Paediatricians can be empowered to address the Priority Mental Health Disorders at primary care level. To evaluate the effectiveness of a collaborative workshop in enhancing the adolescent psychiatry knowledge among paediatricians.A 3-day, 27-hours workshop was held for paediatricians from different regions of India under the auspices of the National Adolescent Paediatric Task Force of the Indian Academy of Paediatrics. A 5-item pretest-posttest questionnaire was developed and administered at the beginning and end of the workshop to evaluate the participants' knowledge acquisition in adolescent psychiatry. Bivariate and multivariate analyses were performed on an intention-to-participate basis.Forty-eight paediatricians completed the questionnaire. There was significant enhancement of the knowledge in understanding the phenomenology, identifying the psychopathology, diagnosing common mental disorder and selecting the psychotropic medication in the bivariate analysis. When the possible confounders of level of training in paediatrics and number of years spent as paediatrician were controlled, in addition to the above areas of adolescent psychiatry, the diagnostic ability involving multiple psychological concepts also gained significance. However, both in the bivariate and multivariate analyses, the ability to refer to appropriate psychotherapy remained unchanged after the workshop.This workshop was effective in enhancing the adolescent psychiatry knowledge of paediatricians. Such workshops could strengthen paediatricians in addressing the priority mental health disorders at the primary-care level in countries with low-human resource for health as advocated by the World Health Organization. However, it remains to be seen if this acquisition of adolescent psychiatry knowledge results in enhancing their adolescent psychiatry practice. In most of the developing countries training in adolescent psychiatry are largely limited to mental health specialists; pediatricians, and other primary care physicians receive little training. As a result, effective diagnostic, treatment and prevention models that have been developed are not yet widely applied at the primary-care paediatric settings ,2. HowevIt has been suggested that gaining practical experience and training in adolescent psychiatry is an effective way for the paediatrician to acquire perspectives and skills that is helpful in hospital or community paediatrics . Many moIt is evident from the mental health burden and resources mismatch in developing countries that national efforts are required to restructure paediatric mental healthcare delivery . ProvidiStrengthening the Paediatrician Project, a collaborative workshop for paediatricians on adolescent psychiatry with psychiatrists. Here we focus on the effectiveness of the workshop in enhancing adolescent psychiatry knowledge among paediatricians.Adolescent Psychiatry training in such special workshops may require evidence of their effectiveness, and this type of data has been difficult to obtain. In an earlier paper we have studied the need, content and process of We review only the relevant aspects of our methods here; an extensive description of the workshop has been presented in the accompanying paper  and detaStrengthening the Paediatrician Project (SAPP), a seminal adolescent psychiatry workshop to explore the need, content, process and effectiveness of a workshop for paediatricians in collaboration with psychiatrists. The workshop was conducted at the Child Development Centre, Thiruvananthapuram from the 19th to 21st of June 2006 under the auspices of the NFLLSE of the Indian Academy of Paediatrics was for 27 hours and spread over three days.Data used in the present analyses are from the content facilitation was done by psychiatrists (facilitators) who were proficient in the theory and practice of psychiatry. The participants were divided in to five groups of about 8-10 each and five psychiatrists invited by the NFLLSE facilitated each group. After the pre-workshop assessment of knowledge related to adolescent psychiatry, the two morning sessions in the first day introduced the Adolescent Psychiatry as well as systems in mind with their phenomenon and related psychopathology identifiable in a mental status examination. The two sessions in the afternoon focused on identifying the psychopathology with case vignettes and interviewing 'cases' (enacted by psychiatrists) for the psychopathology. The morning session of the second day translated the psychopathology noted in the mental status examination of the 'cases' to the International Classification of Diseases: Mental and Behavioral Disorders  - Tenth version (ICD-10) [third day addressed the PMHD that requires medication and pharmacotherapy of these disorders. In the post-lunch session, the post-workshop assessment was conducted.In brief, the process facilitation included didactic teaching using audio-visual materials, interacting with the child psychiatrist to clarify their queries, small group case-work up with case vignettes, presenting the case by a participant from each group supported by the respective group member, identifying the psychopathology and diagnosing the PMHD using role plays, conducting diagnostic interviews of the 'cases' based on ICD-10 diagnosis. Finally of the analysing of the video recording of the interviews by the members of each group and then along with their facilitators as well as the child psychiatrist for interviewing skills, mental status examination and diagnostic formulation was conducted.The A brief questionnaire to assess the acquisition of adolescent psychiatry knowledge by pediatricians was specifically developed and used. It had five multiple choice items and each correct endorsement was given a score of one and thus a score range of 0-5 was possible. Each of the five items was intended to evaluate one of the five areas namely: (1) understanding of the phenomenology, (2) identification of the psychopathology, (3) diagnosis of the PMHD, (4) selection of the appropriate psychotropic medication and (5) non-pharmacological interventions for which appropriate referrals will have to be made. The same multiple-choice questions were completed at the beginning of Day 1 before the first session began and during the last session of Day 3 before the focused group discussion.The descriptive data was presented in percentages and the acquisition of knowledge was analysed using Wilcoxon Matched-Pairs Signed-Ranks test. Multivariate linear regression was done to adjust for the confounding effect of the level of paediatric training, and years of experience in paediatric care. To account for the 14.6% of the participants who left the workshop immediately prior to the closing session to catch commuter and intercity trains we did an intention- to- participate analysis where the pretest scores brought forward as the posttest scores for analysis. Significance was set at P < 0.05 (two tailed) and data was analysed using SPSS 11.5.The participant characteristics are described in the accompanying paper .In the bivariate analysis, the overall knowledge of the paediatricians statistically significantly improved after the workshop. The maximum gain was in the areas of understanding the phenomenology, identifying the psychopathology and diagnosis of common mental disorder as well as selecting the psychotropic medication. The areas that did not show statistically significant gains were making diagnoses that involved multiple psychological constructs  and ability to refer for appropriate psychotherapy Table .In the multivariate regression analysis when the possible confounders namely the level of training in paediatrics and the number of years of experience in treating children were adjusted, the acquisition in overall knowledge, understanding of phenomenology, identifying psychopathology, diagnosing the PMHD and selecting the psychotropic remained significant as in the bivariate analysis Table . HoweverWe are not aware of any study documenting the effectiveness of an inter-disciplinary collaborative workshop to enhance the acquisition of adolescent psychiatry knowledge among academic and practicing paediatricians using multimodal training techniques. However, the findings from our study are consistent with that of other studies found in the pharmacy, nursing and medical education literature.Our findings suggest that this collaborative, multimodal training approach to teaching is enjoyable and effective in the acquisition of theory and clinical skills related to adolescent psychiatry. The authors speculate that paediatricians possibly displayed a positive attitude to learn adolescent psychiatry even before attending the training workshop. However, they acquired adolescent psychiatry knowledge and skill significantly after the workshop. A statistically significant increase in questionnaire responses was observed in 4 of the 5 of the questions and therefore, it can be concluded that there was a relationship between the training intervention and the increase in knowledge for all but one area.When the mental illnesses addressed in the workshop were viewed from a biopsychosocial perspective, the significant increase in knowledge of phenomenology, diagnosis and pharmacological management  and insignificant improvement of knowledge in psychological management and referral for psychotherapy  suggest that the workshop was more successful at increasing 'medical constructs' and less successful at changing 'psychosocial constructs' of the paediatricians relevant to adolescent psychiatry.Research on the outcomes of educational improvement interventions can be utilized to strengthen the theoretical basis for required regulatory training as well as to validate interventions for health-care education. This knowledge and skill acquisition suggests that when this adolescent psychiatry module is added in the various training processes like postgraduate training or CME successfully increase the knowledge towards the identification of psychopathology, a classificatory system based diagnosis of disorders, psychopharmacological management and feasible psychological interventions or referrals as recommended by World Health Organization . Also, cThe workshop elements focused strongly on cognitive knowledge, with the assumption that an increase in knowledge would result in a concomitant improvement of attitudes, and practicing skills. It may be possible to develop an additional training element that specifically addresses underlying assumptions and fears that can compromise the clinical skills that should emerge from the knowledge gained. Such a training workshop might utilize open discussions or hands-on approaches. The addition of a clinical psychologist to the multidisciplinary training team may improve the outcome.Further research is needed to focus on the specific components of the workshop. While this study evaluated the impact of the entire multi-element workshop, no conclusions could be drawn for the individual elements of the intervention such as the didactic sessions, case-vignettes, simulated case workups, or video feedbacks. Which of these intervention elements had the most impact on increasing the knowledge is conjectural. The study should also be extended to other teaching settings (like conference and CME programs) and the teaching elements themselves could then be modified to include other methods designed to specifically address these settings . In the future, based on the positive response, this multimodal training with a collaborative approach will be continued in the Postgraduate Diploma in Adolescent Paediatric health training program at Child Development Centre. The next learning experience will occur in our Postgraduate Diploma in Developmental Neurology program in which neurologist will learn basic theory and practice of adolescent psychiatry.The main caveats of this study are the specific nature of the training subject and the nature of the population. Firstly, the study assumed that the choice of data gathering instruments was appropriate for the task at hand. While the present study utilized a specific set of knowledge evaluation questions that concentrated on what the interdisciplinary team believed represented appropriate concerns of paediatricians facing adolescent mental health issues at the primary care level, all of the specific needs of the paediatricians at different practice settings were not assessed during this study. An expanded and validated knowledge evaluation instrument could be beneficial in identifying real knowledge acquisition. Secondly, this study teases out the adolescent psychiatry component of a multicomponent workshop for measurement and therefore lack of a comprehensive measure inclusive of the various components of the workshop could have negatively affected the performance of the participant in answering the questionnaire. Finally, as this study utilized voluntary participation rather than specific random sampling, extensions of these conclusions to other paediatricians are understandably weakened as possibly paediatricians motivated to learn the discipline of adolescent psychiatry only responded.In conclusion, this model of inter-disciplinary collaborative, multimodal educational workshop is effective in enhancing the adolescent psychiatry knowledge among paediatricians. However, it remains to be seen if the paediatricians are able to retain the acquired knowledge of adolescent psychiatry and apply in their clinical practice as well. If such information retention and application follows, this model of strengthening the paediatricians can partly help reinforce the efforts of WHO in addressing the Priority Mental Health Disorders among the adolescents. Further studies to explore if the acquired adolescent psychiatry knowledge is applied and thus integrated in clinical practice are required.CME: Continuing the Medical Education; ICD-10: International Classification of Diseases: Mental and Behavioral Disorders  - Tenth version; NFLLSE: National task Force on Family Life and Life Skill Education; PMHD: Priority Mental Health Disorders; SAPP: Strengthening the Paediatrician Project.The authors declare that they have no competing interests.PSSR was involved in the conception, designing, data analysis and interpretation, drafting and approving the final version. NMKC was involved in the conception, drafting and revising the final draft. All authors read and approved the final manuscript.


