been examined for purposes of histological grading by two observers working independently. Each found a similar distribution of grade through the series, and a virtually identical influence of grade on prognosis. This close agreement occurred despite a 30% disagreement as to grade in individual cases. It is suggested therefore, that this technique while of relevance to analysis of groups of cases is of very limited reliability in individual patient prognosis.


Although echinococcal disease of the liver is common in some parts of the world, it is rarely seen in theUnited States. Even from endemic areas, few reports deal with its treatment during pregnancy. A 25 year old18 week pregnant Italian woman presented with pruritis and right upper quadrant pain. Ultrasoundrevealed a cystic lesion in the left lobe of the liver. The cyst was treated by operative insertion of hypertonicsaline and capsulorrhaphy. The patient and her fetus had no postoperative complications. We believe thatthe pregnant patient with symptomatic hepatic echinococcal disease should be treated operatively and thatinsertion of hypertonic saline and capsulorrhaphy is the safest and most effective technique for both themother and fetus.


Anxiety is common in cancer patient populations, and must often initially be recognized and managed by cancer care professionals. This article reviews the recent oncology and mental health literature on anxiety. The aim is to help those involved in cancer patient care who are not specialists in mental health to understand the nature of anxiety, and discriminate morbid from normal anxiety. We review recent research into the association of anxiety with events during diagnosis and management of cancer, highlighting the importance of the meaning of events to an individual as an important factor in making people anxious. Lastly we review management strategies which might be used by cancer care professionals, in particular the importance of an awareness of specific patterns of communication which may alleviate or maintain anxiety for some cancer patients. © 2000 Cancer Research Campaign


Selection of cytostatic agents for intrathecal administration is the subject of this paper.Both the toxic side effects—destruction of blood-brain barrier and change of body weight—and the cytostatic effects on intracranially transplanted Yoshida ascites sarcoma were investigated of intrathecal administration of various cytostatic agents. As a result, it may be concluded that Methotrexate and Endoxan and lower dose of mitomycin C are suitable drugs for intrathecal chemotherapy.Based on these findings, clinical cases of malignant brain tumours were treated with intrathecal chemotherapy.Grateful acknowledgement is made to Professor Dennosuke Jinnai for his constant interest and guidance in this investigation.


The second edition of Essentials of Dermatology has come out with a new look and high standard of cover page, color illustrations and printing. Three new chapters on skin in systemic disease, skin changes of pregnancy and old age and anti retroviral therapy (ART) have been added giving a wider dimension to its contents. The existing chapters have also been revised and updated to keep pace with newer developments in dermatology.This handbook has incorporated all basic principles of diagnosis of skin diseases and provided a brief update and essential information on disease processes. An algorithmic approach to diagnosis would have added color to it. This brief but essential information on the diseases and high standard color photographs will make dermatology more accessible to new entrants Post Graduate Trainees (PGTs), general physicians as well as senior dermatologists. It is worth carrying, preserving in any library and is also recommended for all sections of the medical fraternity.One may have some reservations regarding selection criteria of most influential persons in Dermatology, Venereology and Leprosy in India but that does not necessarily undermine the quality of the book.


Baculoviruses are widely used both as protein expression vectors and as insect pest control agents. This video shows how lepidopteran larvae can be infected with polyhedra by droplet feeding and diet plug-based bioassays. This accompanying Springer Protocols section provides an overview of the baculovirus lifecycle and use of baculoviruses as insecticidal agents, including discussion of the pros and cons for use of baculoviruses as insecticides, and progress made in genetic enhancement of baculoviruses for improved insecticidal efficacy. Springer Protocols to learn more about the engineering baculovirus as an insecidical agent and the oral infection techniques used in this assay.Please visit


Background: Isolated caudate lobectomy is a challenging surgical procedure for which safe and reliable techniques have yet to be developed.Methods: Isolated caudate lobectomy was performed by initial inflow control of the caudate lobe, full mobilization of the liver from the inferior vena cava by dividing all short hepatic veins, and parenchymal division dorsal to the major hepatic veins with a clockwise rotation of the liver while the liver was selectively devascularised by Pringle's maneuver and occlusion of the confluence of the major hepatic veins flush with the inferior vena cava.Results: Two patients with cirrhosis underwent this procedure successfully without intraoperative hemodynamic instability or postoperative liver dysfunction.Conclusions: This technique allows safe and truly selective excision of the caudate lobe without the need for occlusion of the inferior vena cava or venovenous bypass.


Resource Allocation during an Influenza Pandemic To the Editor: Planning for pandemic influenza is accepted as an essential healthcare service and has included creation of national and international antiviral drug stockpiles and novel approaches to emergency vaccine development (Even when clear societal goals are established, much work remains to ensure that the healthcare community is equipped to steer healthcare resources to deliver these effectively (The third component of our preparation for optimally deploying standard care in a pandemic is being able to change our approach quickly as new knowledge emerges. In the so-called Spanish influenza pandemic of 1918–19, the unfamiliar clinical course meant that influenza was not even considered when the first cases appeared (


Parental smoking data have been reabstracted from the interview records of the Oxford Survey of Childhood Cancers (deaths from 1971 to 1976). Reported smoking habits for the parents of 2587 children who died with cancer were compared with similar information for the parents of 2587 healthy controls . Maternal daily consumption of cigarettes and paternal use of pipes or cigars were unimportant, but there was a statistically significant positive trend between paternal daily consumption of cigarettes and the risk of childhood cancer (P < 0.001). This association could not be explained by maternal smoking, social class, parental ages at the birth of the survey child, sibship position or obstetric radiography. Relations between maternal consumption of cigarettes and birth weights suggested that  smoking data were equally reliable for case and control subjects. About 14% of all childhood cancers in this series could be attributable to paternal smoking. These data were combined with smoking data from two previously published reports from the Oxford Survey  to obtain further information on risks for different types of cancer and different ages at onset of disease. Paternal cigarette smoking emerged as a potential risk factor both for the generality of childhood cancer and for all ages at onset.


A previous case-control study which utilised the occupational information available on the New Zealand Cancer Registry found an increased risk of multiple myeloma in agricultural workers consistent with previous findings in the United States. The findings are now presented for the second phase of the study which involved interviewing 76 cases of multiple myeloma (who had been included in the previous study) together with 315 controls with other types of cancer. The previous finding on an excess of farmers in the case group was confirmed by the interview data . There were no significant differences between cases and controls regarding potential exposure to phenoxy herbicides or chlorophenols. There were also no significant differences regarding activities involving potential exposure to other agricultural chemicals, although the odds ratio for fencing work, which may involve exposure to arsenic and sodium pentachlorophenate, was 1.6 . The odds ratios were significantly elevated for sheep farming  and exposure to beef cattle . The odds ratio was also elevated for persons reporting a history of hay fever . Overall, these findings suggest that the search for the causes of elevated mortality in farmers from multiple myeloma should be directed to potential causes other than pesticide exposure.


Human herpesvirus (HHSV) and human cytomegalovirus (HCMV) infections during pregnancy are a major concern of public health because of the risk for severe sequelae for the fetuses and the neonates and because primary infections, reinfections and reactivations can be asymptomatic. The risk for neonatal herpes is mostly congenital, while the risk for HCMV infection is either prenatal or congenital. Screening exposed women has not brought definite solutions but is currently being evaluated. Among pregnant women with active infection, evaluation of the fetus for contamination and thus for the risk for severe immediate or long-term sequelae for neonates is the major goal. Diagnostic tools are available, cell culture still being the gold standard, and polymerase chain reaction (PCR) being currently evaluated for its contribution to diagnosis of active infection. Consensus for screening pregnant women as well as achievement of antiviral vaccines are the most urgent intervention strategies to develop in the near future.


Water is used in vast quantities in health-care premises. Many aquatic microorganisms can survive and flourish in water with minimal nutrients and can be transferred to vulnerable hospital patients in direct  and indirect ways . Many outbreaks of infection or pseudoinfection occur through lack of prevention measures and ignorance of the source and transmission of opportunistic pathogens.


A new study described in a set of three articles provides the first comprehensive characterization of DBPs in an indoor pool environment and offers initial evidence of cellular-level effects of these chemicals in swimmers in an indoor chlorinated pool The authors assessed short-term changes in 49 healthy adults after they swam for 40 minutes in a public indoor chlorinated pool. They observed increases in two biomarkers of genotoxicity relative to the concentration of brominated trihalomethanes (THMs) in exhaled breath, which were used as a proxy of the swimmers’ total DBP exposures. Those biomarkers were micronuclei in blood lymphocytes  and urine mutagenicity (a biomarker of exposure to genotoxic agents).The team also took detailed measurements of THMs in air around the pool and in exhaled breath of the swimmers before and after swimming. The investigators measured several biomarkers of respiratory effects after swimming and found changes in only one—a slight increase in serum CC16, which suggests an increase in lung epithelium permeability. However, they found no evidence that DBP exposure affected lung function.In vitro assays showed the swimming pool water was mutagenic at levels similar to that of drinking water but was more cytotoxic (could kill cells at a lower concentration) than drinking water.The research team identified more than 100 DBPs in the water of the chlorinated pool as well as another indoor pool disinfected with bromine. Some of these compounds had never been reported previously in swimming pool water and/or chlorinated drinking water. The researchers acknowledge the need for further research on a variety of swimming pools under various conditions of maintenance and use as well as more complete evaluations of the uptake and potential effects of the compounds present in pool water. They also note the importance of timing in the collection of biological samples—a parameter for which there was no precedent, given the lack of previous studies of this type with swimmers. Above all, they emphasize that positive health effects of swimming can be maintained by minimizing pool levels of DBPs.


