On most common microarray platforms many genes are represented by multiple probes. Although this is quite common no one has systematically explored the concordance between probes mapped to the same gene.Here we present an analysis of all the cases of multiple probe sets measuring the same gene on the Affymetrix U133a GeneChip and found that although in the majority of cases both measurements tend to agree there are a significant number of cases in which the two measurements differ from each other. In these cases the measurements can not be simply averaged but rather should be handled individually.Our analysis allows us to provide a comprehensive list of the correlation between all pairs of probe sets that are mapped to the same gene and thus allows microarray users to sort out the cases that deserve further analysis. Comparison between the set of highly correlated pairs and the set of pairs that tend to differ from each other reveals potential factors that may affect it. High density DNA microarrays are extensively used by biologists in order to gain information about the expression levels of thousands of genes simultaneously. The advantage of the genomic approach is that it allows the study of cell behavior on the systems level rather than on the gene specific level . One of A related issue which has been studied extensively in recent years is the question of cross platform comparisons in which researchers try to compare results obtained for the same gene on different microarray platforms. Overall there is only limited agreement between experiments performed on different platforms . ManyIn order to compare RNA measurements from two different regions of a gene on the same array, we chose to explore the Affymetrix U133a platform since it is a very popular platform with thousands of publicly available datasets. The U133a platform contains 20,267 probe sets which are mapped to 12,942 distinct genes with 4,552 of them represented by multiple probe sets .In order to asses the overall agreement within pairs of probe sets, we decided to look at the Pearson correlation between the set of measurements for each of the probe sets in each dataset. We chose the Pearson correlation as our metric since it is not sensitive to differences in scaling and average expression levels but rather compares the degree of linear relationship between the two probe-sets which is a better indication for the overall similarity. We calculated the correlation coefficient of all the informative pairs in each dataset. Histograms of these correlations and correlations obtained by a random list of pairs are shown in figure Comparison of the correlation values obtained in the different datasets revealed a high degree of correlation between them figure , suggestOne of the main purposes of our analysis was to guide microarray users in cases of genes that are represented by multiple probe sets. The users would like to know when the multiple measurements can be combined and when they should be handled with caution. In order to achieve this goal, we wanted to define a list of pairs which show overall good agreement between them. This list should be based on the combination of the correlation values calculated in each dataset. Thus for each pair, we combined the individual P values obtained for each dataset in which it was informative, resulting in a single combined P value for each pair. A list of all the pairs along with their combined P values is included in Microarrays users frequently ask themselves what to do when a gene is represented by multiple probes. Our analysis provides a partial solution to this problem by mapping all the pairs of probe sets on the Affymetrix U133a platform and providing a significant measurement  as to whether the transcription levels reported by the two different probe sets correlates. In order to demonstrate that the combined P value may be useful in analyzing microarray data, we calculated the number of cases in which averaging the intensity reported by a pair of probe sets is misleading. The clear dependency between the error rate level and the P value  and pairs which did not show a significant concordance between them .Intra array repeats are printed on the same array and therefore they share all the external conditions  and differ from one another only in the particular sequence chosen to be printed on the array. Thus multiple probe sets printed on the same array serve as an excellent case for exploring the contribution of sequence effects to the overall deviation of the transcription values reported by each probe set. To this end we defined two large sub groups of pairs (each containing approximately 1500 pairs) – pairs that were highly correlated  for the s_at and x_at suffixes in the "good" pairs figure , suggestMicroarray users frequently encounter the problem of different values for the same gene resulting from multiple probe sets. Without clear guidelines from the manufacturers, each investigator deals with this problem in a different way, some are not aware of it and therefore either use the first appearance of the gene or use the probe set that fits their expectations better. Alternatively, users may use the average of all probe sets without validating that all indeed report similar transcription rates. In order to help microarray users to chose the right approach for multiple measurements of a gene in the Affymetrix U133a GeneChip we examined all such cases and developed a statistical method to asses the agreement between the measurements in each of these cases. Our method is based on the calculation of the Pearson correlation between all the measured values of a pair of probe sets along all the experiments in a data set. The Pearson correlation gives a good estimation of the overall agreement between such pairs without being sensitive to variability in the average expression level reported by the probe sets. We excluded from the analysis probes that were non informative either because their expression level was below detection or because their expression level did not change (>2 folds) along the experiments. As expected the correlation values obtained between probe sets from the same gene were much higher than those obtained from randomly chosen pairs of probe sets with 77% of the pairs reporting similar values. The pairs of probe sets where sorted according to the statistical significance of the Pearson correlation between them and a list of all the pairs together with their P value is provided see . This liThe division of the pairs of probe sets into those that tend to agree ("good") or disagree ("bad") allows us to examine the factors affecting it. The deviation between two probes that are mapped to the same gene may be due to several reasons including alternative splicing, mistakes in the annotation and differences in the efficiency each probe set reports the transcription. We found no evidence for the contribution of alternative splicing to the disagreement between probe sets figure . On the Recent studies about cross platform comparisons found that the best results are obtained if the comparison is done on the probe level rather than on the probe set level ,18,19, sThe observation that non unique probe sets perform better than unique ones figure  is surprOur analysis suggests that in most cases (77%) pairs of informative probe sets report similar transcription levels. However, it should be noted that our decision to concentrate only on informative probe sets may influence those results. By excluding from the analysis the most problematic cases in which one probe set is informative and the other is not we elevated the percentage of cases with good correlation see . These cThe analysis of the differences between the "good" and the "bad" pairs suggests that biological differences such as alternative splicing have a very limited contribution to the disagreement between probe sets. This conclusion was derived from the current knowledge of the genome sequence and of splicing variants (using fairly strict criteria). Updates of the genome sequence and advancements in the technology of measuring splice variants (such as the use of exon microarrays) may change this conclusion. Although those changes may affect the reasons for the disagreements between probe sets it will not change the definition of "good" and "bad" pairs. Only updating the probe set definition according to the new sequence information  may solvAn important internal control for microarray experiments is multiple array spots that are mapped to different regions of the same genes. In the ideal world these different probe sets should give similar measurements for expression of the gene. Our analysis tested whether this is true using four data sets that used the Affymetrix U133a platform. We found that in the majority of such cases both measurements agree and thus using the average value of the probe sets would be appropriate. However in a significant number of cases this approach is not suitable and our results can guide the user in deciding about each case. Further analysis is needed to define guidelines for choosing better regions in the gene that will represent the transcription level more accurately.For our analysis we downloaded the data of four large experiment series from the gene expression omnibus database . We chosIn order to define intra array repeats, we used Affymetrix annotation and defined 11,722 pairs of probe sets in which both members were mapped to the same gene. In order to compare the RNA levels reported by the two probes in each pair we calculated the Pearson correlation between the expression values (log transformed) reported by each probe set in all the experiments in each dataset. We also performed Spearman correlation and the results see  are verySince we were interested only in the correlations between probe sets of active genes we looked only on probe sets that passed two filtering criteria – they got a present call (P) in at least 10% of the experiments in a dataset and they showed at least 2 fold changes in their expression level over the average in at least 10% of the experiments. This filtering resulted in a different number of informative pair of probe sets for each dataset , pairs with only one informative probe set (red) and pairs in which both probe sets are informative (red). See methods for the definition of informative probe set.Click here for fileExcel file containing information about the Spearman correlation values of all pairs of probe sets in all the four datasets.Click here for file2 values. The only dataset with spots that are not along the diagonal is GSE1133 in which ~5% of the spots deviate from the diagonal by >2 folds, the remaining spots gave R2 = 0.93.Scatter plots showing the Pearson correlation values (X axis) against the Spearman correlation values (y axis) of all the informative pairs in the 4 data sets. Note that the spots are arranged along the diagonal with high RClick here for file


Eighty-one patients with advanced breast cancer completed the Hospital Anxiety and Depression Scale (HADS) and Rotterdam Symptom Checklist (RSCL) to determine how well these questionnaires identified patients suffering from an anxiety state or depressive illness, compared with an independent interview by a psychiatrist who used the Clinical Interview Schedule. A threshold score was defined for each questionnaire which gave the optimal sensitivity and specificity. Seventy-five per cent of patients were correctly identified as suffering from an affective disorder by both the Rotterdam Symptom Checklist and by the Hospital Anxiety and Depression Scale. Twenty-one per cent of 'normal' patients were misclassified by the Rotterdam Checklist and 26% by the Hospital Anxiety and Depression Scale. When the HADs anxiety and depression subscales were analysed separately, the performance of the anxiety items was superior to that of the depression items. Both questionnaires were found to have good predictive value and could be used in patients with advanced cancer to help screen out those with an affective disorder.


The presence of cellular aggregates in cell suspensions derived from human solid tumours often complicates subsequent evaluation of colony formation in primary soft agar cultures . In the present study, performance of a conventional colony formation assay was observed to lack sufficient sensitivity to identify growth and active chemotherapeutic agents in the majority of specimen cultures. Modification of conventional methodologies to include filtration of cell suspensions, use of "proliferation control" and "cytotoxicity control" cultures as well as vital staining were found to be essential for the valid assessment of primary soft agar cultures in our laboratory. In addition, application of drugs to culture surface in place of culture incorporation appeared to facilitate culture performance and drug sensitivity testing.