Dihydropyrimidine dehydrogenase (DPD) is responsible for the breakdown of the widely used antineoplastic agent 5-fluorouracil (5FU), thereby limiting the efficacy of the therapy. To identify patients suffering from a complete or partial DPD deficiency, the activity of DPD is usually determined in peripheral blood mononuclear cells (PBM cells). In this study, we demonstrated that the highest activity of DPD was found in monocytes followed by that of lymphocytes, granulocytes and platelets, whereas no significant activity of DPD could be detected in erythrocytes. The activity of DPD in PBM cells proved to be intermediate compared with the DPD activity observed in monocytes and lymphocytes. The mean percentage of monocytes in the PBM cells obtained from cancer patients proved to be significantly higher than that observed in PBM cells obtained from healthy volunteers. Moreover, a profound positive correlation was observed between the DPD activity of PBM cells and the percentage of monocytes, thus introducing a large inter- and intrapatient variability in the activity of DPD and hindering the detection of patients with a partial DPD deficiency. © 1999 Cancer Research Campaign


High-quality epidemiologic research is essential in reducing chronic diseases. We analyzed the quality of systematic reviews of observational nontherapeutic studies.We searched several databases for systematic reviews of observational nontherapeutic studies that examined the prevalence of or risk factors for chronic diseases and were published in core clinical journals from 1966 through June 2008. We analyzed the quality of such reviews by using prespecified criteria and internal quality evaluation of the included studies.Of the 145 systematic reviews we found, fewer than half met each quality criterion; 49% reported study flow, 27% assessed gray literature, 2% abstracted sponsorship of individual studies, and none abstracted the disclosure of conflict of interest by the authors of individual studies. Planned, formal internal quality evaluation of included studies was reported in 37% of systematic reviews. The journal of publication, topic of review, sponsorship, and conflict of interest were not associated with better quality. Odds of formal internal quality evaluation  and either planned, formal internal quality evaluation or abstraction of quality criteria of included studies  increased over time, without positive trends in other quality criteria from 1990 through June 2008. Systematic reviews with internal quality evaluation did not meet other quality criteria more often than those that ignored the quality of included studies.Collaborative efforts from investigators and journal editors are needed to improve the quality of systematic reviews. The (AMSTAR)  addresse(AMSTAR) -18 or bi(AMSTAR) ,15,19,20Previous research and guidelines ,21-23 foAbridged Index Medicus (119 indexed titles). We defined observational nontherapeutic studies as observations of patient outcomes that did not examine procedures concerned with the remedial treatment or prevention of diseases ; yes indicated that the authors reported the list of retrieved citations, the list of excluded studies, and justification for exclusion.To evaluate selection bias, we abstracted whether the authors of systematic reviews described the search strategy ; We abstracted as dichotomous variables whether the authors of systematic reviews did any of the following:Stated the aim of the review and the primary and secondary hypotheses of the review.Included or justified exclusion of articles published in languages other than English.Searched for gray literature, including abstracts and unpublished studies, to evaluate publication bias .Described any contact with authors of the included studies.Analyzed sponsorship of and conflict of interest in the included studies.We abstracted how the authors of systematic reviews described obtained statistical methods with justification and models for pooling with fixed or random effects models in sufficient detail to be replicated . We abstracted whether the authors of pooling analyses reported statistical tests for heterogeneity and whether heterogeneity was statistically significant .We used 3 categories to classify whether the authors of systematic reviews had evaluated the quality of included studies by using developed or previously published checklists or scales : 1) the We abstracted several explanatory variables that could be related to the quality of systematic reviews:The year of publication, defined as a continuous variable. We created categories of 4- or 5-year periods: 1990 to 1994, 1995 to 1999, 2000 to 2004, and 2005 through June 2008.The journals of publication.The country where the systematic reviews were performed.The sponsorship of the reviews. Those that had either governmental or foundational support or were fellowships were defined as having nonprofit support.The disclosure of conflict of interest by authors of reviews .The number of disclosed relationships with industry, defined as a continuous variable.The sponsor's participation in data collection, analysis, and interpretation of the results of the review.The review outcomes as risk factors for prevalence or incidence of chronic conditions or diseases.2 tests and Fisher's exact tests in cases of small numbers. All calculations were performed at 95% confidence intervals (CIs) by using 2-sided P values with SAS version 9.1.3 .We summarized the results in evidence tables. We used prespecified categories of dependent and independent variables and did not force the data into binary categories for definitive tests of significance. We used univariate logistic regression to examine the association between internal quality evaluation and the year of the publication by using the Wald test. Odds ratios (ORs) were calculated with binary logit models and Fisher's scoring method technique. We computed the fractions of systematic reviews meeting various quality criteria in each of the 4 time periods considered. The proportions of systematic reviews that met different levels of each quality criterion were evaluated by using χWe found 145 eligible systematic reviews of observational nontherapeutic studies , assessed gray literature (27%), or addressed language bias (29%) . Only 2%Planned and detailed quality assessment of included studies was reported in 37% of systematic reviews, and 18% abstracted more than 1 criterion of external or internal quality; significant positive trends were reported during the evaluated time . QualityThe quality of systematic reviews did not differ much by study location or by the journal of publication. Systematic reviews of prevalence or incidence or risk factors of the diseases did not differ in their quality measures. Sponsorship was not associated with quality of the reviews. The role of conflict of interest was impossible to establish because the authors of 56 reviews did not disclose funding and authors of 106 reviews did not disclose conflict of interest.The journal of publication, topic of the review, and continent where the review was conducted were not associated with the likelihood of internal quality evaluation. Systematic reviews of risk factors tended to conduct internal quality evaluation of the included studies more often than reviews of incidence or prevalence or of levels of risk factors. Systematic reviews sponsored by nonprofit organizations conducted internal quality evaluations of individual studies more often than reviews that received corporate funding. Systematic reviews that disclosed conflict of interest conducted internal quality evaluation of individual studies less frequently  than reviews with no disclosure . Odds of formal internal quality evaluation  and either planned, formal internal quality evaluation or abstraction of quality criteria  increased over time. Disclosure of conflict of interest by the authors of systematic reviews was not associated with greater odds of internal quality evaluation.Complete documentation of the literature search including time period, databases searched, and exact literature search strings was less common among reviews with planned, formal internal quality evaluation  than among reviews without it  . HoweverThe association between quality of systematic reviews and sponsor participation in the data collection, analyses, and interpretation was difficult to analyze because this information was either omitted or reported in various ways. Less than 10% of systematic reviews contained a clear statement that the sponsors did not play any role in gathering the studies or analyzing or interpreting the results and did not influence the content of the manuscript. Other reviews omitted mention of the role of the sponsor in approval of the manuscript or provided a general statement that sponsors did not influence the conclusions or the content of the paper. Two reviews included statements of unconditional or unrestricted sponsorship of the meta-analyses.Our analyses showed that less than half of the systematic reviews of nontherapeutic observational studies that were published in core clinical journals met each quality criterion. Quality of systematic reviews did not improve over time. Planned, formal internal quality evaluations of the included studies was reported in less than half of systematic reviews, but the prevalence of internal quality evaluations has increased during the last decade. Our findings are in concordance with previously published methodologic analyses of systematic reviews that also found inconsistent quality and incomplete internal quality evaluation of individual studies . MethodoJournal commitment to high-quality research, however, was associated with improved reporting quality of the publications. For example, adoption by journals of the Consolidated Standards of Reporting Trials (CONSORT) improved the quality of the publications of interventional studies ,180. An We could not identify the factors that can explain differences in quality of systematic reviews. The role of sponsorship and conflict of interest could not be estimated because of poor reporting of this information. The quality and reliability of quality evaluation of the included studies is unclear because development of the appraisals was described in a small proportion of systematic reviews (32 of 80 studies), and only 6 of 80 studies tested interobserver agreement for quality assessment. We did not evaluate all reviews of observational studies that were published in epidemiologic journals. However, it is unlikely that the quality of reviews published in other journals would be better than those in core clinical journals. Future research should investigate the factors that can explain differences in the quality of systematic reviews.Peer reviewed publications of high-quality systematic reviews can provide the best available research evidence for evidence-based public health . Evidenc


The global nature of antimicrobial resistance and the failure to control the emergence of resistant organisms demand the implementation of a global surveillance program involving both developed and developing countries. Because of the urgent need for infection control interventions and for rapid distribution of information about emerging organisms, we initiated the International Network for the Study and Prevention of Emerging Antimicrobial Resistance (INSPEAR). Its main objectives are to serve as an early warning system for emerging antimicrobial-drug resistant pathogens, to facilitate rapid distribution of information about emerging multidrug-resistant pathogens to hospitals and public health authorities worldwide, and to serve as a model for the development and implementation of infection control interventions.