Randomised controlled trials (RCTs) represent the gold standard methodological design to evaluate the effectiveness of an intervention in humans but they are subject to bias, including study publication bias and outcome reporting bias. National and international organisations and charities give recommendations for good research practice in relation to RCTs but to date no review of these guidelines has been undertaken with respect to reporting bias.National and international organisations and UK based charities listed on the Association for Medical Research Charities website were contacted in 2007; they were considered eligible for this review if they funded RCTs. Guidelines were obtained and assessed in relation to what was written about trial registration, protocol adherence and trial publication. It was also noted whether any monitoring against these guidelines was undertaken. This information was necessary to discover how much guidance researchers are given on the publication of results, in order to prevent study publication bias and outcome reporting bias.Seventeen organisations and 56 charities were eligible of 140 surveyed for this review, although there was no response from 12. Trial registration, protocol adherence, trial publication and monitoring against the guidelines were often explicitly discussed or implicitly referred too. However, only eleven of these organisations or charities mentioned the publication of negative as well as positive outcomes and just three of the organisations specifically stated that the statistical analysis plan should be strictly adhered to and all changes should be reported.Our review indicates that there is a need to provide more detailed guidance for those conducting and reporting clinical trials to help prevent the selective reporting of results. Statements found in the guidelines generally refer to publication bias rather than outcome reporting bias. Current guidelines need to be updated and include the statement that all primary and secondary outcomes prespecified in the protocol should be fully reported and should not be selected for inclusion in the final report based on their results. Randomised controlled trials (RCTs) are planned experiments, involving the random assignment of patients to interventions, and are seen as the gold standard of methodological designs to evaluate the effectiveness of a treatment in medical research in humans .However, empirical research consistently suggests that published work is more likely to be statistically significant P < 0.05) than unpublished research, and significant results have a higher probability of being published than non-significant outcomes . Evidenc than unpOutcome reporting bias (ORB) has been defined as the selection on the basis of the results of a subset of the original variables recorded for inclusion in publication of trials . Recent The registration of RCTs before initiation, on clinical trial registries , is one Organisations that fund clinical trials often issue research guidelines to aid trialists in the conduct of their study. A review of these guidelines has been conducted to discover how much guidance research funders give concerning the publication of results. That review is the focus of this report.Particular international guidelines [ICH Harmonised Tripartite Guideline for Good Clinical Practice (E6) , The EU The International Conference on Harmonisation Good Clinical Practice (ICH GCP) guideline came into effect in 1997 and "is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects ." It wasRegarding the primary outcome of a trial, the ICH GCP guidelines state "The primary measurements and endpoints used to determine efficacy should be clearly specified. There should generally only be one primary variable. The primary variable should be specified in the protocol, along with the rationale for its selection. Redefinition of the primary variable after unblinding will almost always be unacceptable, since the biases this introduces are difficult to assess." The guidelines also state that "The results of a clinical trial should be analysed in accordance with the plan prospectively stated in the protocol and all deviations from the plan should be indicated in the study report. In the statistical section of the clinical study report the statistical methodology should be clearly described including when in the clinical trial process methodology decisions were made." This indicates that the primary outcome should usually not change between protocol and publication of the trial report; if there is a change, it should be documented and explained in the trial report.The Declaration of Helsinki  was firsThe CONSORT  Statement is intended to improve the reporting of a randomised controlled trial . It compThe EU Clinical Trials Directive 2001 (updated in 2005)  was tranA survey of major research organisations and UK charities  and 2 charities have been incorporated into Epilepsy Research UK (Epilepsy Research Foundation and Fund for Epilepsy).Data from all organisations and charities were entered into a Microsoft Access database with data entry screens in the form of the original questionnaire  This would cover the issue of ORB as any legitimate changes to changes of outcomes should be reported. Under "trial publication" we sought any statement referring to publication . For "monitoring against guidelines" we looked for a reference to monitoring for adherence to the published guidelines.Descriptive results from the questionnaire are presented. Data are tabulated and excerpts found in the guidelines relating to the issue of outcome reporting are used to support statements made.Twenty five organisations were contacted of which 17 were eligible. There were 115 charities listed on the AMRC website  of which 56 were eligible , while others proved more difficult to find. The websites for Health Technology Assessment (HTA) and National Institute of Health (NIH), for example, provided a lot of information making it difficult to find the required guidelines.Fifty two charities and 14 organisations had guidelines for RCTs or sent the terms and conditions of a grant. There was limited contact with one charity and two organisations (and there was no relevant information on their websites), one charity and one organisation said they had no guidelines and two charities would not send their guidelines/terms and conditions due to confidentiality. Eight of the charities and three of the organisations did not respond when we asked them to check the information we had extracted.The guidelines were requested as per Appendix 2  organisations/charities stated that the guidelines were sent by post/email (11 (37%)), supplied with the grant application (11 (37%)) or researchers were referred to their website (8 (26%)).Table Of the guidelines issued by the organisations and charities, 19 (26%) stated explicitly that a trial should be registered although a further 29 (40%) referred to trial registration implicitly through their reference to other guidelines such as AMRC, MRC or the Department of Health Research Governance Framework. Protocol adherence and protocol amendment were discussed explicitly in 32 (44%) and implicitly in 26 (36%) of the guidelines although not specifically in relation to outcomes; they state only that the protocol should be followed, all major amendments need ethics committee approval (or similar) and minor amendments need to be recorded. Publication was explicitly referred to in 49 (67%) and implicitly in 14 (19%) of the guidelines/terms and conditions. They state that trials should be monitored with regards to the guidelines (47 (64%) explicitly and 12 (16%) implicitly). Publication of negative and positive findings were explicitly referred to in 11 (15%) and implicitly in 27 (37%) of the guidelines/terms and conditions. The large majority refer to other guidelines  or ORB (selective non-publication of outcomes). The empirical evidence of publication bias was first seen in the early 1990's  and muchOrganisations tended to have their own guidelines whereas the charities mostly had terms and conditions but referred to some of the organisations' guidelines. This may reflect some of the charities being small and that some had only recently begun to fund RCTs.p-value only), and in addition may help identify outcomes that have not been reported, these recommendations alone will not prevent the selective reporting of outcomes. The CONSORT statement does not state that all outcomes that were included in the protocol should be stated in the methods section and reported in the results section of the final report. It also does not state that outcomes should not be upgraded or downgraded between the protocol and final report, or that new outcomes should not be added or old outcomes deleted based on their results. Therefore even when trialists follow the CONSORT Statement, it would be impossible to determine whether all outcomes in the protocol are reported in the final report. However, these concerns will be addressed in the revision of CONSORT that is under way. The CONSORT Statement  addresseSince this work has been completed, the members of the WHO Registry Platform Working Group on the Reporting of Findings of Clinical Trials have proposed that "the findings of all clinical trials must be made publicly available ."In the USA legislation is in place so that legally researchers are required to make their findings publicly available within a specific timeframe . The legOutcome Reporting Bias in Trials (ORBIT) project [This review forms part of the  project . It has Our review indicates that there is a need to provide more detailed guidance for those conducting and reporting clinical trials to help prevent the selective reporting of outcomes. Current guidelines need to be updated, as many include statements regarding the publication of 'negative' studies to prevent publication bias but do not go as far as mentioning ORB. In the MRC guidelines the statement 'all outcomes stated in the protocol should be fully analysed' needs to be extended to specify that prespecified primary and secondary outcomes should be fully reported and that outcomes should not be selected for inclusion in the final report based on their results. Recommendations for text to include in research funders' guidelines are suggested (see Additional file The next step is to conduct a systematic review of empirical studies that have compared protocols to publications, to assess their adherence to specified guidelines. It would then be important to conduct a survey of trialists to see which guidelines they follow and their adherence to them, to assess their understanding of the issues discussed in this paper.AMRC: Association for Medical Research Charities; CONSORT: Consolidated Standards of Reporting Trials; HTA: Health Technology Assessment; ICH GCP: The International Conference on Harmonisation Good Clinical Practice; MHRA: The Medicines and Healthcare products Regulatory Agency; MRC: Medical Research Council; NIAID: National Institute for Allergies and Infectious Diseases; NIH: National Institute for Health; ORB: Outcome Reporting Bias; RCT: Randomised Controlled TrialThe authors declare that they have no competing interests.DGA conceived the idea for reviewing guidelines following the DAMOCLES project. All authors contributed to the design of the study.KD contacted all organisations and charities, read through the guidelines obtained and drafted the manuscript. PRW did a random check of the guidelines to ensure all relevant details had been extracted and also provided comments on drafts of the manuscript. DGA and CG provided comments on all drafts of the manuscript.Appendices for review of guidelines. A list of charities and organisations that were contacted and questionnaires that were completed.Click here for fileTable 3 Summary of organisation guidelines. A table of findings for organisations that issue guidelinesClick here for fileTable 4 Summary of findings for charities that issue guidelines or terms and conditions. A table of findings for charities that issue guidelinesClick here for fileText box 1: Recommendations for text to include in research funders' guidelines. Recommendations for text to include in research funders' guidelines.Click here for file


