The effective number of breeders (Nb) describes how many adults effectively contribute to a cohort and is often correlated with Nc. Predicting Nc from Nb or vice versa in species with overlapping generations has important implications for conservation by permitting (i) estimation of the more difficult to quantify variable and (ii) inferences of Nb/Nc relationships in related species lacking data. We quantitatively synthesized Nb/Nc relationships in three salmonid fishes where sufficient data have recently accumulated. Mixed‐effects models were analysed in which each variable was included as a dependent variable or predictor term (Nb from Nc and vice versa). Species‐dependent Nb/Nc slope estimates were significantly positive in two of three species. Variation in species slopes was likely due to varying life histories and reinforce caution when inferring Nb/Nc from taxonomically related species. Models provided maximum probable estimates for Nb and Nc for two species. However, study, population and year effects explained substantial amounts of variation (39%–57%). Consequently, prediction intervals were wide and included or were close to zero for all population sizes and species; model predictive utility was limited. Cost‐benefit trade‐offs when estimating Nb and/or Nc were also discussed using a real‐world system example. Our findings based on salmonids suggest that no short cuts currently exist when estimating population size and researchers should focus on quantifying the variable of interest or be aware of caveats when inferring the desired variable because of cost or logistics. We caution that the salmonid species examined share life‐history traits that may obscure relationships between Nb and Nc. Sufficient data on other taxa were unavailable; additional research examining Nb/Nc relationships in species with potentially relevant life‐history trait differences  is needed.Technological and methodological advances have facilitated the use of genetic data to infer census population size (N Although eDNA is emerging as a potential method through which Nc could be inferred  of natural populations is relatively well developed.Rapid technological and methodological advances in molecular genetics have increased interest in using genetic data to estimate or infer census population size  small number of genetic samples collected during a single collection event or over multiple temporal periods  and Nc are associated with each other is highly valuable for conservation: it may be possible to use Ne to predict or monitor Nc (or vice versa) provided that relationships between Ne and Nc exist among or within populations and/or taxonomic groups   ; these species form the basis of our quantitative analysis of Nb/Nc relationships. The studies examining these species have largely found positive relationships between Nb and Nc  in each species. We then evaluated the efficacy of using one population variable to infer the other by generating population size parameter prediction intervals under which novel previously unsampled populations with only a single known population size variable (either Nb or Nc) are likely to fall. We also explored whether Nb/Nc curves differed for taxonomically related species and whether they could be used to infer population size parameters across species. Lastly, the monetary cost‐benefit trade‐offs of estimating Nb or Nc are discussed using a real‐world example system in which Nb/Nc estimates were obtained across twelve populations.Most taxa still have little N22.1b and Nc estimates were obtained for the same populations, keyword searches were conducted on the academic search engine ISI Web of Science™. A complete keyword search for “Effective number of breeders” was performed. Relevant references within retrieved studies were also searched for usable data. The goal of the analysis was to derive linear relationships between Nb and Nc across multiple species. A particular species was therefore only included in the final data set if a minimum of 10 total Nb/Nc estimates from at least three different populations were found; the only taxa with species for which these data requirement were satisfied were salmonids. A subsequent search of “Effective population size salmon*” was subsequently conducted to find any additional salmonid references missed by the initial search; this search found a single additional article. In most cases, Nc was “correctly linked” with brood year; that is, each Nb estimate generated from a cohort was matched with the Nc estimate of the parental generation. Only in two cases were Nb and Nc incorrectly linked; these were estimates taken from populations in which Nc and Nb were estimated for the same year . Both estimates were still included in the final data set.To find articles in which both Nb which make use of either linkage disequilibrium, heterozygote excess, molecular coancestry or sibship frequency information obtained from genetic markers . To generate models from which we could derive predictions, we evaluated the effect of Nb on Nc (and vice versa) across multiple species using the MCMCglmm package  was included as a continuous fixed effect and “species” was included as a categorical fixed effect. An interaction between both fixed effects terms was also included. Population, study and year‐within‐study terms were included as random effects to account for issues of nonindependence in the data. The year random effect was nested within study except when studies were conducted by the same group of researchers on the same populations, in which case year was nested across the relevant studies. Heterogeneous variances for the residuals were specified using the idh function; residual error variance was allowed to differ for each level of the species variable.Posterior modes for Nb or Nc) variable. This was accomplished by fitting an observation‐level random effect of the form “idh(species:sqrt(1/ln(Nx)):units”  or “idh(species:sqrt(Nx)):units” (when testing if variance increased with the relevant population size variable)  was evaluated by examining 95% prediction intervals generated for each model across a gradient of Nc (when predicting Nb) or Nb (when predicting Nc). For most natural populations, Nb (or Ne) is almost always less than Nc  zero. When predicting Nc from Nb, meaningful predicted values could include any value greater than the predictor Nb value; both upper and lower prediction interval values were considered “informative” at a given size only when they were greater than the predictor Nb value used to obtain them.The efficacy and practicality of predicting Nc from the lower Nb CI reported in each paper as these are relevant for many conservation situations. Namely, when populations are difficult to sample effectively , it can be challenging to obtain bounded Nb point estimates, in which case lower CI may be more informative , Atlantic salmon (14 populations) and Chinook salmon (11 populations) . Nb/Nc estimates for the three salmonid species included in this analysis were typically obtained across multiple years of sampling involving the genotyping of thousands of individuals; they represent the best data presently available in the literature for examining the predictive capacity of Nb to predict Nc (or vice versa).Of the 209 papers reviewed on N3.2c. Estimates of residual variance did not change with Nc; 95% CIs for residual error estimates overlapped for all population size ranges compared . Lower 95% prediction intervals for brook trout and Chinook salmon were uninformative; they included (or were extremely close to) zero for both species . Lower 95% prediction intervals for brook trout and Chinook salmon were uninformative; they included (or were extremely close to) zero for both species  taxonomically related species should not be assumed to exhibit similar Nb/Nc ratios; and (ii) ecological and life‐history characteristics of naturally spawning Atlantic salmon could buffer small populations against a loss of genetic diversity.Another primary study objective was to assess whether the trajectory and magnitude of the relationship between Ne by balancing sex ratios, decreasing variance in reproductive success and increasing outbreeding between cohorts within a population  in all but two (landlocked) Atlantic salmon populations. Most Nc estimates are actually estimates of anadromous adults only and therefore underestimate the number of reproductive individuals within a population , but their spawning behaviour can be similar. Both, for example, prefer spawning habitat with hypoheic upwelling  and affect Nb.Nb or Nc estimates from Nb/Nc curves for species related at the family/subfamily taxonomic level may, in some cases, over‐ or underestimate population size estimates; mixed evidence was found that Nb/Nc relationships differed between these species, with observed differences likely a result of different species‐level life‐history characteristics. If Nb/Nc relationships for a taxonomically related species are used as “proxy” population parameters for another “data‐deficient” species, careful consideration should be taken to evaluate life‐history and behavioural similarities to determine whether such an extrapolation is valid or meaningful.Overall, the among species comparisons suggest that extrapolating N4.3c and Nb in wild populations given the degree of uncertainty in converting one to the other. To help other researchers considering similar research projects, we provided an example of the comparative costs of estimating Nc and Nb in a series of stream brook trout populations of varying size from Cape Race, Newfoundland, Canada . Conversely, estimating Nb is arguably less invasive in relying on sampling juvenile cohorts that naturally experience density dependence, but these Nb estimates may only translate into maximum estimates of Nc.Conservation resources are often limited; it is therefore important to consider the relative costs of quantifying Nda Table . This wa4.4Salmoninae subfamily). The species examined in this study  may share life‐history traits that could potentially obscure the relationship between Nb and Nc. Salmonids, for example, are characterized by type‐III survival curves; species with high fecundity and juvenile mortality typically exhibit low Ne/Nc ratios  did have studies in which both Nb or Nc for novel, previously unsampled populations based on relationships generated from recently published data. While these predictive models were somewhat limited in their practical applications, it may still be possible to use these models to reliably infer one population size variable from the other for populations with well‐established baseline data. Population and temporal model terms often account for a significant component of the variation observed in population size terms  for large populations (Waples & Do, Finally, we found no evidence for heteroscedasticity in any of the modelled N5b/Nc ratios in salmonids and lower prediction intervals were largely uninformative; predicting a precise Nb or Nc estimate for a novel population based off of a single population size variable is, with current data available, not realistically possible. While Nc prediction intervals generated from Nb estimates were marginally worse than prediction intervals in salmonids generated from other molecular data (e.g., eDNA in Baldigo et al., c (e.g., Luikart et al., Although estimating the maximum number of adults present in a given population could help guide management and conservation decisions, the upper prediction intervals determined herein generally represented documented taxonomic extremes for Nc in the future. However, researchers should be cognizant of the limitations of using one population size variable to infer the other; researchers and/or managers should, whenever possible, focus efforts on quantifying the population size variable of interest except when the costs/logistics of measuring that variable are prohibitive. Further research is also necessary to determine whether less variable relationships exist between Nb and Nc for other taxonomic groups with differing life‐history characteristics than salmonids.Molecular technologies and methods are rapidly advancing and could represent a practical means of estimating N6https://doi.org/10.5061/dryad.136bm.Data for this study are available from the Dryad Digital Repository:  Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file.