The free osteocutaneous fibula flap is an established method of reconstruction of maxillary and mandibular defects. The vascularity of the skeletal and the cutaneous components is provided by the peroneal artery via the nutrient artery and the septo- and musculocutaneous perforators. In rare situations, these perforators may arise from other major leg arteries. In such circumstances, the procedure has to be either abandoned or modified so that neither the vascularity of the flap nor the donor limb is compromised. We present a case of an anomalous musculocutaneous perforator, which originated from the proximal part of the posterior tibial artery, passed through the soleus muscle and supplied the skin paddle. The flap was elevated as a single composite unit and was managed by two separate vascular anastomosis at the recipient site, one for the peroneal vessels and the other for the anomalous perforator. The reconstruction of oro-mandibular defect after tumour ablative surgery is a challenging task in terms of anatomical and functional results and this has been fulfilled by the free fibula flap. Ever since described, the free fibula flap has become the procedure of choice for treating post tumour excision of oro-mandibular defects in majority of the cancer centers. Over the years, there are literature reports of various modifications in the surgical technique and so do the reports of variations of normal anatomy of the leg and that of the flap. We describe a unique situation involving the perforators supplying the skin paddle of the flap which is significant in terms of flap survival and management.A 44-year-old female who was diagnosed with carcinoma of the lower alveolus with involvement of the middle third of the mandible, anterior floor of the mouth, gingivo-labial sulcus and the overlying skin. It was planned for composite resection followed by reconstruction with free fibula osteocutaneous flap. During the preoperative assessment, her dorsalis pedis and posterior tibial pulsations in both legs were normal by palpation. The left leg was selected and the fibula with a skin paddle of 22 × 9 cm was raised through standard anterior approach under tourniquet control. After the distal and proximal osteotomies and after ligating the distal end of the peroneal vessels and moving proximally, no septocutaneous perforators were noticed. Further dissection revealed a single musculo cutaneous perforator coming out of the soleus muscle and proceeding to the skin paddle. With the possibility of anomalous perforator in mind, the vessel was dissected along its entire length through the substance of the soleus muscle  and was The osteocutaneous fibula flap was described by Taylor and late5Remove the skin paddle from the flap orUse fibula for bony reconstruction and another flap such as the radial forearm flap for skin and soft tissue orAbandon the procedure and use the other limb.In our case, we were prudent enough to dissect and include the anomalous perforator after confirming that it was the only source of blood supply to the skin paddle. Though there are reports of anomalies involving the axial arteries of the leg and defi10To conclude, the anomalies involving the perforators may be minor when compared to the major leg vessels but awareness about the possibilities will enable the surgeon to salvage the free fibula osteocutaneous flap as a single unit or as two separate [skin and bone] units with appropriate number of anastomosis as required for successful reconstruction.


Fractures of the neck of the femoral component have been reported in uncemented total hip replacements, however, to our knowledge, no fractures of the neck of a cementless forged titanium alloy femoral stem coated in the proximal third with hydroxy-apatite have been reported in the medical literature.This case report describes a fracture of the neck of a cementless forged titanium alloy stem coated in the proximal third with hydroxy-apatite.The neck of the femoral stem failed from fatigue probably because of a combination of factors described analytically below. Fracture of the femoral stem was a frequent complication of first-generation, forged stainless steel or cast cobalt chrome femoral components used for total hip arthroplasty. Charnley estimated a prevalence of 0.23%, although the prevalence was as high as 11% with other stem designs. With the development of femoral stems made of forged cobalt chromium-molybdenum or titanium alloys in the 1980s, this complication became rarer. Fractures of the neck of the femoral component have been reported in uncemented total hip replacements, however, to our knowledge, no fractures of the neck of a cementless forged titanium alloy femoral stem coated in the proximal third with hydroxy-apatite have been reported in the medical literature.A 64 year-old man of weight 70 kg and height 1.65 m underwent a total hip arthroplasty (THA) in January 2003, due to severe osteoarthritis of his left hip following avascular osteonecrosis . These markings lie also on the anterior aspect, when the stem is implanted on a left hip. Scanning electron microscope figures of the fracture surface of the part supporting the head clearly show that the fracture has ended on the posterior side. Typical beach marks can be seen in the middle of the surface  high stresses in the stem due to increased patient weight, a high level of activity, or a relatively undersized prosthesis; b) poor proximal bone support or fixation, which may be due to the absence of the calcar; c) varus orientation of the stem; d) cantilever bending resulting from good distal fixation in the presence of an inadequate proximal cement mantle; e) the presence of a stress riser; and finally f) material defects in the stem itself due to either inadequate design or the fabrication process.Porosity can be generated within the cast during the solidification of the metal, which is accompanied by shrinkage, leaving voids within the metal . Voids can also be generated during expulsion of gases as part of the solidification process .The grain size is another factor closely related to the fatigue properties of the stem . HistoriFinite-element analysis has shown that the highest stress concentrations are around the lateral aspect of the middle third of the femoral stem. A fracture of the stem usually originates from its antero-lateral aspect  correspoFracture of the neck of the femoral stem is a rare phenomenon, and few have been documented ,6,11-13.Burstein and Wright  reportedLee et al  reportedVatani et al  reportedThe neck of the femoral stem failed from fatigue. The stereomicroscope and scanning electron studies cannot give evidence of the exact location of the initiation of the fracture, due to iatrogenic marks of tools at the external surface of the fractured neck as well as due to attrition of the fracture surfaces.2), and the potential stress riser effect of either the laser marking or the edge of neck machining.The implant failed probably because of a combination of factors: the high demands of the patient , the reduced section of the neck  declare that they have no competing interests.TBG was the principal investigator of the study, operated upon the patient, conducted the collection of data and was involved in drafting the article. ODS was involved in drafting the article and in collection of the literature; SAP helped in manuscript drafting and in the collection of the literature; PFB performed the interpretation of stereomicroscopic information, compiled the technical report and was involved in drafting the article; GT, IK, and PA were involved in collection of the literature. All the authors read and approved the final manuscript.Written patient consent was obtained for publication of the report.


Flavonoids can exert beneficial health effects through multiple mechanisms. In             this paper, we address the important, although not fully understood, capacity of             flavonoids to interact with cell membranes. The interactions of polyphenols with             bilayers include: (a) the partition of the more non-polar compounds in the             hydrophobic interior of the membrane, and (b) the formation of hydrogen bonds             between the polar head groups of lipids and the more hydrophilic flavonoids at the             membrane interface. The consequences of these interactions are discussed. The             induction of changes in membrane physical properties can affect the rates of             membrane lipid and protein oxidation. The partition of certain flavonoids in the             hydrophobic core can result in a chain breaking antioxidant activity. We suggest             that interactions of polyphenols at the surface of bilayers through hydrogen             bonding, can act to reduce the access of deleterious             molecules (i.e. oxidants), thus protecting the structure and function of membranes.


