For over a decade, the importance of zinc in the treatment of acute and persistent diarrhea has been recognized. In spite of recently published reviews, there remain several unanswered questions about the role of zinc supplementation in childhood diarrhea in the developing countries. Our study aimed to assess the therapeutic benefits of zinc supplementation in the treatment of acute or persistent diarrhea in children, and to examine the causes of any heterogeneity of response to zinc supplementation.EMBASE®, MEDLINE ® and CINAHL® databases were searched for published reviews and meta-analyses on the use of zinc supplementation for the prevention and treatment of childhood diarrhea. Additional RCTs published following the meta-analyses were also sought. The reviews and published RCTs were qualitatively mapped followed by updated random-effects meta-analyses, subgroup meta-analyses and meta-regression to quantify and characterize the role of zinc supplementation with diarrhea-related outcomes. We found that although there was evidence to support the use of zinc to treat diarrhea in children, there was significant unexplained heterogeneity across the studies for the effect of zinc supplementation in reducing important diarrhea outcomes. Zinc supplementation reduced the mean duration of diarrhea by 19.7% but had no effect on stool frequency or stool output, and increased the risk of vomiting. Our subgroup meta-analyses and meta-regression showed that age, stunting, breast-feeding and baseline zinc levels could not explain the heterogeneity associated with differential reduction in the mean diarrheal duration. However, the baseline zinc levels may not be representative of the existing zinc deficiency state.Understanding the predictors of zinc efficacy including the role of diarrheal disease etiology on the response to zinc would help to identify the populations most likely to benefit from supplementation. To improve the programmatic use of zinc, further evaluations of the zinc salts used, the dose, the frequency and duration of supplementation, and its acceptability are required. The significant heterogeneity of responses to zinc suggests the need to revisit the strategy of universal zinc supplementation in the treatment children with acute diarrhea in developing countries. Despite significant improvements in the interventions to treat diarrhea in children, it continues to pose a daunting public health challenge, especially in children from developing countries. Recent estimates suggest that nearly 3% of neonatal mortality and 17% of under-five child mortality is attributable to diarrhea. Asia and Africa have an alarmingly high incidence of childhood diarrhea. The latter recommendation was based on the results of several randomized controlled trials, meta-analyses First, WHO/UNICEF recommends zinc supplementation for diarrhea in developing countries only. Together, these issues indicate the need for a closer look at the evidence that underpins the policy of blanket zinc supplementation to children with diarrhea in developing countries. This study aimed to assess the therapeutic benefits of zinc supplementation in the treatment of acute or persistent diarrhea in children, and to examine the causes of any heterogeneity of response to zinc supplementation.Data extraction for this study was conducted in two steps. First, we searched the EMBASE®, CINAHL® and MEDLINE® databases for published trials on zinc supplementation. The full strategy for searching these databases and the results obtained are shown in 2 statistic since it is comparable across meta-analyses. 2 statistic was estimated from it using the formula I2 = (Q-df)/Q with the minimum bound set to zero.We constructed a correspondence map of the published studies and meta-analyses to identify which studies were included in the different meta-analyses. We then summarized the findings from these meta-analyses into diarrhea-related clinical end-points. For each outcome, we examined the reported summary effect sizes and the heterogeneity across studies. For quantifying heterogeneity, we used the IFor major outcomes that showed significant summary beneficial effect of zinc on diarrhea, and which showed large heterogeneity across trials, we investigated the potential contributors to the heterogeneity. First, we conducted an updated meta-analysis to include the results from other studies that the previous meta-analyses may have omitted. For these meta-analyses, we used the random effects model of DerSimonian and Laird. In 1998, Black et al 2 statistic ranging from 73% to 85% (2>70%). On the other hand, zinc supplementation does not provide a statistically significant reduction in stool frequency or stool output and this evidence was not heterogeneous . In addition, other outcomes have included stool frequency, stool output, risk of vomiting and risk of watery stools. All the five meta-analyses % to 85% . Alterna% to 85% , althougogeneous .2 69%, Meta-analytical synthesis of the influence of zinc supplementation is available for three more outcomes: persistent diarrhea, vomiting after zinc administration and childhood mortality. A smaller number of trials provide the current evidence for the effects of zinc supplementation on persistent diarrhea compared to acute diarrhea. Nonetheless, zinc supplementation offers a clear benefit for persistent diarrhea and this effect was homogeneous across the published studies . Three mThe systematic map shows that accompanying the influence of zinc supplementation on diarrhea was heterogeneity of the results across the published trials. We therefore conducted an investigation into the potential contributors to this heterogeneity. Summarizing results from 2 86.5%, p<0.001). For this outcome our subgroup meta-analyses . Finally, results of our meta-regression analyses showed .Rates of vomiting after zinc administration have been reported in 14 comparisons from 10 trials 2 statistic after accounting for pre-admission diarrheal duration shrunk from 81.2% to 48.1% indicating that a large proportion of the variability across trials could be explained by the duration of pre-admission diarrhea.In the subgroup analyses  we foundThe results of our systematic review suggest that zinc supplementation reduced the mean duration of acute diarrhea by approximately 20%, and persistent diarrhea by 15–30%, but had no significant effect on stool frequency or stool output. Further it was associated with a two- to three-fold higher risk of regurgitation in acute and persistent diarrhea, respectively. There was a high degree of statistically significant heterogeneity across the published studies for the effects of zinc supplementation on mean diarrheal duration and risk of vomiting following the administration of zinc.Consistent with the existing understanding Interestingly, higher doses of zinc in the therapeutic trials were associated with larger reductions in the mean duration of diarrhea. It is difficult to comment on the potential relationship between zinc dose and diarrheal duration in the context of achieving a balance between the reduction of diarrhea and risk of vomiting. If similar benefits of treatment are possible with lower doses and there is a lower risk of vomiting with these doses then lower doses might be advisable. Specific dose-response trials to examine this question would therefore be more appropriate. Similarly, the fact that subgroup analysis but not meta-regression demonstrated a differential benefit of zinc supplementation indicates that there may be a threshold for age beyond which zinc supplementation may be useful. However, the lack of an association between mean age in a trial and the effect of zinc may also reflect a lack of informative content in mean age as a contributor to heterogeneity and thus trials focused to address these issues would be appropriate.E. coli and rotavirus calls for a closer look into the clinical and public health scenarios where this intervention may be most beneficial. Whether such a strategy of zinc supplementation that is tiered on the basis of the causative organism will be efficacious and effective is currently unknown. The WHO recommendations do not fully address these issues and protocols for the use of zinc in diarrhea treatment programs need revisiting.An important finding from our analyses was that zinc supplementation showed no effect on stool frequency and output. This opens up the possibility that care-givers may not perceive a beneficial impact of treating their children with zinc, which might negatively affect their adherence to the treatment regime. Another potential barrier to treatment adherence with zinc supplements was the significantly increased risk of vomiting. These findings imply that use of zinc supplements is unlikely to improve compliance with the treatment for diarrheal disease. It is noteworthy however, that a recent study of the safety of zinc supplementation in acute diarrhea suggests that most of the patients regurgitate only once – a phenomenon that may not affect the continuation of zinc therapy. Stunted children are likely to be zinc deficient and therefore should benefit from zinc supplementation Esherichia coli and rotavirus were not causes of the diarrhea . The role of other unknown covariates like adherence and acceptability remains unknown. Indeed, we did observe that significant heterogeneity across study results remained even after accounting for the potential predictors of between-study heterogeneity. Lastly, subgroup analyses and meta-regression are, by disposition, exploratory tools to provide pointers towards possible sources of heterogeneity - they cannot be taken as confirmatory tests for definitive conclusions and interpretations about the causes of heterogeneity.Meta-analyses and meta-regression, like any study design, have inherent limitations. For example, because only a few studies reported information on most of the predictor variables simultaneously, we could not conduct multivariate meta-regression analyses. Thus, the importance of the factors that we identified is unknown in a multivariate context. In addition, even though meta-regression can provide important clues into the potential contributors to the summary effect size Our findings for the use of zinc in the treatment of diarrhea indicate the need to improve upon the current strategy of zinc supplementation for all children with diarrhea, by selecting the populations most likely to benefit from supplementation and using the most effective zinc salt. There is a need to optimize the use of zinc supplementation in childhood diarrheas and this will require further investigation of the factors leading to the heterogeneity of the effects of zinc as an adjunct in its treatment.