Dear Sir,I read with interest article by Sarin and Manchanda.Correction of chordeeI think authors had been lucky to correct the chordee by simple penile degloving. In my experience such patients of mid-penile and proximal penile hypospadias with hypoplastic urethra of 1.92 cm have significant chordee which is unlikely to be corrected by penile degloving. The authors have not mentioned whether they performed Gitte's test or not which is a sure way to confirm correction of chordee. Mobilization of hypoplastic and proximal urethra along with corpus spongiosum is my preferred choice for correction of chordee in such cases or alternatively plication procedures can be performed. The added advantage with mobilization of urethra and corpus spongiosum is easy and tension-free tubularization of urethral plate.Rational approach in utilization of hypoplastic urethraThis thin distal urethra is devoid of corpus spongiosum as spongiosum is spread lateral in “Y” manner and is attached to the glans. HypoplasThe issues which need to be resolved in the preservation of hypoplastic urethra:Preservation of hypoplastic urethra depends on the type of hypospadias, degree of chordee and type of repair chosen. The thin urethra can easily be preserved and utilized in urethral plate preservation procedures like TIP in distal hypospadias with minimal or no chordee. Spongioplasty in these cases will reconstruct the near normal urethra and will help in correction of chordee. It is reThe authors have come across one case with chordee without hypospadias but which type, has not been mentioned. But by the description it looks like type III, where corpus spongiosum is well developed, but only dartos fascia is deficient and chordee correction is possible by penile degloving. Though some authors have advised reconstruction of the entire dysplastic urethra when the paper-thin urethra of type I chordee without hypospadias is associated with an abnormal meatus. But with


The majority of human anti-tumour monoclonal antibodies (Mabs) isolated to date have been disappointing. Firstly, they react or cross react with intracellular cytoskeletal proteins or nuclear antigens and therefore are of limited value as blood borne agents. They are also generally of the IgM isotype and show relatively low intrinsic affinity for the primary epitope. Secondly, such Mabs can be generated from normal, non tumour bearing subjects at a frequency comparable to their production from tumour patients. This latter observation is true also for common autoantigens such as DNA and IgG since Mabs to these can also be generated from normal subjects in addition to autoimmune individuals. This article rationalises these observations in the context of the requirement for clinical use for human Mabs. It discusses the evidence that there is a potentially useful B cell response to be immortalised, and examines the consequences of the newly recognised phenomenon of monoclonal antibody multispecificity both on the methodology of their generation and on their subsequent use as imaging and therapeutic tools.


Gravimetric and histological studies of lymphoreticular tissues during growth of a syngeneic squamous cell carcinoma in Wistar rats show that the regional lymph node anergy reported previously in this system is associated with replacement of paracortical small lymphocytes by large blastoid cells. The regional node continued to gain weight throughout the period of anergy and showed no atrophy and minimal necrosis. Over the same period the spleen increased in both weight and cytotoxicity.


Gastrointestinal stromal tumour (GIST) is the commonest mesenchymal tumour to affect the gastrointestinal tract.Appropriate management requires accurate diagnosis and the skills of a multidisciplinary team. Surgery is the only curativetreatment option and should be performed whenever feasible, by experienced personnel. For patients with advancedunresectable or metastatic disease, the receptor tyrosine kinase inhibitor imatinib offers effective therapy and can provideeffective palliation for the majority of patients with this disease. The background to this recent development and aguideline for the management of GIST is proposed.


This approach is thought to be of greater promise than the antiproliferative screens which discovered cytotoxic agents and dominated cancer drug discovery for 60 years. However, one cannot lose sight of the fact that these targets exist in the cellular environment consisting of many additional influences on target function, and that effective drug treatment will take into account drug uptake, metabolism and elimination at the level of the cell as well as the organism. A key goal is to define for the new millennium a path to cancer drug discovery and development which accounts for the cancer cell phenotype in its totality rather than as arising solely from single molecular targets. The US National Cancer Institute maintains a cell-based drug discovery screen which can define a context for drug action in the milieu of more than 300 molecular targets and thousands of gene expression patterns which have been measured in the 60 human tumour cell lines which comprise the screening panel. The challenge of the millennium will be addressed by molecules active against defined targets but with selectivity of action occurring in the milieu of deregulated cancer cell biology in all its aspects. © 2000 Cancer Research Campaign


Recent investigators have used several indications to incorporate laparoscopy in the management of patients with cervical cancer. This manuscript reviews the current literature on the role of modernoperative laparoscopy in early cervical cancer and recommends a simple approach for its use in thesepatients.


A study of parental cancer in 326 children referred to a single Paediatric Oncology Unit found a significant increase in breast cancer in mothers of children with solid tumours. The 5 tumours found were 8.9 times the expected number. This increase could not be accounted for by any of the known risk factors for breast cancer. The incidence of cancer in mothers of leukaemic children and in all groups of fathers was not significantly raised. Further prospective studies in the mothers of young children with soft tissue tumours are needed to clarify the groups at risk and to determine whether counselling and surveillance of these mothers is appropriate.


Bronchogenic carcinoma is an uncommon neoplasm in the Nigerian. Endocrine manifestations of pulmonary neoplasm are even more uncommon in Nigerians or elsewhere. The association of gonadotrophin activity with an anaplastic carcinoma of the lung in a 25-year-old Nigerian housewife forms the basis for this communication. The successful removal of a left lower lobe neoplasm in the patient who had manifested with menometrorrhagia and abnormal breast lactation was followed by a normal pregnancy and delivery of a normal baby boy within 12 months following the lobectomy.


Tobacco use is the largest global threat to public health and is anticipated to kill 1000 million people prematurely this century . This exSubstantial research by health professionals, and public health policy advocates have indicated different avenues through which adolescent smoking can be prevented at a population based level, key points which are depicted in the Tobacco Control Funnel in Figure One of the most discussed ways of reducing tobacco use among adolescents is by increasing the price of tobacco products, through a regulated rise in taxation . AdolescRestricting smoking areas also play a key role in promoting the populations health, not only by reducing the negative ramifications of exposure to second hand smoke but also by reducing cigarette consumption by restricting the smoker's ability to smoke under certain situations. Furthermore, smoke free legislations are also associated with a increased rate of smoking cessation . This enIndustry advertising and brand imagery are also associated with smoking susceptibility among adolescents, with the implementation of advertising bans a core element of comprehensive tobacco control measures and a central part of the Framework Convention on Tobacco Control (FCTC) .Tobacco Induced Diseases by Wilson N et al., who indicated an abnormal distribution of such graphic warning labels within a Canadian community [Research has indicated that adolescent smoking rates are higher in areas with a higher density of tobacco advertisements, thus increasing the community and social acceptance of smoking as part of daily life . In addiommunity .The third aspect of the Tobacco Control Funnel for preventing adolescent smoking is to educate the adolescent, the parent and the community. School based educational programmes that focus on health promotion and tobacco use, are a key element of this avenue and their importance in health education has been stressed by previous researchers . As closTobacco Induced Diseases strongly supports.Taking all the above into account, the need for collecting translational research at a national level is imperative. This community oriented research is needed to provide the society and public health advocates with the original national data required so as to de-normalise tobacco use and prevent adolescent smoking on a country to country basis, an action which


The evidence base for head and neck cancers is low with relatively few randomized controlled trials of the two main treatments, surgery and radiotherapy. The aim of the study was to investigate the patterns of surgery and radiotherapy treatment for head and neck cancers in three large areas of England and to investigate their effects on survival. This was a retrospective study of 13 510 cases of head and neck cancers  diagnosed and treated from 1984 to 1992 in England. We undertook multivariate analyses of survival using a step-wise Cox proportional hazard model and Kaplan–Meier analysis. There were regional variations in the treatments given to patients. Four in ten patients did not receive currently recommended treatments. In multivariate analyses treatment content and timing had an independent effect on survival. Better survival was associated with surgery for mouth cancers, radiotherapy for laryngeal cancers and combined treatment for pharyngeal cancers independent of tumour and demographic factors. Further research is needed to investigate the findings of this study through large randomized controlled trials and multi-centre audits. © 1999 Cancer Research Campaign


Aminoglutethimide has been used in combination with hydrocortisone in patients with advanced prostatic cancer with the rationale that it causes a 'medical adrenalectomy'. Both objective and subjective responses have been recorded. We have examined the effect of AG and HC alone and in combination on plasma androgen levels throughout the day in two studies on 11 such patients. Whilst AG combined with HC led to a significant suppression of both testosterone and androstenedione levels, the suppression with HC alone was significantly greater, indicating that any beneficial clinical effects of AG in these patients is not due to its suppression of adrenal androgen secretion.