Susceptibility to neural tube defects (NTDs), such as anencephaly and spina bifida is influenced by genetic and environmental factors including maternal nutrition. Maternal periconceptional supplementation with folic acid significantly reduces the risk of an NTD‐affected pregnancy, but does not prevent all NTDs, and “folic acid non‐responsive” NTDs continue to occur. Similarly, among mouse models of NTDs, some are responsive to folic acid but others are not.curly tail (Grhl3 hypomorph) mouse, rodent models of hyperglycemia or induced diabetes, and in a folate‐deficiency induced NTD model. NTDs also occur in mice lacking expression of certain inositol kinases. Inositol‐containing phospholipids (phosphoinositides) and soluble inositol phosphates mediate a range of functions, including intracellular signaling, interaction with cytoskeletal proteins, and regulation of membrane identity in trafficking and cell division.Among nutritional factors, inositol deficiency causes cranial NTDs in mice while supplemental inositol prevents spinal and cranial NTDs in the Myo‐inositol has been trialed in humans for a range of conditions and appears safe for use in human pregnancy. In pilot studies in Italy and the United Kingdom, women took inositol together with folic acid preconceptionally, after one or more previous NTD‐affected pregnancies. In nonrandomized cohorts and a randomized double‐blind study in the United Kingdom, no recurrent NTDs were observed among 52 pregnancies reported to date.Larger‐scale fully powered trials are needed to determine whether supplementation with inositol and folic acid would more effectively prevent NTDs than folic acid alone. Birth Defects Research 109:68–80, 2017. © 2016 The Authors Birth Defects Research Published by Wiley Periodicals, Inc. Failure in the process of neural tube closure during embryonic development results in severe birth defects termed neural tube defects, including anencephaly and spina bifida. Patterns of inheritance of NTDs indicate a major genetic contribution to risk of NTDs in the developing fetus, while it is also clear that non‐genetic, environmental, factors play a key role  and occurrence ; this is mostly hydrolyzed to free inositol before absorption from the gut   is a naturally occurring simple six carbon sugar alcohol, sometimes referred to as a pseudo‐vitamin (vitamin Bh or B8), although it can be synthesized from glucose by means of conversion of glucose 6‐phosphate to inositol 1‐phosphate . Hence, phosphorylation of inositol at carbons 3, 4, and 5 generates a series of phosphoinositides which have multiple cellular functions in signaling and membrane dynamics . IP1, IP2, and IP3, are generated by hydrolysis of PIP2 and subsequent recycling of inositol, while more highly phosphorylated forms  and pyro‐phosphates  are generated by the action of specific kinases , which is synthesized from 2 and PIP3 are key mediators of major signaling pathways that influence diverse cellular functions  and diacylglycerol (DAG). IP3 stimulates release of intracellular calcium while DAG stimulates several isoforms of protein kinase C P3 which recruits downstream targets, including the serine‐threonine kinase Akt Pons Fig. . These pons Fig. . In brie2 can be generated from PI(4)P by the action of PI4P 5‐kinases or to a much lesser extent from PI(5)P by the action of PI5P 4‐kinases  strain, which are genetically predisposed to spinal and cranial NTDs . However, inositol‐deficiency caused much higher rates of cranial NTDs (∼70%) and an increased concentration of inositol was required to correct these defects than in other strains tested , which hydrolyses PIP2 or PIP3, and hence opposes the effect of PIP5KIγ on levels of PI(4)P PInpp5E exhibit features of ciliopathies such as polycystic kidneys and polydactyly P , fail to develop beyond E9.5    anchors that link many different proteins to cell surfaces Englund, . InositoRgma   at the end of spinal neurulation results in spina bifida in around 15% of embryos. A further 35 to 40% exhibit only a tail flexion defect, a phenotype which results from delayed completion of PNP closure , the main neural tube closure phenotype in the D‐chiro‐inositol showed a greater protective effect than myo‐inositol, with a larger reduction in incidence of spina bifida at the same dose, and maintained effectiveness even at a lower dose  mimicked by short‐term treatment with a phorbol ester activator of PKC, and (ii) abrogated by broad spectrum and isoform‐specific PKC inhibitors  models  do not develop cranial NTDs under normal dietary conditions but exhibit exencephaly when made folate‐deficient , although a trend toward lower values was recognized , there was a significant association with having a child with spina bifida   are inositol supplements safe to use during pregnancy in humans, and (2) could inositol prevent some human NTDs?myo‐ nor chiro‐inositol had notable side‐effects in the supplemented dams or in the developing fetuses  supplements in improving ovarian function, hormone status and menstrual activity, with no reported side effects at typical doses of 2 to 4 g daily  were reported to have insulin‐sensitizing properties in experimental models of hyperglycemia and diabetes  throughout pregnancy from the first trimester onward was not associated with side effects or increased risk of adverse pregnancy outcomes . The recurrence rate in the folic acid groups was 1% compared with 3.5% in the other groups. Detection of a further significant reduction in recurrence rate, due to inositol supplementation, should require a similar or larger sample size.Another consideration is that any trial for prevention of NTDs now takes place in the context of use of folic acid supplement use and/or food fortification on a population level, including among women without a previous history of NTDs. Hence, it could be hypothesized that those NTDs which occur now may be more enriched for folic acid–non‐responsive NTDs than at the time of the folic acid trials in the 1980s, when use of folic acid supplements was not widespread. Similar lack of response in a subsequent pregnancy would thus lead to a higher rate of recurrence than in the MRC Vitamin Study. However, in the United Kingdom, it is estimated that only around 30 to 35% of women take periconceptional folic acid  study recruited women with one or more previous affected NTD pregnancies, who were planning a further pregnancy  were unwilling to enter the randomized study; almost all cited the possibility of inclusion in the placebo group as their reason for declining randomization. This was despite provision of folic acid to all participants and the unproven nature of inositol's preventive effect. A cohort of 22 women who met the eligibility criteria for the PONTI study but decided against randomization, agreed to be followed up in subsequent pregnancies. Among this nonrandomized group 19 women, 6 of whom had experienced two previous affected pregnancies, used peri‐conceptional supplementation with folic acid (at least 5 mg daily) and inositol . They reported 21 pregnancies without NTDs. A further three nonrandomized women, who subsequently took only 5 mg folic acid reported one normal pregnancy outcome and two pregnancies that were terminated following a diagnosis of anencephaly.curly tail strain, whose multigenic causation perhaps models the etiology of human NTDs more representatively than single gene knockouts. In addition, inositol has been implicated in ameliorating NTDs in diabetes‐induced and folate‐deficiency models, each of which are implicated in human NTDs. Exogenous inositol could potentially act to overcome the underlying causative defect responsible for NTDs and/or enhance the normal processes required for progression of neural tube closure. Indeed, in the curly tail model, inositol has been found to counteract the genetically determined imbalance of cell proliferation in the region of caudal neurulation. Given the multiple functions of inositol in differing cellular signaling pathways and processes it is also plausible that there are differing metabolic and cellular mechanisms underlying the effects of inositol in the cranial and spinal regions and in the various models where it has been shown to act. Further studies will address these questions.Inositol, inositol phosphoinsitides, and inositol polyphosphates are a group of molecules that fulfil a diverse range of cellular functions. Supply and metabolism of inositol is required for cranial neural tube closure, while supplemental inositol can prevent spinal and cranial NTDs in various experimental models. Notably, these include the Clinical use of inositol in adults and during pregnancy does not indicate safety concerns at the doses tested to date and beneficial effects on development of gestational diabetes have been reported. In the context of NTD prevention, the findings of recent non‐randomized and randomized studies are encouraging but these studies are currently of insufficient size to demonstrate a significant protective effect of inositol. Moreover, studies to date have been recurrence trials so the effect of inositol on first occurrence of NTDs has not yet been formally investigated. We propose that a fully powered randomized controlled study is justified to test whether inositol + folic acid has a greater protective effect against NTDs than folic acid alone. Such a study will likely require a multi‐site, multi‐country design. Nevertheless, if inositol does prove to be protective it is a simple, inexpensive compound that could potentially be used on a population‐wide level, to further enhance primary prevention of NTDs.


