Among women, breast cancer (BC) is the leading cancer and the most common cause of cancer-related death between 30 and 69 years. Although lifestyle and diet are considered to have a role in global BC incidence pattern, the specific influence of dyslipidemia in BC onset and progression is not yet completely understood.Fasting lipid profile  was prospectively assessed in 244 women with BC who were enrolled according to pre-set inclusion criteria: diagnosis of non-hereditary invasive ductal carcinoma; selection for surgery as first treatment, and no history of treatment with lipid-lowering or anti-diabetic drugs in the previous year. Pathological and clinical follow-up data were recorded for further inclusion in the statistical analysis.Univariate associations show that BC patients with higher levels of LDL-C at diagnosis have tumors that are larger, with higher differentiation grade, higher proliferative rate (assessed by Ki67 immunostaining), are more frequently Her2-neu positive and are diagnosed in more advanced stages. Cox regression model for disease-free survival (DFS), adjusted to tumor T and N stages of TNM classification, and immunohistochemical subtypes, revealed that high LDL-C at diagnosis is associated with poor DFS. At 25 months of follow up, DFS is 12% higher in BC patients within the third LDL-C tertile compared to those in the first tertile.This is a prospective study where LDL-C levels, at diagnosis, emerge as a prognostic factor; and this parameter can be useful in the identification and follow-up of high-risk groups. Our results further support a possible role for systemic cholesterol in BC progression and show that cholesterol metabolism may be an important therapeutic target in BC patients. Cancer and cardiovascular diseases are the leading causes of death in Europe  and USA In what concerns cancer, breast cancer (BC) is the most frequent diagnosed each year in Europe and USA   and the Lifestyle and diet are frequently indicated as reasons for the global distribution of BC incidence. Nevertheless, while dyslipidemia [high LDL-C (low density lipoprotein cholesterol) and low HDL-C (high density lipoprotein cholesterol) levels] was already shown to play a major role in the etiopathogenesis of cardiovascular diseases , mainly Cholesterol is a structural component of the cell membrane, specially localized in lipid rafts - membrane microdomains that assemble the signal transduction machinery and associate to proteins implicated in key cellular signaling pathways. Many of these pathways closely associate with malignant transformation due to their influence in organization of the cytoskeleton, cell polarity and angiogenesis ,9.Furthermore, cholesterol is also a steroid hormone precursor and the vast majority of BC is known to be hormone responsive . The peain vitro and clinical examination were recorded in the first interview.Treatment was determined by the clinicopathological stage and patient characteristics according to the institutional protocols (following NCCN guidelines ), withouFollow up, after surgery and adjuvant treatment (when appropriate), was scheduled every 6 months for 2 years and annual thereafter. Mammography was performed 1 year after surgery and then repeated yearly.Fasting lipid profile was measured at diagnosis, along with routine preoperative exams. Blood was collected into EDTA-coated tubes and the plasma levels of total cholesterol (TC), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C) and triglycerides were measured automatically by electrophoresis  at the certified Clinical Pathology Laboratory of IPOLFG.in situ hybridation. Immunohistochemical staining for Ki 67 was performed in a Dako Autostainer®  using standard protocols, followed by counting positive cells in an automated cellular imaging system . Technicians were blinded to the lipid profile status of the study participants.Hormonal receptors were measured using standardized immunohistochemistry. Her2-neu receptor was scored according to the World Health Organization guidelines  from 0 tContinuous variables are presented as mean (standard deviation) or median (interquartile range) if they have normal distribution or not, respectively. For categorical variables absolute values and frequencies are shown.Spearman rank correlations coefficients were calculated to examine correlations between continuous variables.Univariate analysis between lipid profile, BC risk factors  and traditional prognostic factors  were performed using parametric tests to variables with normal distribution and non-parametric tests to variables without normal distribution.Multivariate logistic regression to the risk of tumor T stage included the following variables: TC (by tertiles), LDL (by tertiles), Triglycerides (3rd tertile), BMI (by tertiles) and age (by tertiles) by using stepwise conditional forward analysis method .Kaplan-Meier curves were used to determine overall survival (OS) and disease-free survival (DFS) rates with use of log rank tests. Cox proportional hazards models were used to estimate hazard ratios with 95% confidence intervals (CI), relating LDL level to DFS. Multivariate Cox model was adjusted to tumor T stage, N stage and subtype.To assess the internal validity of our results we examined the association of lipid profile with BMI and age. The association of BMI and tumor characteristics, as well as OS and DFS adjusted to BMI were also determined.For statistical purposes, cases were censored at the date of disease progression confirmation, death or at June 9th, 2013, whichever came first.P values are reported to whole variables in the model. All P values are two-tailed.Likelihood ratio The statistical analysis was done using IBM SPSS Statistics for Windows, Version 19.0.A total of 446 women were potential assembled to the study. Of those, 202 were excluded for being on conflicting medications n = 134), for BC histological type (n = 60) and previous treatments (n = 9). Baseline demographic, clinical and tumor related characteristics of the study population (n = 244) are listed in Table 34, for BAll women underwent surgery, being the majority treated with breast-conserving surgery ; 78,3% had adjuvant radiotherapy; 67,7% had systemic chemotherapy; 11,9% are under trastuzumab and 70,1% are under hormone therapy  . As expected, age correlates with BMI  and triglycerides  and BMI correlates with