The effect of the synthetic progesterone, megestrol acetate, on weight loss induced by both tumour necrosis factor alpha (TNF) as a model for the cachexia accompanying the acquired immunodeficiency syndrome and by a cachexia-inducing tumour (MAC16) has been studied in NMRI mice. Megestrol acetate was effective in preventing weight loss in both model systems with treated animals having an increase in intake of both food and water. Megestrol acetate was unable to prevent loss of body weight in animals pair-fed with TNF treated animals, suggesting that the increase in food and water intake was responsible for the increase in body weight. Analysis of body composition showed that the major contribution to the increase in body weight in animals treated with megestrol acetate was an increase in water content, although there was also an increase in carcass fat in animals bearing the MAC16 tumour given the high dose of megestrol acetate. Animals bearing the MAC16 tumour had a significant increase in tumour weight after treatment with megestrol acetate, possibly owing to the increased plasma glucose levels. These results suggest that an increase in appetite and weight gain alone are not sufficient to justify the anticachectic effect of a particular agent and that body composition analysis and tumour growth rate are very important parameters.


The effects of different doses of hydralazine and prostacyclin on the 31P magnetic resonance spectra of the LBDS1 fibrosarcoma were investigated and related to their effects on mean arterial blood pressure (MABP) and heart rate. The effect of reducing MABP by bleeding the animals, via the tail artery, was also investigated. Tumour spectral changes following high dose drug treatment  were consistent with nutrient deprivation. These changes were dose dependent. Changes in MABP and heart rate were consistent with vasodilatation in normal tissues. However, for the same fall in MABP, hydralazine produced a greater rise in tumour inorganic phosphate (Pi) and a greater fall in tumour pH than did prostacyclin. Controlled bleeding was effective in reducing MABP. It also reduced tumour pH but had no significant effect on tumour Pi. The clinical application of the two drugs for reducing tumour blood flow and pH for therapy is likely to be limited by the large degree of hypotension necessary to produce an effect. The differential effect of the two drugs for the same fall in MABP may be related to different degrees of direct tumour vasodilatation or to a direct effect of hydralazine on tumour energy metabolism. The observation that controlled bleeding does not change tumour Pi is further evidence indicating that the degree of arterial hypotension is not the sole factor in determining tumour energy status.


In order to assess whether exposure to stress was associated with an increased risk of breast cancer, 100 women presenting with carcinoma of the breast completed a standard life events inventory documenting life stresses experienced during the previous three years. The same questionnaire was completed by 100 women presenting with benign breast lumps and 100 apparently healthy controls. Both groups of patients with breast disease also completed the Eysenck personality inventory. There was no difference in the number of stressful life events experienced by the patients with benign and malignant breast lesions and the nature and severity of those stresses encountered were similar for both groups. The personality indices were also the same for both groups. The controls, however, recorded significantly higher levels of stress exposure than the patients with breast disease. On the basis of this series, there is no evidence to support the hypothesis that stress predisposes to breast cancer development.


Paragangliomas of the head and neck (glomus tumours) can occur in a hereditary pattern and may be hormonally active as well as being associated with paragangliomas elsewhere. A number of these tumours may be present without symptoms. To detect the presence of subclinical paragangliomas we screened 83 members of a family at risk of developing hereditary paragangliomas using whole body MRI and urinary catecholamine testing. In eight previously diagnosed members, eight known glomus tumours of which one functioning, and two unknown glomus tumours and one unknown pheochromocytoma were present. Six unsuspected members showed ten glomus tumours and one pheochromocytoma. It has been suggested that the manifestation of hereditary glomus tumours is determined by the sex of the transmitting parent. There were no tumours in the descendants of female gene carriers. Comparing the likelihood of inheritance with genomic imprinting versus inheritance without genomic imprinting we found an odds ratio of 23375 in favour of genomic imprinting.


It is now recognised that the breast exhibits a circadian rhythm which reflects its physiology. There is increasing evidence that rhythms associated with malignant cells proliferation are largely non-circadian and that a circadian to ultradian shift may be a general correlation to neoplasia.Cancer development appears to generate its own thermal signatures and the complexity of these signatures may be a reflection of its degree of development.The limitations of mammography as a screening modality especially in young women with dense breasts necessitated the development of novel and more effective screening strategies with a high sensitivity and specificity. Dynamic thermal analysis of the breast is a safe, non invasive approach that seems to be sensitive for the early detection of breast cancer.This article focuses on dynamic thermal analysis as an evolving method in breast cancer detection in pre-menopausal women with dense breast tissue. Prospective multi-centre trials are required to validate this promising modality in screening.The issue of false positives require further investigation using molecular genetic markers of malignancy and novel techniques such as mammary ductoscopy. Breast cancer is one of the most common cancers, it is estimated that one in eight women in the USA will develop breast cancer during their lifetime -4. FurthIn addition to mammography, non invasive new modalities have been developed to allow the early detection of breast cancer in all age groups and more importantly in young women with dense breast tissue and women who have high risk of developing breast cancer such as, women with strong family history and carriers of BRCA1 and/or BRCA2 genes.Currently, magnetic resonance imaging (MRI) is being studied for the early detection of breast cancer. Its sensitivity in high risk women has been found to be much higher than mammography but with a lower specificity ,6. KriegElectrical impedance scanning (EIS) is another modality under development for breast cancer detection especially in young women with dense breasts . The basFurthermore, mammary ductoscopy (MD) and visualization of mammary ducts and proteomics of nipple aspirate fluid (NAF) and serum are promising screening modalities that require further evaluation ,10.The limitations of mammography as a screening modality especially in young women with dense breasts necessitated the development of novel and more effective screening strategies with a high sensitivity and specificity.This article focuses on the dynamic thermal analysis as an evolving non invasive and a safe method in breast cancer detection in pre-menopausal women with dense breast tissue and women at high risk due to family history or genetic predisposition.It is now recognised that the establishment and growth of a tumour depend on neovascularization. This successful recruitment of new blood vessels into a tumour; also known as angiogenesis is dependent on angiogenic growth factors produced by the tumour cells . Such neEarlier technology for assessing thermal abnormalities in the breast focussed on the presence of the abnormal temperature as a crucial marker -17. In aThe superficial thermal patterns measured on the surface of the breast seem to be related to tissue metabolism and vascularization within the underlying tissue. Such thermal patterns change significantly as a result of normal phenomena including menstrual cycle, pregnancy and more importantly the pathologic process itself. Additionally, cancer development represents the summation of a large number of mutations that occur over years, each with its own particular histologic phenotype -23.Such changes appear to generate their own thermal signature and the complexity of these signatures may be a reflection of their degree of development -28.Temperature in a normal breast increases from the skin into the deep tissue and heat conductivity in the healthy breasts is constant in most cases and generally can be characterized in terms of circadian rhythm periodicity . In contFurthermore, the unique relationship between the thermal circadian rhythm and mitotic activity could be considered as a first warning of tumour development, which can be detected using a safe and non-invasive technology. The genes that drive the circadian rhythm are emerging as central players in gene regulation throughout the organism, particularly for cell-cycle regulatory genes and the genes of apoptosis .Recent technological advances have facilitated the recording of circadian rhythm variations of the breast and analysing the recorded data using highly complicated computer statistical software. A miniaturized microprocessor has been developed to record and store thermal information collected from eight separate sites of each breast. Sensors are placed in anatomically critical positions elicited by data obtained from tumour registries as to where cancers are most likely to develop.In the First Warning System , thermal data are collected every five minutes for a period of 48 hours during which time women are encouraged to maintain their daily activities. 9000 pieces of data are recorded by microprocessors during the test period and analysed using specially developed statistical software. Temperature points from each contralateral sensor are plotted against each other to form a thermal motion picture of a lesion's physiological activity.Such a technology was first used by Farrar et al who examined a cohort of 138 women who had been scheduled for open breast biopsies based on the finding of physical examination and mammography . A totalOne of the main challenges to this technology is the false positive cases; confusion could be created in these women who are characterized as being positive or high risk by dynamic thermal analysis in the absence of physical and mammographical signs. This group of women may or may not have cancer in its earliest stages. Further retrospective analysis of the thermal data using a refined neural net algorithm may increase the sensitivity and reduce the number of false positives. Also this group of patients may well benefit from the new advances in the nipple aspirate fluid analysis and proteomic profiling technologies. Research is currently ongoing on this subject and the initial results are promising .Dynamic thermal analysis of the breast is a safe, non invasive approach that seems to be sensitive for the early detection of breast cancer especially in young women where the conventional mammography is of limited value. Such a technology could become the initial breast screening test in pre-menopausal women and those who are classified as positive can then be selected for anatomical imaging with mammography, MRI and/or ultrasonography. Further refinement of the neural net algorithm is required in order to shorten the period of data recording and improve specificity. Prospective multi-centre trials are then required to validate these promising observations. The issue of false positives require further investigation using molecular genetic markers of malignancy and novel techniques such as mammary ductoscopy .Finally, a better understanding of the circadian rhythm biology ,30 and c


In 1999 the membership of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) formed a multisector consortium to address challenges associated with the integration of genomics data into risk assessment . FollowiIn 2004 we have seen considerable progress in many of the areas mentioned above, particularly in our technical ability to execute microarrays and to analyze and interpret the resultant data. The experimental program of the HESI Genomics Committee clearly demonstrated that it is possible to replicate data on biologic pathways across laboratories and technical platforms . The comThe efforts of the HESI Committee on Genomics regarding experimental collaboration and toxicogenomics database development  suggest The risk assessment community is also striving both to harness the collective power of publicly available data sets and to facilitate exchange of single data sets for safety evaluation. As such, numerous formats for the capture and exchange of microarray and toxicology data have become available and/or are under development . DiversiThe HESI Committee on Genomics looks forward to an ongoing role as a multi-stakeholder consortium committed to facilitating discussion on the scientifically sound use of genomics for risk assessment.