We tested the hypothesis that modulation of monoaminergic tone with deep-brain stimulation (DBS) of subthalamic nucleus would reveal a site of reactivity in the ventromedial prefrontal cortex that we previously identified by modulating serotonergic and noradrenergic mechanisms by blocking serotonin-noradrenaline reuptake sites. We tested the hypothesis in patients with Parkinson's disease in whom we had measured the changes of blood flow everywhere in the brain associated with the deep brain stimulation of the subthalamic nucleus. We determined the emotional reactivity of the patients as the average impact of emotive images rated by the patients off the DBS. We then searched for sites in the brain that had significant correlation of the changes of blood flow with the emotional impact rated by the patients. The results indicate a significant link between the emotional impact when patients are not stimulated and the change of blood flow associated with the DBS. In subjects with a low emotional impact, activity measured as blood flow rose when the electrode was turned on, while in subjects of high impact, the activity at this site in the ventromedial prefrontal cortex declined when the electrode was turned on. We conclude that changes of neurotransmission in the ventromedial prefrontal cortex had an effect on the tissue that depends on changes of monoamine concentration interacting with specific combinations of inhibitory and excitatory monoamine receptors. We have shown that activity in a circumscribed region of the medial prefrontal cortex undergoes a change of activity when the region is challenged by administration of the serotonin-noradrenaline reuptake inhibitor clomipramine. In this previous study , the cha1A, 5-HT1B, 5-HT2A, 5-HT3 and 5-HT4) receptors facilitates dopamine (DA) release, with the exception of the 5-HT2C receptors that strongly inhibit DA release in the ventral tegmental area but have no effect on DA release in the frontal cortex 1 and D2 receptors that respectively facilitate and inhibit the excitability of the neurons on which these receptors reside.Serotonergic, noradrenergic and dopaminergic mechanisms interact closely in the frontal cortex. Stimulation of the majority of serotonergic receptors  To test if emotional reactivity relates to changes of neurotransmission in the prefrontal cortex, we obtained PET images of the effect of DBS of the subthalamic nucleus on the cortical activity in seven patients suffering from Parkinson's disease. The patients were approached by one of the authors (JG) of this study and gave written informed consent to the procedures specified in a protocol approved by the official Central Danish Regional Science Ethics Committee.We correlated the changes of activity in these images with the ratings of emotional impact of standardized emotive images recorded by the patients. Selected details of the patients' condition including medication are given in Details of the PET measurements of cerebral blood flow with oxygen-15-labeled water were given by Geday et al. We correlated the change of blood flow with the emotional impact of the emotive images in the seven patients. We recorded the emotional impact of the images in a separate session with the DBS stimulation off and on, respectively. As in the study reported by Geday and Gjedde 3 for all cortical gray matter at an FWHM of 12 mm.We analyzed the PET images by voxel-wise regression of PET volumes with local voxel SD estimates against the ratings of emotional impact, as implemented in the Dot statistical parametric mapping of the Montreal Neurological Institute 3 at an FWHM of 12 mm.In addition to the global analysis of all cortical gray matter (excluding the cerebellum), we restricted a search to a volume of interest (VOI) consisting of one 6-mm-radius sphere centered on a site in the right inferior medial prefrontal cortex (IMPC) previously shown to be deactivated by emotional content We completed the regression analysis of blood flow changes elicited by STN stimulation against emotional impacts ratings, equal to the difference between ratings of pleasant images and ratings of unpleasant images, on a scale from −3 to +3 in the seven subjects. The regression revealed several sites in which the correlation between the two measures reached significance . The correlation is shown as negative in One of the sites at which blood flow underwent this change associated with the DBS in correlation with emotional impact coincided with the area at which blood flow equally underwent a change during the clomipramine challenge reported by Geday and Gjedde We specifically determined the change of relative blood flow values at this site in a specific volume-of-interest with a radius of 6 mm, centred on the previously identified coordinates, as shown in The results support the predicted link between the emotional impact of emotive images and changes of activity in the prefrontal cortex associated with specific drug challenge or electrode stimulation. Thus, in subjects with a low emotional impact, activity measured as blood flow at a site in the ventromedial prefrontal cortex rose in patients with Parkinson's Disease and DBS electrode turned on, as it did in healthy subjects challenged with a serotonin-noradrenaline reuptake inhibitor, while in patients of high impact, the activity at this site in the ventromedial prefrontal cortex declined when the electrode was turned on, as it did in healthy subjects of high impact challenged with the drug. We explain the findings in both groups by the claim that monoamines  are released from terminals in the ventromedial prefrontal cortex and that this release has an effect on the emotional reactivity that depends both on the monoamine concentration and on the relative distributions of inhibitory and excitatory dopamine receptors.1A receptors mediate lower excitability and most other serotonin receptors mediate higher excitability of the cells where they reside, and the dopaminergic receptors among which the D1 receptors when occupied contribute to raised excitability and the D2 receptors when occupied lower the excitability of the cells on which they reside. The direction of the effect (inhibitory or excitatory) of an increment of endogenous ligand occupation then depends on the baseline ligand concentration from which the increment occurs. At low concentrations, the effect of an increment is in one direction, depending on the distribution of excitatory and inhibitory receptors. At concentrations above a certain threshold, the effect of the increment is in the opposite direction. The net effect of the transmitter release therefore reflects the pre-existing transmitter concentration in relation to the receptor distribution, as well as the magnitude of the increment.In the previous study Geday et al. 2 receptor radioligand raclopride in the striatum What is the evidence that there is monoamine release in the ventromedial prefrontal cortex or elsewhere during DBS? One PET study of the binding of the D1 receptors, indicating that the increased excitability is due to release of dopamine. During high frequency stimulation of the STN in rats, intracellular recordings from dopaminergic neurons in substantia nigra pars compacta by Lee et al. However, considerable circumstantial evidence links dopamine release in the prefrontal cortex to the regulation of emotive and cognitive functions subserved by this part of the brain. In rats, Bean et al. Together these studies provide a strong basis for the claim that DBS of the STN directly or indirectly leads to release of monoamines in the ventromedial prefrontal cortex, the effect of which is contingent upon the quantity of monoamines released and the relative densities of excitatory and inhibitory monoamine receptors, with important consequences for the emotional impact of emotive sensations.File S1Related paper by authors. This is a recently published paper to which the submitted ms refers(0.24 MB PDF)Click here for additional data file.


Sir,Tracheal intubation is older than the recognized history of general anesthesia itself. In the late 18th century, the royal humane society of London used tracheal intubation for resuscitating the near-drowned.The first reported use of a lighted stylet used to facilitate intubation came in 1957 when Sir Robert Macintosh describeCurrent lightwands are largely fiberoptic in design and have either external or internal light sources. Newer devices have been developed that use trans-illumination or transmission of sound, in combination with other intubating guides. The newer ones combine a lighted stylet with a fiberoptic scope. This combination is intended to provide trans-illumination and internal visualization of the larynx either directly or on a screen. The costLighted stylet tracheal intubation requires practice, but is easy to learn. The distal end of the stylet should be lubricated water-based surgical lubricant and the tracheal tube loaded onto it. For oral intubation, the nondominant hand is used to open the mouth with the thumb placed against the mandibular molars while the opposing index finger is pressed against the ramus of the mandible; this hand should be kept as far lateral as possible to allow unobstructed midline placement of the lighted stylet. A firm anterocaudad jaw thrust elevates the epiglottis, improves tactile sensation, and facilitates intubation via gentle lighted stylet motions with the dominant hand. The lighted stylet is introduced into the oropharynx from the side and brought into the midline following the midsagittal plane transecting the tongue. The tip of the lightwand should be passed under the tongue, and with gentle anterior traction, a bright well circumscribed circle of light at the level of the hyoid indicates that the tip lies in the vallecula. Gentle forward pressure may displace the epiglottis, allowing immediate tracheal intubation. If a bright red glow is seen off the midline, then the tip of the lightwand may lie in one of the pyriform fossae, and the unit should be withdrawn slightly and rotated back toward the midline. If resistance is felt preventing passage into the trachea, then the obstructing epiglottis may be circumvented by a series of rocking or scooping movements redirecting the tip to the thyroid prominence by using the light as a guide after careful withdrawal of the stylet following the contour of the oropharynx, the 15-mm adapter is reconnected and the tracheal tube placement is confirmed in the usual manner.[There are chances of the dislodgement of the bulb attached at the distal end while removing the lighted styletThe lighted stylet can be used only for adult patients.The bulb might get heated and may be a source of thermal injury and the possibility of heat damage to the tracheal mucosa during prolonged intubation attempts should be kept in mind.Minor trauma to upper airway leading to bleeding, sore throat, hoarseness, and dysphagiaThe most severe upper airway damages reported after lighted stylet intubation are reported cases of arytenoid cartilage dislocation.


This paper reports a survey of nasal cancer in Northamptonshire during the period 1950-79. An increased risk of various histological types of nasal tumour has been observed within the footwear manufacturing industry, which seems to be limited to the minority of men and women exposed to the dust of leather soles and heels. In Northamptonshire this exposure has usually occurred in the preparation, press and finishing rooms of factories making boots and shoes by the welted process. This type of leather is tanned by treatment with vegetable extracts, not chrome salts. Although the population of workers involved has diminished over the period of the study there has been no evidence of a decline in incidence of these tumours within it.


During studies of the ability of antilymphocyte serum (ALS) to suppress the immune mechanism of mice and thereby allow HeLa cells to grow into a large tumour in the mice, it was observed that many tumours continued to grow even after the ALS treatment had been stopped and full immunological competence of the mice had returned. The HeLa cells of such tumours appeared to be unchanged in their ability to induce further tumours in ALS treated mice to which they were transferred and, furthermore, the mice which were carrying such tumours in the presence of immunological competence were able to reject additional injections of HeLa cells or other human tumour cells. The four possible explanations for this phenomenon, (i) depression of cellular response; (ii) local reaction at the graft site; (iii) the presence of a blocking factor; and (iv) the elevation of the humoral response, have been investigated.