Cost‐effectiveness analyses (CEA) conducted alongside randomised trials provide key evidence for informing healthcare decision making, but missing data pose substantive challenges. Recently, there have been a number of developments in methods and guidelines addressing missing data in trials. However, it is unclear whether these developments have permeated CEA practice. This paper critically reviews the extent of and methods used to address missing data in recently published trial‐based CEA.Issues of the Health Technology Assessment journal from 2013 to 2015 were searched. Fifty‐two eligible studies were identified. Missing data were very common; the median proportion of trial participants with complete cost‐effectiveness data was 63% (interquartile range: 47%–81%). The most common approach for the primary analysis was to restrict analysis to those with complete data (43%), followed by multiple imputation (30%). Half of the studies conducted some sort of sensitivity analyses, but only 2 (4%) considered possible departures from the missing‐at‐random assumption.Further improvements are needed to address missing data in cost‐effectiveness analyses conducted alongside randomised trials. These should focus on limiting the extent of missing data, choosing an appropriate method for the primary analysis that is valid under contextually plausible assumptions, and conducting sensitivity analyses to departures from the missing‐at‐random assumption. However, clinical trials rarely succeed in collecting all the intended information  journal, as it provides an ideal source for assessing whether recommendations have permeated CEA practice. These reports give substantially more information than a typical medical journal article, allowing authors the space to clearly describe the issues raised by missing data in their study and the methods they used to address these. Our primary objectives were to determine the extent of missing data, how these were addressed in the analysis, and whether sensitivity analyses to different missing data assumptions were performed. We also provide a critical review of our findings and recommendations to improve practice.2The PubMed database was used to identify all trial‐based CEA published in HTA between the January 1, 2013, and December 31, 2015. We combined search terms such as “randomised,” “trial,” “cost,” or “economic” to capture relevant articles  conducted a follow‐up with repeated assessments over time . Other outcomes included score on clinical measures, or dichotomous outcomes such as “smoking status”.Sixty‐five articles were identified in our search Figure , and 52 3.2p value < .001) and as the study duration increased .Missing data was an issue in almost all studies, with only five studies 10%) having less than 5% of participants with missing data. The median proportion of complete cases was 63% , multiple imputation , and ad hoc hybrid methods . For the primary analysis, CCA was the most commonly used method , followed by MI  did not conduct any sensitivity analysis around missing data, with 21% (n = 10) reporting CCA results alone and 11% (n = 5) MI results under MAR alone  assessed the sensitivity of their primary analysis results to other approaches for the missing data. This was usually performing either MI under MAR, or CCA, when the other approach was used in the primary analysis. Other sensitivity analyses included using last observation carried forward or regression imputation.Over half of the studies  conducted sensitivity analyses, assuming data could be MNAR. In both studies, values imputed under a standard MI were modified to incorporate possible departures from the MAR assumption for both the cost and effectiveness data using a simplified pattern‐mixture model approach . In addition, almost two‐thirds of the studies  reported the breakdown of missing data by arm, time point, and endpoint. Only about one‐third of the studies have clearly reported the reasons for the missing data  and the approach used for handling the missing data and its underlying assumptions . Only one study (2%) appropriately discussed the implications of missing data in their cost‐effectiveness conclusions.Table 44.1Missing data remain ubiquitous in trial‐based CEA. The median proportion of participants with complete cost‐effectiveness data was only 63%. This reflects the typical challenges faced by CEA of randomised controlled trials, which often rely on patient questionnaires to collect key resource use and health outcome data. Despite best efforts to ensure completeness, a significant proportion of nonresponse is likely. This is consistent with other reviews, which also found no reduction of the extent of missing data in trials over time  conducted comprehensive sensitivity analyses and assessed whether the study's conclusions were sensitive to departures from the MAR assumption . Half of the studies did not conduct any sensitivity analysis regarding the missing data. The remaining studies performed some sort of sensitivity analyses, but usually consisting of simple variations from the primary analysis, such as reporting CCA results in addition to MI. This may be more for completeness than proper missing data sensitivity analyses. For example, if MI is used for the primary analysis , a sensitivity analysis that involves CCA will make stronger missing data assumptions.4.2Our review follows naturally from the review of Noble et al.  and give4.3A list of recommendations to address missing data in trial‐based CEA is presented in Figure For any study with missing data, clear reporting of the issue is required. Ideally, the study should report details of the pattern of missing data  across the different time points tends to be large. Other approaches valid under more plausible MAR assumptions and making use of all the observed data, such as MI Rubin, ; likelihAn area with clear room for improvement is the conduct of sensitivity analyses. This review found that many studies used CCA for the primary analysis and MI as a sensitivity analysis, or vice‐versa, and concluded that the results were robust to missing data. This is misleading because both of these methods rely on the assumption that the missingness is independent of the unobserved data. Although the MAR assumption provides a sensible starting point, it is not possible to determine the true missing‐data mechanism from the observed data. Studies should therefore assess whether their conclusions are sensitive to possible departures from that assumption  that can incorporate those in the analysis. However, there is substantial room for improvement. Firstly, more efforts are needed to reduce missing data. Secondly, the extent and patterns of missing data should be more clearly reported. Thirdly, the primary analysis should consider methods that make contextually plausible assumptions rather than resort automatically to CCA. Lastly, sensitivity analyses to assess the robustness of the study's results to potential MNAR mechanisms should be conducted.The authors have no conflict of interest.


Growth charts and child growth assessment have become prime global instruments in child health practice over the 30 years. An updated, continuous growth standard that bridges size at birth values with postnatal growth values can improve child growth screening and monitoring.This novel growth chart was constructed from two sources of information. Size at birth  reference values were updated based on information of normal deliveries  from the Swedish Medical Birth Registry, 1990–1999 (n = 810393). Weight was evaluated using logarithmic transformation as for postnatal weight. Standard deviations were estimated from data within the empirical mean ± 1.0 SD for each gestational week and gender. These values were smoothed by empirical curve-fitting together with values from our recently published postnatal growth reference including 3650 longitudinally followed children from birth to final height [This study presents the first continuous gender specific growth chart from birth irrespective of gestational age at birth until 2 years of age for weight, length and head circumference. Birth weight at 40 weeks of gestation increased approximately 100 gram and length increased only 1 mm compared with earlier Swedish reference from 1977–81. The curve is now less S-shaped as compared with earlier curves and compared with 4 curves from other countries and with more constant variation over the whole range.Our values picture the unrestricted pattern of growth improving the detection of a deviating growth pattern, when the growth of an individual infant is plotted on the charts. Especially for very preterm infants age corrected growth can be more easily evaluated although it must be recognized that the early comparison is with what is estimated as normal growth in uterus. The reference values are useful in child health care systems for population screening, but also in research or in the clinic for evaluating various growth promoting interventions – either nutritional, surgical or therapeutic – that might affect a child in early life.