Dopamine acts as neurotransmitter in the central and peripheral sympathetic nervous system. Determination of dopamine (DO) was performed by spectrophotometric analysis depending on the formation of new colored compound. The proposed procedure was efficient in quantitative determination of DO as pure material in pharmaceutical preparations and in urine samples. DO concentration in urine sample of patient confirms the affection with schizophrenia and the proposed procedure was used to facilitate diagnosis and followup of schizophrenic patients. It is recommended to apply the proposed procedures as routine analysis in pharmaceutical companies for quality control and in analytical laboratories to diagnose and follow up schizophrenia.


Standard (UICC) crocidolite was subjected to ball milling to reduce the length of the fibre. These milled materials and the original standard sample were injected into the pleural cavity of rats to determine their ability to induce mesothelioma. Previous in vitro work on the same materials had suggested that biological activity was related to fibres greater than 6.5 microns in length and that the material milled for 4 and 8 h did not contain fibres in this range and was biologically inactive. The results of the animal work, however, did not follow this pattern; mesotheliomas occurred in rats in all treatment groups including the 4 and 8 h milled samples. Examination of the tissues and the dust recovered from them showed the presence of fibres greater than the suggested threshold. Attention is drawn to the problems associated with drawing conclusions from size distributions and in vitro studies without considering in vivo mechanisms.


Programmes of education in breast self-examination with specialist clinics for self-referral were introduced in two health districts around 1980. Combining the results from the two centres showed no reduction in mortality from breast cancer over the following 10 years but the mortality was low in one of the centres whilst in the other it was higher than in four geographically separate comparison centres in which there was similar careful monitoring of breast cancer incidence and mortality. Because this was not a randomised controlled trial and lacked a uniform treatment protocol, biases may be responsible for the differences observed, but it is also possible that BSE education with annual reinforcement contributed to the breast cancer mortality reduction seen in one district. The overall conclusion however is that the value of breast self-examination remains unproven.


In this issue of the Journal of Medical Internet Research, the reader is presented with two important studies that focus on the challenges of integrating patient participation and partnership in medical informatics. Both studies address the enormous potential of information technology to effect change in health by influencing patient behavior.The study by Ross et al is a randomized controlled trial of SPPARO (System Providing Patients Access to Records Online), a patient-accessible electronic patient records (EPR) system implemented at the University of Colorado, measuring its impact on health outcomes and patient satisfaction . SPPARO The SPPARO study also serves to illustrate two key dilemmas facing clinical informatics researchers. In defining the unit of analysis, is "access" the antecedent for change in outcomes, or is it more appropriate to look for some kind of behavioral change, like technology acceptance or actual system utilization ? FurtherThe second study by Kim and Johnson observes the contributory role of format on the subsequent accuracy of data entry by patients in personal health records (PHR), and vividly illustrates the most important challenge facing developers: how to make the PHR useful for patients . The intIn conclusion, medical informatics research must continuously develop the capacity to demonstrate that information technology can effect positive change for patients . These t


To explain the possible effects of exposure to weather conditions on population health outcomes, weather data need to be calculated at a level in space and time that is appropriate for the health data. There are various ways of estimating exposure values from raw data collected at weather stations but the rationale for using one technique rather than another; the significance of the difference in the values obtained; and the effect these have on a research question are factors often not explicitly considered. In this study we compare different techniques for allocating weather data observations to small geographical areas and different options for weighting averages of these observations when calculating estimates of daily precipitation and temperature for Australian Postal Areas. Options that weight observations based on distance from population centroids and population size are more computationally intensive but give estimates that conceptually are more closely related to the experience of the population.Options based on values derived from sites internal to postal areas, or from nearest neighbour sites – that is, using proximity polygons around weather stations intersected with postal areas – tended to include fewer stations' observations in their estimates, and missing values were common. Options based on observations from stations within 50 kilometres radius of centroids and weighting of data by distance from centroids gave more complete estimates. Using the geographic centroid of the postal area gave estimates that differed slightly from the population weighted centroids and the population weighted average of sub-unit estimates.To calculate daily weather exposure values for analysis of health outcome data for small areas, the use of data from weather stations internal to the area only, or from neighbouring weather stations , is too limited. The most appropriate method conceptually is the use of weather data from sites within 50 kilometres radius of the area weighted to population centres, but a simpler acceptable option is to weight to the geographic centroid. A study of the possible effect of temperature and precipitation on gastroenteritis inspired an assessment of different methods for small area population exposure estimation techniques. The health data were obtained from a survey with respondents from Australia conducted between September 2001 and August 2002 . Microsoft Access was used to join the concordance table of POA-to-monitoring station proximity polygons to the daily observations, and averaged these whilst grouping by POA code and date in Options 1 and 2. Options 3 and 4 used "joinby" and "collapse" commands in STATA 8  to join Individual station files of daily meteorological data for 1990–2005 were parsed for integration in MS Access databases using visual basic code written by Melissa Goodwin at the National Centre for Epidemiology and Population Health.The CD populations from the 2001 census were obtained from the ABS . These dSome postcodes don't exist as POA and for these the locality names were found using the online postcode finder from the electronic telephone directory . These lMultipart POA were assessed by first using the ArcGIS multipart to single-part tool (features toolbox) and then counting the number of parts per feature (using the frequency tool).Internal stations were found using the intersect tool in the ArcGIS Spatial Analyst extension. This information was joined to the meteorological data using Microsoft Access.Nearest neighbour concordances were calculated by first creating proximity polygons of the appropriate stations (using the coverage tools), then overlaying and intersecting these with POA .Centroids were calculated using the Visual Basic for Applications script from the ArcGIS help menu. Then distances were calculated using the coverage toolbox "point-distance" tool. The projection was set to Albers South Asia Conic (metres) projection. This is necessary to avoid the distortion of length inherent with other cartographic projections .The author(s) declare that they have no competing interests.IH carried out the GIS analysis and drafted the manuscript. GH conceived the study, conducted the health analysis and helped to draft the manuscript. KD provided theoretical and conceptual guidance and helped to draft the manuscript. All authors read and approved the final manuscript.


The multivariate lognormal survival model can be used to determine the relationship of prognostic covariates to two important parameters of malignancy. Cured fraction and median survival time among uncured patients. Analysis with this model revealed that cured fraction is primarily a function of histologic type and node status, while median survival time is primarily a function of age and node status. Patient sex was also related to likelihood of cure, but this association was of marginal significance. The symmetric impact of node status on both cured fraction and median survival time is consistent with known biologic principles. The strongly asymmetric relationships of histologic grade to cured fraction and age to survival time suggest, however, that likelihood of cure and survival time may not operate by identical biologic mechanisms.


We read with special interest the article by We would like to focus on the potential neuroprotective role of iron against the deleterious effect of lead on the development of ADHD symptoms.Although the mechanisms underlying ADHD remain unclear, both genetic and environmental factors have been implicated. In a recent review on the implication of the dopaminergic system in the etiology of ADHD, Lead in the central nervous system may contribute to dopaminergic dysfunction inducing alteration of dopamine release and dopamine receptor density . MoreoveIn a controlled comparison group study, we  showed tGiven that lead exposure may contribute to ADHD and iron deficiency may exacerbate deleterious effects caused by lead, we recommend systematically seeking for iron deficiency in children with ADHD. We also think that controlled studies assessing the potential effectiveness of iron supplementation on ADHD symptoms should be encouraged. Such studies could aid the understanding of the complex pathophysiology underlying ADHD and provide effective therapeutic strategies for this disorder.


Pathology observer agreement studies are clearly important in the development of new pathology assessments and in the quality control of those assessments in common use. Setting up such studies, and reporting and interpreting their results requires careful thought and statistical expertise. Investigators are advised to seek collaboration with a statistician before embarking on these studies. Pathology reference panel reviews in multicentre studies are useful for checking eligibility when there is a high level of disagreement on the eligibility criterion between local pathologists and the reference panel members, but good agreement between members of the panel. However, such situations are uncommon.