age, LDL-C , HDL  and triglycerides .Exploratory correlations between lipid profile, age, BMI, primary tumor size and lymph node metastasis ratio , showed that systemic levels of LDL-C and TC correlates positively with tumor size  , with higher proliferative rate , and are diagnosed in more advanced stages. This analysis does not demonstrate differences in lipid profiles between breast tumor immunohistochemical subtypes  . Nevert) Figure .A multivariate logistic regression to the risk of tumor T stage was then modeled. All the variables significantly associated at univariate analysis    Table .Multiple epidemiological studies exploring causal associations between dyslipidemia and BC incidence produced contradictory results -37. Sevein vivo pre-clinical studies , In the present study, fasting lipid profile (with discrimination between lipids and lipoproteins fractions) was prospectively assessed in a cohort of patients with invasive carcinoma, in initial stages, before any treatment and with no history of being on antidiabetic or lipid lowering drugs . Population characteristics are similar to other series, concerning to demographic and tumor characteristics -66. A slResults show that systemic LDL-C level above 117 mg/dL is a predictive factor of tumor T stage, at diagnosis. These levels are also positively associated with worse prognostic characteristics such as higher histological grade, higher proliferative rate  and moreOther published studies, also focused on assessing lipid profile in BC patients, found higher TC levels in BC patients, compared to healthy control patients ,52 and aTo our knowledge this is the first cohort of BC patients in which the correlation of lipid profile and tumor characteristics was done in a setting of pre-treatment and with all patients free of lipid lowering drugs. Despite we did not accessed variables that may also influence the lipid profile such as smoking habits, type of diet, residence area or socioeconomic status, the most important co-variables, BMI, age and lipid lowering drugs were controlled.P 0,013). Differences of DFS in the LDL tertiles groups, adjusted to BMI remains statistically significant  primary tumors have a cancer-fuelling effect and are a co-causative factor, in patients with chronic hypercholesterolemia. But, on the other hand, the high LDL-C levels that we observed may actually reflect a shift in cholesterol synthesis (by the liver or tumor cells themselves) in patients with aggressive tumors; accordingly, Zielinski et al.  followedin vitro cell proliferation, attesting that cholesterol biosynthesis should be important to tumor growth [Considering that proliferating cancer cells have an increased demanding of cholesterol and intermediates of cholesterol biosynthesis pathway, the up-regulation of cholesterol biosynthesis and reduced cellular efflux are expected. In cancer cells, cholesterol synthesis has been shown to be increased, due to availability of precursors or to increased transcription , and thir growth . Moreover growth  and acylr growth .However, despite cancer cells increases intracellular cholesterol synthesis, this effect is not expected to produce hypercholesterolemia and justify the observed associations.in vitro experiments, was also demonstrated that cancer cells can also consume HDL-C through the scavenger receptor class B, type I (SR-BI) [Some other published data supports the notion that cancer cells are able to uptake cholesterol from the bloodstream. High LDL-C receptor expression was demonstrated in BC tissue, compared to normal tissue . So plas (SR-BI) ,16,78 an (SR-BI) . In our Corroborating this hypothesis are laboratory studies showing that both exogenous LDL-C and HDL-C can promote proliferation and migration, features of aggressive tumors -16. AlsoThe exogenous cholesterol could be mobilized from body storage, through HDL-C or from diet, through hepatic metabolism and LDL-C. Mobilization is not likely to contribute to hyperlipidemia, since we saw the same pattern of lipid profile in BC patients and in the age and sex-matched non-cancer portuguese population ,68.High LDL-C and low HDL-C is the most common lipid profile induced by western diet and is highly frequent .Initial studies on cholesterol and cancer showed an increased risk in patients with lower plasma cholesterol. Once demonstrated that reduction in cholesterol level does not cause cancer this has been assumed as a preclinical effect of malignancy considering that cancer cells up take cholesterol and decreases its levels. ,63. We fThe causal relationship between systemic cholesterol has been hard to demonstrate because of the length of time to the event, multifactorial etiology of BC, concomitant medication, statistical analysis and event definitions. However, assuming that cholesterol is essential to cell proliferation, once a tumor develops in a hypercholesterolemic environment it is well adapted to progress and this may be the explanation for the observed association of LDL-C level, tumor size and disease progression.We also found that tumors of the LDL-C highest tertile are more commonly Her2-neu (ErbB2) positive. Moreover, as mentioned earlier, membrane cholesterol is specially localized in the lipid rafts domains. Such areas are enriched in transmembrane molecules that are key in signaling pathways associated with malignant progression: Fas receptor, TNF related apoptosis-inducing ligand, AKT, integrins, cadherins and growth factor receptors  includinIn vitro and in vivo studies have showed contradictory results concerning the effect of cholesterol, in promoting ER positive breast cancer proliferation [Although synthesis of estrogen and progesterone require cholesterol, no association of LDL-C and ER status was seen. feration ,20.The pro-inflammatory microenvironment induced by high-cholesterol levels, as seen in atherosclerosis, in which LDL-C is the most important causative factor ,84, can In our prospective study, patients with high levels of LDL-C at diagnosis had reduced disease free survival, even adjusting to tumor type, stage and BMI. This may reflect that high levels of LDL-C potentiate micrometatasis development or that hypercholesterolemia previously selected aggressive tumors but reinforces a role for systemic cholesterol in BC progression and cholesterol metabolism as a therapeutic target.We found that LDL-C fraction is significantly associated with BC progression and may actually be useful in the identification and follow-up of high-risk groups of BC patients. LDL-C levels at diagnosis, therefore emerge as a prognostic factor in BC. Additionally, results support a role for systemic cholesterol in BC progression and indicate that cholesterol metabolism could be a therapeutic target in BC treatment.The authors have no financial or non-financial competing interests.CRS: Study design, patient enrollment, data collection and analysis, manuscript writing. IF: Pathological data validation and analysis, manuscript revision. SD: Study design, data analysis, manuscript writing. MA: Study supervision, data analysis, manuscript revision. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/14/132/prepubBreast Cancer Treatment (N=244).Click here for fileFollow up (N=244).Click here for fileLipid Profile in Tumor Stage and in Prognostic Groups.Click here for fileTumor Characteristics in BMI Tertiles Groups. A. Tumor size across BMI tertiles groups does not show significant differences. Line represents the median value of tumor size in each BMI tertile. B. Frequency of tumor characteristics in BMI tertiles groups. Kruskall-Wallis test. ER: Estrogen Receptor; PR: Progesterone Receptor; LVI: Lymphovascular Invasion; LN: Lymph Nodes.Click here for filePatient Characteristics in LDL-C level tertiles.Click here for fileUnivariate Logistic Regression to the Risk of Tumor Size ≥20 mm.Click here for fileOverall and Disease-free Survival in LDL-C Tertiles Groups adjusted to BMI. Kaplan–Meier Curves for overall survival and disease free survival to each BMI tertile. are shown. At 25 months of follow up disease-free survival shows differences across LDL-C tertiles, BMI adjusted . But overall survival is not different in LDL-C tertiles .Click here for file


Functional regulatory sequences are present in many transposable element (TE) copies, resulting in TEs being frequently exapted by host genes. Today, many examples of TEs impacting host gene expression can be found in the literature and we believe a new catalogue of such exaptations would be useful for the field.catalogue of genes affected by transposable elements (C-GATE), which can be found at https://sites.google.com/site/tecatalog/. To date, it holds 221 cases of biologically verified TE exaptations and more than 10,000 in silico TE-gene partnerships. C-GATE is interactive and allows users to include missed or new TE exaptation data. C-GATE provides a graphic representation of the entire library, which may be used for future statistical analysis of TE impact on host gene expression.We have established the We hope C-GATE will be valuable for the TE community but also for others who have realized the role that TEs may have in their research. Transposable elements (TEs) are DNA sequences able to jump throughout the genome and increase in copy number. Through transposition, TEs have a direct impact on genome size and therefore increase the genetic repertoire, which in consequence may be the target of de novo evolution. Furthermore, TEs have ready-to-use regulatory sequences that may be exapted as promoters and enhancers, binding sites, splice sites, polyadenylation signals, insulators and termination sites. Since some TE families are species-specific, TEs could also account for species-specific regulatory sequences. In agreement with this, the number of examples of TEs impacting host gene expression is increasing in the literature, particularly with the advent of genome-wide next-generation sequencing technologies. For instance, several groups have found transcription start sites in mammals to be frequently positioned within TE sequences [NAIP promoters in mouse and human for example [Regulation of gene expression is essential for the correct development of an organism, as it dictates where, when and how much of a gene transcript should be produced. Differences in gene expression patterns can also be associated with the divergence of species -3, suggeequences -7. Whileequences ,9, compaequences . Interes example .catalogue of genes affected by transposable elements (C-GATE) is available at https://sites.google.com/site/tecatalog/. We thank the efforts of others to catalogue such exaptations, in particular Brosius [Because of the large amount of data on TE exaptations present in the literature today, including lists in large non-ergonomic supplementary tables, we have decided to create an online database that catalogues published examples of TE exaptations allowing for researchers to easily browse the data. The  Brosius  and Maka Brosius  and othe Brosius ,14. Whilin silico analysis of seven vertebrates and invertebrates species. While TranspoGene remains an interesting resource for genome-wide impact of TE copies, it does not contain TE exaptations described in the literature, but solely examples observed by the authors, at the time of their analysis. C-GATE contains all the data on exaptation available at TranspoGene but also aims to include all exaptation events described in the literature. Furthermore, C-GATE contains two types of data, a general C-GATE data-set that holds only biologically confirmed and published TE exaptation examples, and a pC-GATE that holds data-sets of putative TE exaptations from ESTs, chromatin immunoprecipitation sequencing and other published in silico-only analyses. In order to be part of C-GATE, a TE exaptation needs to be observed in wild-type species, not only in mutants or cancer cell lines. TEs impacting specific inbred strains, as Drosophila melanogaster P element collections, or mouse endogenous retrovirus insertions are considered as genetic mutations and not true TE exaptations. C-GATE also does not include open reading frame domestication, as described for syncytin genes for instance and often reviewed in the literature [It is important to note that another currently active online catalogue of TE exaptations exists, TranspoGene , which iterature ,17. DepeC-GATE is formatted as shown in Table C-GATE: catalogue of genes affected by transposable elements; EST: expression sequence tag; pC-GATE: putative C-GATE; TE: transposable elements.The authors declare that they have no competing interests.RR designed the website. RR, SF and DM included cases to the website. RR and DM wrote the paper. All authors read and approved the final manuscript.