The incidence of oesophageal adenocarcinoma and gastric cardia cancer increased strikingly in Scotland between 1977 and 1996. In contrast to other cancers of the oesophagus and stomach, which showed a clear relationship with socioeconomic status, no trend was evident for oesophageal adenocarcinoma or gastric cardia cancer during 1987–1996. © 2000 Cancer Research Campaign


Human Resources for Health • American Journal of Public Health • Archives of Iranian Medicine • Croatian Medical Journal • Education for Health • International Nursing Review • Leadership in Health Services • Journal of the Brazilian Association of Medical Schools• New Zealand Medical Journal • Nursing Ethics • Online Brazilian Journal of Nursing • Open Medicine • Papua New Guinea Medical Journal • PLoS Medicine • Progress in Community Health Partnerships • Public Health • South African Medical Journal • Sudanese Journal of Public Health • Human Resources for Health are leading an international joint special issue which is now accepting papers for joint special issues addressing the critical need for a skilled, sustainable health workforce in the developing world. Submitted articles must fall under the broad theme:WHO "Towards a scaling-up of training and education for health workers"Working together for health, recognized the centrality of the health workforce for the effective operation of country health systems and outlined proposals to tackle a global shortage of 4.3 million health workers. There is increasing evidence that that this shortage is interfering with efforts to achieve international development goals, including those contained in the Millenium Declaration and those of WHO's priority programmes.The World Health Report 2006: The health workforce crisis in developing countries derives principally from inadequate educational opportunities for health workers and a lack of relevance of their training to community health care practice. Additional contributing factors include: inadequate compensation and working conditions, the deteriorating health of the workforce in many developing countries, urban/rural and workforce imbalance, and migration of the workforce from developing to developed countries.We are seeking manuscripts concerned with the scaling-up of training and education for health workers. Possible sub-themes include, but are not limited to:• private sector engagement• regulatory frameworks for education and practice• labour market dynamics after the production of health workers (e.g. retention)• training teams rather than individuals• skills mix• multi-skilled workers, responsive to exiting needs• task-shifting/role substitution• competency-based education and trainingExamples of questions that could be considered are:• What ongoing efforts to increase graduate level primary care training have been established in developing countries. What has been their impact and what have been their problems?• What effective strategies have been developed and tested for customizing the workforce skill mix to local health service needs? For example, what impact have recent health sector reforms had on the local health workforce?• What is the status of existing efforts to train health workers using innovative methods, including distance learning and various forms of information technology? How will training by protocol differ from, and complement, traditional community health worker training?• How can the health professional training be better aligned with local health needs and be more socially accountable?• What is the status of existing collaborations between developing countries aiming to improve health worker education?• How have modifications in healthcare management had an impact upon health workforce capacity at the local level?Papers will be accepted in two formats:Full papers of 3000 words or less for policy and research papersBrief communications of less than 1200 words: better suited to program or project descriptions or commentaries.Planned publication will be for a period of several months, starting from June 2008. There will be an online facility to respond to published articles in order to accommodate a live debate.If you would like to submit either an article or brief, please send us a provisional title and a short outline of the major topics you would address.Proposals for manuscripts are due by 15 September 2007 and should be submitted by e-mail to hrhspecial@who.int. Instructions for submission of articles will then be provided with feedback. Final manuscripts are due by 30 November 2007.


Objective —To evaluate the results and complications of choledochoduodenostomyand choledochojejunostomy for benign and malignant disease and to reviewthem in the light of the survival of the underlying disorders.		Design —Retrospective analysis of medical records completed by a thoroughinquiry for all patients who were lost to follow-up.		Setting —Referrals for primary and secondary surgery for obstructive biliary diseaseto a university hospital from 1974–1987.		Patients —After exclusion of patients who underwent a pancreaticoduodenectomyfor cancer (Whipple procedure) 113 patients were included in the study . Acomplete follow-up was achieved in 105 of 113 patients (93%).		Interventions —An inquiry was made at the civil registration office if the patientswere alive or not. The general practitioners of the patients who had died werecontacted about the cause of death and the possible biliary symptoms precedingdeath and the patients who were still alive received a questionaire which scrutinizedall possible complications and side effects of the operation.		Endpoints —Cholangitis, recurrence of the underlying disease or death of the patient.		Measurements  and main results —Operative mortality was 4.7% following CD and12.2% following CJ. Procedure-related complications were found in 10.9% and28.6% respectively. Recurrent cholangitis was not seen after CD and in three patientswith a CJ (6.1%). Survival following biliodigestive anastomosis for benign obstructionwas comparable for age and sex matched survival.		Conclusions  —Although CD for choledocholithiasis has largely been replaced byendoscopic papillotomy and although the choice between the two procedures inmalignant disease is most frequently dictated by the operative findings, we concludethat the choledochoduodenostomy is a relative simple operation with a low risk ofcholangitis.


Environ Health Perspect 115:138–145 (2007)], benzene was incorrectly noted to be associated with the development of childhood acute lymphocytic leukemia (ALL) and acute myelogenous leukemia (AML). The authors note that although benzene is a known carcinogen associated with adult leukemia, in general, it is not associated with the development of childhood AML or ALL. Ionizing radiation is the only environmental exposure strongly associated with the development of childhood leukemia.In the conclusion of the article “Risk Factors for Acute Leukemia in Children: A Review” by Belson et al. [