We aimed to examine the co-authorship networks in three successful Iranian academic research centers, in order to find the association between the scientific productivity and impact indicators with network features in a case study.We searched for English articles of the three research centers. We drew co-authorship maps of each center and calculated social network measures.The collaboration networks in centers shared many structural features, including a "star-like" pattern of relations. Centers with more successful scientific profile showed denser and more cooperative networks. Key figures in each center were interviewed for their understandings of the reasons for the emergence of these patterns.Star shape network structure and dependency on a single big member is a common feature observed in our case study. Scientific output measures correlate with the network structure of research centers. Network analysis seems a useful method to explore the subtle scientific contexts in research organizations. The process of research evaluation is of major importance for the development of health systems,2. In thSocial network analysis provides a number of methods for revealing patterns of interpersonal relationships, and have frequently been applied to study collaboration through co-authorship networks -5. NetwoIn the present study, we examined the co-authorship networks of researchers in three high profile Iranian research centers, and aimed to use it as a case study to investigate the association between the overall scientific productivity and impact indicators with collaboration network features.Data were collected on co-authorship of papers published in English by members of three research centers: Endocrinology and Metabolism Research Center (EMRC), Digestive Diseases Research Center (DDRC) and Pharmaceutical Sciences Research Center (PSRC); which were the first three highest ranked research centers in Tehran University of Medical Sciences respectively and each has been at least once the top Iranian research center in the past 5 years . These cWe generated a table for each research center, with the rows formed by the list of members and the columns by the articles. A "co-authorship matrix" showing the number of collaborations between each pair of members was generated. The information regarding authors who were not considered as the members of centers was gathered as a single "outsiders" row.We used ISI Web of Knowledge database to obtain following information for each article: the impact factors of the publishing journals (of the years of publication of the articles), and the number of citations received during two years after publication. We also obtained some other scientific productivity measures from an evaluation project conducted by the deputy for research of Tehran University of Medical Sciences in 2005–6. These mThe impact factors, the number of received citations and other scientific productivity measures were compared between three centers, and post hoc pairwise comparisons were performed when needed. Ucinet and PajeWe calculated basic network descriptive measures and the average number of collaborators per author, regardless of the volume of production. To examine this, the data were dichotomized (i.e. if two actors co-authored any papers they were coded one) making a "collaboration matrix". Analyses of the structure of collaboration are based on the dichotomized data, showing whether two persons had ever collaborated.Because of the considerable skewness of network measures, non-parametric measures of central tendency and dispersion were used. These measures were compared between the centers using Kruskall-Wallis test.Degree centralization, and betweenness centralization measures were used to investigate whether collaboration is equally distributed across the researchers in each center, or there is a tendency for some actors to be more "central" to the web of collaboration [degree centralization measure examines the inequality in the distribution of collaborators across researchers, varying between 0% to 100%, which shows the similarity of the network to star-shaped pattern[betweenness centralization measure examines the extent to which the shortest paths between pairs of actors in the collaboration network pass through a third actor [boration . At one boration ,13. The d pattern. The betrd actor . To the clustering coefficient; which measures the probability that two of a scientist's coauthors have themselves coauthored a paper) combined with relatively low average geodesic distances . Creative scientific research on the one hand requires the close support of a community of peers who are expert in closely related areas, and on the other hand, needs getting access to the diverse sources of knowledge in other specialties. The simultaneous presence of dense local clustering with short social network distance to diverse others [A frequent finding in collaboration networks is that they resemble "Small worlds", particue others  is a chae others ,17.One approach to examine the structure of collaboration  is called "structural block modeling". In thisUsing different centralization measures, three most central actors were identified in each network. We interviewed some active members of each center and discussed the potential reasons for importance of core people, the similarities in the roles of members of clusters, and the relationships between the observed clustering and formal and informal categorizations in the centers.The scientific activity measures of three centers are shown in table Some descriptive statistics of three centers and their comparisons are shown in table There were notable differences in the absolute number of co-authorships between centers. All three centers displayed significant positive skewness in the distribution of co-authorship figure . It was The overall collaboration (regardless of the volume of production) in DDRC and EMRC was higher than PSRC; moreover, the distribution of the volume of production was more unequal than the distribution of collaboration.degree centralization, though it was less in PSRC. The DDRC and EMRC had a more characteristic single "star" pattern. The PSRC is characterized by two actors who were somewhat more involved in collaborations than the others, but similar to one another. The betweenness centralization was greatest at PSRC.All three centers displayed high clustering. The average distance between members of the center, however, was much greater in PSRC (2.3) than DDRC or EMRC (both 1.6); This greater distance suggests that, in PSRC there were less actors who connect multiple clusters, showing a less typical "small-world".As shown in table The DDRC was distinguished by the very high rate of collaboration with outsiders (non-members). The relative amount of collaboration "inside" and "outside" the organization was about the same for DDRC (14/21) and PSRC members (5/5.5) while EMRC members (10/6) showed a tendency toward relatively more "internal" activity.Spearman's correlation coefficients for the association between the amount of inside and outside collaborations are shown in table structural block modeling, are shown with colors in figures The groups of "similar" actors, defined by One plausible block model divided the actors into five groups figure . This moA five-group block model provided a plausible summary of the data for EMRC (R-square = .491). Structurally, the pattern of collaboration at EMRC was similar to that of DDRC. Compared with DDRC, local clusters were tighter, and more separated from one another figure . The rolA six group model was used, because one actor was unique in forming a "group" (figure There were two tight clusters (oblique lines and grey), which did hot have strong ties to one-another figure . Actors The network structures associated with the scientific productivity and impact indicators in our case study. Centers with denser, more decentralized, and more open to outside connections networks showed better scientific outputs. Even though, all three centers shared many network features, demonstrating common infrastructural characteristics and obstacles of research organizations in developing countries.betweenness in few people in a network makes it highly susceptible to break down after the removal of such actors[All three networks were structurally star shaped and centralized. The central actors consisted of similarly the heads of the centers. This is a phenomenon which is seen in many team works in developing world. A single charismatic person, who initiates, maintains and pushes the organization. Two main reasons for this limited autonomy of members and involvement of the big person on almost all operations may be the lack of professional trained researchers who are able to manage the projects independently, and the instability of the system, in which only the organizations with support from a powerful actor are able to survive. This dependency could threat the sustainability of research centers and diminish the knowledge flow between members. Rulke and Galaskiewicz showed that hierarchical structures are not efficient for complicated problems while more intense and decentralized networks provide the maximal knowledge flow between actors . In addich actors.One explanation for the observed difference in the average authors per paper in three centers is the higher likelihood of guest authorship, because of the presence of more prestigious and socially important members in some centers. Guest authorship is prevalent in scientific papers. As showdensity, and least betweenness centralization, and mean geodesic distance). The scientific output measures were consistent with the network findings; depicting that the production of more cited research  seems to be associated with the inter-actor associations and knowledge flow inside research organizations.In our case study one network (DDRC) showed denser and more distributed network measures (highest average co-authorship, average collaboration, cohesion and collaboration; the latter pattern may contribute to factionalization and lower social density, which was seen more apparently in PSRC network, where articles received relatively high citations while network showed lowest productivity measures comparing to other centers. One reason for PSRC's high median citations per article in spite of lower productivity indicators and network measures, is the attractiveness of pharmacological research in comparison to clinical research, as shown by other scientometric studies [DDRC members had more collaboration with outsiders, which made the center more open, and facilitated the potential of idea exchange and conducting interdisciplinary and multi-centric projects. Research centers are communities of a sort. At one extreme, they may be very "open" where members are equally likely to have ties outside, as inside the center. At the other extreme, they may be quite "closed". Some degree of closure probably contributes to "identity" and a "sense of mission". Too much closure may contribute to isolation from the larger world of science. It also may matter where the openness occurs. In many centers, the central figures and leaders act as the primary liaison between the center and the larger community; in other centers, many individuals – and not always central individuals – may have strong external ties. The former pattern may contribute to  studies .clustering preserves the independence and autonomy of the clusters, while the paths of the knowledge exchange among them are open. DDRC and EMRC showed to be more typical small worlds. Several studies have demonstrated that the information diffusion and knowledge exchange are faster in small worlds[An