In relation to pharmacognosy, an objective of many ethnobotanical studies is to identify plant species to be further investigated, for example, tested in disease models related to the ethnomedicinal application. To further warrant such testing, research evidence for medicinal applications of these plants  is typically analyzed in biomedical databases.® database.As a model of this process, the current report presents novel information regarding traditional anti-inflammation and anti-infection medicinal plant use. This information was obtained from an interview-based ethnobotanical study; and was compared with current biomedical evidence using the MedlineOf the 8 anti-infection plant species identified in the ethnobotanical study, 7 have related activities reported in the database; and of the 6 anti-inflammation plants, 4 have related activities in the database.Based on novel and complimentary results from the ethnobotanical and biomedical database analyses, it is suggested that some of these plants warrant additional investigation of potential anti-inflammatory or anti-infection activities in related disease models, and also additional studies in other population groups. Ethnobotanical studies of medicinal plants often provide a first step in the process of selecting plants  to be tested in experimental models of various diseases. To further warrant such testing, another typical step is to search biomedical databases for existing research evidence that links these plants  to the same therapeutic applications. As a model of this process, the current report presents novel information regarding traditional anti-inflammation and anti-infection medicinal plant use in a region of the Iberian Peninsula; and this information is compared with current biomedical evidence.Over the past 2 decades, there have been several ethnobotanical studies of medicinal plants in the Iberian Peninsula.–3 There 4® biomedical database. Common applications of a given medicinal plant or its main phytochemical constituent(s) are reported and suggested as warranting further analyses in biomedical models or, for comparative purposes, in other regions and populations.The current study provides some novel information regarding traditional medicinal plant use in this region . Information from plant-application associations in this region is compared for the specific medicinal plants with that in the Medlinead hoc from, elder residents  of villages near the northwest PNSAC border. Plants were identified by several methods: visual inspection, name searches in dictionaries and official botanical websites, and primarily from Flora Digital de Portugal (http://www.jb.utad.pt/pt/herbario/cons_reg.asp), a service provided by the botanical garden of Universidade de Trás-os-Montes e Alto Douro (UTAD) in Portugal.Information was obtained from interviews with, and acquired Analysis of the Medline database  was performed to assess both the extent of overall biomedical research on each of the medicinal plants and biomedical research evidence for the ethnobotanical, plant disease, and association that was identified for each of the plants.Allium cepa and Sambucus nigra. Based on the database search, the least researched of the plants identified in this study include Malva sylvestris, Mentha pulegium, and Capsella bursa-pastoris.The compilation of medicinal plants with traditional anti-infection or anti-inflammation uses is shown in References for biomedical research evidence related to the ethnobotanical applications are also indicated in Ruscus aculeatus, ruscogenin, has recently been shown to inhibit proinflammatory factors, including tumor necrosis factor-α effects and nuclear factor-κB activation;[A steroidal phytochemical of tivation; this plaM. pulegium (over 70% piperitone/piperitenone) was demonstrated to have antimicrobial activity, especially against gram-positive bacteria, minimum inhibitory concentration (MIC) of approximately 2 µL/mL[The essential oil of Allium species, including A. cepa, onion, used locally to treat infections. A quercetin derivative isolated from A. cepa, 3-(quercetin-8-yl)-2,3-epoxyflavanone, exhibited antimicrobial activity against Helicobacter pylori and methicillin-resistant Staphylococcus aureus.[There are many publications of antimicrobial activities of Rosa canina and M. sylvestris were demonstrated to have growth inhibitory activity, IC50 less than 32 mg/mL for biofilm inhibition, against methicillin-resistant S. aureus[Both S. aureus; both plS. aureus has also been documented for 8-hydroxydihydro-sanguinarine  extracted from Chelidonium majus;[Inhibitory activity against methicillin-resistant um majus; this plaRuscus and Chelidonium, warrant further investigation of their respective anti-inflammatory and anti-microbial activities in other population groups and in additional experimental models of disease.In conclusion, the current study provides novel information on medicinal plants with traditional anti-infection and anti-inflammation usage in the PNSAC region. Complementary activities of these plants, or of their phytochemical constituents, are presented. It is suggested that some of these plants, especially


Noncommunicable diseases are an increasing health concern worldwide, but particularly in low- and middle-income countries. This study quantified and compared education- and wealth-based inequalities in the prevalence of five noncommunicable diseases  and comorbidity in low- and middle-income country groups.Using 2002–04 World Health Survey data from 41 low- and middle-income countries, the prevalence estimates of angina, arthritis, asthma, depression, diabetes and comorbidity in adults aged 18 years or above are presented for wealth quintiles and five education levels, by sex and country income group. Symptom-based classification was used to determine angina, arthritis, asthma and depression rates, and diabetes diagnoses were self-reported. Socioeconomic inequalities according to wealth and education were measured absolutely, using the slope index of inequality, and relatively, using the relative index of inequality.Wealth and education inequalities were more pronounced in the low-income country group than the middle-income country group. Both wealth and education were inversely associated with angina, arthritis, asthma, depression and comorbidity prevalence, with strongest inequalities reported for angina, asthma and comorbidity. Diabetes prevalence was positively associated with wealth and, to a lesser extent, education. Adjustments for confounding variables tended to decrease the magnitude of the inequality.Noncommunicable diseases are not necessarily diseases of the wealthy, and showed unequal distribution across socioeconomic groups in low- and middle-income country groups. Disaggregated research is warranted to assess the impact of individual noncommunicable diseases according to socioeconomic indicators. Globall century . Non-fat century  and arth century  also con century .NCDs are unequally distributed within populations, often disproportionally affecting the socioeconomically disadvantaged ,6-9. ForIn 2011, the international community convened at the United Nations High Level Summit to discuss approaches to address the rising trend of NCDs and their risk factors. In the absence of a concerted commitment amongst stakeholders, the international response thus far to alleviate this crisis has been deemed inadequate ,32. The The 2002–04 World Health Survey (WHS) gathered data about the symptoms of four major NCDs: angina, arthritis, asthma and depression as well as the self-reported diagnosis of diabetes. The objective of this study was to quantify and compare the socioeconomic inequalities in prevalence estimates of these five NCDs and comorbidity in LMICs.Data were obtained from the 2002–04 WHS, conducted by the World Health Organization . The WHSThis study focused on LMICs, classified according to the World Bank’s development categories in 2003 , consistWe analyzed data for angina, arthritis, asthma, depression, and diabetes. These represent five of the six chronic conditions included in section 6000 of the WHS individual questionnaire, and prominent NCDs worldwide.  