Disease status and preharvest chemotherapy details were obtained on 24 patients. The median age was 22 years (range 13–29). Seven of 24 patients had infradiaphragmatic disease at time of harvest. Nine of 20 patients had received chemotherapy preharvest =7, other regimens=2). The seven receiving ABVD showed no difference in follicle density compared to patients not receiving treatment (n=14); (median=1555 vs 1620 mm3P=0.97). Follicle density measurement showed no correlation with patient age . There was no evidence of HL involvement in the 26 samples examined (95% CI=0–11%). In conclusion, subclinical involvement of HL has not been identified in ovarian tissue, even when patients have infradiaphragmatic disease. Furthermore, the quality of tissue harvested does not appear to be adversely affected by patient's age or prior ABVD chemotherapy.Ovarian cryopreservation is a promising technique to preserve fertility in women with Hodgkin lymphoma (HL) treated with chemotherapy. Thus, the aim of this study was to examine harvested ovarian tissue for subclinical involvement by HL by morphology/immunohistochemistry, and to define patient and treatment factors predictive of oocyte yield. This was a retrospective analysis of 26 ovarian tissue samples harvested for cryopreservation from women with HL. Histology, immunohistochemistry and follicle density (number mm As Hodgkin lymphoma (HL) is a common malignancy in young people  with ABVD   to high Unlike sperm cryopreservation, oocyte preservation is invasive and burdensome for patients and has so far had limited applicability in humans. Embryo cryopreservation has a pregnancy rate of 15–25%, but as considerable time is required to obtain mature follicles chemotherapy administration may be delayed with potential detrimental effect on patient outcome. Moreover, this option requires donor sperm, often not available to women without a stable partner, which will often be the case among adolescents and young adult women  was removed in all but two patients in whom a whole ovary was removed. A small area was fixed immediately in 10% formalin for histological and immunohistochemical analysis. The remaining tissue was trimmed to approximately 1 mm thick, removing all medulla and subsequently cut into small slices (∼2 × 4 mm). The cryopreservation procedure has been previously described in detail  for 90 min, followed by cooling in a control rate freezing machine to −150°C and stored in liquid nitrogen vapour.A wedge section of ovary  cells characteristic of HL. A minimum of 10 sections selected randomly throughout the fixed piece of ovarian tissue were examined to determine follicle density (number per cubic mm).Additional sections were examined for the presence of malignant cells expressing the surface markers CD15 and CD30 characteristic of HL. These two markers were chosen as RS cells are positive for CD30 in up to 100% of cases  for 30 min at room temperature. Sections were washed and incubated with a second antibody conjugated to a horseradish peroxidase DAB detection system .Following heat antigen retrieval for 2 min in 10 mmol lAll statistical analyses were performed using Minitab software.Data regarding patient's disease status were available for 24 of the 26 patients and are outlined in Nine patients had received chemotherapy prior to harvest with seven patients receiving ABVD, one received Stanford V  of infradiaphragmatic disease at the time of harvest were not recorded.There was no evidence of HL involvement by morphology or immunohistochemistry in any of the 26 samples examined (95% CI for ‘true’ rate of involvement=0–11%). No inflammatory infiltrate or any other atypical findings were noted in the samples examined.−3 for the 26 patients. The seven patients who had received ABVD chemotherapy preharvest showed no statistical difference in follicle density compared to patients not receiving treatment (n=14) (median number of follicles for those receiving ABVD was 1555 mm3 (range 45–4512 mm3) vs 1620 mm3, (range 459–2840 mm3) for those not receiving prior treatment, P=0.97). Follicle density measurement for the entire cohort and for the 14 untreated patients showed no correlation with patient age .The range of follicle densities was 45–4512 follicles mmWith technology continually improving for cryopreservation and now with successful pregnancies from this technique, the safety and timing of ovarian harvesting are important issues to address.We did not identify any histological evidence of lymphomatous involvement in 26 patients with HL undergoing ovarian harvesting despite some patients having definite intra-abdominal disease at the time of ovarian collection. While we cannot exclude the possibility of disease involvement in all cases, our data suggest the frequency is likely to be very low. Possible risk factors for involvement may be predicted to be intra-abdominal disease and the presence of B symptoms at the time of collection as these features imply more aggressive disease behaviour. Studies of ‘high risk’ patients are needed to better define the risk of ovarian involvement in these specific settings.One of the main hurdles to overcome with ovarian cryopreservation is the loss of primordial follicles due to ischaemia prior to revascularisation. Thus, optimal follicle yield is of paramount importance. Although follicle density was determined from a single biopsy and distribution varies throughout the ovary, the follicle densities for the HL patients are similar to those observed for a group of young women with other types of cancer , age did not adversely affect the quality of the tissue harvested. Furthermore, we also found no difference in the quality of tissue harvested between those patients who had prior ABVD chemotherapy and those who had no prior treatment. This is relevant given that a large proportion of patients are cured of their disease with ABVD chemotherapy with the retention of their fertility. Thus, we do not recommend routine collection prior to ABVD chemotherapy, but rather at relapse prior to salvage therapy or at primary diagnosis if intensified therapy  is planned. This is in contrast to the Edinburgh criteria recently published (In conclusion, ovarian harvesting appears to be a feasible consideration in young female patients with HL even in those with intra-abdominal involvement and that prior chemotherapy with nonsterilising regimes such as ABVD does not adversely influence the follicle yield.T.Seshadri drafted the article and collated and analysed the data; D Gook drafted the Materials and methods sections and developed the ovarian tissue cryopreservation procedure and assessed follicle density and assisted with data collection; C Stern coordinated and harvested the ovarian tissue; S Lade performed histological and immunohistochemical analysis for HL. A Spencer, A Grigg, K Tiedemann, J McKendrick, P Mitchell provided patient data and reviewed the manuscript. J Seymour provided original thought and ideas, assisted with drafting and provided all statistical analyses.


Myodes glareolus rodents (reservoir hosts). Despite raised awareness and preparedness, the number of human cases during July 2007–June 2008 was 1,483, a new high.An increased risk for hemorrhagic fever with renal syndrome caused by Puumala hantavirus was forecast for Sweden in 2007. The forecast was based on a predicted increase in the number of  Myodes (Clethrionomys) glareolus, one of the most widespread and abundant mammal species on the continent, is a natural reservoir  is the etiologic agent of nephropathia epidemica, a mild form of hemorrhagic fever with renal syndrome (HFRS). PUUV is likely to be the most prevalent hantavirus in Europe  per month from HFRS-endemic Västerbotten County, Sweden, July 2004 through June 2008, and measured snow depth at 3 locations through February 2008. The season 2004–05 represents the most recent epidemic peak year, before the large outbreak of 2006–07; 2005–06 represents an ordinary low-incidence season. The exceptional increase of HFRS cases in midwinter 2006–07 followed a rapid snowmelt and complete loss of protective snow cover to the voles during December 2006 in inland and coastal areas. Similarly, the less pronounced increase in midwinter 2007–08 followed a less abundant loss of snow cover only in the coastal area.


This case report shows a genealogical study where a woman has limb hypertrophy and her son has an association of Sturge–Weber syndrome with Klippel–Trenaunay–Weber syndrome. The Sturge–Weber and Klippel–Trenaunay–Weber syndromes appear to be different manifestations of the same affliction. Familial aggregation exists and transmission may be almost imperceptible between generations. Identification of minor manifestations may prove to be a valuable contribution to genetic counseling of families and the prevention of new cases. The clinical manifestation of Klippel–Trenaunay–Weber Syndrome KTW-OMIM 149000) includes irregular and asymmetrical capillary and cavernous hemangiomas on the trunk or limbs, arteriovenous fistulae, lymphedema, varicosities, asymmetrical hypertrophy and visceromegaly.49000 inc Sturge–W3VG5Q gene , or from translocations involving this gene. There are suggestions that the majority of cases result from somatic mutations involving genes that play significant roles in embryonic vasculogenesis and angiogenesis.[9Both diseases occur almost always sporadically, but a dominant autosomal inheritance has already been described in some families.–8 Only sogenesis.910VG5Q gene were not evaluated.This work describes a 16-year-old male patient consulted in the Vascular Surgery and Genetics Departments of the Medical School in São José do Rio Preto, São Paulo, Brazil (FAMERP). The patient presented with a clinical overlap between the SW and KTW syndromes. An interdisciplinary evaluation of the patient and the complementary examinations  revealed the presence of low stature (<3%), extensive hemangiomas on the face, trunk and limbs, asymmetrical hypertrophy of the cranium, meningeal hemangiomas, glaucoma, enlarged kidney and pyelonephritis of the renal pelvis of the left kidney and varicose veins on the legs . A geneaThe present study shows hemihypertrophy of the leg of a woman and the association of Sturge–Weber with Klippel–Trenaunay–Weber syndromes in her son. We question whetherthe anatomical differences of these malformations could be caused by the intensity of genetic transmission of the same genetic alteration. A dominant inheritance pattern is the most satisfactory explanation for the findings in this family. The SW and KTW syndromes appear to be different manifestations of the same affliction. Familial aggregation exists and transmission may be almost imperceptible between generations. Identification of minor manifestations may prove to be a valuable contribution in genetic counseling of families and the prevention of new cases.