archetypical small-world network as stated by Moody "will have many distinct clusters, connected to each other by a small number of links" . This clll worlds,23. Coexll worlds,25.authors per paper, mean papers per author, density, and highest mean geodesic distance between members, and betweenness centralization. Lower mean authors per paper means the involvement of smaller number of researchers in common projects, and lower potential for team working. This measure highly depends on the research discipline. Newman showed that the average authors per paper is 3.75 in biological sciences, 2.53 in physics and 1.45 in mathematics. He explained this difference because of involvement of large groups of field and laboratory scientists in biological research in comparison to more theoretical and individual nature of mathematical sciences [PSRC had lowest mean sciences .Taking a closer look at networks and inter-relationships between entities as an important aspect of sustainable capacity development  is essenOur study is limited in some ways. Co-authorship relationship seems a rational- but stringent- definition of scientific collaboration. Knowing each other is a pre-requirement for writing a paper together . Co-authThe scientific productivity and impact of research organizations was associated with their network structure in our case study. Social network analysis seems a useful method to explore and visualize the subtle scientific norms and customs in research centers and hidden structural and functional sources of their success or failure. Qualitative approaches to obtain the network members' views regarding network analysis outputs lead in more meaningful and less mechanical interpretations of the hidden structure.The authors are not members of any of the research centers under study. No conflicts of interests are declared. AE is working as an associate editor in a peer reviewed journal which is founded by the dean of one research center under study.conception of the research: RYN, MAK, AE; performing the research: RYN, MAK; data analysis and interpretation of findings: RYN, MAK, RAH; preparation and reviewing of manuscript: RYN, MAK, RAH, AE


Cognitive dysfunction is common among depressed patients. However, the pattern and magnitude of impairment during episodes of major depressive disorder (MDD) through to clinical remission remains unclear. Heterogeneity of depressive patients and the lack of longitudinal studies may account for contradictory results in previous research.This longitudinal study will analyze cognitive differences between CORE-defined melancholic depressed patients (n = 60) and non-melancholic depressed patients (n = 60). A comprehensive clinical and cognitive assessment will be performed at admission and after 6 months. Cognitive dysfunction in both groups will be longitudinally compared, and the persistence of cognitive impairment after clinical remission will be determined.The study of neuropsychological dysfunction and the cognitive changes through the different phases of depression arise a wide variety of difficulties. Several confounding variables must be controlled to determine if the presence of depression could be considered the only factor accounting for group differences. Over the last years cognitive dysfunction has increasingly been recognized as a core feature of major depressive disorder (MDD). Clinical studies have focused on the pattern and magnitude of impairment during and between episodes of MDD as well as the neuropsychological domains affected and the origin of these abnormalities . HoweverTo overcome the limitation derived from the first methodological factor, a more acurate selection of depressed patients is required. A pattern of cognitive dysfunction may be more evident in a form of depression characterized by biological markers than in more heterogeneous depressed samples. Melancholia is a disorder with definable clinical signs that identifies more specific populations than the DSM-IV . It descOvercoming the limitation derived from the lack of longitudinal data imply the development of cohort studies. Longitudinal assessment of cognitive functions seems to be a potentially powerful method of identifying and distinguishing state-related from trait-related cognitive deficits . PreviouThe course of cognitive changes through to clinical improvement in samples of depressed participants with and without melancholia has scarcely been longitudinally studied . The preThe general aim of this study is to analyze cognitive differences between melancholic depression (MD) and non-melancholic depression (NMD), and compare longitudinally the cognitive dysfunction in both types of patients, determining whether these alterations remain after clinical remission. This will enable to define a specific cognitive dysfunction pattern depending on these subtypes of depression. Finally, the study will analyze the correlation between the severity of these dysfunctions and the number of previous depressive episodes.Our hypotheses are that specific cognitive deficits during acute phase of MDD will be different between patients with MD and NMD. Melancholic depressed patients are expected to show a poorer performance on memory, attention and executive function tasks at baseline. We hypothesize that cognitive deficits in the group with melancholia will persist at the follow-up assessment despite the presence or absence of clinical remission. Cognitive deficits in the non-melancholic depression group will only be expected to persist in those patients who fail to achieve clinical remission at the 6-month follow-up assessment while is presumed to be reduced or to disappear in those who have achieved it. Finally, the number of previous episodes of depression of melancholic patients is predicted to positively correlate with cognitive deficits severity.This is a multicenter, observational longitudinal cohort study that will include 120 outpatients treated for an acute episode of MDD. 60 patients with melancholic depression will be compared to 60 non-melancholic depressed patients matched by age, gender and education level. All patients will be included during an acute phase of the disorder and will undertake standard psychopharmacological treatment for depression.Information regarding socio-demographic and clinical features will be collected at the baseline evaluation. A neuropsychological protocol will be administrated both at the baseline and the six-month follow-up assessments. The obtained results will be compared between four groups: melancholic patients showing clinical remission, melancholic patients who fail to achieve clinical remission, non-melancholic patients showing clinical remission and, finally, non-melancholic patients who fail to achieve clinical remission.In our study clinical remission will be operatively conceptualized as having a HDRS total score ≤ 7 both at the 6-month follow-up assessment and in an additional interview that will be performed two weeks later.This study will be performed in accordance with the Helsinki Declaration of the World Medical Association Assembly and the Madrid Declaration of the World Psychiatric Association (WPA). The study protocol has received the approval of the Ethics and Clinical Research Committee of the Balearic Islands .All patients will be identified and recruited from different centers across the island of Majorca (Spain), including 4 Outpatient Psychiatric Units , 2 Mental Health Units and 9 Primary Care Centers.Sociodemographic and clinical questionnaire designed specifically for this study. Relevant sociodemographic information regarding gender, date of birth and age, marital status, education level and occupational status, as well as clinical data regarding age of disorder onset, number of previous episodes and current pharmacological treatment  will be collected.1. DSM-IV criteria for Major Depressive Disorder [2. Disorder .17-item Hamilton Depression Rating Scale (HDRS) [3. e (HDRS) . This ise (HDRS) ,13.The CORE system for melancholia (CORE) [4. a (CORE)  is an 18The Mini-Mental State Examination (MMSE) [5. n (MMSE)  has beenThe Clinical Global Impression rating scales  [6. , CGI-I)  are commCognitive assessment, administered in this fixed order:Trail Making Test-Parts A and B [1.  A and B  In this  A and B  suggest Digit Span subtest of the Weschler Adult Intelligence Scale, 3rd edition (WAIS-III) [2. AIS-III) . Digit sAIS-III) .Stroop Colour Word Test (SCWT) [3. t (SCWT) . This tat (SCWT) . Three 4Tower of London, 2nd Edition (TOL-DX) [4. (TOL-DX) . This is(TOL-DX) .The Controlled Verbal Fluency Task (FAS) [5. sk (FAS) . This isSemantic Verbal Fluency (ANIMALS). This test requires the generation of words corresponding to a specific semantic category. The number of correct words in one minute is counted. A mean of 16 words is expected to be produced as a standard score [6. rd score .Finger Tapping Test (FTT) [7. st (FTT) . OriginaThe recruitment strategy will be performed by General Practicioners and Psychiatrists involved in the study. Any outpatient who might fulfil all the inclusion criteria will be offered to participate in the study. Male and female outpatients who are eligible and sign the written informed consent will be entered into the study.At the screening interview the Hamilton Depression Rating Scale (HDRS) will be used to determine depression severity while the CORE Scale  will allClinical interview will be performed both at baseline and follow-up assessments. The structured clinical interview will address sociodemographic characteristics, medical history and current medication prescription. Clinical scales and questionnaires will also be administrated. The cognitive assessment will follow the clinical interview. It will also be conducted at baseline and 6 months later. The follow-up assessment will take place after 6 month of inclusion in the study independently of the patient clinical state . All patients showing a HDRS total score ≤ 7 in the follow-up assessment will be re-interviewed after two weeks. They will be considered as being in remission of depressive symptoms if the HDRS total score at this time remains equal or under 7 points. All assessments will be performed by two trained psychologists , and will be carried out in the morning in order to avoid the confounding effects of diurnal fluctuation in mood and cortisol levels which have been pointed out to influence cognitive performance .Obtained data regarding sociodemographic and clinical features of the depresive episode at baseline assessment will be compared between melancholic and non-melancholic depressed patients in order to detect any significant difference.Intergroup analysis will provide information regarding test score differences between melancholic and non-melancholic depressed patients both at baseline and the follow-up assesments. Furthermore, comparisons between melancholic and non-melancholic depressed patients showing clinical remission will be carried out. Melancholic and non-melancholic depressed patients who fail to achieve clinical remission will be compared as well.Intragroup comparisons will provide information regarding test score differences between the baseline and the follow-up assessment for each group. Thus, the cognitive profile of melancholic depressed patients at baseline will be compared to the cognitive profile obtained at follow-up assessment and the cognitive profile of non-melancholic patients will be compared likewise. Test scores obtained by melancholic depressed patients who show clinical remission will be compared at both times of assessment. Test scores of non-melancholic depressed patients showing clinical remission will be compared likewise. The same comparisons will be undertaken