PLoS Medicine for initiating a students' forum [We congratulate and acknowledge s' forum  and for PLoS Medicine, which is composed of articles selected by student representatives across the world. The unique integration of student associations with PLoS Medicine, and the journal's policy of not publishing advertisements for drugs or medical devices, will also enlighten students about the influence of drug companies in medical practice and enable students to realize their priorities in poorer countries for the future. Thereby, students may focus their attention on becoming professionals in developing new strategies to combat killer infectious diseases like malaria and tuberculosis, and malnutrition—such as vitamin deficiencies among children and iron deficiency among pregnant women—that are dreaded and very common in poorer countries.It will be really motivating for students from developing countries to actively take part in debate through the Student Forum of


There is ample evidence of the efficacy of cytological screening in the prevention of cervical cancer but disagreement on the form which screening programmes should take. Simulation models have been used as a convenient and rapid method of exploring the outcome of different screening policies and of demonstrating the importance and interrelationships of the variables concerned. However, most such models are either too abstract or too simplistic to be of practical value in planning screening programmes. A model is described which reproduces demographic events in a female population  over a 30 year period, and onto this superimposes the natural history of cervical carcinoma, using data derived from published studies. A microsimulation approach--each individual in the population being retained as a unit--allows factors such as disease onset and screening uptake to be dependent upon personal characteristics and past events. Screening can be offered as part of a routine programme, or incidentally--for example during pregnancy or hospital attendance. The model allows quantitative evaluation of the complex patterns of screening that are actually observed and the relative importance of the different components of such screening programmes. Assumptions about natural history can thus be studied.


Health Assessment (HA) items were introduced in 1999 for Aboriginal and Torres Strait Islander people aged at least 55 years and all Australians aged over 75 years. In 2004 a new item was introduced for HAs among adult Aboriginal and Torres Strait Islander people aged 15–54 years. The new item has been applauded as a major policy innovation however this enthusiasm has been tempered with concern about potential barriers to its uptake. In this study we aim to determine whether there are disparities in uptake of HA items for Aboriginal and Torres Strait Islander people compared to other Australians.The analysis was based on Health Insurance Commission data. Indigenous status was ascertained based on the item number used. Logistic regression was used to compare uptake of HA items for older people among Aboriginal and Torres Strait Islander people compared to other Australians. Adjustments were made for dual eligibility. Uptake of the HA items for older people was compared to the uptake of the new item for Aboriginal and Torres Strait Islander people aged 15–44 years.Our analyses suggest a significant and persistent disparity in the uptake of items for older patients among Aboriginal and Torres Strait Islander people compared to other Australians. A similar disparity appears to exist in the uptake of the new adult Aboriginal and Torres Strait Islander HA item.Further engagement of primary care providers and the community around the uptake of the new HA items may be required to ensure that the anticipated health benefits eventuate. The introduction of Medical Benefits Scheme (MBS) item numbers to reimburse health assessments (HAs) represented a major shift in support for access to health promotion and preventive care in primary care settings. The HA items provide reimbursement for doctors to evaluate patient's physical, psychological and social function in order to optimise health care and education. HA items were first introduced for older patients in 1999. [The uptake of the HA items and other items introduced as part of the Enhanced Primary Care (EPC) program from 1999–2001 has been rigorously evaluated. HA items had the highest uptake of the Enhanced Primary Care items with around 18% of the eligible population using them.  No inforIn May 2004, a new item item 710) was introduced for HAs among adult Aboriginal and Torres Strait Islander people aged 15–54 years. ,9 Adult  was intrIn this study we aim to establish whether there are likely to be barriers to the uptake of the new HA item by comparing the uptake of the HA items for older people among Aboriginal and Torres Strait Islander people and the rest of the community. We also examine differences in uptake over time and differences between States and Territories. Finally we compare uptake of the HA items for older people to the uptake of the new items for Aboriginal and Torres Strait Islander people aged 15–44 years in the first three quarters after their introduction. It would be expected that structural barriers to the introduction of HAs should have decreased over since 1999 because of the introduction of the HA items. Accordingly it might be expected that the uptake of the new item might be more rapid than the uptake of the items for older Australians.Data on the use of item numbers  by year and by State and Territory were obtained from the Health Insurance Commission statistical reports.  Data on Data on the use of item numbers  in the first three quarters of their introduction was also obtained from the Health Insurance Commission statistical reports.  These daIn addition to the other eligibility requirements, only one claim could be made per person in a 12 month period. Accordingly quarterly and annual data reports should only contain one observation per person. Data are available for smaller geographic areas than State and Territory, such as general practice divisions, however low numbers and a high level of suppressed data made small area analysis problematic.Population estimates for the Aboriginal and Torres Strait Islander population aged at least 55 years and aged 15–44 years by State and Territory were obtained for the Australian Bureau of Statistics (ABS) projections from the 2001 census for the years 2001 to 2004.  PopulatiA logistic regression was conducted to analyse differences in the uptake of consulting room  and non-consulting room  HA items according to Indigenous status and year taking into account variation due to State and Territory. Consulting room and non-consulting room items were analysed separately because there is geographic variation in their use which may be potential source of confounding. The dependent variable was coded dichotomously using service use data to estimate the number of people who used the service and population data to estimate the number of people who did not. Year was coded to enable linear trends in uptake to be tested. Indigenous status was coded dichotomously based on whether the items were only available to Aboriginal and Torres Strait Islander people or available to all Australians.The 12.2% of Aboriginal and Torres Strait Islander people aged at least 75 years would be eligible for the general population items as well as the Aboriginal and Torres Strait Islander specific items. All analyses were conducted twice to explore whether dual eligibility could have an impact on the results. The first set of analyses was based on observed service use. Service use among Aboriginal and Torres Strait Islander people would be underestimated in these analyses if people with dual eligibility were using general population items. The data were also analysed assuming that Aboriginal and Torres Strait Islander people aged at least 75 years accessed HAs through general population items at the same rate as the rest of community. These instances of service use were then attributed to Aboriginal and Torres Strait Islander people rather than to other Australians. Service use among Aboriginal and Torres Strait Islander people would be overestimated in these analyses because some of the people using the Aboriginal and Torres Strait Islander items are likely to be aged at least 75 years and therefore would be counted twice. Some overestimation would also be expected to occur because the observed rate of service use among Aboriginal and Torres Strait Islander people aged over 75 years is likely to be less than that for the general population.Differences in rates of consulting room and non-consulting room service use for Aboriginal and Torres Strait Islander people and the rest of the community were calculated for each State and Territory.A logistic regression was conducted to compare the uptake of older all Australian (700), older Aboriginal and Torres Strait Islander (704) and adult Aboriginal and Torres Strait Islander people (710) HA items. The HA item for adult Aboriginal and Torres Strait Islander people (710) was used as the reference category for comparisons. Quarter was coded to enable linear and quadratic trends in uptake to be tested. The dependent variable was coded dichotomously using service use data to estimate the number of people who used the service and population data to estimate the number of people who did not.The result of the logistic regression for use of consulting room HA items  was lower than for the uptake of the general population item (700) but was higher than uptake of the item for older Aboriginal and Torres Strait Islander people  declare that they have no competing interests.Margaret Kelaher conceptualised the paper and conducted the analysis. David Dunt, Ian Anderson and David Thomas collaborated in drafting the paper.


Three hundred and sixty-nine patients in an MRC study of combination chemotherapy and radiotherapy for small-cell lung cancer of limited extent were asked to complete a Daily Diary Card which enabled an assessment of their quality of life to be made during and after treatment. The information derived from the card suggests that although cytotoxic chemotherapy has an adverse effect upon quality of life, this impairment only affects the first 2 or 3 days following each course of treatment, although there is also a small deterioration which may be associated with the 'nadir' effect of the blood counts about 10 days after each course. These results should assist physicians in counselling patients about the likely effects of treatment. Just over half of the patients (196) were subsequently randomised to either a further six courses of maintenance chemotherapy or no further chemotherapy, and it is also shown that the patients allocated to no maintenance chemotherapy experienced a gradually deteriorating quality of life, as opposed to the brief but more severe adverse effects which occurred following each course in the maintenance chemotherapy group; this supports the hypothesis of a palliative effect in this latter group. The findings demonstrate that the Daily Diary Card is a sensitive instrument capable of yielding useful information.


Although the need for a method of measuring the quality of life of patients undergoing therapy for cancer has been widely recognised, no adequately evaluated or feasible method has been established. We describe a method in which 31 items were assessed by patient self report using linear analogue scales. Eighteen items inquiring about general health problems were derived from the Sickness Impact Profile, an established method of assessing the effect of health upon behaviour and function. Thirteen items inquiring about major problems associated with breast cancer were derived from clinical experience and the opinions of patients with this disease. Each item of the measurement method (instrument) has been evaluated for content, feasibility, reliability and validity by methods that are widely used in psychometry but less familiar in medicine. It appeared easy to use, acceptable and reliable in these assessment. Validity was evaluated indirectly since no standard measurements of quality of life exist for comparison. Most items appeared valid when compared to alternative measurement methods including the Sickness Impact Profile and evaluation by a physician in a structured interview. The correlations between items in the instrument were analysed by factor analysis and seemed to fit with the clinical features of breast cancer. The method distinguished between clinically distinct groups of patients and detected changes with time. The study illustrates the possible approaches to the scientific evaluation of methods for measuring subjective features of patients lives. This method appears suitable for some purposes to measure quality of life in breast cancer and is intended to be flexible enough to be modified for other diseases. However, further evaluation, development and refinement will be needed before routine clinical application can be recommended.