Chromosome damage in vitro after bleomycin treatment during the late S and G2 phases of the cell cycle was studied in the peripheral lymphocytes of 19 untreated patients with primary testicular tumours and 22 age-matched healthy men with no excess of cancer incidence in the families. The occurrence of spontaneous chromosome aberrations was not shown to be different in the studied groups. However, in the lymphocytes treated with bleomycin, cancer patients exhibited higher numbers of break events per cell  and increased frequency of cells with aberrations  than control group. Aberrant cells of cancer patients had more aberrations than cells of the control sample . The frequency of chromosome 1 aberrations, often encountered in cancer cells of testicular and other solid tumours, was significantly higher in lymphocytes of patients with testicular cancer , the long arm of this chromosome being predominantly affected . These results support the view that a genome disposed to testicular cancer is less effective in the ability to repair non-specific DNA damage in this region, more susceptible to damage, or both.


The presence of pancreatic islets alone in the peripancreatic region and splenic hilum is an uncommon occurrence. Herein, we describe their presence in this rare location. Ectopic pancreatic tissue may occur from displacement of small amounts of pancreas during embryonic development, resulting in formation of a nodule which is independent of the pancreas. It often has a proper ductal system and circulation ,2. In maRare case reports of pancreatitis occurring in the ectopic pancreatic tissue in the mesentry of the small intestine of a child have been described in the literature . Ectopic


The records of 1243 patients with myasthenia gravis (M.G.) have been reviewed in a retrospective study of the incidence of extrathymic neoplasms. Ninety-four malignant neoplasms were traced.The onset of the disease (M.G.) coincided with a marked increase in the incidence of extrathymic neoplasms. The observed number of neoplasms in the year of onset of M.G. was three times higher than the expected in a control group. This was in sharp contrast to the lower than expected incidence in the years preceding the onset of M.G.The incidence remained at higher than the expected levels throughout the course of the disease in patients who did not undergo thymectomy, while in those patients who had thymectomy the incidence decreased to the levels of the general population after the second postoperative year.These observations suggest an oncogenic thymic influence. The possibility is discussed of the potential oncogenic role of abnormal clones of immunocompetent small lymphocytes of thymic origin.


Sir,+FOXP3+ regulatory T cells (Tregs) (Carcinogen-induced tumours in intact mice exhibit a substantial enrichment of CD4Evidence collected from mice suggests that depletion of Tregs enhances immunosurveillance of tumours and uncovers new responses to tumour antigens in patients (The optimal vaccination/depletion strategy needs to be established by defining the impact of preoperative chemotherapy and surgery on the development of antitumour immune responses. Surgical removal of malignant disease is likely to remove the bulk of Treg TIL and reduce the production of suppressive signalling networks, which would undoubtedly improve the likelihood of successful antitumour immune responses to clear residual malignant cells. However, the impact of major surgery on the capacity of the immune response needs to be established. It is also important to weigh up the benefit of postoperative immunotherapy and adjuvant chemotherapy. Chemo/radiotherapy might reduce the capacity of the immune system to mount antitumour immunity. In light of conflicting reports describing the ability of certain treatments to deplete Treg efficiently (


Crotalus durissus terrificus venom into the foot pad of mice did not induce a significant inflammatory response as evaluated by oedema formation, increased vascular permeability and cell migration. The subcutaneous injection of the venom, or its addition to cell cultures, had an inhibitory effect on the spreading and phagocytosis of resident macrophages, without affecting the viability of the cells. This effect was not observed when the venom was added to cultures of thioglycollate elicited macrophages, but it was able to inhibit these macrophage functions when the cells were obtained from animals injected simultaneously with the venom and thioglycollate. These observations suggest that the venom interferes with the mechanisms of macrophage activation. Leukocyte migration induced by intraperitoneal injection of thioglycollate was also inhibited by previous venom injection. This down-regulatory activity of the venom on macrophage functions could account for the mild inflammatory response observed in the site of the snake bite in Crotalus durissus terrificus envenomation in man.The injection of


A detailed casenote review was performed on all 65 patients registered with testicular non-seminomatous germ cell tumours (NSGCT) during 1989 under the Scottish Cancer Registration Scheme. Details of management at presentation and 2 years following diagnosis were recorded and analysed. In a small number of patients an unacceptable delay in diagnosis was noted. Variation was found in the frequency and type of investigations performed on patients placed on surveillance, types of chemotherapy regimens used and numbers of patients entered into trials. Three per cent of patients had a biopsy of the contralateral testis and 27% of patients defaulted from clinic attendance. Considerable variation in the management of testicular NSGCT in Scotland has been identified. The introduction of management guidelines should result in a more consistent approach to the care of these patients. Support, both financial and psychological, may reduce the unacceptable rate of default.


Intrapleural growth of transplanted rat tumours was prevented or retarded by intrapleural administration of double-stranded RNA. A similar suppression of growth was achieved with peitoneal tumours by the intraperitoneal injection of the compound. These studies indicate the possible potential of this form of treatment of thoracic and peritoneal tumours for clinical application in the treatment of mesothelioma.


Both primary leiomyosarcoma of bone and sarcoma arising in association with a bone infarct are rare events. In this casereport we describe for the first time a case of leiomyosarcoma arising in a bone infarct. The tumour arose in a medullaryinfarct in the proximal femur of an elderly patient. As in other cases of sarcoma arising in a bone infarct, the prognosis waspoor, the patient dying within 6 months of diagnosis.


Within 48 hours of the institution of severe phenylhydrazineinduced anaemia in mice bearing ascites tumours or generalised leukaemia, a substantial proportion of the malignant cells disappeared respectively from the peritoneal cavity or infiltrated liver. The results of radiobiological experiments permitting determination of the proportion of viable leukaemia cells which were severely hypoxic and relatively radioresistant in the livers of leukaemic mice, showed that induction of anaemia was associated with a several hundredfold increase in the proportion of such cells. The proportion of hypoxic cells was greatly reduced when the anaemic leukaemic mice were transfused with packed erythrocytes or allowed to breathe oxygen under high pressure. Similar experi - ments with solid sarcomas indicated that a high proportion of the tumour cells were hypoxic in non-anaemic mice breathing air. The hypoxic fraction was not significantly reduced when tumour-bearing mice were made severely anaemic during growth of the tumour and were later transfused. Thus, the hypoxic cells in leukaemic livers and those in solid tumours are markedly different in their capacity for oxygenation following the induction of relative hyperoxaemia.