with melancholic and non-melancholic depressed patients who fail to achieve clinical remission.Obtained data will be analyzed with the Statistical Package for the Social Sciences (SPSS) version 17. Univariate descriptive analysis of the included variables will be performed. For metric variables, central tendency measures, measures of statistical dispersion and measures of position will be applied. In the case of categorical variables, univariate description will be obtained with relative frequencies. Bivariate analysis will be performed by means of the Student's t-test for the comparison of two means, the Analysis of Variance (ANOVA) for the mean comparison of more than two groups, the Mann-Whitney test for ordinal variables and the Chi-square test for categorical variables. Multivariate analysis will be calculated with multiple linear regression and logistic regression models.The sample size was calculated assuming an alpha risk of 0.05 and accepting a beta error rate of 20%, which corresponds to a study power of 80%. Expecting a 20% loss, the necessary sample size will be 60 patients in each group, constituting thus a total sample of 120 patients.To our knowledge, this will be the first study design that longitudinally compares cognitive functioning in depressed patients with and without CORE-defined melancholic features. The imprecision of depressive symptoms limit the capacity of any measure to delineate and measure melancholia . NowadayIn the present study, the cognitive profile of those patients showing clinical remission of depressive symptoms will be separately analyzed from the cognitive profile of those patients who fail to achieve remission of symptoms. The design seeks to overcome two important methodological limitations of previous investigation: the heterogeneity of depressed patients samples and the lack of longitudinal studies focusing on cognitive functioning changes from the acute phase of depression to clinical remission.The study of neuropsychological dysfunction and the cognitive changes through the different phases of depression arise a wide variety of problems. Some of them are closely related to the nature and intrinsic characteristics of neuropsychological assessment and the interpretation of results. Most of the neuropsychological tests that will be used in our study were primarily developed for brain-damaged patient examination. As highlighted by Austin et al. , the appAnother major difficulty is related to the wide variety of confounding variables that must be controlled in neuropsychological testing. The presence of depression should be the only difference likely to impact on cognitive function . DiffereFew studies of neuropsychological impairment in MDD have considered the effects of gender on cognitive performance . The preAge is associated with a progressive decline in cognitive function. Difficulties produced by age   involve Many studies have investigated the effect of severity of depression on neurocognitive task performance. Overall, results suggest the importance of applying corrections for depression severity when comparing patients with different subtypes of MDD, as it seems quite clear that differences in mean depression scores of patient samples could account in part for the different levels and patterns of cognitive impairment observed . In factThe use of medication during neuropsychological assessment is an important confounding variable. It is therefore surprising that most of the works studying the persistence of cognitive disturbances beyond the symptomatic phase of MDD have overlooked the possible impact of medication on cognitive function . AntidepControl for the potential effects of medication will be applied in our study by establishing treatment type as a covariate in statistical analysis. Electroconvulsive therapy received in the six months preceding study admission was established as an exclusion criteria.Little is known regarding the influence of age of onset, duration and number of episodes of MDD on cognitive function in depressed patients. A great part of the studies concerning number of episodes and cognitive performance in depression have mainly been related to memory rather than to attention or executive functions . Some stAmong the strengths of this study it must be highlighted the large number of participants to be included as well as the homogeneity of the sample of depressed patients, especially with respect to their melancholic or non-melancholic condition. We have applied a narrow definition of melancholia (measured by the CORE system) instead of the broad definition of the DSM which, although being 'the most frequently used' reference point, have been pointed out to have poor agreement with the core features of melancholia derived from empirical studies .As noted above, only few studies have compared cognitive performance in melancholic MDD patients longitudinally. However, it has been suggested that a measure of chronic depressive symptoms taken over a period of time may share a closer relationship with cognitive function .Another major strength of the present study is related to the conceptualization of remission in depression. Establishing a standarized definition of remission is a controversial issue. According to most definitions, it is described as a state of minimal to no symptoms and a return to normal functioning . Most stThe number of significant confounders in neuropsychological testing is high. However, control of a variety of confounders such as gender, age or type of treatment among others will be applied.The present study shows some limitations as well. Although the neuropsychological assessment is comprehensive, not every cognitive function will be assessed.Patients using other medication different to antidepressants or benzodiazepines will be excluded. So will be patients who have received electroconvulsive therapy in the six months previous to screening for this study. This could limit somehow the extent of results' applicability.Another possible limitation is that the presence of comorbid Axis I, Axis II or Axis III DSM-IV disorders will not be taken into account. Although it is possible that in some way this could increase the cognitive impairment associated with MDD, everyday practice shows that comorbidity is not uncommon and exclusion of patients due to comorbid disorders could limit generalisability of results. All eligible patients with a history of medical conditions that could entail cognitive deterioration or with a history of head injury or neurological disorder will be excluded. However, it is possible that some of the patients that will be included in the study may present clinical symptoms of an incipient undiagnosed clinical picture. This possibility must be taken into account and calls for caution in the interpretation of results.Findings of the present study will contribute to bring light to the melancholic subtype of depression debate. Moreover, they may help to identify differential neurocognitive profiles between those depressed patients who remit and those who do not achieve remission and would give rise to future research of specifically tailored treatments.MDD: Major Depresive Disorder; MD: Melancholic depression; NMD: Non-melancholic depression; HDRS: Hamilton Depression Rating Scale.The authors declare that they have no competing interests.SM, MG, MR, MG-T and JS are the principal researchers and developed the original idea of the study. MG, RM, and JLL developed the study design and will perform the statistical analysis. SM, MV, NB and MJS will perform all the clinical and neuropsychological assessments. All authors have read and corrected draft versions of the present manuscript and approved the final version.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/10/48/prepub


Tomophobia refers to fear or anxiety caused by forthcoming surgical procedures and/or medical interventions.We present the case of a 69-year-old Caucasian man who refused urgently indicated medical intervention because of severe tomophobia.Due to the rising number of surgical interventions in modern medicine, as well as the high number of unrecognised cases of tomophobia, this common but underdiagnosed anxiety disorder should be highlighted. Phobia  is defined as an irrational, intense and persistent sensation of fear in relation to specific situations, activities, objects or individuals. Phobic anxiety disorders are conceptualized as a diagnostic subclass within the anxiety disorders. One of the main symptoms of this disorder is the excessive and unreasonable desire to avoid a feared subject or situation. When the fear is beyond one's cognitive or emotional control, or when the fear interferes with daily life activities, an anxiety disorder can be diagnosed.The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) differentiates three groups of phobic anxiety disorder: social phobia, specific phobia, and agoraphobia . AccordiAccording to the Dresden Mental Health Study, the estimated life time prevalence of any specific phobia is 12.8% [In many cases, patients present with more than one type of specific phobia (DSM-IV). The characteristics of the "blood-injection-injury" phobia include fear of seeing blood, becoming injured, or receiving an injection or other invasive medical procedure . The higThe patient was a 69-year-old Caucasian man without a history of mental illness or any previous psychiatric treatment. He was initially transferred to a medical emergency department with marked dyspnoeic symptoms and tachycardia, where an acute coronary syndrome was diagnosed. After laboratory testing and an electrocardiogram a non-ST elevation myocardial infarction (NSTEMI) was diagnosed. The following coronary angiography (an intervention that was endured by the patient with enormous dread), revealed severe three-vessel disease.The patient was informed of the urgent indication of a bypass operation, which was planned as an emergency intervention on the same day. At the end of the angiographic intervention, this information caused a severe panic reaction with hyperventilation, tachycardia and the feeling of loss of control, which was successfully treated with benzodiazepines. He described an intensely irrational and unavoidable fear of putting himself in the hands of others -surgeons and anaesthetists in this case. Moreover, the fear of losing control of his body through loss of consciousness or compromise of physical integrity during an operation or surgical intervention was reported. The patient was not able to give his agreement for the operative intervention because of overwhelming panic and anxiety. Due to his intense fear he eventually refused the bypass operation. This dramatic situation led to a condition of anxiety, strain and severe agitation, which led to a psychiatric referral and, consecutively, to an in-patient psychiatric admission.The patient was relieved by the psychiatric admission and the understanding of his phobic fear. He reported a 20-year history of severe coxarthrosis, which caused serious pain and progressive leg deformation and malfunction, and which had never been operated on because of his fear of surgery. The clinical examination revealed that his left leg was 4.5 cm shorter than his right leg. He also had a marked impaired gait due to a limp in his left leg. Additionally, the coxarthrosis led to an extensive inguinal hernia due to pain induced mismovement. He also refused the necessary inguinal operation for over five years due to the same phobic symptoms. Further phobic symptoms and other symptoms of anxiety were explored, such as his fear about GP visits and discussions with superior colleagues. The patient reported an age of onset in the early adult