In vivo nuclear magnetic resonance 31P spectroscopy was used to demonstrate different patterns of high energy phosphate metabolism in a group of malignant tumours of glial origin. In some of the more malignant tumours a decrease in adenylate energy charge was found. This was associated with a decline in phosphocreatine and an increase in sugar phosphate and inorganic phosphorus.


A seasonal variation in the month of initial detection of breast cancer has been previously observed in pre-menopausal women, and it has been proposed that this may be due to cyclic changes in tumour growth mediated by the effects of melatonin on ovarian function. To investigate this possibility serum melatonin concentrations have been measured every 2 h for 24 h at the summer and winter solstice in 20 pre-menopausal women with previous breast cancer and nine controls. Twelve women had detected their tumour in winter and eight in summer. Overall melatonin secretion assessed by either amplitude of the nocturnal melatonin pulse or the area under the 24 h melatonin curve (AUC) was not different between breast cancer women or controls. However, the amplitude and AUC fell in winter in breast cancer patients , whereas the winter minus summer values were significantly positive in controls compared with cancer patients. The abnormal fall in winter values in the women with previous breast cancer was confined to the group of women who had been winter detectors  whereas there was no significant seasonal alteration in these measurements in summer detectors. The acrophase of the nocturnal pulse of serum melatonin was significantly advanced in both groups of women with previous breast cancer  with a similar although nonsignificant trend in control women. The abnormal reduction of serum melatonin seen in wintertime in winter detectors of breast cancer could promote tumour growth at this season and so contribute to the decreased survival previously observed in this group compared with summer detectors. The relatively normal seasonal profile of melatonin observed in summer detectors could allow increased ovarian steroidogenesis in spring/summer with a resulting increase in tumour growth and consequent rise in tumour detection rate at this time.


To our surprise we also found that acute perfusion of low concentrations of lead onto brain slices from control animals resulted in reduction of long-term potentiation, suggesting that the effect is more pharmacologic than developmental. The results of In their article about blood lead and IQ in older children,


We examined the ability of primary human tumour cells to secrete diffusible factors capable of stimulating anchorage independent growth of normal rat kidney fibroblast (NRK) cells. Conditioned media (CM) prepared from cells derived from 31/43 patients with adenocarcinoma of the breast, colon, ovary or lung were found to induce growth of NRK cells in soft agar. The ability of the CM to induce anchorage independent growth was enhanced in 25/35 cases by the presence of epidermal growth factor (EGF). The CM did not compete with EGF for binding to the EGF receptor site. CM from cells derived from nonmalignant effusions also supported the growth of NRK cells in soft agar. There was no significant difference in the ability of the CM derived from malignant or normal cells to support NRK colony growth. The ability of primary human tumour cells to clone in soft agar was compared to the ability of these cells to produce diffusible colony stimulating factors for NRK cells. No correlation was observed between the ability of the primary human tumour cells to clone in soft agar and their ability to induce anchorage independent growth of NRK cells. The secretion of substances with TGF like activity may be a property of many types of primary human cells.