Symptom-based classification was used to determine angina, arthritis, asthma and depression rates, and diabetes diagnoses were self-reported. The diagnostic criteria to estimate the prevalence of each disease has been previously described . BrieflySocioeconomic status was derived from household wealth status and individual highest-attained level of education. To measure household wealth, a dichotomous hierarchical ordered probit model was used to develop an index of the long-running economic status of households based on owning selected assets and/or using certain services -50. The Confounders included sex, age , marital status , area of residence , and country of residence.Prevalence rates for each NCD and comorbidity were calculated for men and women in LIC and MIC groups, according to wealth quintiles and education level. Both age-standardized  and crud"regular" inequality, and conversely, "reverse" inequality if prevalence was higher among those with higher socioeconomic position [Socioeconomic inequality in each NCD and comorbidity prevalence was measured using the slope index of inequality (SII) and the relative index of inequality (RII), measures that take into account the distribution of the population across wealth quintiles or education levels . Poissonposition . Data weStata® 11 was used for all analyses. We imputed missing values five times using Multiple Imputation by Integrated Chained Equations Technique . All anaTableTableWe generally found regular inequality in prevalence values of angina, arthritis, asthma and depression in both absolute and relative terms, after controlling for respondents' age and country of residence (Model 1). Of all NCDs, angina consistently demonstrated the highest absolute inequality. Notably, the absolute difference of angina prevalence between poorest and richest women of the MIC group was over 10% points . Arthritis demonstrated the weakest inequality, and was non-significant after controlling for other study confounders (Model 2). Diabetes prevalence was positively associated with increasing wealth quintile. This reverse inequality was more pronounced in the LIC group, and lost significance in MICs when data were adjusted for confounders (Model 2). For example, diabetes prevalence in the poorest women living in the study LIC group was one fourth of the richest in Model 2 .Comorbidity prevalence showed an inverse association with wealth quintile in all four sex-income groups; i.e. regular inequality. In both country income groups comorbidity was around 1.5 times more prevalent in the poorest women than in the richest in Model 1 . Comorbidity was 2.5 times more prevalent in the poorest men of study LICs than in the richest . Wealth-related inequalities in comorbidity remained statistically significant in Model 2 in all sex-income groups except for women living in the LIC group. Excluding diabetes from the comorbidity measure strengthened regular inequality, which was robust to adjustment for confounding.TableControlling for age and country of residence, regular inequalities were reported for the prevalence of angina and asthma in most study populations. Education-related inequality was weak or non-significant for arthritis prevalence (except among men of LICs), and also for depression prevalence (except among women of LICs). Depression was twice as prevalent among LIC women with no formal education as women with college/university education . The strongest education-related regular inequality was found among LIC populations for angina. The absolute difference of angina prevalence between adults with no formal education and those with college/university education was near 8% points . In MICs, all education-related inverse associations were non-significant after adjusting for other confounding factors (Model 2). Diabetes prevalence was associated with increasing education level , demonstrating a significant relationship in LICs, after adjusting for all confounding factors .Comorbidity showed regular inequality, with an inverse association between comorbidity prevalence and education level in all sex-income groups. The absolute difference in comorbidity prevalence among adults living in the LIC group was about 5% points across educational levels in Model 1. Education-related inequality was robust to adjustment for confounding in the LIC group, but not the MIC group.Within LICs and MICs, wealth- and education-related inequalities of variable magnitudes and direction were quantified for the five NCDs. In most populations, regular inequalities in terms of wealth and education were reported for angina, arthritis, asthma and depression, with the strongest associations for angina, asthma and comorbidity. For all NCDs, additional adjustments for confounding factors in Model 2  tended to decrease the magnitude of inequality, and may thus help to explain disparities in NCD prevalence.These findings are in accordance with previous reports from a variety of settings, which also reported inverse associations between socioeconomic position and prevalence of angina ,11,56, aThe connection between socioeconomic status and health is complex, and shaped by diverse circumstantial factors as well as political, social and economic forces . For exaUnlike the other four NCDs, we reported higher diabetes prevalence among the wealthier and more educated, especially in LICs. These findings conflict with trends reported by previous studies conducted in higher-income countries ,26. EpidComorbidity significantly lowers quality of life, affecting physical, social and psychological well-being . Our finLike other studies, NCD prevalence tended to be higher in women than men , and theData for five NCDs were collected systematically in a large sample of LMICs that participated in the WHS, allowing for comparisons of standardized data across pooled data sets. Consistent diagnostic criteria in WHS data facilitated broad-scale analyses and comparisons across several countries, minimizing limitations associated with variable measurement tools and disease classifications. However, the use of pooled data from geographically- and culturally-diverse settings inevitably masks problems of comparability between countries . Nine stWealth and education levels were determined nationally, and pooled across LICs and MICs. We acknowledge that patterns of wealth distribution vary between countries, however, quintile classification provided a widely accepted method to compare respondents based on relative wealth position within their country. Levels of education were standardized to be comparable across countries.The use of symptom-based diagnoses for angina, arthritis, asthma and depression was a strength, as other methods that rely on medical charts or self-reported diagnoses may introduce biases related to health system access. Self-reported data could reflect systematic over- or under-reporting, which may vary by socioeconomic status . A tendeIt is possible that a selection bias may have occurred in the sampling process, especially in countries with lower response rate, although we are not aware of evidence to suggest that this had occurred. The main reasons for household non-response included inability to locate the selected household, or household refusal to participate even before a roster could be obtained.Action taken in the next 20 years will be critical in determining the outcome of the mounting NCD epidemic . One of The focus of this study was to assess within-country socioeconomic distribution of five NCDs and comorbidity in LMICs. We reported disparities between subpopulations of different wealth- and education-levels, which varied according to the type of NCD. With the exception