years. With regard to childhood and adolescence, he described fear symptoms while knocking on or opening 'foreign' doors. Though the patient showed avoidant personality traits, no personality disorder could be diagnosed.The psychopathological findings at the time of psychiatric exploration were limited to intense fear in relation to the forthcoming surgical procedures and interventions. During the psychiatric exploration, the patient was polite, friendly, and honest. Compulsive symptoms were limited to the repeated checking of electric appliances. As a consequence of his lifelong avoidance strategies he seemed not to feel oppressive limitations in everyday life. Until then, he had never consulted a psychiatrist or a psychotherapist regarding his phobic symptoms. He described being ashamed of his unreasonable fear symptoms. Panic disorder symptoms were not observed at any time during the psychiatric exploration. No history of syncope was found. Family history revealed a suspected anxiety disorder in the patient's father, although he reportedly never consulted any physician or other healthcare professional. Further examinations of the patient such as laboratory tests, duplex sonography, an electroencephalogram and a cranial magnetic resonance imaging were entirely normal. A Specific Phobia was diagnosed according to DSM-IV criteria.To improve the intense fear reported by the patient when being confronted with the problem of the necessity of the operation, a psychotropic treatment with escitalopram 10 mg once a day and pregabalin 150 mg twice a day was initiated. The patient described an improvement of these fear symptoms. Supported by intensive conversational therapy based on cognitive behavioural techniques, he stabilized and was subsequently discharged. The patient still refused the invasive procedure, as his fear of the procedure continued to overwhelm his fear of dying from a heart attack. Behavioural psychotherapy as an out-patient treatment was recommended in order to diminish the patient's phobic fears.Our patient suffered from a specific phobia "blood-injection-injury type", in this particular case provoked by medical interventions including the forthcoming coronary bypass operation. This specific phobia is also termed "tomophobia" . According to related studies, "blood-injection-injury" phobia is characterized by combined fear and disgust responses . A frequTomophobia is sometimes accompanied by the irrational fear of dying under anaesthetics during a chirurgic intervention. Our patient neither experienced syncope nor symptoms of massive disgust while being confronted with the phobic stimuli, but he complained of intense fears related to the impending operation. Considering the absence of disgust response and fainting, the assignment to the situational subtype or a combined form of phobia could be the more appropriate diagnostic category for the reported case of tomophobia.et al. reported a study of 1920 subjects, which showed a prevalence of the "blood-injection-injury" phobia of 3.5%. None of these patients was receiving mental health treatment specifically for phobia [Bienvenu r phobia . With rer phobia .Due to progress in the development of invasive treatment and an increased number of established intervention procedures in modern medicine, cases of diagnosed tomophobia might increase in the near future. Above all, surgeons and general physicians may be increasingly confronted with patients who refuse medically urgent procedures due to tomophobic fears. Our patient became symptomatic when he was informed about the indication of the necessary operation. The patient's refusal of the surgical intervention can be comprehended as typical avoidance behaviour as a result of his permanent phobic disorder. The patient was always cognitively capable of understanding the consequences of his unreasonable decision, but the fear of impairment of physical integrity and of losing control while accepting the bypass operation was greater than the fear of dying as a consequence of the detected heart disease.We present the case of a patient who refused recommended urgent coronary bypass surgery because of tomophobic fears. Due to the rapid progress of modern medicine, including frequent use of invasive medical procedures, tomophobia will likely be an increasingly common and clinically impairing anxiety disorder. We assume that tomophobia is often unrecognised, which consequently limits its diagnosis and treatment. With this case report we would like to highlight a common but still largely unappreciated anxiety disorder and encourage improved diagnosis and treatment of patients suffering from it.DSM IV: The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV); ICD 10: International Classification of Disorders; NSTEMI: non-ST elevation myocardial infarction.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.MS and CS admitted the patient and were responsible for his treatment. They also contributed in writing the manuscript, together with RC and RF. All authors read and approved the final manuscript.


The effects of long-term anticoagulation with phenprocoumon on growth of the Lewis lung carcinoma (3LL) were studied. Oral anticoagulation initiated at the day of i.m. transplantation of the 3LL into C57BL mice significantly inhibited primary tumour growth and reduced the number of spontaneous metastases to the lungs. Intermittent anticoagulation was without effect on metastasis formation but still retarded primary growth. There was no influence of anticoagulation on the mean survival time (MST) of tumour-bearing animals. Phenprocoumon appears to improve the results of cyclophosphamide of 5-fluorouracil treatment, but there were no statisticially significant differences. In contrast, bleomycin treatment in combination with adjuvant anticoagulation suggested a possible drug synergy. No significant influence of anticoagulation on the response of the primary tumour to irradiattion was found, though the MST of irradiated and anticoagulated animals was greater than in the solely irradiated controls. The present investigations suggest that coumarin derivatives have some direct tumour-inhibiting capacities, but exert their antimetastatic action via deceleration of the blood clotting mechanism.


Previous osteotomy may compromise subsequent knee replacement, but no guidelines considering knee arthroplasty after prior osteotomy have been developed. We describe a systematic review of non-randomized studies to analyze the effect of high tibial osteotomy on total knee arthroplasty.A computerized search for relevant studies published up to September 2007 was performed in Medline and Embase using a search strategy that is highly sensitive to find nonrandomized studies. Included were observational studies in which patients had total knee arthroplasty performed after prior high tibial osteotomy. Studies that fulfilled these criteria, were assessed for methodologic quality by two independent reviewers using the critical appraisal of observational studies developed by Deeks and the MINORS instrument. The study characteristics and data on the intervention, follow-up, and outcome measures, were extracted using a pre-tested standardized form. Primary outcomes were: knee range of motion, knee clinical score, and revision surgery. The grade of evidence was determined using the guidelines of the GRADE working group.Of the 458 articles identified using our search strategy, 17 met the inclusion criteria. Fifteen studies were cohort study with a concurrent control group, one was a historical cohort study and one a case-control study. Nine studies scored 50% or more on both methodological quality assessments. Pooling of the results was not possible due to the heterogeneity of the studies, and our analysis could not raise the overall low quality of evidence. No significant differences between primary total knee arthroplasty and total knee arthroplasty after osteotomy were found for knee range of motion in four out of six studies, knee clinical scores in eight out of nine studies, and revision surgery in eight out of eight studies after a median follow-up of 5 years.Our analysis suggests that osteotomy does not compromise subsequent knee replacement. However, the low quality of evidence precludes solid clinical conclusions. High tibial osteotomy (HTO) is an accepted surgical treatment of medial unicompartmental osteoarthritis (OA) of the knee with varus mal-alignment in young patients. However, there is no sound evidence that an osteotomy is more effective than alternative non-operative therapies, such as valgus bracing or laterally wedged insoles . FurtherThe aim of this study was to collect the best available scientific evidence from clinical studies examining TKA after HTO compared with primary TKA, and determine whether an osteotomy influences clinical outcome after TKA. Although randomized controlled trials (RCT) are considered the ideal and highest level of evidence in making decisions about the care of individual patients, numerous "good" surgical practices have evolved into "standard of care" without being randomized against placebo or ineffective treatment options . This prA search of all relevant studies published in Medline and Embase up to September 2007 was performed to identify those investigating TKA after earlier HTO. The search strategy combined all phases of the optimal non-randomized studies strategy and used fixed method B, based on the study of Furlan et al. . Key worTwo reviewers  assessed the studies and whether they met the following inclusion criteria:▪ patients in the study had TKA performed after prior HTO;▪ the study had an observational design between 4 and 7 using the taxonomy of study designs described by Deeks et al.  ;▪ the article was written in English, German, or Dutch;▪ full text was available for the article;Disagreements on inclusion were resolved by discussion, and the final decision of a third reviewer (JV) was not necessary.Two reviewers  assessed the methodologic quality independently from each other. In order to avoid conflict of interest two other reviewers  re-assessed one study that was (co)-authored by TR and MR . The criTwo reviewers  independently extracted the study characteristics and data on the intervention , clinical outcome measures (postoperative knee range of motion (ROM) and clinical knee scores), and revision surgery , using a pre-tested standardized form. Agreement on data extraction was reached by consensus.The grade of evidence was determined following the guidelines of the GRADE  working group . GRADE aOf the 458 articles identified using our search strategy, 17 met the inclusion criteria  pair comparison design. An overview of the characteristics is presented in Table Intra-operative results are shown in Table th or 7th decade of life receiving TKA because of symptomatic knee osteoarthritis. Knee replacement, regardless of prosthesis type, has more or less the same relative effects across most patients, therefore we judged the evidence obtained as direct [No important inconsistencies among the nine studies were found in the direction of effect and the size of differences in effect; prolonged operation time, extra operative procedures, less postoperative knee ROM, and no increase of revision surgery was noticed for patients receiving TKA after prior HTO in the studies reflecting on the aforementioned outcomes. All studies described patients in their 6s direct . Table 6Patients who require TKA for a failed HTO comprises a significant portion of those patients undergoing TKA . PreviouWell-designed observational studies may provide high quality of evidence in circumstances described by the GRADE working group. The present study, however, could not