Gross cystic breast disease is a common condition. Women with apocrine breast cysts may be at higher risk of breast cancer than women with cysts which are lined by flattened epithelium. Apocrine cysts have been shown to be associated with higher intracystic levels of dehydroepiandrosterone sulphate and intracystic sodium to potassium ratios of less than 3. In this study we measured the concentrations of epidermal growth factor, dehydroepiandrosterone and its sulphate in breast cyst fluid. The concentrations of all three analytes were significantly higher in cysts with intracystic Na+/K+ ratios of less than 3 than in cysts with electrolyte ratios of greater than or equal to 3 (P less than 0.001). The higher levels of EGF in cysts with low intracystic electrolyte ratios may provide an explanation of why women with apocrine cysts may be at greater risk of breast cancer. Positive correlations were obtained between concentrations of EGF and DHAS and between EGF and DHA, compatible with the view that intracystic EGF levels may be androgen-modulated. A positive correlation was also obtained between DHA and DHAS concentrations which supports the view that DHA in cyst fluid may be derived from the metabolism of DHAS in the breast cyst wall.


Inocula of cultured sheep cells that had been transformed with FeSV were injected into the legs of sheep so that the changes in the cellular and humoral composition of the efferent lymph from the regional node could be studied throughout the immune responses. The times at which immunoblasts and specific antibodies appeared in the lymph were similar to those recorded during responses to conventional antigens. The antiboides were mainly 7S, G1 immunoglobulins directed against virion antigens on the membranes of the transformed cells.


First and foremost, our data from Nevada  should np = 0.05 , thus indicating the temporal correspondence between elevated tungsten in Fallon and the childhood leukemia cluster.The comparison of real interest was between Fallon and other towns of west-central Nevada. Tree-ring tungsten in Fallon was not significantly different from that of other towns of west central Nevada during the tree-ring period centered on 1991 [Figure 4 in our article ], beforeThe Centers for Disease Control and Prevention (CDC) conclusion that tungsten is not mathematically associated with the leukemia cases of Fallon  is basedOur environmental research in Fallon has followed an ecologic approach with the philosophy that greater variability in exposure between different towns is more important than the minor variability in exposure within communities . The entEven with this preponderance of evidence showing spatial and temporal patterns of airborne tungsten in Fallon, we still have not concluded in any of our reports on Fallon that exposure to tungsten causes leukemia. Quite the opposite: We have acknowledged that environmental data alone cannot lead to such a conclusion and that direct biomedical testing is needed to establish a causal linkage between tungsten and leukemia.Years ago in an article on disease cluster research,


The cytolethal response to treatment with prednisolone was investigated in vitro in eight human lymphoblastoid cell lines containing varying concentrations of specific cytoplasmic glucocorticoid receptors. A similar response was observed in seven of the lines irrespective of their concentration of cytoplasmic receptors and pharmacological doses of steroid, well above those required to saturate receptors in cell-free extracts, were required for a massive lethal response. One cell line derived from Burkitt's lymphoma was refractory to lethal effects even with pharmacological doses of steroid. A similar unresponsiveness to the cytolethal effect of prednisolone in vitro was observed in fresh lymphoblasts derived from patients with acute lymphoblastic leukaemia despite evidence of a satisfactory clinical response to therapy which included steroid. The resistance of human lymphoblastoid cells to treatment with glucocorticoids in vitro may result from a defect in activation subsequent to the binding of steroid to cytoplasmic receptors.


The cylindrical/polygonal mouse holder has semitransparent rainbow bands on its side surface forthe acquisition of spectrally resolved data. Numerical studies and experiments are performed to demonstratethe feasibility of this system. It is shown that bioluminescent signals collected using our system can producea similar BLT reconstruction quality while reducing the data acquisition time, as compared to the sequential dataacquisition mode.We describe the system design of the first bioluminescence tomography (BLT) system for parallel acquisition of multiple bioluminescent views around a mouse in a number of spectral channels simultaneously. The primarycomponent of this BLT system is a novel mirror module and a unique mouse holder. The mirror module consists ofa mounting plate and four mirrors with stages. These mirror stages are right triangular blocks symmetricallyarranged and attached to the mounting plate such thatthe hypotenuse surfaces of the triangular blocks all make 45


Four human and 4 rat astrocytomata and mammalian adult brain and spinal cord were examined by indirect immunofluorescence with human serum containing smooth muscle antibody. Cryostat sections of astrocytomata showed staining of the tumour cell cytoplasm and processes while in normal adult brain and spinal cord the entire astrocyte stained. Impression film and tissue culture monolayers of astrocytomata showed staining of cell processes and a fine, filamentous network in the cell body. The reaction with astrocytoma tumour cells was stronger than that with the corresponding normal astrocytes. Specificity of the staining reaction was established by its prevention on neutralization absorptions of the serum with extracts or homogeneous of smooth muscle. The presence of smooth muscle-associated antigen in astrocytes and astrocytomata is indicative of contractile protein providing a mechanism of cell movement in vivo.


Noradrenaline induced changes in the distribution of blood flow in implanted tumour and normal liver tissue was measured using blood flow tracer microspheres. The ratio of embolised microspheres in tumour compared to normal tissue was determined before and after the intravenous infusion of noradrenaline, propranolol and a combination of the two drugs. The ratio was significantly decreased by noradrenaline alone but significantly increased when propranolol was added to the infusate. Propranolol had no effect on the ratio. The drug combination increased the tumour to normal ratio by approximately 69% and also doubled the proportion of microspheres entering the internal tumour circulation. This represents an enhanced relative blood supply to tumour and would provide a means of preferential carriage of blood borne cytotoxic agents to tumour tissue rather than normal tissue.


The effect of exogenous sex hormones on the cell mediated response in male and female mice has been studied by measuring the subcutaneous growth of HeLa tumour nodules and the variation in the total lymphocyte count. It was found that oestrogen treated male and female mice experienced a profound lymphopenia which was vary rapid in onset. Concurrent with the lymphopenia there was prolongation of HeLa tumour nodule growth in female mice, but not in males. A lymphopenia occurred in androgen treated male mice with subsequent prolongation of HeLa tumour nodule growth, and a lymphocytosis in female mice, with reduction of HeLa tumour nodule growth.


The role in which electronic endoscopy plays is important in EMR. It is useful in diagnosis and treatment of gastric cancer from a clinical viewpoint. EMR with use of electronic endoscopy allows bettercoordination between the operator and assistants, and thus improves the results further.


The use of cryotherapy for the treatment of some unresectable liver tumours has been clearlyestablished as a therapeutic option. Intra-operative ultrasound has enhanced the process by enablingthe surgeon to identify hepatic lesions and to allow visualisation of the freezing process to ensure thatthe cryolesion will include the tumour mass. The purpose of this paper is to provide a practical guide tosurgeons who wish to perform cryotherapy of liver tumours. Patient selection and anaestheticconsiderations are important. The surgeon should be able to deal with the complications ofcryotherapy, particularly the intra-operative haemorrhage which may arise from cracking of thehepatic parenchyma as the iceball thaws. Follow-up is based on tumour marker assay and imaging ofthe liver and repeat cryotherapy can be considered for selected cases.


Background. Metastatic spread of soft tissue sarcomas to the digits is            extremely rare and metastasis of MFH to the fingers and toes has not been documented.            Purpose. We present two case reports of metastatic spread from a giant            cell rich malignant fibrous histiocytoma to the digits and discuss their management.


D. latum and the closely related sea gull tapeworm, D. dendriticum, have well-established endemic life cycles in a series of glacial lakes that dot Region XIX and Region X in northern Chilean Patagonia. Infections with these parasites have been detected in this geographic area since the 1950s in persons who ingested uncooked fish from these lakes and also in animals (–D. latum is transmitted to humans by plerocercoid larvae present in fish meat and visceral organs (–––During the past 55 years, work by Chilean parasitologists has demonstrated that native species and introduced salmonid fish are infested with Diphyllobothrium plerocercoids in these lakes (––,–The Brazilian studies did not detect Diphyllobothrium plerocercoids in several samples of Chilean salmon tested after the first human cases of diphylobothriasis appeared (–,–Traditionally in Europe and North America, infections with fish tapeworms were incurred during the preparation of gefilte fish by Jewish women who tasted bits of uncooked freshwater fish and thus ingested plerocercoids (–Thus, to avoid new human outbreaks of fish tapeworm in other geographic areas where this parasite does not exist, salmon originated from aquaculture should not be eaten raw, at least not until it has been frozen under the conditions discussed above. Assuming the epidemiologic information presented here explains the appearance of the fish tapeworm outbreak in Brazil, it would be preferable, in terms of sanitation, for the Chilean aquaculture industry to stop growing salmon smolt in the lakes in the areas where diphyllobothriasis is endemic in humans and animals (,This epidemiologic event may also be understood as cautionary tale, and 1 more example of the dangers entailed by the globalization of food supply and of the rapidly changing global eating habits that facilitate the distribution of human and animal pathogens worldwide. The expansion of diphyllobothriasis-endemic areas in Chile may, in turn, facilitate the appearance of future outbreaks of this disease as the aquaculture industry expands to these new infested areas and the market for Chilean salmon enlarges worldwide. The increased popularity of eating uncooked fish in sushi and ceviche will also be a factor in the emergence of future outbreaks of this disease (


The choice of calibration policy is of basic importance in analyticalchemistry. A prototype of the practical calibration problem isformulated as a mathematical task and a Bayesian solution of theresulting decision problem is presented. The optimum feedbackcalibration policy can then be found by dynamic programming. Theunderlying parameter estimation and filtering are solved byupdating relevant conditional distributions. In this way: thenecessary information is specified ; the relationship of the information gained from acalibration experiment to the ultimate goal of calibration, i.e., tothe estimation of unknown samples, is explained; an ideal solutionis given which can serve for comparing various ways of calibration;and a consistent and conceptually simple guideline is given forusing decision theory when solving problems of analytical chemistrycontaining uncertain data. The abstract formulation is systematicallyillustrated by an example taken from gas chromatography.