The extent of Lymh node dissection (LND) during radical cystectomy is a subject of increasing importance with several studies suggesting that an extended LND may improve staging accuracy and outcome. Significant numbers of patients have lymph node metastasis above the boundaries of standard LND. Extended LND yields higher number of lymph nodes which may result in better staging. Various retrospective studies have reported better oncological outcomes with extended LND compared to limited LND. No difference in the mortality and the incidence of lymphocele formation has been found between ‘standard’ and ‘extended’ LND. Till we have a well-designed randomized controlled trial to address these issues for level 1 evidence, it is not justified to deny our patients the advantages of ‘extended’ lymphadenectomy based on the current level of evidence. Radical cystectomy (RC) with bilateral pelvic lymph node dissection (LND) is the standard treatment for invasive bladder cancer done with the intention to enhance local disease control and possibly to improve overall survival. However, the extent of LND has not been standardized and its relevance for staging and prognosis is still not clear. Boundaries of ‘standard’ LND include bifurcation of common iliac artery superiorly, the genitofemoral nerve laterally, the circumflex iliac vein and lymph node of Cloquet distally, and the hypogastric vessels posteriorly. In ‘extended’ LND, lateral and distal limits are similar to the ‘standard’ LND and it involves removal of presacral nodes also. The superior extent is not well defined and has been described as the aortic bifurcation, 1–2 cm aet al. reported that 24.4% had lymph nodes involvement at places other than the ‘standard’ template and 9% had disease above the common iliac bifurcation while ‘skip metastasis’ above the common iliac bifurcation was reported in only one patient, which was also attributed to labeling error.[et al. reported that 34% of patients had positive nodes above the common iliac bifurcation.[A prospective lymph node mapping study showed that though the positive lymph nodes were most common in the obturator and the iliac groups, 16% of lymph node metastases were above the aortic bifurcation while 8% of nodal metastases were in the presacral region. Among patients with nodal metastases located within the limits of a ‘standard’ dissection, a significant proportion also had nodal involvement at the level of the common iliac vessels and above the aortic bifurcation . Furthermore, there were no isolated nodal metastases above the aortic bifurcation, suggesting that ‘skip lesions’ are rare.[et al. reported an increase in the mean number of lymph nodes removed (25 vs. 14 in a standard dissection) and Bochner et al. confirmed these findings, reporting significantly more nodes removed with an ‘extended’ LND (36.5 vs. 8.5 nodes).[5By extending the boundaries of the LND, Poulsen et al. reported that in 336 patients who underwent RC with ‘extended’ LND the overall five-year survival rates was similar in patients with lymph node involvement above the bifurcation of the common iliac vessels and in those with lymphatic metastases confined to the true pelvis.[et al. retrospectively compared outcomes in patients undergoing RC who either had ‘standard’  and ‘extended’ LND . The overall lymph node positive rate and five-year survival was 13% and 7% for patients with standard and 26% and 35% for those who had extended pelvic lymph node dissection, respectively.[Radical cystectomy including ‘extended’ LND was reported to improve survival by 21% compared to that obtained by ‘standard’ LND for patients with invasive bladder cancer confined to the bladder wall. In anothectively.et al. 46 patients undergoing an extended LND were compared to 46 well-matched patients undergoing ‘standard’ PLND. Although the extended lymphadenectomy increased the operative duration by 63 minutes, there was no significant difference in perioperative mortality, early complications, or the need for blood transfusions between the groups.[In the study by Brossner e groups. In anothe groups.Although the absolute limits of the lymph node dissection remain to be determined, available evidence supports doing an ‘extended’ LND with RC as it improves staging accuracy and outcome without increasing the morbidity. Despite variation in the extent of superior boundary, dissection up to the aortic bifurcation is a uniform extent in all the studies. Till we have a well-designed randomized controlled trial to address these issues for level 1 evidence, it is not justified to deny our patients the advantages of ‘extended’ lymphadenectomy based on the current level of evidence.


Modelling deformation electron density using interatomic scatters is simpler than multipolar methods, produces comparable results at subatomic resolution and can easily be applied to macromolecules. phenix.refine of the PHENIX package.A study of the accurate electron-density distribution in molecular crystals at subatomic resolution (better than ∼1.0 Å) requires more detailed models than those based on independent spherical atoms. A tool that is conventionally used in small-molecule crystallography is the multipolar model. Even at upper resolution limits of 0.8–1.0 Å, the number of experimental data is insufficient for full multipolar model refinement. As an alternative, a simpler model composed of conventional independent spherical atoms augmented by additional scatterers to model bonding effects has been proposed. Refinement of these mixed models for several benchmark data sets gave results that were comparable in quality with the results of multipolar refinement and superior to those for conventional models. Applications to several data sets of both small molecules and macromolecules are shown. These refinements were performed using the general-purpose macromolecular refinement module  The new information obtained from such macromolecular studies has been discussed in a number of articles  and other characteristics.Model refinement of small molecules at subatomic resolution largely uses the multipolar formalism of Hansen & Coppens 1978. For theet al., 2005et al., 2007Lecomte and coworkers have reported a number of multipolar refinements of amino acids and nucleic acids to determine a database of multipole parameters and have described several cases of polypeptide and protein refinement using this database .The modelling of structures at subatomic resolution with multipolar models takes into account the delocalization of electron density from atomic centres owing to the formation of interatomic bonds. The IAM–IAS model , which is not explicitly stated in Volkov et al., 2007R            free analysis biased. Therefore, when performing the IAS refinements we only note that R            free is lower than the corresponding values for the refined IAM models.Unfortunately, the YGG and P2A4 models had been refined previously against the full set of data [in fact, the set selected with PHENIX. Table 2et al., 1997et al., 2003et al., 2006R            free shows that refinement of IAS did not overfit the experimental data and indeed improved the models. When refining at ‘low resolution’, the ADP values obtained with the IAS are smaller than those from the refinement of corresponding IAMs. Based on previous work .Several macromolecular structures were used as another benchmark Table 1. PreviouR factors; the R            free factors are lower for IAS–IAM than for IAM. The RBT value systematically decreases after the introduction of IAS. We observe that the mean ADP slightly increased for the scorpion toxin data, which may indicate that the resolution (0.96 Å) approaches the limit for the use of the IAM–IAS method.In all cases, the full round of completely automated IAS model building and IAS–IAM refinement, with no manual intervention, took from a few minutes to 1 h on a modern Linux computer. For all protein refinements, completing IAM by IAS decreases the 3.Currently, multipolar modelling is the most precise and powerful tool for crystallographic studies at subatomic resolution when the crystals diffract to ultrahigh resolution of about 0.6 Å or higher and the data-to-parameter ratio justifies refinement of the model parameters. At a resolution near 0.8–0.9 Å, which is more common for macromolecular crystals at sub-angstrom resolutions, multipolar modelling typically requires too many parameters to be refined. As an alternative to the multipolar method, IAM–IAS models may be used, where IAM atoms are augmented by small interatomic scatterers. This approach makes model building and refinement a very transparent and easily monitored procedure. The results of automated refinement of such models for both small molecules and macromolecules at subatomic resolution confirm the efficiency of these models both in terms of model quality and CPU resources required. The tests show that these models can be used even at ultrahigh resolution, producing results that are comparable with those obtained with multipolar models.


The formaldehyde-sulphite clock reaction was studied using anOrion SA 720 pH/ISE meter interfaced to an IBM PC. Thelaboratory software ‘ASYST’ was employed to facilitate dataacquisition and data treatment. Experimental pH profiles thusobtained for the first time were simulated by invoking a theoreticalmodel based on the reaction mechanism suggested by Burnett [1].The variation of rate constants with compositions of reactionmixtures was also discuseed in light of the empirical expressionproposed by Bell and Evans [2] for instantaneous rate constant ofthe clock reaction.