raise the current low quality level of evidence. All studies presented relative small sample sizes, and pooling of the data would have provided a more precise association with the clinical outcomes. The heterogeneity of the studies, mainly due to differences in gender, osteotomy techniques, and time of follow-up, made quantitative pooling of the data impossible and a systematic review represented the best available method to synthesize the current literature . This obSurgical methods have been recognized to be important factors in the longevity of knee implants . SubperiSurgical treatment options for younger patients with unicompartmental OA of the knee remain controversial. Arthroplasty may have adverse effects. In an update study of data from the Swedish Knee Arthroplasty Register younger age was associated with an increased risk of prosthetic revision . The cumIn summary our analysis represents the best available evidence on TKA after prior osteotomy, which seems to suggest that osteotomy does not compromise subsequent TKA. However, the overall low quality of evidence could not be raised by this review. Therefore, knee arthroplasty register data or multi-center high quality observational studies are needed to produce larger numbers and potentially generate higher quality of evidence to reach more solid conclusions.The authors declare that they have no competing interests.TR designed the study, acquired the data and drafted the manuscript. MR contributed substantially to the acquisition of data, carried out the statistical analysis and has been involved in interpretation of the data. AF and JV participated in the study design, and have been involved in critically revising the manuscript for important intellectual content. All authors read and approved of the final manuscript.The pre-publication history for this paper can be accessed here:


Ruptured abdominal aortic aneurysm (AAA) is responsible for 1–2% of all male deaths over the age of 65 years. Early detection of AAA and elective surgery can reduce the mortality risk associated with AAA. However, many patients will not be diagnosed with AAA and have therefore an increased death risk due to the untreated AAA. It has been suggested that population screening for AAA in elderly males is effective and cost-effective. The purpose of this study was to perform a systematic review of published cost-effectiveness analyses of screening elderly men for AAA.We performed a systematic search for economic evaluations in NHSEED, EconLit, Medline, Cochrane, Embase, Cinahl and two Scandinavian HTA data bases (DACEHTA and SBU). All identified studies were read in full and each study was systematically assessed according to international guidelines for critical assessment of economic evaluations in health care.The search identified 16 cost-effectiveness studies. Most studies considered only short term cost consequences. The studies seemed to employ a number of "optimistic" assumptions in favour of AAA screening, and included only few sensitivity analyses that assessed less optimistic assumptions.Further analyses of cost-effectiveness of AAA screening are recommended. The annual number of deaths attributable to ruptured abdominal aortic aneurysm (AAA) in Denmark is approximately 400–500 ,2, correFour randomized controlled trials (RCTs) have shown a reduction in AAA-related mortality from screening programs aimed at elderly males . An expeThe purpose of this study was to review cost-effectiveness studies of screening programs for AAA in elderly males, and to assess the evidence of cost-effectiveness of such programs.Systematic searches were undertaken in NHSEED, EconLit, Medline, Cochrane, Embase, Cinahl, and two Scandinavian health technology assessment databases (DACEHTA and SBU). The search was from 01.01.1997 to 01.06.2008. Search strategies  were thesaurus-guided: aortic-aneurysm-abdominal (MeSH) AND mass-screening (MeSH), and aortic-aneurysm-abdominal, added subheading "prevention and control". Free text search on AAA screening was also done. Reference lists of identified studies and other recent relevant publications were inspected for additional references.Only studies in English or Scandinavian languages in peer-reviewed journals were included. Studies had to be a full health economic evaluation considering cost and effects  of screening males for AAA.Studies -23 were Sixteen studies were included Table . An exteBased on the reviewed studies, the main types of costs associated with population screening, surveillance and surgery for AAA have been compiled as shown in Table There were great variations between the studies in the type of costs. Most studies included only short-term costs, i.e. it was implicitly assumed that there is no difference in the long-term costs between the alternatives. Only three studies ,15,18 inAll studies included the costs of invitation to screening, ultrasonography, and surgery. Only three of the 16 studies included private cost to patients  ,17,18. NCost amount varied considerably between studies (data not shown). An example is the cost of ultrasonography in the MASS study , which wUltrasonography is the "gold standard" for AAA screening, and has been used in all AAA trials and decision analytic models. All studies assumed that ultrasonography was done by a mobile team of hospital specialists. Surveillance of patients with small AAAs was assumed to be handled by the same team. There were differences with regard to the: (i) number and type of screening locations; (ii) average distances of travel for the team and patients; and (iii) role of the general practitioner. Organizational models in all studies were described only superficially, which restricted transferability.Six economic evaluations were conducted alongside trials using patient-level data in evaluation of the cost-effectiveness of AAA screening. Three studies -10 used Ten studies used decision analytic modelling to estimate long-term cost-effectiveness of AAA screening. The general conclusion from these studies was that AAA screening seems to be cost-effective, but the ICER varies considerably and a direct comparison of results is not possible due to considerable differences in the analytical basis. Studies employed different methods  and different assumptions  for their analysis.Half of the modelling studies were based on evidence of the effectiveness of AAA screening from RCTs. All used evidence from screening a group of men  to estimate effectiveness of screening a single age group . Other modelling studies were based on effectiveness data from trials with lower levels of evidence.In general, the main advantage of screening is assumed to be an increase in the number of patients diagnosed with AAA and offered elective AAA repair. All studies assumed a constant risk of rupture depending on AAA size. The gained life-years/QALYs arise because the total number of elective surgeries increases, and the need for emergency surgery of ruptured AAA is therefore assumed to decrease.Most of the studies used national mortality rates for the average population as proxy for long-term survival after elective surgery, but some studies made more realistic assumptions. Wanheinen et al.  assumed Seven of the decision analytic studies calculated ICER as the incremental cost per gained QALY. These studies implicitly assumed that postoperative QOL (and after recovery) was similar to the QOL of the age-matched general population. Only one study  includeOnly two studies carried out sensitivity analyses of QOL assumptions. Wanheinen et al.  assumed The purpose of this review was to carry out a critical assessment of cost-effectiveness studies of screening older males for AAA. Based on our review of 16 studies, it seems that most of the health economic analyses of screening for AAA employed "optimistic" assumptions about the cost effectiveness of AAA screening.The MASS cost-effectiveness study at four years  has the In all published decision analytic models of AAA screening hypothetical patients with an AAA ≥ 5.5 cm were assumed to face a constant probability of rupture  no matter how many years they have had a large AAA. In cohort simulations such a constant probability of rupture gives a wrong distribution of death over time and a mean age of males having emergency surgery for ruptured AAA that is much too low. For instance in Denmark the mean age of death from ruptured AAA is 76 years (range 65–92) for males aged ≥ 65. One way to "build memory" into a model is to implement time dependency, but none of the modelling studies seems to have done so. Accordingly, when underestimating the age of males dying of ruptured AAA in the non-screening group the calculated number of "gained life-years" due to screening and avoiding ruptures is too high.Most of the health economic studies of AAA screening only included short term hospital costs. Major implications for society due to comorbidity and severe surgical complications  were not included because most studies did not consider cost after hospital discharge. Patient pathways after such events can be very costly . FurtherEconomic evaluations did not incorporate evidence that the lives of tobacco smokers are generally shorter than those of the general population, and that they have a higher demand for health services  and a lower QOL in the remaining life-years -27 . Only studies of QOL with poorer designs have been published.Furthermore, the clinical literature of QOL after elective repair that are being referred to seems to be in conflict with public health evidence that smokers experience a lower QOL in their remaining years of life compared to the average population. At least more sensitivity analyses should have been done to evaluate the possibility of lower QOL due to comorbidity and severe surgical complications such as chronic renal failure, major amputation or stroke.Various other factors likely to reduce cost-effectiveness were ignored in the economic evaluations. In most cases, cost calculations were based on open repair and not on endovascular aneurysm repair. Despite lack of evidence of cost-effectiveness, this method of treating AAAs is being used increasingly in many countries. It may reduce early mortality more effectively, but it may substantially reduce the cost-effectiveness of screening .ad hoc detection of AAA cases will gradually increase as imaging (mostly ultrasonography) becomes more widely utilized for other reasons. This may reduce the prevalent pool of undiagnosed AAAs and hence screening effectiveness [The possibility is that tiveness .Our findings are in accordance with those of Campbell et al. ; they reThe individual conclusions of cost effectiveness cannot be rejected on the basis of this systematic review, but we can seriously challenge the assumptions on which the studies of cost-effectiveness are based. Our review leaves little doubt that the reported cost-effectiveness ratios of AAA screening in most cases have been too low.Our findings should have implications for future research recommendations in cardiovascular medicine and surgery. It appears that existing analyses have overrated the advantages of AAA screening in terms of the expected number of gained life-years/QALYs and cost of a screening programme. Different patient pathways after surgery are ignored, and sensitivity analyses of long-term QOL after surgery are not satisfactory.We therefore strongly recommend that an "updated" cost-effectiveness analysis should be carried out based on more realistic assumptions.This review indicates that most of the existing health economic evaluations have employed a number of "optimistic" assumptions in favour of AAA screening, and included only few sensitivity analyses that assessed less optimistic assumptions. Further analyses of cost-effectiveness of AAA screening are recommended.The authors declare that they have no competing interests.LE carried out the main study and drafted the manuscript. LS, MB, LGJ and MK participated in the analyses and discussion of the results. LGJ also carried out the literature search. All authors approved the final manuscript.The pre-publication history for this paper can be accessed here:Studies of cost-effectiveness of AAA screening. The additional file is an extended version of Table Click here for file