In order to predict the metabolic fate of an arbitrary compound based solely onstructure, it is useful to be able to identify substructural ‘functional groups’ that arebiochemically reactive. These functional groups are the substructural elements thatcan be removed and replaced to transform one compound into another. This problemof identifying functional groups is related to the problem of classifying compounds.The research presented here discusses the state of the art in biochemical databasesand how these sources may be applied to the problem of classifying compounds basedsolely on structure. We describe a biochemical informatics system for processingmolecular data and describe how 100 255 compositional (hasA) relationships areinferred between 835 abstractions and 9500 metabolites from the KEGG Liganddatabase. Specifically, we focus on the identification of amino acids and consider waysin which the inference of biochemical ontologies for metabolites will be improved inthe future.


An attempt has been made to construct an assay potentially suitable for use with primary cultures of human tumours to measure the survival of exponentially growing monolayer cultures after exposure to anti-neoplastic drugs. Cell survival was assessed using their protein synthetic capacity after removal of drugs. HeLa cells were employed to avoid the ingerent variability and heterogeneity of primary cultures from human tumours, and an assay has been constructed using microtitration trays to provide large numbers of replicate cultures without the requirement of a large number cells. An increase in the duration of the exposure to drug increased sensitivity in nearly all cases examined. Similarly, an increase in the period of culture following drug removal produced increased sensitivity to alkylating agents but allowed recovery from exposure to certain cycle-dependent drugs. Some of the drugs used were shown to be unstable under culture conditions and vinblastine was actively metabolized, although this instability was not necessarily reflected in the time course of the drug's effect. Mustine sensitivity was shown to be reduced by an increase in cell density at a level where density limitation of 3H-thymidine incorporation becomes apparent. These variations and possible methods of minimizing their effects are discussed.


We surveyed physicians and veterinarians in Wisconsin about the risk for and prevention of zoonotic diseases in immunocompromised persons. We found that physicians and veterinarians hold significantly different views about the risks posed by certain infectious agents and species of animals and communicate very little about zoonotic issues; moreover, physicians believe that veterinarians should be involved in many aspects of zoonotic disease prevention, including patient education.


The blastogenic response to a crude cell extract of ovarian cancer cells has been studied in 48 patients with ovarian cancer , in 26 female controls matched for age and in 18 female patients with other types of cancer in remission from disease. The responses in ovarian cancer patients in remission and relapse were considered separately. The blastogenic responses to cell extracts of foetal ovary, foetal lung, foetal liver and normal adult ovary were also assessed in a proportion of all 3 groups. The blastogenic responses to ovarian cancer and foetal ovary cell extracts were found to be significantly greater in the ovarian cancer patients in remission than in the controls, but the responses to ovarian cancer extract were not greater in the relapse group or in patients with other cancers. As a blastogenic response to normal ovarian extract was also present in some of these patients, the data so far do not support the hypothesis of a tumour specific antigen. This tumour associated response may be occurring to determinants in foetal or adult ovarian tissue to which the patient becomes sensitized in malignant disease. The response is complex and the nature of the antigen requires further analysis.


Metastatic melanoma of the common bile duct (CBD) is very rare, with only 18 cases reported so far.. A compuThe first case of a metastatic melanoma to the bile duct was described by Spigelberg in 1895 and the second by Duval in 1908. The melaIt seems reasonable to perform radical surgical resection in patients with potentially curable disease and isolated deposits in the bile duct. If there is a concurrent metastatic disease elsewhere, it is prudent to adopt a less-aggressive approach in order to relieve obstructive jaundice, such as the bypass procedure or stenting.Patients with gastrointestinal symptoms and a history of melanoma should be investigated for the presence of gastrointestinal metastases even if the original primary malignancy was diagnosed years before the patient presentation.


Sir,Chlamydia trachomatis infection also lies in the fact that it is the most common reportable infectious disease in the United States of America.[Chlamydia trachomatis infection. This change occurred because of recent evidence supporting azithromicin as safe and effective during pregnancy.[We agree with the readers of our article “Approach to Urinary Tract Infection” when they point out that it is important to treat both gonorrhoea and Chlamydia in a patient of urethritis simultaneously. Gonorrhoea need not be treated if excluded after proper testing and investigation. Importance of  America. Azithromregnancy.Both Gonococal and Chlamydial infections are sexually transmitted diseases (STDs) and the standard practice is to recommend treatment of sex partners of the patients of these infections to decrease the risk of reinfection. The primary goal is for the patient’s sex partner to be examined by a physician for testing, treatment and education. However, there may be clinical situations in which this cannot be accomplished . In these circumstances, the Center for Disease Control recommends that physicians consider using “expedited partner treatment.” This is the practice of treating sex partners of persons diagnosed with an STD without medical evaluation or prevention counseling by providing the patient with appropriate treatment to administer to his or her partner.


The T lymphocytes populations of 22 young healthy adults, 21 healthy middle aged and older blood donors, 35 non-pregnant women of child bearing age and 14 patients with advanced malignant disease were assessed and compared. It was found that the mean T cell counts in the middle aged and older controls were significantly lower than in the healthy young adults and were further reduced in the patients with malignant disease. The addition of the proteolytic agent brinase (protease 1 obtained from Aspergillus oryzae) to the rosetting test increased the T cell counts signficantly in all groups. This was mot marked in the older age groups and the patients with malignant disease. The proteolytic agent is shown to exert its effect on the lymphocytes in the test. Slow intravenous infusion of either brinase or streptokinase into patients with malignant disease is shown to result in increased T lymphocyte counts pari passu with a restoration of skin allergy. The significance of these findings and possible mode of action of the proteolytic agents in increasing T cell activity are discussed.


Insecticide resistance has been a problem in all insect groups that serve as vectors of emerging diseases. Although mechanisms by which insecticides become less effective are similar across all vector taxa, each resistance problem is potentially unique and may involve a complex pattern of resistance foci. The main defense against resistance is close surveillance of the susceptibility of vector populations. We describe the mechanisms of insecticide resistance, as well as specific instances of resistance emergence worldwide, and discuss prospects for resistance management and priorities for detection and surveillance.


The cytocidal properties of metronidazole against hypoxic mammalian cells are described. This chemotherapeutic action has been shown to be dependent on drug concentration and duration of exposure. The x-ray TCD50 for a murine anaplastic carcinoma was reduced from 6081 rad to 4643 rad when animals were given metronidazole orally for 36 h before radiation treatment. The effect is attributed to the direct killing of hypoxic tumour cells by a mechanism analogous to that proposed for the action of the drug on anaerobic micro-organisms. It is concluded that further work with metronidazole as a cytotoxin specific for hypoxic cells is warranted, particularly in view of the reported lack of toxicity associated with the preliminary clinical use of the drug as a radiosensitizer in man.