Disabling fatigue is the main illness related reason for prolonged absence from school. Although there are accepted criteria for diagnosing chronic fatigue in adults, it remains uncertain as to how best to define disabling fatigue and Chronic Fatigue Syndrome (CFS) in children and adolescents. In this population-based study, the aim was to identify children who had experienced an episode of disabling fatigue and examine the clinical and demographic differences between those individuals who fulfilled a narrow definition of disabling fatigue and those who fulfilled broader definitions of disabling fatigue.Participants (aged 8–17 years) were identified from a population-based twin register. Parent report was used to identify children who had ever experienced a period of disabling fatigue. Standardised telephone interviews were then conducted with the parents of these affected children. Data on clinical and demographic characteristics, including age of onset, gender, days per week affected, hours per day spent resting, absence from school, comorbidity with depression and a global measure of impairment due to the fatigue, were examined. A narrow definition was defined as a minimum of 6 months disabling fatigue plus at least 4 associated symptoms, which is comparable to the operational criteria for CFS in adults. Broader definitions included those with at least 3 months of disabling fatigue and 4 or more of the associated symptoms and those with simply a minimum of 3 months of disabling fatigue. Groups were mutually exclusive.Questionnaires were returned by 1468 families (65% response rate) and telephone interviews were completed on 99 of the 129 participants (77%) who had experienced fatigue. There were no significant differences in demographic and clinical characteristics or levels of impairment between those who fulfilled the narrower definition and those who fulfilled the broader definitions. The only exception was the reported number of days per week that the child was affected by the fatigue. All groups demonstrated evidence of substantial impairment associated with the fatigue.Children and adolescents who do not fulfil the current narrow definition of CFS but do suffer from disabling fatigue show comparable and substantial impairment. In primary care settings, a broader definition of disabling fatigue would improve the identification of impaired children and adolescents who require support. Disabling fatigue in children and adolescents is an important clinical problem given that it is associated with severe functional impairment that has an impact upon the child's education and social development ,2. It isThere have been several attempts to define disabling fatigue as a disorder in adults and perhaps the most accepted is the Center for Disease Control (CDC) definition . This reA number of authors have raised the concern that the current criteria for CFS were designed for use in adults and that there has been relatively little work in assessing how appropriate these criteria are for children and adolescents -14. AlthThe importance that these associated symptoms play in CFS and whether they contribute to defining a homogenous group of individuals with disabling fatigue has been increasingly questioned . As the Given the current discussion about the role of the associated symptoms in CFS in adults, the lack of empirical testing about the appropriateness of the adult CFS criteria in children it seems pertinent to examine whether the clinical and demographic features of children and adolescents differ in those who fulfil CFS criteria and those who fulfil broader criteria for disabling fatigue. Evidence that those individuals with "adult like CFS" did differ significantly would give credence to the idea that adult CFS criteria do identify a specific group of fatigued individuals.There is also evidence to suggest that the majority (two thirds) of adults who attend GP clinics regarding disabling fatigue lasting more then 6 months do not fulfil the CDC definition of CFS, but do have substantial associated impairment . Given tIn this paper, we set out to identify children and adolescents with a lifetime ever episode of disabling fatigue in a population-based sample and test whether those who fulfilled a narrow definition were more severely impaired and different in terms of clinical and demographic characteristics than those who only fulfilled broader definitions of chronic disabling fatigue. Specifically, three groups of individuals with disabling fatigue were defined; those who had a similar symptom profile, duration and impairment as the CDC operational criteria for CFS in adults ("adult like CFS"), those who also had a similar symptom profile and impairment but whose fatigue, at time of interview, had lasted for a period of between 3–6 months disabling fatigue ("child like CFS") and those that did not fulfil the symptom profile for operationally defined CFS but who had had more than 3 months disabling fatigue ("3 months plus disabling fatigue").Cardiff Study of All Wales and North West England Twins). Previous studies have shown that the register is representative of the local population [Participants were identified from the population based twin register CaStANET . The duration of the fatigue at the time of interview was used to classify the twins into the different categories regardless of whether the fatigue was currently ongoing. The nature and degree of impairment associated with the fatigue was assessed by enquiring about whether the twin needed to rest for at least 1 hour daily, and whether there was interference with school attendance, and/or usual leisure activities and with family and peer relationships. To be classed as suffering from "disabling fatigue" the twin was required to need to rest for at least 1 hr daily and for there to be a report of some interference in at least one of these areas.Individuals who did not fulfil the associated symptom requirement but had experienced a period of disabling fatigue of greater than 3 months at the time of interview were classed as suffering from "three months plus disabling fatigue". Those who did fulfil the associated symptom requirement but had only experienced a period of between 3–6 months of the disabling fatigue at the time of interview were classed as suffering from "child like CFS" and those who has experienced a period of more than 6 months disabling fatigue were classed as suffering from "adult like CFS"Information was also sought about the age of onset of the fatigue, the number of days per week affected by the fatigue, the number of hours per day that the affected child required to rest/sleep, whether the child or adolescent was absent from school due to the fatigue, and whether they were taken to visit a General Practioner with regard to the fatigue. A global measure of impairment was created by asking whether the fatigue had interfered with the following 4 areas; i) the child's schoolwork, ii) peer relations, iii) family relations and iv) their usual leisure pursuits. The possible response's to these questions were on a discrete adjective scale consisting of "Not much", "A little" or "A lot" and were scored as 0, 1, or 2 respectively. The answers to these questions were then summed to give the overall score which ranged from 0 to 8.Parents were asked whether any diagnoses or explanation for the disabling fatigue had been offered by GP's or hospital specialists, when these had been visited. Their responses were recorded verbatim. This information was then reviewed by one of the authors (PD) who was blind to other information from the data collection and who determined those cases where the diagnosis could entirely explain the chronic fatigue in the twin. These cases were then excluded from further analysis.The second part of the interview consisted of the depression section of the parent version Child and Adolescent Psychiatric Assessment (CAPA) . This isAs it was determined that the most important analysis to undertake was to assess whether those individuals who fulfilled just the broad definitions of disabling fatigue ("child like CFS" and "3 months plus disabling fatigue") differed from those who fulfilled the narrow definition ("adult like CFS") and to reduce multiple testing no comparisons were made between individual classed as suffering from "child like CFS" and those who had "3 months plus disabling fatigue". Two sets of comparisons were therefore made, the first between those individuals who had "adult like CFS" and those who had "child like CFS", the second between those individuals who had "adult like CFS" and "3 months plus disabling fatigue". Independent t-tests and chi-square tests were used as appropriate.However, although the twin register is population based, each twin pair could potentially contributes two observations, and where this is the case the individual twin cannot be classed as statistically independent. Reduced variance due to the correlation between twins' scores can cause high false positive rates . To adjuParents from 1468 families returned questionnaires (65% response rate). There were no significant socio-demographic differences between the responding and non-responding families . The scrTwins classed as suffering from "3 months plus disabling fatigue" had an average duration of fatigue of 25.8 months  of which 27% still had ongoing fatigue at the time of interview. Twins classed as suffering from "adult like CFS" had an average duration of 23.5 months of fatigue (SEM 6.1) with 41% with ongoing fatigue at the time of interview. Those classed as suffering "child like CFS" had by definition between 3–6 months disabling fatigue, of which 27% had ongoing fatigue at the time of interview. Table The results of the statistical analysis suggested no significant difference (P > 0.1) between the groups. The only exception to this was the number of days that the child was affected during the episode of fatigue, for which there is a significant difference between individuals who were classed as suffering from "adult like CFS" and those classed as suffering from "child like CFS" . These analyses were repeated using non-parametric tests, however there was no difference in results.The descriptive statistics suggested that there was greater variability in individuals classed as suffering from "3 months plus disabling fatigue" than in individuals in the other two groups, particularly for the age of onset and number days per term absent from school. Less individuals from this group had visited a GP with regard to the fatigue. Although no significant differences or trends were found between individuals classed as suffering from "3 months plus disabling fatigue" and those classed as suffering from "adult like CFS" for these 3 variables, because of the descriptive statistics, a post hoc set of analyses was also conducted. For the post hoc analyses individuals classed as suffering from "adult like CFS" and "child like CFS"  were combined into one group and compared to those classed as suffering from "3 months plus disabling fatigue". However no significant differences were found between these groups for age of onset, number of days absent from school per term or visits to the GP. As in the previous statistical analyses, these tests were also repeated using non-parametric tests however there was no difference in the pattern of results.The results indicate that the clinical and demographic characteristics and level of impairment of children with narrowly defined disabling fatigue and more broadly defined fatigue are similar. There was no significant difference in gender ratio, the average age of onset or the rate of comorbidity with depression between the groups. Likewise affected young people seemed to spend a similar number of hours resting and/or sleeping, there was parental report of similar levels of global impairment, they were absent for a similar number of days from school during the term in which they were most affected by the fatigue and a similar percentage of individuals were contacting their GP about the fatigue.A lack of significant findings cannot necessarily be interpreted as meaning there is no differences between these groups but there are still a number of implications of these results. Specifically, the results suggest that a longer duration of fatigue and accompanying symptoms are not necessary in defining disabling, impairing fatigue in children and adolescents. Children who present with shorter histories of fatigue and/or in the absence of CFS associated symptoms have high levels of parent reported impairment, both in terms of family and peer relationships and school work. They also appear to be absent for a substantial number of days from school and it causes enough worry for the parents to take the majority of these children and adolescents to a GP. Even though their was a significant difference for the number of days affected by the disabling fatigue between those individuals classed as suffering from "adult like CFS" and "child like CFS", all groups reported that they were affected by the disabling fatigue for most days of the week.The descriptive statistics also suggested the possibility that individuals within the "three months plus disabling fatigue group" may be more heterogeneous, given that there is a relatively large amount of variance in this group in comparison to the other groups. Although this may have nosological implications it does not negate the high level of impairment this group also appears to be experiencing.One important limitation of this study is that the individual's symptoms were identified by telephone interview rather than medical examination. Although every effort was made to exclude individuals who may have had an alternative diagnosis that would explain the fatigue this does not guarantee that if an in depth medical assessment were undertaken with these individuals that a number would not be classed as fulfilling the CDC definition of CFS. This may in some way explain why over half individuals in this population based sample showed a similar symptom profile to the CDC criteria for CFS whereas in the adult population only one third were categorised as fulfilling this criteria , althougA further possible limitation is that parent report of disabling fatigue was used to identify individuals for further data collection and the analysis is based on information from parental interview only. There are often low levels of agreement between parent and child/adolescent report of behavioural/psychiatric symptoms  and therThese findings have clinical significance in that they imply episodes of fatigue in children and adolescents which last at least 3 months warrant investigation regardless of whether or not a diagnosis of CFS can be made. This is because the degree of impairment is substantial in terms of interference with usual activities, family and peer relationships, school absence and school work, and the impairment does not appear to differ from the level of impairment found in more narrowly defined disabling fatigue.There was no indication that the group of children with shorter periods of fatigue differed on a number of associated characteristics  or in terms of impairment from the group of children who had a symptom profile similar to the CDC criteria for CFS. Although this does not prove that there is no differences between individuals in these groups it does indicate that within a primary care setting it may be appropriate to consider a broader definition of disabling fatigue in children for clinical and research purposes.The author(s) declare that they have no competing interests.TF interviewed the families, performed the statistical analysis and drafted the manuscript. PM provided clinical advice when conducting the analysis and helped drafted the manuscript. AT participated in the design and coordination of the study. AF conceived of the study, and participated in its design and coordination.The pre-publication history for this paper can be accessed here:


Epidemiological and environmental surveys in the Cappadocian region of Turkey have linked the high incidence of pleural and peritoneal mesothelioma in the occupants of some villages with the zeolite fibres released from the locally occurring volcanic tuff. In view of the low ambient fibre concentrations and the extraordinary incidence of mesothelioma a study to test the hypothesis of high biological activity for the zeolite fibres was required. Experimental studies using both intrapleural inoculation and inhalation techniques have been undertaken with the erionite from this region and from Oregon in the United States. Additionally a non-fibrous zeolite from Japan and a synthetic non-fibrous zeolite of similar chemical composition to erionite have been included in the experiments. In these studies the samples from Oregon and Turkey produced a very high incidence of tumours. All the rats inoculated intrapleurally with Oregon erionite and almost all those inoculated with the Turkish fibre died with a mesothelioma. Inhalation of the Oregon erionite induced a similar effect. No other dusts we have investigated have produced this high incidence of tumours particularly following inhalation. These studies demonstrate that we now have a valuable new fibre for experimental study and a possible hazard to man in regions other then Turkey.


The psychometric properties of a method of measuring the quality of life of cancer patients based on multiple linear analogue scales have been assessed in a group of 294 patients with breast cancer attending one clinical unit. The method was found to be readily managed by patients although a small number of scales presented difficulties of understanding to patients and difficulties of analysis. The scales distinguished readily between patients of different disease and treatment status. Factor analysis revealed a 5 factor structure which we interpret as relating to physical activities of everyday living, emotional disturbance, alimentary disturbances, appearance and cosmetic problems and a fifth factor which is more difficult to interpret and includes impairment of speech, writing and concentration. We feel the essential factors determining quality of life in cancer patients have been demonstrated in this and our earlier studies and there is now a substantial level of agreement in the factors that have been identified by groups taking quite different approaches. The major factors determining quality of life in cancer patients are now known and should be assessed in clinical research and clinical trials. The method by which they should be assessed is not as yet so clear.


Molecular monitoring by the polymerase chain reaction was used to detect and follow minimal disease in working formulation category B and C on non-Hodgkin's lymphoma. Rearrangement of the bcl-2 gene served as the target for gene amplification. Thirty patients were studied. Bone marrow histology was compared to PCR analysis of bone marrow aspirate and blood. PCR upstaged disease status in approximately 50% of patients. Results are shown from a patient whose disease was followed with PCR during chemotherapy from initial remission to relapse. We conclude that PCR of bone marrow and blood can be used to upstage disease status in low grade lymphoma and PCR of blood may be used to monitor response to treatment with obvious patient benefit. The general approach of molecular monitoring provides a means for appraising therapies in the setting of subclinical disease.