Necrotizing enterocolitis (NEC) is a severe disease of the gastrointestinal tract of pre-term babies and is thought to be related to the physiological immaturity of the intestine and altered levels of normal flora in the gut. Understanding the factors that contribute to the pathology of NEC may lead to the development of treatment strategies aimed at re-establishing the integrity of the epithelial wall and preventing the propagation of inflammation in NEC. Several studies have shown a reduced incidence and severity of NEC in neonates treated with probiotics .The objective of this study is to use a mathematical model to predict the conditions under which probiotics may be successful in promoting the health of infants suffering from NEC. An ordinary differential equation model is developed that tracks the populations of pathogenic and probiotic bacteria in the intestinal lumen and in the blood/tissue region. The permeability of the intestinal epithelial layer is treated as a variable, and the role of the inflammatory response is included. The model predicts that in the presence of probiotics health is restored in many cases that would have been otherwise pathogenic. The timing of probiotic administration is also shown to determine whether or not health is restored. Finally, the model predicts that probiotics may be harmful to the NEC patient under very specific conditions, perhaps explaining the detrimental effects of probiotics observed in some clinical studies.The reduced, experimentally motivated mathematical model that we have developed suggests how a certain general set of characteristics of probiotics can lead to beneficial or detrimental outcomes for infants suffering from NEC, depending on the influences of probiotics on defined features of the inflammatory response. Necrotizing enterocolitis (NEC) is a severe disease of the gastrointestinal (GI) tract that is characterized by increased permeability of the intestine and is primarily observed in pre-term babies. Although the causes of this disease are not fully known, most studies conclude that prematurity is the greatest risk factor. NEC affects Although its pathophysiology is not entirely understood, NEC is thought to be related to the physiological immaturity of the GI tract and altered levels of normal flora in the intestines. A mature intestine contains many defense mechanisms that act as barriers to harmful bacteria. Many of these defense mechanisms, such as peristalsis and tight junctions between intestinal epithelial cells Bifidobacterium and Lactobacillus is necessary for the normal development and protective function of the newborn intestine Bifidobacteria than the amount found in breast-fed infants, and indeed, pre-term infants fed formula have significantly higher rates of NEC than those fed breast milk An abnormal pattern of bacterial colonization in pre-term infants may also contribute to the pathogenesis of NEC. Colonization by normal  flora such as Recently, Toll-like receptor-4 (TLR-4) has been shown to be significantly increased in mice and humans with NEC compared with healthy infants Bifidobacterium and Lactobacillus. Probiotics compete with pathogenic bacteria for host binding sites and nutrients while also stimulating host defense mechanisms and enhancing intestinal maturation. Probiotic bacteria can protect against systemic bacterial invasion by decreasing the permeability of the gastrointestinal wall Given this growing understanding and identification of the factors that contribute to NEC, it seems important to develop treatment strategies aimed at bolstering the integrity of the epithelial wall, preventing excessive inflammation, and limiting the presence of pathogenic bacteria. One proposed treatment method is the administration of probiotics, which are defined as non-pathogenic species of bacteria that promote the health of the host Lactobacillus acidophilus and Bifidobacterium infantis. Infants treated with a probiotic mixture in two separate studies Lactobacillus were shown to have an increased incidence of sepsis, and the observed decrease in NEC incidence was not statistically significant. Similarly, Land et al. Lactobacillus sepsis in infants treated with probiotics. However, lactobacillemia can occur naturally and thus may or may not have been related to probiotic treatment.Several studies have shown a reduced incidence and severity of NEC in neonates treated with probiotics Experimental studies have shown a potential clinical benefit of probiotics in NEC patients but have not identified the mechanisms underlying the efficacy of probiotic treatment. It is hypothesized that probiotics improve the barrier function of the intestine by increasing transepithelial resistance, protecting against cell death, inducing specific mucus genes, and stimulating the production of nonfunctional receptor decoys in the intestinal lining We hypothesized that the protective potential of these mechanisms can be analyzed using a mathematical model. Building upon insights established by theoretical models of the acute inflammatory response A system of ordinary differential equations is used to track both pathogenic and probiotic bacteria in two compartments: an intestinal lumen compartment and a combined blood/tissue compartment see . The ratThe majority of the parameter values for this model are taken directly from two previous models of the inflammatory response In the intestinal lumen, pathogenic bacteria (Equations (4)–(6) represent the evolution of pathogenic bacteria  in the blood/tissue at rates To investigate various features of probiotic treatment for NEC, we first consider equations (1)–(6) in the absence of probiotics for varying levels of initial pathogenic insult, Inspection of system (1)–(6) shows that model steady states can take two forms, one with baseline bacterial permeability . For example, studies have shown that breast-fed infants acquire a more desirable intestinal flora than formula-fed infants, since breast milk contains many antimicrobial products and factors that promote the colonization of helpful bacteria in the infant intestine in utero growth restriction Studies have also shown that infants born vaginally tend to be colonized earlier with beneficial species of bacteria, while infants delivered by cesarean section have a delayed colonization by desirable bacteria Determining the correct probiotic dosing strategy is a key question for the realization of effective probiotic treatment for infants suffering from NEC. Our mathematical model predicts that probiotics will be most effective for low rates of pathogenic growth (Our main motivation in designing this study was to incorporate experimental observations of probiotics into a mathematical model that can be used to gain insight into key interactions of pathogens, probiotics, and the inflammatory response in the context of NEC. In this way, we hope to improve clinical translation, as part of our larger Translational Systems Biology framework Our basic modeling assumption is that the inflammatory response that takes place at the lumen/blood interface, and that involves an interplay among intestinal flora, intestinal epithelial cells, and inflammatory cells in the blood, serves to maintain a dynamic equilibrium that defines the health steady state. It is likely that an effective inflammatory response requires some small, baseline rate of efflux of luminal bacteria into the blood/tissue. The ensuing minor, self-limiting inflammatory response may serve to maintain the mostly beneficial population of intestinal bacteria while providing a sampling of intestinal contents that could lead to an early warning of changes in the proportion of pathogenic bacteria in the intestinal lumen. F or a developing infant, this equilibrium may require a constant influx of factors present in maternal breast milk. To incorporate such a baseline inflammatory response, which we currently omit, the model should be augmented to include the roles of pro- and anti-inflammatory cytokines in the inflammatory response. One important effect of anti-inflammatory cytokines is the reduction of damage to the epithelium caused by the inflammatory response. In our current model, the omission of anti-inflammatory cytokines provides a worst-case scenario with respect to the harmful effects of the inflammatory response. The qualitative relationships established in this study that indicate both beneficial and harmful effects of probiotics are still expected to hold in the presence of cytokines, but additional insight into the interplay of the immune response and probiotic treatment will require future modeling of cytokine populations The number of experimental and clinical studies that have been performed for NEC is limited due to the nature of the disease and the complexity of carrying out studies and obtaining samples in pre-term infants, and thus we used a combination of human and animal studies to provide an experimental grounding for the model presented. Additional experimental data would help to determine some of the parameter values estimated in this study and may also highlight additional factors contributing to NEC that have not been explored by this model. Interactions between bacteria and the inflammatory response are defined within the context of two lumped compartments that are assumed to be well-mixed, and thus there is no spatial component in this present model. Immune mechanisms specific to regions such as the gut mucosa and lamina propria In conclusion, based on experimental and clinical studies, we have developed a simplified mathematical model of the complex host-pathogen interaction that occurs in the setting of NEC and used it to analyze the impact of probiotic administration on the ensuing dynamics. The predictions derived from this computational study may help to explain the diverse outcomes that may arise in this setting and may be useful for guiding future experimental and clinical studies.


The following recollections are taken from a series of 14 extended interviews conducted with Richard W. (Dick) Hornabrook between February 1995 and February 1998, as part of a larger ethnographic study of the kuru investigation  and examined one of the largest groups of patients suffering from kuru , and gav


Twelve enzymes related to the direct oxidative and glycolytic pathways of glucose metabolism were assayed in 88 cancers of the cervix and 48 cancers of the endometrium of the human uterus, and the activities compared with those obtained from a group of control tissues. Significant increases for all but one of the enzymes studied  were found in cancer of the cervix, when compared with normal cervix epithelium. Hexokinase, phoshofructokinase, and aldolase appear to be rate-limiting in normal cervix epithelium; however, since the increase in activity of the first two in cancers was least of all the glycolytic enzymes, redundant enzyme synthesis probably occurs in the malignant cell for the enzymes catalysing reversible reactions. There was virtually no correlation between the activity of any enzyme measured in the cancer sample and histological assessments of the degree of malignancy of the tumour, or the clinical stage of the disease. All enzymes except pyruvate kinase had significantly higher activity in normal endometrium than in normal cervix epithelium, presumably reflecting the greater metabolic requirements of the former tissue. Only phosphoglucose isomerase and pyruvate kinase were significantly higher in endometrial cancer than in normal endometrium, and there were few significant differences between cancers of the cervix and of the endometrium, despite the marked differences in their tissues of origin. These results suggest the changes occur during malignant transformation to the activities of both regulatory enzymes and those catalysing reversible reactions, in a manner justifying the conclusion that the general metabolism of tumours is convergent.


The growth pattern and morphology of two transplantable acute leukaemias which arose spontaneously in pure line rats are described. They differ morphologically and on the basis of their behaviour in vivo, such as infiltration of lymphoid organs and presence in thoracic duct lymph, the leukaemia syngeneic to the August strain (referred to as the SAL) appears to be of myeloid type whereas the leukaemia syngeneic to the Hooded strain (referred to as the HRL) resembles acute lymphoblastic leukaemia. The HRL cells, but not the SAL cells, are lysed by murine anti-theta serum plus complement. These two transplantable acute leukaemias appear to be useful animal counterparts ot the human acute leukaemias and may be valuable models for studies on chemotherapy and immunotherapy.


The immunohistochemical expression of tenascin was examined in the normal adult mucosa of the stomach, primary tumours and lymph node metastases of gastric cancer patients. In normal gastric tissue tenascin was expressed in the muscularis mucosae, muscularis propria and vessel walls, however it was not expressed in either the mucosal connective tissue or the stromal tissue in the submucosal layer. In gastric cancer, tenascin was expressed in 35 of 85 primary tumours, and in 8 of 25 metastases in lymph nodes. Tenascin was located in the fibrous stroma surrounding foci of cancer. The expression of tenascin in the primary tumour did not correlate with the depth of invasion, lymph node metastasis or prognosis. Tenascin appears during the process of either malignant transformation or tumour progression in gastric cancer, and the positive expression of tenascin may be useful as a stromal marker for the early detection of gastric cancer.