Should a medical practitioner be aware of ethics? Does knowledge of ethics make you a thoughtful and competent doctor? The society expects medical practice to be based on sound ethical principles. But then what are these principles? Who decides what is unethical? Does ethics vary among different groups, societies or countries? Why more and more medical trials are now being conducted in the third world countries? Does the poor unsuspecting population of the third world become a guinea pig for the multinational companies? To what extent can learning ethics in a medical school produce a caring physician? How many of us put ourselves or our near and dear ones in the position of the patient before making a medical decision, more so in a difficult situation.Surgical workshop is the order of the day and has become very popular among surgeons. Are there any ethical guidelines to govern them? How often does a new surgical procedure go through proper checks and balances before being adopted widely in medical practice? This has led to see one, do one and teach one principle and has resulted in an undisciplined introduction of laparoscopy and many other similar surgical procedures in Urology and General surgery and has earned dubious distinction of the biggest unaudited free for all in the history of surgery. The terminology of surgical learning curve has gained popularity due to the mishaps, which have occurred during the learning of laparoscopy. I am sure that the aviation industry that trains pilots would be in for a rude shock if they knew how we are trained before we adopt these new procedures.Medical Ethics and Legal Issues may not necessarily discuss the above issues but if we want to salvage the reputation and integrity of our profession, we certainly need to think and draw our own “Lakshman Rekha.” Ethics should be taught in medical schools by senior medical/paramedical faculty who are either practicing (or have practiced) medicine and have the experience of making difficult medical decisions and have learnt from their mistakes.This symposium on Dr. Joseph Thomas, Professor and Head of Urology at KMC, Manipal, who has a special interest in this field and holds a degree in medical law has guest edited this symposium. I am optimistic that it would sensitize all of us toward these important issues and provide an opportunity for further deliberation. I thank Dr. Thomas and his team for their efforts.By the time you all receive this issue you would be aware of the sudden demise of Dr. Atul Thakre. He was a brilliant urologist and the rising star in the field of Pediatric Urology. He took keen interest in the activities of the IJU. We are all deeply saddened by this loss and I feel a fitting tribute to Dr. Atul Thakre would be development of Pediatric Urology in India.


The interpretation of time trends in disease rates can be facilitated using estimable contrasts from age-period-cohort models. Cohort and period trends in breast cancer incidence and mortality rates in Scotland were investigated using contrasts that measure the changes in the linear trends. These contrasts were compared with estimates obtained from mortality rates in the USA and Japan. A significant moderation of both breast cancer incidence and mortality rates was observed in Scotland, associated with cohorts of women born after the Second World War compared with women born between the two world wars. The moderation of breast cancer mortality among cohorts born after 1925 compared with cohorts born before 1925 that was observed in the USA and Japan was also observed in this study. This moderation is not present in the incidence rates. The relative decline in the risk of breast cancer seen in younger cohorts seems to be contradictory to the temporal pattern present among breast cancer risk factors. It may well be that the alteration of eating patterns as a result of rationing in the wartime and immediate post-war period, and the subsequent influence on certain breast cancer risk factors probably produced by such changes, may have had some influence on the development of healthier girls and women. Such speculation could be addressed in a well-designed epidemiological study. There have been no changes in the mortality rate trends with period in Scotland, although the changes in the incidence rate trends with period are consistent with an increase in registration coverage.


Two patients with stricture of the extrahepatic biliary tree are described. Both patients presented with aclinical picture of obstructive jaundice one to two years following radiotherapy for a malignantcondition. As no recurrent tumour was detected in either of the patients the strictures were consideredto be the result of radiation therapy. Bilio-enteric decompression was performed in both patients whoare well at follow up one and ten years after the procedure.


Mycobacterium tuberculosis and dysregulation of the heat shock response results in increased immune recognition of the bacterium and reducedsurvival during chronic infection. In this study we use a whole genome spottedmicroarray to characterize the heat shock response of M. tuberculosis. We also begin a dissection of this important stress response by generating deletion mutants that lackspecific transcriptional regulators and examining their transcriptional profiles underdifferent stresses. Understanding the stimuli and mechanisms that govern heat shockin mycobacteria will allow us to relate observed in vivo expression patterns of HSPsto particular stresses and physiological conditions. The mechanisms controlling HSPexpression also make attractive drug targets as part of a strategy designed to enhanceimmune recognition of the bacterium.The regulation of heat shock protein (HSP) expression is critically important to pathogens such as


The articles in this special issue reflect a convergence of developments in the fields of bioinformatics and plant genomics. Bioinformatics has its roots vaguely seated in the early 1980s, a time when personal computers began appearing in research laboratories and researchers began recognizing that those computers could be used as tools to organize, analyze and visualize their data. In the ensuing years bioinformatics tools began appearing at various sites including the European Molecular Biology Laboratory, the Molecular Biology Research Resource at the Dana-Farber Cancer Institute in the mid 1980s, the National Center for Biotechnology Information (NCBI) in 1988, the Genome Database Project at Johns Hopkins University in early 1989, and in countless laboratories throughout the world. These last efforts resulted in the development of many of the tools described in this special issue.Arabidopsis thaliana was published. Since then many genome sequencing projects have been undertaken that include poplar (Populus), grape (Vitis), the moss Physcomitrella, the biflagellate algae Chlamydomonas and several globally crucial crop plants such as corn (Maize) and rice (Oryza). However, as we have witnessed on numerous occasions, determining the sequence of a genome is only the first step toward understanding genome organization, gene structure, gene expression patterns, disease pathogenesis and a host of other features of both scientific and commercial interests. Computational tools of genomic annotation and comparative genomics must be applied to gain a useful understanding of any genome.Progress and interest in plant genomics have been accelerating since the time in late 2000 when the genome of In this special issue we present a collection of papers that together describe a powerful and impactful toolbox of applications and resources for plant genomic analysis. Among those articles you will find a description of research performed by the Mexican headquartered Generation Challenge Programme (GCP) which led to the GCP Platform . This research support tool supports a number of data formats and web services and provides access to high performance computing facilities and platform-specific middleware collectively designed to support crop science research.Probably one of the most promising empirical tools for investigating gene expression developed in the last 15 or so years is that of microarray technology. While the technology has become commonplace, with tools for generating and hybridizing arrays available to all, the analysis of microarray-derived data has been challenging. Many laboratories have struggled not only with this challenge but also with the task of sorting through the plethora of analytical tools available in an effort to find the ones that may be best suited to their own work. In this issue there are two reviews by Page and Coulibaly which examine and describe bioinformatics tools for inferring functional information from plant microarray data. Together these papers step the reader through a collection of tools, and their applications, for analyzing the expression of single and multiple gene expression profiles.This theme of microarray analysis is continued in the description of the cross chip probe matching tool (CCPMT) by Page et al. Indeed it expands the readers horizons beyond the analysis of individual microarrays with the ability to associate probes across species. And of course, microarray analysis is facilitated by careful experimental design from the start so Robert Tempelman provides a review of statistical methods used to design efficient two-color microarray experiments. Taken together, these microarray papers provide an overview of the design of microarray experiments and the interpretation of the complex results of those experiments that will be informative for new and experienced laboratorians alike.Several other novel tools are described herein. One, Blast2GO is a suite of tools for the analysis and functional annotation of plant genomes (Conesa and Goetz). It provides an intuitive interface for identifying functional regions within DNA sequences. Another sequence analysis tool described by da Maia et al. is the SSR locator. That tool enables researchers to identify suitable targets for binding PCR primers in order to ensure that those targets are unique within the genome. It also assists with primer design and has a PCR simulator which facilitates comparisons of hypothetical amplification products among different species.Another challenge facing scientists today is the need to stay abreast of advances in a field that is progressing rapidly as a consequence of newly available technologies. In order to address this challenge there are two review articles that together provide insights into the discovery of relationships among a varied array of plant species. The first article, by Abdurakhmonov and Abdukarimov, describes the application of association mapping to understanding traits in crop species. Their work is directed toward novices within the crop breeding community in order to expose them to potential problems that they may face and solutions they may employ to overcome those problems. The second article describes the tools available for phylogenetic analyses and the increased use of Bayesian methods in those tools (Aris-Brosou and Xia). Constructing phylogenies has traditionally been a challenge to even the most experienced researcher but modern bioinformatics tools are lowering the bar for those interested in detecting adaptive evolution and estimating divergence among species.Zea mays which includes genomic sequences as well as functional information and the tools to explore both.The wealth of information available to researchers today can be overwhelming. In order to address this potential, two papers describe information resources which consolidate and organize related information. PPNEMA is a database resource for those interested in plant-parasitic nematode ribosomal genes . That resource allows the user to browse, search and generally explore phytoparasite ribosomal DNA. A second database described in these pages is the MaizeGDB . This resource contains information about The body of the papers in this special issue represents the leading edge of plant genomics research. Together they provide the reader with descriptions of the tools and resources necessary to understand and promote advances in this important field.Gary R. SkuseGary R. SkuseChunguang DuChunguang Du


The inhibitory effect of the protease inhibitor aprotinin (Trasylol) on the invasion of mouse kidney explants by polyoma virus transformed BHK21 cells was investigated using a mixed cell/organ culture technique. The extent of invasion was monitored by following the changes in LDH isoenzyme pattern in the explants and by histological assessment. The kidney explants containing aprotinin were found to maintain a normal kidney LDH pattern and to suffer considerably less invasion than the explants not containing the drug. These results support the idea that proteolytic enzymes are associated with invasion and that inhibitors of protease activity could possibly be useful in the management of clinical cancer.