of diabetes, four NCDs and their comorbidity showed some evidence for unequal distribution in populations, to the detriment of those with lower wealth or education levels. Angina, asthma and comorbidity prevalence demonstrated the strongest inverse associations with wealth and education; arthritis and depression also reported inverse wealth and education associations in most cases. In LICs, diabetes prevalence was significantly positively associated with wealth and education.Overall, our mixed findings substantiate the need for disaggregated research to delineate the impact of individual NCDs on various socioeconomic groups. High quality epidemiological evidence is a cornerstone of effective policy development, deployment and monitoring. The present study has shown that NCDs are not necessarily diseases of the wealthy, demonstrating unequal distribution across socioeconomic groups. Further investigation of the risk factors and root causes of socioeconomic inequality are warranted to formulate sustainable and effective approaches to prevent and manage NCDs among the poor and low educated.LICs: Low-income countries; LMICs: Low- and middle-income countries; MICs: Middle-income countries; NCDs: Noncommunicable diseases; RII: Relative index of inequality; SII: Slope index of inequality; WHS: World Health Survey.The authors declare that they have no competing interests.AH designed the study. AH did the statistical analysis with inputs from EV. NB wrote the first draft with inputs from AH. AK, SH, SM, SC read the draft and provided critical comments. All authors read and approved the final draft.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/12/474/prepubLocal review boards for study countries. Lists each study country and its corresponding local review board. Click here for fileStudy sample size by country and sex, World Health Survey 2002–04. Displays the study sample size of men and women (aged 18 or higher) from 41 low- and middle-income countries that participated in the 2002–04 World Health Survey. Click here for fileNoncommunicable diseases non-response rates, by country and sex, World Health Survey 2002–04. Displays the non-response rates to World Health Survey individual questionnaires for each studied noncommunicable disease, grouped by sex and low- or middle-income country status. Data represent 41 low- and middle-income countries that participated in the 2002–04 World Health Survey. Click here for fileCrude prevalence (%) of noncommunicable diseases among adults aged 18 or higher living in 41 low- and middle-income countries, World Health Survey 2002–04. Displays the crude prevalence rates (percentage) of each studied noncommunicable disease and comorbidity among adults (aged 18 or higher), grouped by sex and low- or middle-income country status. Data represent 41 low- and middle-income countries that participated in the 2002–04 World Health Survey. Click here for fileWealth-related relative inequality in noncommunicable disease prevalence among adults aged 18 or higher living in 41 low- and middle-income countries, World Health Survey 2002–04. Displays the relative index of inequality and corresponding 95% confidence interval for each studied noncommunicable disease and comorbidity among adults (aged 18 or higher), according to wealth quintile. Data are grouped by sex and low- or middle-income country status, and represent 41 low- and middle-income countries that participated in the 2002–04 World Health Survey. Model 1 data are adjusted for country of residence and age; model 2 data are adjusted for country of residence, age, marital status, urban/rural area and education. Click here for fileCrude prevalence (%) of non-communicable diseases among adults aged 18 or higher living in 41 low- and middle-income countries, by wealth, World Health Survey 2002–04. Displays the crude prevalence rates (percentage) of each studied noncommunicable disease and comorbidity among adults (aged 18 or higher), according to wealth quintile. Data are grouped by sex and low- or middle-income country status, and represent 41 low- and middle-income countries that participated in the 2002–04 World Health Survey. Click here for fileEducation-related relative inequality in noncommunicable disease prevalence among adults aged 18 or higher living in 41 low- and middle-income countries, World Health Survey 2002–04. Displays the relative index of inequality and corresponding 95% confidence interval for each studied noncommunicable disease and comorbidity among adults (aged 18 or higher), according to education level. Data are grouped by sex and low- or middle-income country status, and represent 41 low- and middle-income countries that participated in the 2002–04 World Health Survey. Model 1 data are adjusted for country of residence and age; model 2 data are adjusted for country of residence, age, marital status, urban/rural area and wealth. Click here for fileCrude prevalence (%) of noncommunicable diseases among adults aged 18 or higher living in 41 low- and middle-income countries, by education, World Health Survey 2002–04. Displays the crude prevalence rates (percentage) of each studied noncommunicable disease and comorbidity among adults (aged 18 or higher), according to education level. Data are grouped by sex and low- or middle-income country status, and represent 41 low- and middle-income countries that participated in the 2002–04 World Health Survey. Click here for file


Urothelial bladder cancer represents a heterogeneous disease with divergent pathways of tumorigenesis. Tumor invasion and progression are a multifactorial process promoted by microenvironmental changes that include overexpression of matrix metalloproteinases (MMPs). Recent data clearly challenge the classic dogma that MMPs promote metastasis only by modulating the remodeling of extracellular matrix. Indeed, MMPs have also been attributed as an impact on tumor cell behavior in vivo as a consequence of their ability to cleave growth factors, cell surface receptors, cell adhesion molecules, and chemokines/cytokines. Levels of the different MMPs can be measured in several sample types, including tissue, blood (serum and plasma), and urine, and using different methodologies, such as immunohistochemistry, real-time PCR, western and northern blot analyses, enzyme-linked immunosorbent assay, and zymography. Several MMPs have been identified as having potential diagnostic or prognostic utility, whether alone or in combination with cytology. Although MMP inhibitors have shown limited efficacy, advances in the understanding of the complex physiologic and pathologic roles of MMPs might permit the development of new MMP-specific and tumor-specific therapies. In this paper we update the understanding of MMPs based on a systematic PubMed search encompassing papers published up to December 2011. Urothelial bladder carcinoma (UBC) represents a heterogeneous disease with high morbidity and mortality. It ranks fifth among all cancers in the Western world, and there are 336,000 new cases and 132,000 deaths annually worldwide . EffortsUrothelial tumors arise and evolve through divergent phenotypic pathways. Less aggressive tumors range from urothelial hyperplasia to low-grade NMI papillary tumors. The latter low-grade variant is often multifocal and presents high rates of recurrence. More aggressive variants either arise from high-grade and flat lesions of CIS and progress to become invasive tumors or initially develop as invasive tumors. Despite BCG or cystectomy, metastases often develop .HRAS gene and the fibroblast growth factor receptor 3 gene [The low-grade NMI variant is characterized by activation of mutations in the r 3 gene . High-grr 3 gene . Deletior 3 gene .Tumor invasion and progression in the bladder represent a multifactorial process promoted by microenvironmental changes that include upregulation of N-cadherin, downregulation of E-cadherin, overexpression of matrix