We evaluated a new ultrasound microhandpiece (Dissectron PenstyleWe used under magnifying lenses the ultrasound microhandpiece to decalcify 30 explanted aortic valves. In the cases with embedded calcifications the thin top of the probe could be introduced into the thickness of the leaflet preserving covering layers.The leaflets were totally decalcified and flexible, and surrounding structures were preserved as assessed by histological examination.This new approach of ultrasonic aortic valve decalcification gives good in vitro results which allow to consider a clinical evaluation of this procedure. This probe is more handy and more precise than the previous ones. Therefore the reintroduction of valve decalcification by ultrasound is envisageable.The aortic valve debridement by ultrasound in degenerative-calcific aortic stenosis appeared to be an alternative treatment for severe calcified aortic stenosis , but was® Penstyle  used in neuro and general surgery but never used in cardiac surgery. This ultrasonic system consists of a control console with a handheld aspirator that contains a magnetostrictive transducer which converts electrical energy into mechanical motion (piezoelectric technology). The handpiece  to perform the process and the operating surgeon determined the adequacy of decalcification by inspection and palpation of the leaflets. A preliminary study on 10 other valves had allowed us to familiarise with the device and to adjust the settings. The completeness of the leaflet decalcification was studied by palpation and by histopathological examination with the help of a nonparametric grading system (from 1+ to 4+).We used ultrasonic energy to decalcify 30 aortic human tricuspid valves after they had been surgically removed during an aortic valve replacement. The valves had not been selected and were severely calcified in accordance with the necessity of the valve replacement. Ultrasonic decalcification was performed with the Dissectrone Figure  has a ho® handpiece was very ergonomic. The calcium was disintegrated in about 15 minutes in all the 30 cases. At the end of the process all the leaflets were observed as flexible again by palpation assessment. In 26 cases leaflets were totally decalcified (4+)  we performed the decalcification by introducing the probe through the aortic surface and directing it inside the thickness of the valve in contact with the calcification  declare that they have no competing interests.SA did all the research and wrote the paper.EV had been involved in the research.LC had been involved in the anatomopathology examination.FF had been involved in the analysis of the data.OJ had been involved in the final approval of the version to be published.


The effect of adriamycin on human and mouse CFUGM was examined at concentrations and times suggested by plasma clearance data derived from the results of a number of published studies. Our results suggest that the high concentrations of drug present in the plasma for short periods of time following infusion are only weakly cytotoxic towards the CFUGM when incubated for similar times. In contrast, there was a considerably greater cytotoxic effect when the drug was examined at low concentrations for periods similar to those described for the terminal phase of adriamycin clearance. The principal metabolite, adriamycinol, was poorly cytotoxic.


We have assessed the effects of clodronate  in 17 episodes of hypercalcaemia and osteolysis due to carcinoma. Clodronate reduced serum calcium in 14 episodes and bone resorption in all patients. These remained suppressed for the duration of treatment, but recurred promptly when treatment was stopped. Clodronate may be a useful measure for controlling hypercalcaemia and osteolysis in patients with carcinoma.


With increased emphasis being placed on the importance of environmental health comes the need for an expanded variety of environmental health care practitioners. Nursing is one of several professions that are augmenting and advancing the capabilities of their practitioners to meet this need. Now the Community Outreach and Education Program (COEP) of the University of New Mexico’s Center for Environmental Health Sciences has partnered with the New Mexico Environment Department to create an environmental health nursing internship as a component of its outreach program.In cooperation with the university College of Nursing, the partners recruit nursing students who are interested in implementing environmental health care initiatives in the surrounding community. For four years, the program has taken nursing students beyond the traditional curriculum and shown them firsthand how interaction with environmental factors affects human health. The program also gives students valuable experience in taking measures to abate hazardous exposures in communities.The interns are currently working on a number of projects that will affect different community members. They are helping to develop surveys and compiling data for a project investigating uranium exposure and subsequent kidney damage among the Navajo Nation, whose members live near and work in uranium mines. They are gathering and assembling materials for a community education and survey project on mercury in surface waters and other environmental health concerns among the Cheyenne River Sioux Tribe. They are helping COEP staff write and field-test an integrated environmental health curriculum on diabetes for middle school students. And in a fourth project, they are helping to develop a best-practices manual for applying farm waste fertilizer to croplands in a way that minimizes human exposure to aerosolized waste.The local ties of some of the nursing interns have enhanced the program’s role as an effective community advocate. Intern Krystyn Yepa is a Native American from the Pueblo of Jemez who became interested in environmental health nursing because she wanted to understand some of the health effects in her tribe resulting from exposure to different pollutants in the environment. “Learning about the different environmental health problems that exist in New Mexico has given me the willpower to finish nursing school to ultimately achieve my goal of improving the health and lifestyles of my people by placing importance on the environment,” she says.Yepa explains further, “As a Native American, I was raised to respect and appreciate the environment, and working at the COEP has only strengthened my values related to the environment.” She also credits the internship with teaching her important assessment tools that lay emphasis on the environment when completing a health history on patients, something a traditional nursing internship would not likely provide.“The nursing interns have been an incredible asset to our COEP,” says staff member Stefani Hines. “It is a mutually beneficial situation on many levels—the student nurses gather valuable real-world experiences in environmental health; the nursing school has access to additional, unique placements for their students; we have additional support for projects, which helps make them better; and the communities we work with benefit from the students’ efforts as well.”Dedicated, enthusiastic environmental health nursing interns will only continue to play an important role in advancing the COEP mission. One project currently in development will help community members get involved in city and county zoning processes, which will both encourage a healthy community mindset and minimize exposures to pollutants.


Rat mammary tumour cells were grafted to parietal bones as an experimental model to study the nature of bone resorption around metastatic carcinomas in the skeleton. After periods of growth of from 6 to 56 days bones and tumours were removed and embedded in epoxy resin. The appearances were compared with those found when whole parathyroid glands were grafted in similar positions. Tumours were evident in all animals at the time of death and some were palpable five days after grafting. In 15 of the 21 animals with tumour, osteoclasts and resorption were found, and in only two of these were the tumour cells not separated from the bone surfaces. In 6 animals killed between 6 and 12 days after grafting there was new bone formation without resorption. There were osteoclasts and resorption under the grafted parathyroid glands which were always separated from the resorbing cells by fibrous tissue. The appearances of the bone surfaces under the tumours and the parathyroid glands suggested that the resorption in both situations was similar, was brought about by the secretion of a locally active agent and mediated by osteoclasts. This is further support for the role of osteoclasts in bone resorption around metastatic carcinomas.


The outcome of treatment by age and socio-economic status was examined for 1,588 women with invasive cancer of cervix resident in the West of Scotland and diagnosed between 1980 and 1987. There was no difference in prognosis according to either variable once analysis was controlled for stage at presentation, treatment type and tumour grade. Tumour histology, date of treatment and health board of residence had no significant effect on survival independent of other variables. A strong correlation was found between socio-economic status and the incidence of cervical cancer in the West of Scotland. Women aged 45 and over and living in deprived areas were more likely to present with later stage tumours and to survive less well than younger patients from the more affluent parts of the region. Any additional resources which may be made available for cervical cancer screening should be directed more effectively towards those most at risk.


Mothers of a population-based series of young adults with bone and soft tissue sarcoma were traced and their cancer risks estimated. No overall excess of cancers compared with expected numbers calculated from population rates was seen but mothers of patients with synovial sarcoma had significantly more cancers than expected and this was accounted for mainly by an excess of breast cancer. In addition there were strong indications that a proportion of cases were members of families with inherited cancer-prone syndromes, in particular with neurofibromatosis or with the Li Fraumeni cancer family syndrome.


The hepatic perfusion index, the ratio of hepatic arterial to total liver blood flow, was measured in 50 consecutive patients with colorectal cancer using radiolabelled colloid with high administered activity. In patients with proven liver metastases the diagnostic sensitivity of the HPI was 96% and the predictive value of a negative test was 92%. Dynamic hepatic scintigraphy is of value in the management of patients with colorectal cancer.


In the economic evaluation section of the protocol , we statA further issue is that the Office of Scottish Health Statistics does not provide cost estimates for different types of delivery. Although costs in Scotland have been estimated using data collected in the early 1990s , we consThe pre-publication history for this paper can be accessed here:


Ninety-two consecutive adult patients admitted with acute life-threatening complications of haematological malignancy were studied to determine long term outcome. The quality of life was evaluated in seven long term survivors who are currently alive more than 1 year after hospital discharge using three validated methods: the Nottingham Health Profile, the Hospital Anxiety and Depression Scale and the Perceived Quality of Life Scale. Patients were also asked whether they had returned to work, whether their daily activities were limited and whether they would be willing to undergo intensive care again under the same circumstances. The in-hospital mortality rate was 77%. Median duration of long term survival was 23 months (range 6 weeks to 8 years). Long term survival did not appear to be related to either the aetiology or the severity of the acute illness, but seemed to be determined solely by the nature and progress of the underlying malignancy. The quality of life of six of the seven long term survivors is good, while that of the other is acceptable. None of the patients reported any increased limitation of their daily activities, five had returned to full time employment and all seven stated that they would be willing to undergo intensive care again under the same circumstances.


The inhibition of 3H-thymidine incorporation into the DNA of mitogen-stimulated lymphocytes from patients with chronic lymphocytic leukaemia by chlorambucil was measured in vitro and the results related to clinical drug resistance. The assay proved to be both sensitive and specific showing a clear separation of those patients with responsive disease from those with disease resistant to treatment. There was evidence of primary drug resistance in untreated patients. In almost all patients who received treatment this led to increasing resistance to chlorambucil in vitro. The assay is predictive of clinical responsiveness and provides a potential means whereby new therapeutic agents and treatment modifiers may be investigated.