The area of osteonecrosis of the head of femur affected by the disease process varies from a small localized lesion to a global lesion. Without specific treatment 80% of the clinically diagnosed cases will progress, and most will eventually require arthroplasty. Therefore the goal is to diagnose and treat the condition in the earliest stage. A number of surgical procedures have been described to retard or prevent progression of the disease and to preserve the femoral head. An implant made of porous tantalum has been developed to function as a structural graft to provide mechanical support to the subchondral plate of the necrotic femoral head, and possibly allow bone growth into the avascular region. Porous tantalum implant failure with associated radiological progression of the disease is reported in the literature; however, there is no report of clinical failure of the implant without radiological progression of the disease. We report a case of clinical failure of porous tantalum implant, seven months after surgery without any radiological progression of the disease, and with histopathological evidence of new bone formation around the porous tantalum implant. The patient was succesfully treated by total hip arthroplasty. The area of osteonecrosis of the head of femur affected by the disease process varies from a small localized lesion to a global lesion. Without specific treatment 80% of the clinically diagnosed cases will progress, and most will eventually require arthroplasty.3A 42-year-old male patient presented to out patient department (OPD) with a complaint of severe pain in right hip joint. After routine clinical and radiological examination, he was diagnosed to be suffering from advanced osteonecrosis of the right femoral head. Total hip arthroplasty (THA) was planned for the right hip. At the same time he had a mild pain in left hip joint. Radiographs of the left hip joint were normal. Taking into consideration the patient complaint and osteonecrosis of the right femur head, magnetic resonance imaging (MRI) scan was performed for the left hip joint to rule out early osteonecrotic changes as a cause of pain. MRI revealed large osteonecrotic lesion involving more than 80% geographical area of articular surface with MR crescent sign . There wOn gross examination, the implant was well placed in the center of necrotic area . There wThe HPE  at 12× mThese findings could be compared with failure cases in our study, which had associated radiological progression. The pores of the failed implants had dead marrow tissue with fat necrosis and infiltration of chronic inflammatory cells.Porous tantalum has demonstrated bone ingrowth and rapid fixation in animal models1710In our case, the porous tantalum rod had provided effective mechanical support to the joint surface as there was no collapse of the articular surface on MRI or HPE of the retrieved femoral head with implant in situ.A retrieval study has reported small shards of bone stacked up on the rounded tip of the implant in nine of the fifteen cases,It seems that this continuous shell of new bony ingrowth might have nullified the effect of core decompression, by blocking the porous tantalum. Thick mantle of cancellous bone around the tip, which appeared to be reactive new bone formation on MRI might have added to the blocking effect. Though the porous tantalum rod provided good structural support to the articular cartilage and helped maintain the integrity of the articular surface, the new bone formation blocked the porous rod completely, probably leading to gradual increase in the intramedullary pressure and patient started experiencing pain. The pain was severe enough to quote this case as clinical failure and plan THA for the affected hip.The current case suggests a new mode of clinical failure of porous tantalum rod, by which the new bony ingrowth leads to blockage of the core decompression effect of the porous tantalum, leading to arise in the intramedullary pressure and reappearance of the clinical symptoms of osteonecrosis. The iatrogenic part seems to be the cancellous bone around the tip of the tantalum rod, which is not new bone, but may be cancellous bone from neck that was pushed along the tip of the implant during insertion. In the suggested scenario, steps should be taken to avoid this iatrogenic factor in the clinical failure of the porous tantalum rod.


Fifteen percent of all tobacco-related cancers are bladder cancers. Curiously, in Northern India this disease seems to affect younger patients. The majority of the patients present with superficial disease and are treated by transurethral resection of the bladder tumor. More than half of these patients experience recurrence, with about 20% progressing to muscle invasive disease. Outcomes in superficial and muscle invasive disease have improved over time. Intravesical chemotherapy has been found to prevent recurrence in superficial bladder cancer and the immediate postoperative instillation of mitomycin C has become the standard of care for small superficial tumors that have been resected completely without perforation. With improvements in surgical technique, and the evolution in urinary diversion procedure from ureterosigmoidostomy to orthotopic neobladder, the outcome in muscle invasive carcinoma of the bladder has improved remarkably with respect to both cancer control and quality of life.According to the Delhi Cancer Registry, in 2003, bladder cancer was the 6This edition of the Indian Journal of Urology focuses on carcinoma of the bladder.Theodorescu has discussed the molecular aspects of carcinoma bladder. The molecular level understanding of the mechanism of cancer genesis is increasing and carcinoma bladder is no exception. The authors have analyzed, at the molecular level, the factors responsible for two types of carcinoma bladder that have distinct behaviors. They discuss their potential implications (either therapeutic or prognostic) in the clinical management of the disease.Dr. Jagdish N. Kulkarni has discussed in detail the changes in the staging of carcinoma bladder, with emphasis on the importance of cystoscopy and bimanual examination even in this era of MRI and CT scans.Ashish Kamat (Prashant) has discussed the management of T1G3 bladder cancer and the role of radical cystectomy in these patients. They have also explored the role of molecular markers such as epidermal growth factor receptor (EGFR) in stage progression of non-muscle-invasive carcinoma of the urinary bladder and the potential therapeutic role of cell cycle inhibitors.The article by Dr. Rakesh Kapoor of the Sanjay Gandhi Post-Graduate Institute of Medical Sciences (SGPGI), Lucknow, explores the role of BCG in non-muscle-invasive carcinoma bladder and its mechanism of action; he also discusses their experiences at the center.Dr. Markand Kochikar has reviewed the existing literature in detail for his article on the role of surgery and adjuvant and neoadjuvant chemotherapy in the treatment of locally advanced and metastatic bladder cancer.Marcus Kcukuz and Axel D. Merseburger have analyzed their results in 21 patients of T4 carcinoma bladder who were offered primary surgery in the form of radical cystoprostatectomy. Finally, there is the article by Dr. Deepak Jain from our center, which discusses the type of urinary diversion done after cystectomy in our country at various centers.Invasive bladder cancer continues to be a very difficult disease to manage. All of us who are engaged in managing these individuals realize the limitations of aggressive therapy, as most of them do not live long and would succumb to bladder cancer. It is obvious that only surgical or radiation therapy is not the answer.There is a need to develop better molecular markers, effective chemotherapy and hopefully a gene therapy to alleviate sufferings of patients who get cancer of bladder.Finally, I take this opportunity to thank all my contributors who have helped me in organizing this symposium. I am grateful to the Editor, Indian Journal of Urology for having provided me this opportunity.With best wishes for Happy New Year.