metalloproteinases (MMP) 2 and 9, imbalance between angiogenic and antiangiogenic factors, and increased synthesis of prostaglandin.Levels of the different MMPs can be measured in several sample types, including paraffin-embedded or fresh-frozen tissue, serum, plasma, and urine, and by various analytical methodologies, such as immunohistochemistry, real-time PCR, western and northern blot analyses, enzyme-linked immunosorbent assay, and zymography. Several MMPs have been identified as having potential diagnostic or prognostic utility, whether alone or in combination with currently available diagnostic tests or imaging modalities. Although the early broad-spectrum anti-MMP agents showed a lack of efficacy, our continually improving understanding of the complex physiologic and pathologic roles of MMPs might enable the development of new MMP-specific and tumor-specific therapies.MMPs are a large family—there are at least 26 human MMPs—of calcium-dependent zinc-containing endopeptidases, which are responsible for the tissue remodeling and degradation of proteins of the extracellular matrix (ECM), including collagens, elastins, gelatin, matrix glycoproteins, and proteoglycans. On the basis of their specificity, MMPs are classified into collagenases, gelatinases, stromelysins, and matrilysins.Another subclass of MMPs is represented by the membrane-type MMPs (MT-MMPs), which contain a transmembrane and an intracellular domain a membrane linker domain or are membrane associated  Table 1Table 1.The exact domain organization, polypeptide fold, and main specificity determinants are provided by the crystal structures of MMPs . Most MMMMPs can be activated in vitro by several mechanisms, including mercurial compounds, SH reagents, chaotropic agents, and other proteases . This prα2-macroglobulin and tissue inhibitors of MMPs (TIMPs). Human α2-macroglobulin is a plasma glycoprotein of 725 kDa consisting of four identical subunits of 180 kDa. It inhibits most proteinases by entrapping the proteinase within the macroglobulin, and the complex is rapidly cleared by receptor-mediated endocytosis [MMP activities are regulated by two major types of endogenous inhibitor: ocytosis . TIMPs aEach domain contains three conserved disulfide bonds and the N-terminal domain folds as an independent unit with MMP-inhibitory activity. TIMPs inhibit all MMPs tested so far; however, TIMP-1 is a poor inhibitor for MT1-MMP, MT3-MMP, MT5-MMP, and MMP-19. TIMP-3 has been shown to inhibit members of both the ADAM family  and the ADAMTS family . In addition, TIMP-1 inhibits ADAM-10. Crystal structures of the TIMP-MMP complexes have been shown to be central to the mechanism of TIMP inhibition of MMPs . TIMPs h1′ subsite pocket. This leads to structural and chemical differences in the S1′ subsite that are reflected in the substrate preferences of the shallow pocket MMPs (1 and 7) compared with deep pocket MMPs  [1′ pocket. An additional small region termed the “S1′ side-pocket” was used to specifically target MMP-13. The success of these inhibitors clearly demonstrates the benefits of good mechanistic and structural information for inhibitor design.Differences in MMP active sites reside in specificity loop residues that form the S and 13) . The dev2+-chelating hydroxamates have been favored in MMP inhibitor design. However, in some cases they overwhelm the contribution from the rest of the compound, reducing opportunities for improved specificity. Indeed, hydroxamate activity-based MMP probes bind many off-target metalloproteases outside the MMP family. The use of union to Zn2+ ion seems to require an improvement in specificity.ZnUpon binding, these inhibitors covalently modify residues in the active site of the enzyme. Since the reactive species is formed only within the active site of the targeted enzyme, it provides high specificity and in vivo selectivity. Thiirane sulfur-containing anti-MMP-2 and -9 inhibitor forms a reversible covalent bond with the active site glutamate and was found to exert a great effect in an aggressive murine model of T-cell lymphoma . The devThe main function of MMPs is to degrade structural components of the ECM. However, MMP proteolysis can create space for cell migration, produce specific substrate-cleavage fragments with independent biological activity, regulate tissue architecture through effects on the ECM and intercellular junctions, and modify the activity of signaling molecules, both directly and indirectly . Also, MHowever, some MMP degradation products of ECM are antiangiogenic . In summSeveral analytical methods can be used to measure MMPs, the choice of technique depending on the aim of the analysis. Here, we present the most widely used techniques. Zymography can be used to determine protease activity in both tissue homogenates and body fluids. Zymography and reverse zymography are simple, sensitive, quantifiable, and functional assays to analyze MMPs and TIMPs in biological samples . ZymograThis continuous doubling is accomplished by specific proteins known as polymerases, enzymes that are able to string together individual DNA building blocks to form long molecular strands .Some of the best candidates for a biological marker in bladder cancer are the MMPs, which have a well-known role in the degradation of connective tissue stroma and basement membranes (key barriers to tumor progression), promoting invasion, immune escape, and many other events.In addition, recent data clearly challenge the classic dogma that MMPs promote metastasis only by modulating the remodeling of ECM. In fact, MMPs have also been attributed as an impact on tumor cell behavior in vivo as a consequence of their ability to cleave growth factors, cell surface receptors, cell adhesion molecules, and chemokines/cytokines , 29. FurDavies et al.  reportedKanayama et al.  evaluateMMP-2 activity as determined by zymography has shown a strong correlation with tumor invasion. Papathoma et al.  reportedBlood is a good medium for analysis of markers for screening and detection purposes and can also be used for evaluation of prognostic markers. Advantages over tissue are that blood sampling is minimally invasive and provides information before surgery. However, blood sampling methods can strongly affect MMP measurements. Significantly lower MMP-1, MMP-2, and MMP-7 levels have been found in EDTA-treated plasma samples compared with citrate-stabilized or heparin-treated plasma. Also, MMP-8 and MMP-9 showed significantly higher serum concentrations when collected in tubes with clot activator than when collected in tubes without such activator. Gohji et al. reported the prognostic significance of serum MMPs and TIMPs and the value of imbalance between serum MMP-2 and its inhibitor as a predictor of recurrence , 62–64. In patients with bladder cancer, urine is a particularly useful medium to detect tumor markers owing to its enhanced potential to contain high concentrations of tumor-derived proteins. Recent data have also shown that elevated urinary MMP levels and activity correlate with the presence of different cancers located outside the urinary tract .Offersen et al. found MMP-9  measuredBladder cancer represents the most common tumor of the urinary tract. The prognosis of the tumors diagnosed at an early stage is excellent, emphasizing the importance of early diagnosis. Measurements of MMPs in urine, especially MMP-2 and MMP-9, show a superior diagnostic performance compared with cytology but are less sensitive than determination of other diagnostic markers such as NMP-22. MMPs could be useful when used in combination with other methods rather than alone. The need for lifelong surveillance makes bladder cancer one of the most expensive cancers; thus MMPs are needed to allow the identification of patients at risk of recurrence. Urinary MMP-9 levels, serum MMP-7 levels, and tissue levels of MMP-2, MMP-7, and MMP-14 have been identified as prognostic markers of bladder cancer.