Since the publication of our article on counterfeit artesunate in June 2006 , furtherIn addition, we would like to bring readers' attention to the newspaper reports of counterfeit artesunate and dihydroartemisinin seized from ladies' handbags at Lagos airport .


Improving the quality of health care requires a range of evidence-based activities. Audit and feedback is commonly used as a quality improvement tool in the UK National Health Service [NHS]. We set out to assess whether current guidance and systematic review evidence can sufficiently inform practical decisions about how to use audit and feedback to improve quality of care.We selected an important chronic disease encountered in primary care: diabetes mellitus. We identified recommendations from National Institute for Clinical Excellence (NICE) guidance on conducting audit and generated questions which would be relevant to any attempt to operationalise audit and feedback in a healthcare service setting. We explored the extent to which a systematic review of audit and feedback could provide practical guidance about whether audit and feedback should be used to improve quality of diabetes care and, if so, how audit and feedback could be optimised.National guidance suggests the importance of securing the right organisational conditions and processes. Review evidence suggests that audit and feedback can be effective in changing healthcare professional practice. However, the available evidence says relatively little about the detail of how to use audit and feedback most efficiently.Audit and feedback will continue to be an unreliable approach to quality improvement until we learn how and when it works best. Conceptualising audit and feedback within a theoretical framework offers a way forward. A range of strategies exist to promote the uptake of clinical research findings into the routine care of patients. They seek to change the behaviour of healthcare professionals and thereby improve the quality of patient care Table . For eacAll healthcare systems are concerned with improving the quality of care that they deliver as demonstrated by their establishment of structures  and high profile reports. Across cThe strategies in Table While rising prevalence and changing patterns of service delivery diabetes mellitus increasingly contributes to the primary care workload  and therThe UK NHS has produced a framework and set of measurable criteria by which to judge the quality of care for patients with diabetes mellitus. The National Service Framework (NSF) for Diabetes was launched in 2002. It suggePrinciples for Best Practice in Clinical Audit [We informed the study with two definitions of audit and feedback Table . The sysal Audit  which ofWe explored the extent to which a systematic review of audit and feedback could provide practical guidance about whether audit and feedback should be used to improve quality of diabetes care and, if so, how audit and feedback could be optimised. Based upon discussions with those responsible for conducting audit and feedback at a local level as well as our own experiences of doing so, we identified several questions which would be relevant to any attempt to operationalise audit and feedback in a healthcare service setting.• Does audit and feedback work for this condition and setting, specifically improving the care of patients with a chronic disease – diabetes mellitus – in primary care?• Does it work equally across all dimensions of care – from simple recording of cardiovascular risk factors to more complex areas of care such as glycaemic control? The latter requires a greater number of actions to achieve which include measuring blood glucose levels, reviewing the patient, checking compliance with drug and dietary therapies and checking patients' understanding of the condition.• How should it be prepared? Should data be comparative and if so, what should the comparator group be? Should data be anonymised?• How intensive should feedback be? Intuitively, providing more and personalised feedback on a recurrent and regular basis should have a greater impact on practice than a one-off report of (say) PCT-level aggregated data. However, it is uncertain whether the extra time and costs of ongoing data collection and preparing more frequent feedback would be matched by additional benefits.• How should it be delivered – by post or by a messenger in person? And if by a messenger who should this be? Professionals might be more convinced by a message delivered by a colleague with a recognised interest in diabetes care rather than a non-clinical facilitator.• What activities, if any, should accompany feedback? The likely costs and possible benefits of (say) educational meetings or outreach visits need to be weighed up against providing feedback via paper or computerised formats alone.• What should be done about the poorest performers detected by the audit? Targeting such practices may help close the gap between the poorest and best performers. Alternatively, spreading effort to improve quality more equally amongst all practices may improve average performance for the whole PCT.We identified a systematic review of audit and feedback that identified and appraised 85 randomised trial.[• audit and feedback can improve professional practice, although the effects are generally small to moderate• effectiveness varies substantially among different studies• variation may be related to different methods of providing feedback or contextual factors, such as targeted behaviours and professionalsThe review identified only five direct (head-to-head) comparisons of different methods of providing feedback Table . One comThe review also evaluated 14 direct comparisons of audit and feedback alone compared to audit and feedback combined with other interventions (multifaceted interventions). There was no evidence that multifaceted interventions worked better than audit and feedback alone. A multivariate analysis explored potential causes of heterogeneity in the results . Only low baseline compliance was associated with greater effect sizes for multifaceted interventions. There was no evidence of larger effects with increasing intensity of feedback.Fifteen studies relate to chronic disease management . Just over half of comparisons indicated that audit and feedback was more effective than doing nothing Table . Using mFour studies evaluated audit and feedback in diabetes care, three set in primary care. Two comparisons addressed one of our key questions (Does audit and feedback work for this condition and setting?) and showed that audit and feedback, with or without other interventions, was more effective than doing nothing.,13 A UK Two studies partially addressed three of our key questions about how to conduct audit and feedback . In US secondary care, there was no difference between continuing feedback against withdrawal of feedback in the accuracy of capillary blood glucose monitoring. An AustrThe review evidence was of limited use in informing the operationalisation of evidence based audit and feedback. A number of issues contributed to this – the heterogeneity of the studies in the overall review, the problems of interpreting sub-groups of studies within the larger review, and the lack of direct evidence (particularly from head-to-head comparisons) to answer key questions.It is unclear how to use the review to extract generalisable lessons about how audit and feedback achieves its effects. For example, individual level feedback could reasonably be assumed to be more personally relevant and persuasive and thus more effective than feedback at a group level; there are no such direct comparisons available. Four out of 10 studies using individual feedback for chronic disease management reported no effect whilst both studies using group feedback reported positive effects. Therefore group feedback might be more effective than individual feedback, possibly by promoting peer pressure, consensus and subsequent action. Unfortunately this must all remain conjecture given the paucity of data to test different hypotheses about the causal mechanisms that make audit and feedback work.a priori, reasons as to why these studies should be examined separately from others in the review.Based upon a limited number of comparisons, audit and feedback appears to work better for diabetes than for other conditions. It is unclear whether this is because there is something intrinsically different about diabetes (or the audit methods used in diabetes) compared to other conditions, or whether this is an unreliable sub-group analysis of four studies selected from the 85 available. It is hard to have confidence in the findings of the diabetes studies in the absence of good, preferably Similar pitfalls exist in judging the relative effectiveness of different feedback methods. This is mainly because of the limited number of head-to-head comparisons comparing audit and feedback alone against combined interventions or variations in providing feedback. Across all studies, audit and feedback alone appears similarly effective to multifaceted strategies. However, the lack of difference in effect size could have occurred because multifaceted strategies were used in situations where investigators judged them necessary to overcome greater obstacles to improving care. In the absence of primary studies, the review cannot address some of the key questions such as whether intensive feedback would improve more complex outcomes (gylcaemic control) at an acceptable cost.Mapped back onto the principles for good clinical audit, the evidence only supports doing audit if there is low baseline compliance Table . This evThe issues of external validity of randomised controlled trials  have been aired in the context of clinical studies.,16. HoweA rational approach to this situation is to develop a conceptual framework within which to describe common elements of settings, individuals, targeted behaviours and interventions -20. ThisReview evidence was of limited use in informing the operationalisation of evidence based audit and feedback. This is mainly because of the heterogeneity of the studies in the overall review, the problems of interpreting sub-groups of studies within the larger review, and the lack of head-to-head comparisons to answer key questions. Audit and feedback will continue to be an unreliable approach to quality improvement until we learn how and when it works best. Conceptualising audit and feedback within a theoretical framework offers a way forward.UK NHS United Kingdom National Health ServiceNSF National Service FrameworkGP General PractitionerNICE National Institute for Clinical ExcellenceHbA1c Glycosylated haemoglobinPCT Primary Care TrustThe author(s) declare that they have no competing interests.Principles for Best Practice in Clinical Audit. ME suggested the idea for this paper. RF wrote the first draft and is guarantor. All other authors helped draft the manuscript and have approved the final manuscript.GJ and JY undertook the Cochrane Review of audit and feedback. RB co-authored The pre-publication history for this paper can be accessed here:


This data article along with original article provide the basic data required for ideal characterization of BCP and other bioceramics in an attempt to provide basic standardized protocols for future studies.The data presented in this article are related to the research article entitled “Biphasic calcium phosphates bioceramics (HA/TCP): Concept, physicochemical properties and the impact of standardization of study protocols in biomaterials research”  Specifications TableValue of the data:•To provide basic standard data for proper characterization of BCP and other bone substitutes.•To encourage researchers to standardize their study protocols.•To help in reducing the discrepancies among the findings of future studies.1This paper presents the required data and examples on proper characterization of BCP. This can be applied to other similar materials in the field of bone tissue engineering 2An electronic data base search on PubMed was performed to recruit related literature on BCP including data on basic biomaterials science, synthesis and characterization. Interested readers are referred to full text of this review paper for comprehensive review and recommendations