The level of galactosyltransferase activity was measured in the serum of 220 patients with a variety of solid tumours. There was a significantly greater proportion of patients with elevated galactosyltransferase in the group with metastatic disease (43%) than for the group with localised disease (16%). Galactosyltransferase was elevated in 69% of patients with liver metastasis compared to 32% of patients with metastatic disease at sites other than liver and this difference was also significant. High resolution agarose isoelectric-focusing was used to determine the 'isoenzyme' pattern of serum galactosyltransferase of 6 patients with liver metastasis and 2 patients with primary hepatoma and these were compared to those of 6 patients with similar primary tumours without liver involvement. There were no qualitative differences in the patterns from the two groups. The average peak height for each of the 19 peaks of activity identified was generally higher in the group with liver involvement, except for those peaks known to contain little or no attached sialic acid. Liver involvement appears not to contribute in any specific way to the altered pattern of serum galactosyltransferase often seen in patients with solid tumours. The tumour rather than the liver is therefore the most likely source of these alterations.


To describe early cancerous and precancerous lesions of the laryngeal vocal folds as well as of themost common differential diagnoses, based on a series of microlaryngoscopic photographs. Someintroductory remarks about terminology and the classification of epithelial lesions of the vocal foldsare included. The paper ends with some comments as to the management of epithelial thickenings(or leukoplakias) of the vocal folds. Malignancy should be suspected as long as it has not been ruledout by histologic diagnosis on adequate biopsies, which is the only way to correctly evaluate the characterof such lesions. Precancerous lesions should be controlled by regular follow up examinationsas carefully as invasive carcinomas (posttreatment), because there is a high tendency for recurrencesor for later development of malignancy in these cases.


The growing consensus that most valuable data source for biomedical discoveries is derived from human samples is clearly reflected in the growing number of translational medicine and translational sciences departments across pharma as well as academic and government supported initiatives such as Clinical and Translational Science Awards (CTSA) in the US and the Seventh Framework Programme (FP7) of EU with emphasis on translating research for human health.The pharmaceutical companies of Johnson and Johnson have established translational and biomarker departments and implemented an effective knowledge management framework including building a data warehouse and the associated data mining applications. The implemented resource is built from open source systems such as i2b2 and GenePattern.The system has been deployed across multiple therapeutic areas within the pharmaceutical companies of Johnson and Johnsons and being used actively to integrate and mine internal and public data to support drug discovery and development decisions such as indication selection and trial design in a translational medicine setting. Our results show that the established system allows scientist to quickly re-validate hypotheses or generate new ones with the use of an intuitive graphical interface.The implemented resource can serve as the basis of precompetitive sharing and mining of studies involving samples from human subjects thus enhancing our understanding of human biology and pathophysiology and ultimately leading to more effective treatment of diseases which represent unmet medical needs. The effective management of knowledge in translational research setting ,2 is a mMerck has developed a system which enables sharing of human subject data in oncology trials with the Moffit Cancer Center and Research Institute . This syThere is a growing set of data being deposited in NCBI GEO , EBI ArrThese databases enforce standards for some of the elements of the experimental metadata . In geneThe computational experiments can lead to validation of the primary findings or to novel discoveries such as in the case of meta-analysis of multiple datasets. The burden of deconvoluting the phenotypes from source files downloaded from these primary sources and coding them in a standard to enable large-scale meta-analyses makes these types of discoveries very costly and in fact quite rare -13.Data curation is a way to tackle some of these issues. Typically, derived databases of omics experiments are curated to create comparisons for specialized mining with specific questions in mind. For example, there are multiple resources being developed to integrate and analyze gene expression and other omic data and create contrasts (A vs. B comparisons) or signatures ,15. The The treasure trove of high-content data derived from human samples can be much more effectively mined if standard dictionaries applied to all these studies and each subject's clinical and the associated sample's genomics data is stored and analyzed through a system which enables efficient access and mining. An example of such standardized infrastructure and potential for pre-competitive sharing is presented below.Johnson & Johnson has invested in translational research by establishing within its pharmaceutical R&D division a set of translational and biomarker groups and focusing also on the management and mining of the data emanating from integrative settings crossing the drug discovery and development stages. One of the deliverables of this enhanced governance structure was the development of a translational medicine informatics infrastructure. This infrastructure is a combination of dedicated people, robust processes and informatics solution - tranSMART.We have established a strong cooperation across the R&D of the pharmaceutical companies of Johnson & Johnson and an open innovation partnerships with the Cancer Institute of New Jersey and St. Jude Children's Research Hospital . The R&DAn important aspect of successfully introducing a paradigm shift within a large pharmaceutical organization is change management. From the start we have recruited biologists, pharmacologists and physicians from various therapeutic areas to help champion the adaptation of the newly developed translational infrastructure but also to guide us through the development of the application in an agile environment.The translational medicine data warehouse - tranSMART - was developed in partnership with Recombinant Data Corporation Fig.  and detaData is stored in an Oracle 11 database which is fully auditable. We selected a set of open-source components to assemble the application in contrast to the strategy followed by Merck. A user interface providing a biological concept search of analyzed data sets and an i2b2  based coClinical trial and experimental medicine study data sets were transformed by curators and ETL  developers into an i2b2  EAV  of this complex query. In subset one (denoted by S1_... sample ids) most of the samples have low expression of the gene of interest (denoted by blue color) whereas in subset two (denoted by S2_... sample ids) most of the samples have high expression of the gene of interest (denoted by red color).Queries can use Boolean operators such as OR and AND as illustrated in Figures EGFR gene with k = 2 can stratify the subjects into high and low expressors.Cross-study meta-analyses are also available in the application Figure . In thisThe tranSMART system allows clinicians, translational scientists and discovery biologists to interrogate aligned phenotype/genotype data to enable better clinical trial design or to stratify disease into molecular subtypes with great efficiency. Initial successes of applying this system point towards the high value of translational data in proposing indications for drugs with new mechanism of actions  and selecting biomarkers for stratified medicine.The system has been in wide use across multiple therapeutic areas within the pharmaceutical companies of Johnson and Johnson. Comparing biological processes and pathways between multiple data sets from related disease or even across multiple therapeutic areas is an important benefit of such a system. Through the examples presented above we have shown that the tranSMART system allows scientist to quickly re-validate hypotheses or generate new ones with the use of an intuitive graphical user interface. The use cases supported by tranSMART have been developed in close collaboration with key users and the solution was built from many open source systems making the adaptation of the system straightforward.We have implemented a fine-grained, role-based authorization model throughout the application so that study level permissions are enabled and can be controlled by the study owners. During curation the study owners are actively involved in reviewing and approving the loading and standardization of the data from their studies. This approach greatly enhanced the cooperation of the study owners and the ultimate success of the data warehouse.A well-constructed system can enable scientist to test but also generate new hypotheses using well-curated, high-content translational medicine data leading to deeper understanding of various biological processes and eventually helping to develop better treatment options.Active curation and enterprise data governance have proven to be critical aspects of success. The capability of the system to query both internal and public data and that during the development and implementation full organizational alignment was ensured turned out to be crucial.Because large part of tranSMART is built from open source systems it is much more amenable for being shared with academic institutions in a pre-competitive setting enabling collaborations aimed at developing deeper understanding disease biology.The tranSMART system is under active development including active curation of additional studies, implementing new modalities and adding novel workflows. Future development may include connection to the internal biobank. By the established system and the robust processes our research and development organization can now effectively manage not just the complex and multimodal data but can also unlock the potential of the data by transforming it into actionable knowledge.SS, VK and EP are employees of Johnson and Johnson.SS and EP conceived and designed the study. VK and TK assisted with the experiments. SS drafted the manuscript. All authors read and proofed the final manuscript.


Although serologic evidence suggests the presence of Q fever in humans and animals in Saudi Arabia and the United Arab Emirates, acute Q fever has not been reported on the Arabian Peninsula. We report the first two cases of acute Q fever in Oman.


A high-performance continuous flow analyser is described, based on gas pressure driven carrier and reagents controlled by computer switched solenoid valves. The principal characteristics of the analyser are discussed and examples of its performance are provided in the form of results obtained using a standard procedure for the determination of Cr(VI). The system was also tested in use with real samples using an ammonium ion analysis on potable and effluent water samples, and the results compared with those obtained using a segmented continuous flow method operated at the Laboratory of the Government Chemist.