The objective was to determine the expression of estrogen and progesterone receptors in vestibular schwannomas as well as to determine predictive factors for estrogen and progesterone receptor positivity.The study included 100 cases of vestibular schwannomas operated from January 2006 to June 2009. The clinical details were noted from the medical case files. Formaldehyde-fixed parafiin-embedded archival vestibular schwannomas specimens were used for the immunohistochemical assessment of estrogen and progesterone receptors.Neither estrogen nor progesterone receptors could be detected in any of our cases by means of well known immunohistochemical method using well documented monoclonal antibodies. In the control specimens, a strongly positive reaction could be seen.No estrogen and progesterone receptor could be found in any of our 100 cases of vestibular schwannomas. Hence our study does not support a causative role of estrogen and progesterone in the growth of vestibular schwannoma as well as hormonal manipulation in the treatment of this tumor. Estrogen and progesterone receptors have been reported in various human tumors, including endometrial carcinoma, breast carcinoma, and carcinoma of prostate. They play a crucial role in the treatment of breast carcinoma. The presence of these receptors has been examined in a number of intracranial tumors, in particular in meningiomas. It has been suggested that these hormones could be involved in the development of meningiomas and that their influence could explain the greater frequency of meningiomas in women than in men, their increased growth rate during pregnancy, and their association with breast cancer ,2. SchwaVestibular schwannoma also known as acoustic schwannoma is the most common cerebellopontine angle tumor and represents 9% of all brain tumors Figure . ExpressThe objective of the present study was to retrospectively determine the expression of estrogen and progesterone receptors by means of immunohistochemical methods using monoclonal antibodies in 100 cases of vestibular schwannomas and also to determine predictive factors for estrogen and progesterone receptor positivity.This retrospective study included 100 cases of vestibular schwannomas operated from January 2006 to June 2009 in the Department of Neurosurgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. The clinical parameters like age, sex, evidence of cutaneous marker for Neurofibroatosis, and menopausal status were noted from the medical case files. All patients were operated by suboccipital retrosigmoid approach.Formaldehyde-fixed parafiin-embedded archival vestibular schwannomas specimens from the patients were obtained from the Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. Five micron thick sections were obtained and the standard streptavidin biotin peroxidase immunohistochemical method was used for the expression of estrogen and progesterone receptors. Estrogen receptor  and progesterone receptor  monoclonal antibodies were used for the study. Estrogen and progesterone positive breast tissue was used as positive control for estrogen and progesterone receptors. For negative control, primary antibody step was omitted while performing immunohistochemistry.Table Vestibular schwannoma is a benign cerebellopontine angle tumor and it expresses various hormone receptors for examples estrogen, progesterone, androgen, somatostatin and glucocorticoid. The clinical significance of these receptors is that they play a possible role in tumor growth ,14. StudKasantikul and Brown  analyzedCurley et al  studied This study demonstrated no evidence to support the clinical hypothesis that vestibular schwannomas might be hormone dependent tumours. The methods of assay used were both specific and sensitive. No estrogen and progesterone receptor could be found in any of our 100 cases of vestibular schwannoma. Hence our study does not support a causative role of estrogen and progesterone in the growth of vestibular schwannoma as well as hormonal manipulation in the treatment of this tumor.The authors declare that they have no competing interests.SJ: Principal investigator - did the study, collected data and wrote the paper; VA: Co-investigator - helped in doing the study and collecting the data; AKJ: Co-investigator - collected the articles; RP: Co-investigator - provided the advice and coordinated the study; AKM: Co-investigator - gave the idea and advice for the study.


Musculoskeletal disorders (MSDs) due to repetitive work are common in manufacturing industries, such as the automotive industry. However, it's still unclear which MSDs of the upper limb are to be expected in the automotive industry in a first aid unit as well as in occupational precaution examinations. It is also unclear which examination method could be performed effectively for practical reasons and under rehabilitation aspects. Additionally, it was to discuss whether the conception of unspecific description for MSDs has advantages or disadvantages in contrast to a precise medical diagnosis.We investigated the health status of two study populations working at two automotive plants in Germany. The first part included 67 consecutive patients who were seen for acute or chronic MSDs at the forearm over a 4-month period at the plants' medical services. Information about patients' working conditions and musculoskeletal symptoms was obtained during a standardized interview, which was followed by a standardized orthopedic-chiropractic physical examination. In the second part, 209 workers with daily exposure to video display terminals (VDT) completed a standardized questionnaire and were examined with function-oriented muscular tests on the occasion of their routine occupational precaution medical check-up.The majority of the 67 patients seen by the company's medical services were blue-collar works from the assembly lines and trainees rather than white-collar workers from offices. Rates of musculoskeletal complaints were disproportionately higher among experienced people performing new tasks and younger trainees. The most common MSD in this group were disorders of flexor tendons of the forearm. By contrast, among the 209 employees working at VDT disorders of the neck and shoulders were more common than discomfort in the forearm. A positive tendency between restricted rotation of the cervical vertebrae and years worked at VDT was observed. In addition, only less than 8% of unspecific disorders of the upper limb (esp. wrist and forearm) were found.Functional tests for the upper limb seemed to be very helpful to give precise medical advice to the employees to prevent individual complaints. The results are also helpful for developing specific training programs before beginning new tasks as well as for rehabilitation reasons. There's no need to use uncertain terminology (such as RSI) as it may not be representative of the actual underlying disorders as diagnosed by more thorough physical examinations. The increased automation of the car manufacturing process, in which much of the assembly has been delegated from man to machine, has done much to relieve workers the burden of heavy lifting . HoweverThe main objective of this two-part study was to determine the type of upper limb musculoskeletal disorders (MSDs) among both blue-collar  and white-collar (office) workers in large automotive manufacturing plants. A secondary objective was to relate the individual disorders to the results of the functional examinations and, if possible, to type of repetitive work they perform. It was also of interest whether functional testing can be helpful in developing individual training or rehabilitation programs. Additionally, it was of interest whether the conception of unspecific descriptions for MSDs in the upper extremity has advantages compared with functional-oriented muscular tests and developing a precise medical diagnosis.Workers from two automotive manufacturing plants in Germany participated in this study. Plant A assembled gearboxes and small service parts for two German car manufacturers, plant B manufactured light duty vehicles and small passenger busses. Both plants employed roughly 15,000 workers each, only a quarter of whom were white-collar workers. Trainees comprised approximately 5% of the workforce in both plants. Blue-collar work included repetitive tasks such as assembling product, connecting cables, polishing metal and drilling (Plant A) respectively working in a press shop, body shop or car assembly lines (Plant B). All participants provided informed consent.The study group in the first part of the investigation consisted of 67 consecutive employees who were seen on their own decision in the company's medical service units in plant A over the 4-month study period for acute or chronic musculoskeletal disorders in the forearm . Seventy-four percent of the participants were blue-collar workers, whose jobs required manual force; only 16% of the participants worked at computer monitors for more than 6 hours per day. Information about the presenting symptoms and the patient's respective working environment were obtained during a standardized interview, after which an experienced occupational physician examined the patient. The physical examination of affected joint and other selected joints consisted of range of motion tests and resisted motion maneuvers  were diagnosed with clinical signs for tendovaginitis of the forearm. Disorders of flexors of the forearm outnumbered disorders of the forearm extensors almost 3:1. The diagnosis rates of traumatic injuries and treatable chiropractic disorders were roughly equivalent  MSDs of the upper extremity, the study of the 209 employees working at VDTs demonstrated that 24.4% of the subjects had restrictions of motion. The shoulder region and the neck were more often affected than the forearm fig In the two studies we were able to demonstrate the usefulness of systematic functional tests in the diagnosis of work-related musculoskeletal disorders of the upper limb of workers due to long-term occupational stress in the automotive industry. The disorders of the forearm flexor tendons were most common among blue-collar workers at assembly lines and trainees, whereas the cervical rotation and side-flexion was most affected in white-collar workers with different VDT tasks, which is in good accordance with information in the literature . DespiteControversy remains in occupational health literature as to the prevalence of unspecific diagnosis terms like RSI in industries with assembly line and VDT-work . The resIn this study, methodological functional testing allowed the occupational physician to identify and specifically diagnose injured structures as described by Kuhn and Spallek . The resThe authors declare that they have no competing interests.MS and WK carried out the physical examinations and drafted the manuscript, SU and AvM participated in the design of the study and in the evaluation. DQ contributed to the discussion and interpretation of the results. All authors read and approved the manuscript. Part of this study was presented at the XIIIth Annual International Occupational Ergonomics and Safety Conference.