Previous studies detected both lethal and cumulative chromosomal aberrations in bone marrow and peripheral blood of patients with worn hip and knee replacements. This study shows that wear debris from a worn titanium metal on high-density polyethylene hip replacement also produces chromosomal instability and reproductive failure in cell culture. The progeny of these treated cells also displayed chromosomal instability, mainly consisting of chromatid breaks and minutes, and reproductive failure as determined by clonogenic survival many generations postexposure. These delayed effects are similar to those caused by the heavy metals cadmium and nickel and to those seen for low-dose radiation. These findings may have important implications with regard to the long-term risks of joint replacement surgery. This highlights the need for long-term epidemiological studies of patients with surgical implants. However, because of mechanical and biological disturbance the destabilisation of this oxide layer is inevitable leading to the release of titanium ions and particulate debris . It has also been shown by our group to be induced by heavy metals and other environmental toxins  at 37° until confluent. The cell number was then expanded to provide sufficient cells for all planned experiments. Passage 5 cells were used for all experiments.The cells used in this study were early passage, normal human fibroblasts (HF19 cells). These cells have been well characterised for the cytogenetic and survival end points used in this study and have the advantage of a normal karyotype , cells were harvested for cytogenetic analysis to examine the initial effects caused by titanium debris. The delayed effects were assessed at passage 2 (approximately 10 population doublings postexposure). Chromosome preparations were made by accumulating metaphases in the presence of 0.05 μg ml−1 colcemid for 2 h, followed by treatment with 0.5% (w v−1) potassium chloride and fixation in methanol : acetic acid (3 : 1 v v−1). Fixed cells were spread on to slides and air dried. These were then stained using 5% Giemsa. A minimum of 100 well-spread metaphases was scored per dose point to determine the frequency of aberrations.5×102 flasks  at dilutions adjusted to yield approximately 100 viable colonies according to the method established by HF19 cells were plated in 24 cmAll experiments were repeated three times and within each experiment points were set up in triplicate. Results are expressed as the mean±s.e. Fisher's exact test was performed on the cytogenetic results where treatments were compared to controls.Chromosomal instability has been defined as the persistence of nonclonal chromosomal aberrations with a high frequency of chromatid-type aberrations in the clonal descendants of a single treated cell. It is evident from this study that the induction and transmission of chromosomal instability in the progeny of primary human fibroblasts occurs as a result of exposure to titanium debris  and manifestation of neoplastic transformation . Thus, t


Anorexia and cachexia are serious complications frequently found in patients with cancer . They arThe objective of these guidelines is to define which drugs have a certain or probable appetite-stimulating effect, which ones have no demonstrated effect and to describe any adverse effects in adult patients with cancer. These guidelines do not cover specific clinical cancer situations in which these drugs must be used.The details of the full methodology have been previously published (Medline® (January 1990–June 1999), Cancerlit® (January 1990–April 1999), Embase® (January 1990–July 1999) and the Cochrane Library® . The following key words were used: appetite stimulants or anorexia/drug therapy or cachexia/drug therapy or appetite associated with neoplasms. The list of references thus identified was completed by the members of the working group with pertinent references from their personal bibliographic databases.A literature search was performed in four database: A total of 55 reports of randomised clinical trials, published in English or French, evaluating the appetite-stimulating effect of corticosteroids, synthetic progestogens and other drugs in cancer patients were selected for these guidelines. Since appetite stimulants are used to increase appetite in patients, this was the primary outcome used in the analysis of the results in these trials. The secondary outcomes were: improved quality of life; increase in body weight; increased food consumption; decrease in nausea and/or vomiting and improvement of anthropometric and biological parameters. In the absence of the primary outcome (increased appetite), none of the secondary outcomes are considered sufficient to confirm an appetite stimulating effect.After selection and critical appraisal of this literature, the working group defined the ‘Standards’, ‘Options’ and ‘Recommendations’ (SOR) for the use of appetite stimulants in patients with cancer, based on a synthesis of the best available evidence.‘Standards’ identify clinical situations for which there exist strong indications or contraindications for a particular intervention and ‘Options’ identify situations for which there are several alternatives, none of which have shown clear superiority over the others  and finalised after taking into consideration their comments. This summary version is based on an integral version that was validated and published in 2000 (Corticosteroids are appetite stimulants (level of evidence: B1). There is insufficient information available to define the optimal dose and scheduling for their use in this indication (recommendation).−1 (level of evidence: B1). If there is no response, 480 mg day−1, which seems to be the optimal dose, can be used . There is no evidence that doses greater than 480 mg day−1 have a higher efficacy (level of evidence: B1).Megesterol acetate is an appetite stimulant (level of evidence: B1). It results in a significant increase in appetite and there is a beneficial effect on body weight in patients with cancer . The minimum efficacious dose is 160 mg day−1 .Medroxyprogesterone acetate is an appetite stimulant (level of evidence: B1). It results in a significant increase in appetite (level of evidence: B1). The effect on weight gain has not been confirmed (level of evidence: C). Randomised clinical trials should be undertaken to investigate the optimal dose and duration of administration of this drug, although the minimum dose, shown to have a positive effect on appetite in published trials was 200 mg dayCyproheptadine may be an appetite stimulant, but adverse effects have been reported (level of evidence: C). Dronabinol, metoclopramide, nandrolone and pentoxifylline have not been shown to have any appetite-stimulating effects (level of evidence: C). These drugs should not be used outside the setting of a randomised clinical trial . Hydrazine sulphate is not an appetite stimulant (level of evidence: A).Corticosteroids (no French product licence), megestrol acetate (no French product licence) and MPA (French product licence) can be used in the treatment of anorexia and weight loss in patients with cancer . Appetite stimulants can be used in combination with or after failure of dietetic and oral nutritional management .The use of appetite stimulants is particularly warranted in patients with incurable disease . Appetite stimulants can be administered to patients with any type of tumour . The optimal mode of administration for these products is not known. Hydrazine sulphate should not be used .Cyproheptadine, dronabinol, metoclopramide, nandrolone and pentoxifylline should only be used in the setting of a randomised clinical trial .


A prospective analysis of olfaction was performed in 21 patients receiving cisplatin. A reduction in olfactory function was noted in only one patient. Hearing impairment was documented in nine patients, none of whom had impaired sense of smell. We conclude that cisplatin has no major deleterious effect on olfactory function at doses which cause hearing impairment. Disorders associated with a decreased taste sensation may result in a deleterious effect on quality of life and may contribute to reduced food intake and malnutrition, thereby increasing the side effects of cancer therapy  committee and all participating patients gave written informed consent before inclusion in this study. All patients had normal blood count and renal function (24 h creatinine clearance >50 ml min−1) and received standard hydration (>2500 ml) and a standard intravenous antiemetic protocol (8 mg Ondansetron or 3 mg Granisetron together with 8 mg dexamethasone).Patients over 18 years of age admitted to the oncology department at the Chaim Sheba Medical Center for intravenous chemotherapy including cisplatin at a dose of at least 75 mg m−2 cycle−1 or more combined with either 5-fluorouracil, or with etoposide (VP-16) (with or without bleomycin), or with temozolomide according to tumour type. The patients' ages ranged from 28 to 78 years (mean 53.6 years). At enrolment, a detailed history was obtained, including demographic details, smoking history, tumour type and co-morbid pathology.The study group comprised 21 consecutive patients  admitted between July 2003 and June 2004 for the treatment of a variety of primary tumours . The patients were treated with standard departmental chemotherapy protocols for their tumour types, all of which included cisplatin in doses of 75 mg mOlfactory function was tested before beginning chemotherapy (baseline), and after each course of cisplatin. The final olfactory assessment was performed at least 3 weeks after the last course of cisplatin.Olfaction was assessed using the ‘Sniffin’ Sticks®' kit consisting of odorants in felt-tip pens . In one patient, a 60% decrease in olfaction was noted after the third course of treatment and a cumulative dose of cisplatin of 225 mg m−2. No decrease in olfactory function was found in 20 (95.3%) patients and in fact 10 patients had a final olfaction score that was higher than the pretreatment score. These score changes were statistically significant (P=0.0117 for the sign test and P=0.0322 for the Wilcoxon test). However, the rank correlation between the number of measurements and the improvement in olfactory function in these patients  suggests that this may be a result of learning effect.In all, 21 patients completed the planned chemotherapeutic treatment. They received one to six (mean 3.4) cycles of chemotherapy, with cumulative doses of cisplatin ranging from 180 to 945 mg and a mean cumulative dose of 525 mg . The single patient whose olfaction decreased had no hearing loss.−1). In two patients reduced levels of zinc were seen after the second and third chemotherapeutic course, respectively. Neither of these patients had impaired olfaction. In one of them hearing impairment was registered. The patient whose olfactory function deteriorated had normal serum zinc levels.Of 14 patients whose serum zinc levels were analysed, it was normal or increased in 12, according to normal ranges  in our study. The cumulative dose of cisplatin given to this patient was relatively low and chemotherapy was discontinued after three cycles because of disease progression. Our results are in accordance with the results of Ovesen In our study, the incidence of hearing impairment, an accepted indicator of cisplatin neurotoxicity, was 48%, which is comparable with results of similar studies . The sinOur study has several limitations. It is a single-blind study and did not include a control group of patients who were not receiving cisplatin through the comparable period of the study. The ‘Sniffin’ Sticks®' kit used allows assessment of odour differentiation acuity rather than olfactory thresholds evaluation. Minimal and maximal limits of olfactory performance measured with this kit do not allow recording of further improvement of olfactory function in patients with maximal score or further deterioration in patients with minimal score. The fact that in 10 of 21 patients the final olfaction score was higher than the pretreatment score can possibly be explained by the patients learning the odours used in the test over time. The rank correlation between the number of measurements and the improvement in measured olfaction supports the contention that this may be a result of learning effect. Despite these limitations to our study, the lack of a decrease in olfactory function in all 10 patients who developed cisplatin-induced hearing reduction indicates that cisplatin has no significant deleterious effect on olfactory function.Based on several subjective reports, cisplatin has often been cited as a cause of altered olfactory perception. The result of our study and the single other prospective study reported (