The increased focus on the epistemology—the theory of knowledge—that underlies both healthcare improvement and patient safety has brought a fresh vitality to the scholarly healthcare improvement literature.2Quality and Safety in Health Care in 2005 as draft guidelines to advance the scholarship of improvement and to address the underlying theory of experiential learning that is central to much of healthcare improvement research.QSHC supplement.2SQUIRE was originally promulgated by Davidoff and Batalden in Colleagues who labour daily at improving health care in their clinical and institutional settings do not necessarily have incentives or the inclination to publish their original improvement work. Indeed, healthcare improvement is often its own reward. Academics, on the other hand, have strong incentives to publish their original work because publication provides a measure of professional productivity, one of the criteria by which they are judged by their peers and by academic institutions. Improvement researchers may use methods—for example, qualitative techniques, particularly those that reflect critical experiential learning that are less commonly used in biomedical research.SQUIRE was preceded by concise guidelines for quality improvement reports (QIR), which provided guidance for reporting local improvement projects.–Authors and editors will find that SQUIRE and QIR both emphasise the central importance of context and of the effective communication of improvement strategies.3QSHC website by over 15 000 unique viewers. Authors who were early adopters7–After the initial publication of the draft SQUIRE guidelines in 2005, their theory and utility underwent considerable scrutiny. The original draft guidelines were accessed online via the Now that the revised SQUIRE guidelines are available, what are potential unforeseen and unintended consequences of SQUIRE’s wider application to healthcare improvement reports? An example of the more worrying questions include: is there a risk that improvement scholars—in their commitment to the unique epistemology of improvement science—have created potentially controversial theory that could contribute to possible isolation of this scholarly field? Might initiatives to consider deeper underlying issues of epistemology discourage valuable reporting by clinicians, administrators and scholars for whom improvement is not a first or primary discipline? The authors of SQUIRE hope it will offer guidance that, in fact, serves to circumvent these concerns and contribute to the development of a lively community of scholarly inquiry and practice about the improvement of healthcare.2Nevertheless, these questions highlight the importance and value of the “Explanation and Elaboration” (E & E) document that accompanies the publication of SQUIRE in this supplement.In addition, a SQUIRE website has been established for its promulgation and systematic evaluation.Authors and editors can readily test the utility of the SQUIRE guidelines for making healthcare improvement research more accessible to a wider audience, and the opportunities they provide for increasing the clarity of improvement research reportsQSHC and other scholarly journals. Finally, we encourage active interaction, specifically on the SQUIRE website and directly with the editors of QSHC, as the healthcare improvement community endeavours to enhance the rigour and utility of the scholarly healthcare improvement literature.We encourage authors to consider the use of either SQUIRE or QIR—based on the nature of their healthcare improvement activity—as they craft their reports for


The clinical features of 19 patients with malignant infiltration of the retroperitoneal tissues are described. These patients usually presented with unexplained uraemia and nonspecific symptoms; only a few had other evidence of malignancy. The diagnosis was resolved only by histological examination of multiple biopsy specimens. Since the prognosis is usually very poor it is essential to distinguish this condition from non-malignant causes of retroperitoneal fibrosis.


The Epithelial Membrane Antigen (EMA) has until now only been described in immunological terms and has been shown immunohistochemically to be present on a variety of human non-squamous epithelial surfaces. It is a valuable marker in diagnostic tumour pathology and enables the detection of small deposits of malignant cells in organs such as liver and bone marrow. Its discovery in soluble form in human milk has enabled a purification of the antigen from this source. The antigenic activity in the milk is spread over a wide range of mol. wts and although purification causes a general reduction in size, the antigen remains heterogeneous. Carbohydrate forms the major component of the antigen with galactose and N-acetylglucosamine as the two major sugars. The protein content of EMA is low and shows considerable variation in amino acid composition from one sample to another. A high content of inorganic material has also been found in EMA but is not due to high sulphate or phosphate levels.


With progressive growth of syngeneic sarcomata in rats there was a rise in serum levels of lysozyme which correlated with their immunogenicity and their macrophage content. By an examination of lymph/blood differences in normal and in tumour bearing rats and of the production of lysozyme by cells obtained from the tumours and maintained in vitro, it is apparent that the macrophages resident in a tumour mass make a massive contribution to the elevation in serum lysozyme concentrations. Tumour cells did not release detectable lysozyme activity. Tumour amputation led to a rapid fall in lysozyme levels. Irradiation of the host rats abolished the lysozyme response and the subsequent development of metastases in these rats was associated with a rise in serum lysozyme. The serum concentration of this enzyme reflects the macrophage content of a tumour mass and the draining lymph nodes. We conclude that under well defined conditions serum lysozyme activity may be a useful marker of macrophage mediated host responses to a tumour.


Records of approximately 310,000 patients admitted to the 10 hospitals in Botswana between 1960 and 1972 have been studied and details of 1445 patients with malignant tumours abstracted. For the 894 tumours for which there was some supporting evidence--at best histological proof and minimally a clinical description of symptoms--proportional frequencies have been calculated for all sites and comparison made with the findings of other surveys. Cancer of the cervix uteri is overwhelmingly the most commonly occurring malignant tumour and the proportional frequency is among the highest observed in Africa south of the Sahara. Skin tumours are unusually common for Southern Africa in both sexes. In males, penile and prostatic tumours have a relatively high frequency whilst the frequencies for liver and lung are lower than in other parts of Southern Africa. Oesophageal cancer in males has a moderate frequency. Other tumours which show a marked variation of frequency within Africa--Kaposi's sarcoma and cancers of the stomach and bladder--are all low in frequency in Botswana. Tumours which are rare throughout Africa but common in Western Europe and North America--cancers of the colon, rectum and corpus uteri--are also rare in Botswana.


Atherosclerosis is nowadays generally accepted as an inflammatory disease             but the mechanism of its origin and development have not yet been fully clarified.              The present review focuses on the role of the local immune system as one of the              key players in the pathogenesis of the complex process. Its part represented by               vascular-associated lymphoid tissue (VALT) within the arterial wall participates               directly in the vascular wall's homeostatis. Its inordinate activation during               ontogenic development of an individual, this formerly defensive and physiologic               mechanism transform into a pathological process resulting in an impairing                inflammation. Hsp60, CRP and oxidized or otherwise modified LDL are serious                 candidates for triggering these pathological changes. The principal role is played                 by anti-Hsp60 antibodies and by shear stress originating on the surface of                 endothelium due to blood flow. The experimental and clinical data             supporting this immunological hypothesis of atherosclerosis are discussed.


This paper describes a PC  based titrator which was developed for gradient flow titrations. Concentration gradients were generated electrolytically or volumetrically in small tubes. Complete titration curves can be recorded on-line and evaluated automatically. The titrator can be used with all liquid flow detectors with low axial dispersion. The titrator was evaluated for the titration of thiosulphate with electrogenerated triiodide and for the titration of ammonia with electrogenerated hypobromite after continuous gas dialytic separation of ammonia from the sample solution.


After surgery for hepatic injury as a result of blunt abdominal trauma from a motorcycleaccident, an external biliary fistula developed in a young patient. The authorsdescribe the rapid and complete healing of the fistula by use of a nasobiliary catheter.These findings emphasize the importance of endoscopic operative technique for postoperativeand traumatic external biliary fistulas.


Endothelial cells play an important, active role in the onset and regulation of inflammatory and immune reactions. Through the production of chemokines they attract leukocytes and activate their adhesive receptors. This leads to the anchorage of leukocytes to the adhesive molecules expressed on the endothelial surface. Leukocyte adhesion to endothelial cells is frequently followed by their extravasation. The mechanisms which regulate the passage of leukocytes through endothelial clefts remain to be clarified. Many indirect data suggest that leukocytes might transfer signals to endothelial cells both through the release of active agents and adhesion to the endothelial cell surface. Adhesive molecules (such as PECAM) on the endothelial cell surface might also ‘direct’ leukocytes through the intercellular junction by haptotaxis. The information available on the molecular structure and functional properties of endothelial chemokines, adhesive molecules or junction organization is still fragmentary. Further work is needed to clarify how they interplay in regulating leukocyte infiltration into tissues.


The possibility of detecting pre-clinical ovarian carcinoma by ovarian cytology taken at the time of laparotomy has been studied in 472 patients. Malignant cells have been recovered from ovarian carcinomas but never from macroscopically normal ovaries. It is suggested that this simple, inexpensive technique of sampling cells from the ovarian surface should be continued to be practised on all occasions at which ovaries present such as at laparotomy or at laparoscopy, as with further experience this technique may prove to be of help in the early diagnosis of ovarian carcinoma.


Histological sections of the primary tumour and of homolateral axillary lymph nodes from 500 women with operable invasive breast cancer have been examined. The tumours have been graded and the degree of round cell infiltration assessed. These features, together with clinical palpability and pathological involvement of axillary nodes, have been related to survival.It was found that prognosis was worse in patients with a high grade tumour and in those with histological evidence of axillary node spread. Round cell infiltration of the primary tumour did not confer improved survival.The clinical state of the axillary nodes was associated with prognosis in so far that palpable nodes were twice as commonly the seat of metastatic spread as were impalpable nodes.


A squamous cell carcinoma of spontaneous orgin in a WHT/Ht mouse was used to study the frequency with which the regional axillary lymph nodes draining subcutaneous or intradermal tumours gave rise to tumours after their isogeneic transplantation as whole nodes. This frequency (similar to 40%) was found not to vary significantly with the size or duration of the tumour drained and not to be increased by coincident infective, traumatic or antigenic stimuli acting at the tumour site or in adjacent tissue. Because tumour growth occurred in only 2/55 (4%) nodes which were left in situ in mice whose tumours were radically excised, it was concluded that tumour forming node transplants reflected a small and limited content (estimated to be about 13) of transnodally passing tumour cells destined to pass on to the blood; separate experiments showed that tumour cells reaching the blood survived for only a few hours. Nodes from tumour-excised mice gave rise to tumours as frequently when autografted as when isografted to mice with no previous expose to the tumour. A review of the finding reported here and of previous quantitative data for this system enabled us to exclude any implication of anti-tumour immunity from our interpretation of the results of the experiments.