Outbreak investigation is a core function of public health agencies. Suboptimal outbreak investigation endangers both public health and agency reputations. While audits of clinical medical and nursing practice are conducted as part of continuous quality improvement, public health agencies rarely make systematic use of structured audits to ensure best practice for outbreak responses, and there is limited guidance or policy to guide outbreak audit.A framework for prioritising which outbreak investigations to audit, an approach for conducting a successful audit, and a template for audit trigger questions was developed and trialled in four foodborne outbreaks and a respiratory disease outbreak in Australia.The following issues were identified across several structured audits: the need for clear definitions of roles and responsibilities both within and between agencies, improved communication between agencies and with external stakeholders involved in outbreaks, and the need for development of performance standards in outbreak investigations - particularly in relation to timeliness of response. Participants considered the audit process and methodology to be clear, useful, and non-threatening. Most audits can be conducted within two to three hours, however, some participants felt this limited the scope of the audit.The framework was acceptable to participants, provided an opportunity for clarifying perceptions and enhancing partnership approaches, and provided useful recommendations for approaching future outbreaks. Future challenges include incorporating feedback from broader stakeholder groups, for example those of affected cases, institutions and businesses; assessing the quality of a specific audit; developing training for both participants and facilitators; and building a central capacity to support jurisdictions embarking on an audit. The incorporation of measurable performance criteria or sharing of benchmark performance criteria will assist in the standardisation of outbreak investigation audit and further quality improvement. Outbreak investigation is a core function of public health agencies. Suboptimal outbreak investigation endangers both public health and agency reputations. Surprisingly, there is little guidance on enhancing the quality of outbreak investigation and control provided to public health agencies. Audits of clinical medical and nursing practice are conducted as part of continuous quality improvement and particularly where significant events have occurred, such as unexpected deaths. They arWhile recommendations for practice improvement in outbreak investigation may be found in the discussion section of journal articles reporting on outbreak responses and published reports may critique limited aspects of outbreak response performance, a comprehensive review of outbreak investigation practice often only follows high profile events subjected to an independent government audit, or a coronial inquiry-5. PubliA framework for prioritising which outbreak investigations to audit and how to conduct an audit of outbreak investigation practice is presented. The application of this approach in four foodborne outbreaks and a respiratory disease outbreak in an Australian context is reviewed.The audit methodology has evolved since its initial trial during a national workshop to test outbreak response guidelines in 1997 which focused primarily on the rationale, selection of outbreaks, and development and use of the Audit Trigger Questions The success of a structured audit is dependent upon the appropriate:• Selection of outbreaks to be audited• Engagement and preparation of stakeholders• Process of the audit• Confidentiality agreement, where necessary• Implementation and dissemination of recommendationsPublic health activities should be evaluated as part of quality assurance and outbreaks almost always hold lessons for service improvement. However, some outbreaks, characterised by criteria in Table A benefit of normalising structured audit as part of routine practice is that audits associated with inter-jurisdictional conflict will be less threatening to stakeholders if the process is regarded as routine. It is important that audits not only be conducted following perceived system "failures" but also to identify and promote good practice. Ideally, agencies responsible for outbreak investigation should audit at least one or two investigations annually, even where specific selection criteria are not satisfied, as there can be significant learning from small or "routine" investigations.While there are costs involved in conducting a structured audit, proactively addressing communication and system performance issues may well be cost saving from an organisational perspective, however, awareness of the opportunity costs involved in conducting an audit should influence the careful selection of outbreaks to be audited and the efficient conduct of the audit. We believe most structured audits can be conducted within two to three hours and should be restricted to this time limit.It is essential that the focus of the audit is on improving future practice rather than on laying blame or identifying individual people or agencies for criticism. Participants may have endured a stressful experience during the outbreak period and extensive media scrutiny. In some outbreak investigations, legal and media scrutiny can lead to criticism of key personnel investigating outbreaks. Staff may be sensitive to an audit of their work. It is important that all participants come to the audit with the expectation of a positive outcome that will improve future practice, rather than fearing further criticism.Participants should be drawn from the pool of stakeholders who can assist in the process of the audit or those who's future practice will benefit from participation including both higher level managers and frontline staff. Including participants from external but collaborative agencies will bring more divergent viewpoints to the audit and extend the range of issues explored and resolutions available. We have conducted audits with up to 20 participants, however, the number of participants should be balanced with the scope of the audit, the issues to be reviewed and the time available.Generally, it is preferable to use a skilled facilitator. Using an external facilitator has the advantage of independence and bringing a fresh perspective. However, an external facilitator may not know the roles of key people and agencies involved in the outbreak response. A facilitator should have some experience of outbreak investigation but their key expertise should be in the process of facilitation. The facilitator should ensure constructive framing of discussion and reorient interpersonal conflict to address system issues if possible through interest-based negotiation that focuses on the underlying interest of the parties rather than their competing claims or positions.The facilitator is responsible for 1) explaining the aims, ground rules, and principles of the audit, 2) maintaining the structure of the audit, 3) facilitating the process including seeking agreement on key themes and scope of the audit, encouraging contributions broadly across participants, managing time, clarifying and summarising issues, clarifying assumptions, 4) maintaining an impartial perspective, 5) summarising the outcome of the audit and assisting in writing a report, and 6) checking on progress of actions approximately six weeks after the audit.The lead agency in the investigation will usually call for an audit of an investigation and define the expectations of the audit outcome at the outset. The terms of reference, the scope of the audit, attendees, duration and the expected product should be defined in consultation with participants and in advance so that participants are supportive and prepared for the meeting. The major objective of the audit should be framed as a neutral system performance statement or question.We use the term "structured" to describe two aspects of this methodology - first to denote the structure used in the Audit Trigger Questions to ensure a comprehensive range of issues are addressed and secondly to denote the structure for audit meeting preparation and conduct. The Audit Trigger Questions  was the process/methodology clear? 2) did the structured methodology assist or inhibit the debrief? 3) do you have any suggestions for the facilitator to improve facilitation of debriefs in the future? and 4) other general comments.Five outbreaks have undergone structured audit between 1997 and 2008, with participants ranging from a single regional health protection unit through to inter-agency and multi-jurisdictional audits. These identified a broad range of outbreak response quality improvement measures at national, state and local level (Table We trialled qualitatively rating outbreak investigation performance against the Audit Trigger Questions using criteria such as "adequate" or "needs improvement", however, it was found to be cumbersome and slowed down the preparation for the audit and subsequently this was dropped in favour of placing a tick beside those questions that should be addressed in the audit.Initial results from confidential written evaluations from eight participants from the last two structured audits demonstrate that participants consider the process and methodology to be clear and useful. Some participants find that while the structure of the audit assists and helps to make the process "neutral" and "non-threatening" it may also limit the discussion of issues that arise during the audit because these are considered "out of scope". The circulation of a document summarising the outbreak, the scope of the audit and issues suggested for discussion prior to the audit was considered valuable. It was suggested that where possible the facilitator should be a neutral party and that sometimes limiting the audit to two hours inhibited exploration of issues such as future prevention measures.The following issues were repeatedly identified across several structured audits: the need for clear definitions of roles and responsibilities both within and between agencies, communication between agencies and with external stakeholders involved in outbreaks, and the need for development of performance standards in outbreak investigations - particularly in relation to timeliness of response.The methodology used in the audit is acceptable to participants and there is support for continued use and development of the tool. We have found that the focus on common interests of the parties, positive reframing of issues, and compliance with the structure of the audit has minimised the potential for interpersonal conflict during the audit meetings. Agencies welcome guidance in approaching the evaluation of complex outbreak responses and this methodology has been chosen by the Public Health Laboratory Network of Australia to review the laboratory response to the 2009 influenza pandemic.The methodology for the audit has evolved over time, while it was initially structured around the Audit Trigger Questions in Additional file The importance of a supportive environment for structured audit cannot be over emphasised. In clinical audit, the most frequently cited barrier to successful clinical audit is the failure of organisations to provide sufficient protected time for healthcare teams and it likely the same would apply to public health agencies. In our Kipping et al highlighted the lack of published standards for auditing outbreak response and emphasised that further development and promotion of such standards was required.http://groups.google.com/group/outbreak-audits to promote use of the methodology and the development of a collaborative network to share learning and modifications of the structured audit methodology.This methodology is evolving with practice and we encourage feedback and modification of the process from practitioners. Future challenges include incorporating feedback from broader stakeholder groups, for example those of affected cases, institutions and businesses; assessing the quality of audit; developing training for both participants and facilitators; and building a central capacity to support jurisdictions conducting audits. The incorporation of measurable performance criteria or sharing of benchmarkable performance criteria will assist in the standardisation of audit and further quality improvement. A Google Group has been initiated at The framework was acceptable to participants, provided an opportunity for clarifying perceptions and enhancing partnership approaches, and provided useful recommendations for approaching future outbreaks. Future challenges include incorporating feedback from broader stakeholder groups, for example those of affected cases, institutions and businesses; assessing the quality of a specific audit; developing training for both participants and facilitators; and building a central capacity to support jurisdictions embarking on an audit. The incorporation of measurable performance criteria or sharing of benchmark performance criteria will assist in the standardisation of outbreak investigation audit and further quality improvement.The authors declare that they have no competing interests.CBD developed the initial drafts of the Audit Trigger Questions and criteria for auditing outbreaks, introduced the alternative dispute resolution principles to the audit and drafted the initial manuscript. TDM and SAM developed the template for reporting the outcome of the audits and further refined the audit process. DND and MDK provided intellectual input into design and conduct of the audit. All authors helped draft and revise the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/9/472/prepubAppendix 1 - Audit Trigger Questions. Tabular checklist of questions to trigger further exploration in the structured audit.Click here for fileAppendix 2 - Post-audit Action Plan Template. Tabular template for recording post-audit actions and recommendations.Click here for file


Sixteen groups, each of 50 Swiss female SPF mice, were treated thrice weekly with various combinations of 3,4-benzopyrene (BP) and/or the neutral fraction of cigarette smoke (NF) in acetone applied to the skin. Some groups received one carcinogen, some the other and some a mixture of the two. Skin tumour incidence rates were found to increase both with the dose of NF and with the dose of BP. With BP alone a threshold dose was found beyond which a very heavy incidence rate of malignant skin tumours occurred. After correction of the results for intercurrent deaths it was found that when NF and BP are applied together as a mixture they do not act independently in the production of malignant skin tumours but interact positively. This suggests that some of the components of NF act as cocarcinogens rather than as complete carcinogens. Treatment with NF appeared to increase the incidence of malignant lymphomas. The data were not suitable for deciding whether the various treatments influenced the rates of incidence of internal tumours of other types, for example, lung tumours.


Patient. We describe a case of chondroblastoma of the os calcis which metastasized to the tibia, soft tissues and lung. A complete response of the lung lesions was noted with chemotherapy.Discussion. Review of the published literature shows that metastatic chondroblastoma only arises following local recurrence of the tumour.


Vitamin A and its biologically active derivatives, retinal and retinoic acid (RA), together with a large repertoire of synthetic analogues are collectively referred to as retinoids. Naturally occurring retinoids regulate the growth and differentiation of a wide variety of cell types and play a crucial role in the physiology of vision and as morphogenic agents during embryonic development. Retinoids and their analogues have been evaluated as chemoprevention agents, and also in the management of acute promyelocytic leukaemia. Retinoids exert most of their effects by binding to specific receptors and modulating gene expression. The development of new active retinoids and the identification of two distinct families of retinoid receptors has led to an increased understanding of the cellular effects of activation of these receptors. In this article we review the use of retinoids in chemoprevention strategies, discuss the cellular consequences of activated retinoid receptors, and speculate on how our increasing understanding of retinoid-induced signalling pathways may contribute to future therapeutic strategies in the management of malignant disease. © 1999 Cancer Research Campaign


In an attempt to probe nucleic acid structures, numerous Ru(II) complexes with different ligands have been synthesized and investigated. In this contribution we focus on the DNA-binding properties ofruthenium(II) complexes containing asymmetric ligands that have attracted little attention in the past decades.The influences of the shape and size of the ligand on the binding modes, affinity, enantioselectivities and photocleavage of the complexes to DNA are described.


The metal-binding abilities of a wide variety of bioactive aminophosphonates, from thesimple aminoethanephosphonic acids to the rather large macrocyclic polyaza derivatives, arediscussed with special emphasis on a comparison of the analogous carboxylic acid andphosphonic  acid  systems.  Examples are  given  of  the biological importance of metalion – aminophosphonate interactions in living systems, and also of their actual and potentialapplicability in medicine.


The National Registry of Childhood Tumours contains over 51000 records of children born in Great Britain who developed cancer under the age of 15 years. Patterns of childhood cancer among families containing more than one child with cancer have been studied. A total of 225 "sib pair' families have been ascertained from interviews with parents of affected children, from hospital and general practitioner records and from manual and computer searches of names and addresses of patients. A number of special groups have been identified, including those with a known genetic aetiology such as retinoblastoma, twins and families with three or more affected children. A further 148 families not in any of the above groups contain two children with cancer: in 46 families the children had tumours of the same type, most commonly leukaemia. Some of the families are examples of the Li-Fraumeni syndrome; some are associated with other conditions, including Down's syndrome. There is clearly a genetic element in the aetiology of cancer in some families discussed here; shared exposure to environmental causes may account for others and some will be simply due to chance.