Animals were recovered following surgery, killed 3 days later and the photodynamic therapy lesion measured macroscopically. The effects of reperfusion injury were removed from the experiments either through the administration of free radical scavengers (superoxide dismutase (10 mg kg−1) and catalase (7.5 mg kg−1) in combination) or allopurinol (an inhibitor of xanthine oxidase (50 mg kg−1)). Prior administration of the free radical scavengers and allopurinol abolished the macroscopic damage produced by 5-aminolaevulinic acid photodynamic therapy in this model, regardless of the light regime employed. As the specific inhibitor of xanthine oxidase  protected against photodynamic therapy damage, it is concluded that reperfusion injury is involved in the mechanism of photodynamic therapy in the rat colon.Reperfusion injury can occur when blood flow is restored after a transient period of ischaemia. The resulting cascade of reactive oxygen species damages tissue. This mechanism may contribute to the tissue damage produced by 5-aminolaevulinic acid-induced photodynamic therapy, if this treatment temporarily depletes oxygen in an area that is subsequently reoxygenated. This was investigated in the normal colon of female Wistar rats. All animals received 200 mg kgBritish Journal of Cancer (2002) 86, 989–992. DOI: 10.1038/sj/bjc/6600178www.bjcancer.comCancer Research UK© 2002  There is particular interest for treating pulmonary, gastrointestinal, skin and brain tumours as well as superficial bladder cancer (r oxygen .PDT with the exogenous administration of 5-aminolaevulinic acid (ALA) is currently of interest, particularly for the treatment of superficial cutaneous tumours . HoweverReperfusion injury can occur as the blood supply is restored after a transient period of ischaemia. This happens as the enzyme, xanthine oxidase, becomes activated in a poorly oxygenated environment. Concomitantly, ATP is broken down, producing the purine substrates necessary for this enzyme to produce superoxide when oxygen is reintroduced . A schemFigure 1Superoxide is produced in most, if not all aerobic cells and the enzyme superoxide dismutase (SOD) is present intracellularly to remove it. Dismutation of superoxide produces hydrogen peroxide and the enzymes catalase (CAT) and glutathione peroxidase exist to remove this compound. Together, these enzymes protect cells against the reduced oxygen intermediates produced during normal aerobic metabolism. When superoxide and hydrogen peroxide production is excessive, however, such as following reperfusion injury, the protective enzymes are unable to cope, thus resulting in cell damage. Some of this damage may be mediated by the transition metal, iron, which can convert superoxide and hydrogen peroxide into aggressive oxidants such as the hydroxyl radical (by Haber-Weiss and Fenton-type reactions), which can then damage DNA, proteins and lipids, resulting in cell death. It is also possible that hydroxyl radicals can be produced  from peroxynitrite (which itself can damage the cell membrane). Peroxynitrite can be produced from superoxide and nitric oxygen  both of which can be increased when ischaemic tissues are reperfused . The ultFigure 2If SOD and CAT are present together in large quantities prior to ischaemia or at the start of reperfusion (through exogenous administration), they can produce significant protection against reperfusion injury  and an enzyme inhibitor  to prevent any tissue damage caused by this mechanism. PDT is being developed for cancer therapy, but most of the studies designed to elucidate its mechanism of action and enhance the effect have been undertaken on normal tissues . Reperfu−1 and a maximum volume of 0.2 ml. Superoxide dismutase and catalase  were dissolved together in PBS and were administered intravenously at a concentration of 23.3 and 10 KU ml−1 respectively, maximum volume 0.2 ml. Allopurinol  was dissolved in PBS and administered intravenously at a concentration of 50 mg ml−1 and a maximum volume of 0.2 ml.ALA powder  was dissolved in physiological strength phosphate buffered saline (PBS) and given intravenously at a concentration of 200 mg mlNormal, female, Wistar rats (120–200 g) were used throughout and all procedures were conducted under licences granted by the UK Home Office in accordance with their regulations and the UKCCCR Guidelines . The ani−1 ALA intravenously, 2 h prior to surgery. The colon was accessed for PDT via a laparotomy. The light source used was a 628 nm diode laser . A total energy of 25 J was delivered via a 200 μm plane cleaved optical fibre passed through the anti-mesenteric colon wall  so that it just touched the mucosa of the opposite side (area of contact=0.03 mm2). The power output of the optical fibre was kept at 100 mW. The rest of the abdominal viscera were shielded from forward light scatter by a piece of opaque paper positioned so that it did not touch the colon or affect its light distribution. This is a model that we have used many times in the past (2) but no thermal effect was observed macroscopically in the light only control group at 3 days. As the light fluence rate falls rapidly with increasing distance along the colon wall from the fibre tip, measuring the area of the zone of necrosis in the wall of the colon is a convenient way of comparing the efficacy of PDT with different treatment parameters. The light dose was either delivered continuously or fractionated by a single interval of 150 s after one fifth of the energy dose had been delivered.All animals were given 200 mg kg−1 SOD and 7.5 mg kg−1 CAT or 50 mg kg−1 allopurinol) were given intravenously either just before or immediately after illumination, the dosage and timing being chosen to mimic those of previous studies, where these compounds had been used successfully to prevent reperfusion injury  produced by each of the treatment regimes is shown in Table 1At post mortem, the lesions seen in the colon were approximately elliptical when the colon was opened and laid flat. Histological analysis on representative specimens showed necrosis of the same extent as that measured macroscopically on the mucosa surface. The area of necrosis (mmThis study has shown that the administration of either the scavenging enzymes, SOD and CAT, or the xanthine oxidase inhibitor, allopurinol, prior to illumination, can prevent ALA-PDT from producing damage in the normal rat colon, whether the light dose is fractionated or continuous.SOD and CAT remove harmful superoxide and hydrogen peroxide. These are known to be produced during reperfusion injury, but the effect is not specific. It is conceivable that cellular damage via singlet oxygen production would trigger a similar cascade of oxygen free radicals and reduced oxygen intermediates, particularly as the mitochondrion is reported to be a major site of ALA-PDT induced damage (The experiments with allopurinol are different. Allopurinol is known to be a specific inhibitor of the conversion of xanthine dehydrogenase into xanthine oxidase, which results in allopurinol being a specific inhibitor of reperfusion injury. The pre-administration of this compound would not be expected to have any effect on the production of reactive oxygen species or free radicals by any mechanism other than reperfusion injury. As the presence of this compound prior to light irradiation prevented the necrosis normally produced by ALA-PDT, it can be concluded that reperfusion injury must be playing some role in producing the necrosis in this animal model. It is known that if a tissue is not perfused, even for a period of time as short as 10 s , it is pOur results suggest that reperfusion injury may play a part in producing PDT necrosis, at least with ALA. It could also explain the increased area of necrosis produced by fractionating the light as a result of reperfusion injury following reversal of temporary ischaemia in the treated area after the first light fraction as well as after completion of the final light fraction.