Traumatic injury and surgical meniscectomy of a medial meniscus are known to cause subsequent knee osteoarthritis. However, the difference in the prevalence of osteoarthritis caused by the individual type of the medial meniscal tear has not been elucidated. The aim of this study was to investigate what type of tear is predominantly responsible for the degradation of articular cartilage in the medial compartment of knee joints.Five hundred and forty eight cadaveric knees  were registered in this study. The average age of cadavers at death was 78.8 years old (range: 52-103 years). The knees were macroscopically examined and their medial menisci were classified into four groups according to types of tears: "no tear", "radial tear of posterior horn", "other types of tear" and "worn-out meniscus" groups. The severity of cartilage degradation in their medial compartment of knee joints was evaluated using the international cartilage repair society (ICRS) grading system. We statistically compared the ICRS grades among the groups using Mann-Whitney U test.The knees were assigned into the four groups: 416 "no tear" knees, 51 "radial tear of posterior horn" knees, 71 "other types of tear" knees, and 10 "worn-out meniscus" knees. The knees with substantial meniscal tears showed the severer ICRS grades of cartilage degradation than those without meniscal tears. In addition, the ICRS grades were significantly severer in the "radial tear of posterior horn" group than in the "other types of tear" group, suggesting that the radial tear of posterior horn in the medial meniscus is one of the risk factors for cartilage degradation of joint surface.We have clarified the relationship between the radial tear of posterior horn in the medial meniscus and the severer grade of cartilage degradation. This study indicates that the efforts should be made to restore the anatomical role of the posterior horn in keeping the hoop strain, when patients' physical activity levels are high and the tear pattern is simple enough to be securely sutured. A meniscus is a crescent-shaped fibrocartilagious structure and has multifunctional roles in normal motion of knee joints -3. It plA radial tear of posterior horn in the medial meniscus is not rare in the elderly people . HoweverA meniscus protects the adjacent articular cartilage by keeping the congruency of the femorotibial articulation and distributing axial load properly on the surface of femorotibial articular cartilage . Actuallt-test was used to evaluate the age distribution among groups in the study. Mann-Whitney U test was used to evaluate the relationship between the ICRS grades and types of meniscal tears. In all analyses, a p-value less than 0.05 was considered significant.We performed an anatomical study using cadaveric knees. Cadavers who had history of some injuries or surgeries in their knees were excluded from this study. All cadavers were donated to science via the Nihon University after written approval from bereaved families. Five hundred and forty eight knees  were registered in this study. The average age of cadavers at death was 78.8 years old (range: 52-103 years). The meniscal tears were examined macroscopically and were assigned into four groups according to types of tears in the medial meniscus: "no tear" group, "radial tear of posterior horn" group, "other types of tear" group, and "worn-out meniscus" group. "No tear" meant that no substantial tears in the medial menisci were detected by macroscopic examinations. The posterior horn of the medial meniscus is attached to the tibial plateau via the insertional ligament Figure . The "raThe knees were assigned into four groups according to types of tears in the medial meniscus: 416 "no tear" knees, 51 "radial tear of posterior horn" knees, 71 "other types of tear" knees, and 10 "worn-out meniscus" knees. The average age of cadavers at death in each group was 77.7, 82.3, 82.3 and 80.5 years old, respectively. Although the average age in the "no tear" group was younger than that in the "radial tear of posterior horn" group or the "other types of tear" groups (p < 0.001), there was no significant differences among the "radial tear of posterior horn" group, the "other types of tear" group and the "worn-out meniscus" group. A gender distribution was also comparable among the three groups (Table The cartilage degradation of medial compartment was compared using the ICRS grading system among the four groups. The knees with no meniscal tears revealed 288 grade 0 or 1, 62 grade 2, 50 grade 3, and 16 grade 4 ICRS grades of cartilage degradation in their medial compartments. The "radial tear of posterior horn" group was 4, 3, 17 and 27 cases, the "other types of tear" group was 15, 9, 22 and 25 cases, and the "worn-out meniscus" group was 0, 1, 1 and 8 cases, respectively (Table We demonstrated that the radial tear of posterior horn in the elderly was associated with the severer grade of cartilage degradation by the cadaveric study. Our data showed that knees with substantial meniscal tears were susceptible to the severer cartilage degradation than those with no tears, although this may partly be explained by the fact that the average age in the "no tear" group was younger than that in the other groups. On the other hand, since the age and gender distributions among the "radial tear of posterior horn", "other types of tear" and "worn-out meniscus" groups were comparable, we can precisely compare the prevalence of cartilage degradation among the three groups. As a result, the "radial tear of posterior horn" group exhibited the severer ICRS grades than "other types of tear" group, indicating a predominant involvement of the radial tear of posterior horn in cartilage degradation.However, there are several limitations in this study. At first, we have only evaluated degrees of cartilage degradation on the articular surface without taking account of the existence of osteophyte, which is one of the considerable factors of knee osteoarthritis. Therefore, the prevalence of osteoarthritis in this study may be lower than that of radiographic osteoarthritis evaluated by the conventional classification using Kellgren-Laurence grading system . Second,Our current study suggests the anatomical importance of the posterior horn of medial meniscus. Hence, we must carefully check the posterior horns during arthroscopic examinations and try to repair the tear site and maintain the function as possible. There are several reports on the arthroscopic repair of the posterior horn's injury in the medial meniscus -20. We aThe current study is the first report to address the involvement of the radial tear of posterior horn in cartilage degradation of joint surface by a human cadaveric study. To further investigate the anatomical significance of the posterior horn of medial meniscus will lead the correct understanding of the knee kinematics and the improvement in treatments of its tear.We have clarified that there is a significant relationship between the radial tear of posterior horn and the cartilage degradation of joint surface.The authors declare that they have no competing interests.AK participated in analyzing the data and drafting the manuscript. MO, SO, MI and SO participated in the design of the study and collect the data. TN revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.


The illustrated case is a 55-year-old asymptomatic multiparous post-menopausal female who was diagnosed to have microscopic hematuria on serial urine cytology examinations . There were 5-10 isomorphic erythrocytes per high-power field, without any proteinuria or pus cells in any examination. There was no history of diabetes, hypertension or any major illness in the past. The complete blood cell count, serum biochemistry and coagulation profile were within normal limits. Ultrasound examination did not reveal any definite structural abnormality in the urinary system. The multi-detector computed tomography examination, however, showed significant dilatation of the left ovarian vein with formation of pelvic varices in the broad ligament  and b. Tet al., suggest the abnormal angle of the origin and course of the proximal part of SMA to be responsible for this phenomenon.[Nutcracker phenomenon was first described by de Schepper in 1972, as compression of the LRV, usually in the fork between the aorta and superior mesenteric artery.2 The abnoenomenon. The roleenomenon. Aberrantenomenon.et al., described the role of LRV diameter and peak flow velocity measurements on B-mode ultrasound and Doppler respectively.[Kim ectively. The LRV ectively. The B-moThe patients with nutcracker phenomenon are usually young and thin. The nutcracker phenomenon may be an important cause of pediatric varicocele. In children, the role of Doppler US for the diagnosis of nutcracker phenomenon is affected by the fact that the LRV sampling area is smaller. Apart from this, the Doppler angle is larger in children than in adults. The high reno-caval pressure gradient may lead to retrograde blood flow from the LRV into the testicular vein. Doppler spectral analysis and venography of the LRV are useful in children with varicocele to look for the presence of underlying nutcracker phenomena. Compress9The MDCT provides an important noninvasive alternative to diagnose this condition based on LRV dimensions, reflux of contrast medium from LRV into left ovarian vein and delineation of collaterals. The LRV dimensions are measured as antero-posterior dimension in the axial planes at two different points. The first measurement is done for the lateral segment of LRV at a point where the left ovarian vein drains into the LRV. The second measurement is done for the aorto-mesenteric segment of LRV at the narrowest point where the LRV passes between the aorta and the superior mesenteric artery. The dimensions are expressed as LRV ratio which is the ratio of measurements in the lateral segment and aorto-mesenteric segments of LRV. Reflux iThe treatment of NS significantly depends on the patient symptoms and urine microscopy findings. The patients with mild hematuria can be offered conservative treatment with close follow-up. The illu21In the absence of structural causes, LRV hypertension or ‘nutcracker syndrome’ should always be ruled out in a case of macroscopic or microscopic hematuria. The phase-contrast urine microscopy shows isomorphic erythrocytes. B-mode ultrasound including Doppler assessment and MDCT are the primary imaging modalities. Invasive venography may be required for further evaluation. It is, however, important to differentiate asymptomatic dilatation of LRV (nutcracker phenomenon) and ‘nutcracker syndrome’ presenting with gross or microscopic hematuria, orthostatic proteinuria, varicocele and hypertension. The diagnosis of LRV hypertension should be made with caution in multiparous women. As illustrated in the present case of ‘hematuria of unknown origin’, the MDCT diagnosis of LRV hypertension is feasible in clinical practice if due attention is paid to finer imaging details and the index of suspicion is high.