We investigated whether patients with chronic obstructive pulmonary disease (COPD) who were enrolled in disease-management programmes (DMPs) felt that they received a better quality of care than non-enrolled COPD patients.Our cross-sectional study was performed among patients (n=665) enrolled in four DMPs in the Netherlands. We also evaluated COPD patients (n=227) not enrolled in such programmes. Patients’ assessment of chronic-illness care (PACIC) was measured with a 20-item questionnaire. The instrument had five pre-defined domains: patient activation (three items), delivery-system/practice design (three items), goal setting/tailoring (five items), problem solving/contextual (four items), and follow-up/coordination (five items).The mean overall PACIC score  of enrolled DMP patients was 2.94, and that of non-enrolled DMP patients was 2.73 (p≤0.01). Differences in the same direction were found in the subscales of patient activation (p≤0.01), delivery-system/practice design (p≤0.001), and problem solving/contextual (p≤0.001).Our results suggest that even in the early stages of implementation, DMPs for COPD may significantly improve care. Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease characterised by progressive and incompletely reversible airflow limitation . COPD isCurrently, the extent to which DMPs provide patients with better experiences and higher quality of care remains unclear. Assuming that the rationale underlying DMPs  is legitimate and favours better outcomes, we should expect healthcare professionals participating in DMPs to provide higher-quality patient care than non-participating providers –13, and The Netherlands has implemented several parallel policies that target specific elements of the chronic-care continuum. To facilitate regulated competition, Dutch authorities have taken measures to improve information on healthcare quality, thereby supporting negotiations between healthcare purchasers and providers. Such measures have resulted in the development of a care standard for COPD that includes multidisciplinary evidence-based guidelines, process protocols, and performance indicators. Patients were involved in developing the measures to ensure patient empowerment within the context of regulated competition . FurtherThe Dutch policies as well as most DMPs are based on the chronic care model (CCM) introduced by Edward Wagner , 18, 19.The CCM has received widespread attention , includiOur cross-sectional study included COPD patients recently enrolled in four newly implemented DMPs in various regions in the Netherlands . These DMPs are initiated and controlled by the practices. A national programme on ‘disease management of chronic diseases’ carried out by ZonMw  and commissioned by the Dutch Ministry of Health, provided funding for practices planning a redesigning of primary care for COPD patients according to the CCM. Requirements of the national programme were that the practices had to have some experience with the delivery of chronic care and were equipped to implement all systems needed for the delivery of sufficient chronic care, which resulted in the inclusion of these four DMPs for COPD patients. COPD patients not enrolled in DMPs were also included in the study sample. Randomisations of patients did not take place. Patients not enrolled in DMPs received regular care from GPs in 20 healthcare practices in the Netherlands. In addition, these healthcare practices implemented the COPD care standard but they did not implement a combination of patient-related, professionally-directed, and organisational interventions and are therefore not considered a DMP. The DMPs did implement a combination of patient-related, professionally-directed, and organisational interventions.The DMP includes everyone who is diagnosed with COPD (based on GOLD criteria) no additional inclusion criteria were applied. The DMPs comprised a variety of collaborations—primarily GPs, physiotherapists, and dieticians—undergoing internal practice redesign to improve effective chronic-care management in 38 primary care practices. The DMPs, initiated and controlled by the practices, addressed shortcomings in acute care models by identifying essential elements that fostered high-quality chronic-disease care. We evaluated the four DMPs in their early stages to enhance our knowledge of disease-management experiments in chronic care and to stimulate successful programme implementation . All DMPThe patients were handed questionnaires during consultations or received them by mail. A reminder and a copy of the questionnaire were sent to non-respondents a few weeks later. Because the professionals were often time-strapped with implementation duties, they in some cases received hands-on support to administer questionnaires. The study was approved by the ethics committee of the Erasmus University Medical Centre of Rotterdam in September 2009. Data were collected anonymously and treated confidentially to protect sensitive patient information.Patients’ assessments of care were measured with the 20-item PACIC questionnaire, which used a five-point response scale ranging from ‘almost never’ to ‘almost always’ . Higher Basic demographic data on age, gender, marital status, self-rated health and educational level were also gathered. Educational level was dichotomised into ‘low’ and ‘high’, with low representing no or only some primary/secondary education.The PACIC was scored by summing each participant’s responses to all 20 items, then dividing by 20, the number of items in the scale. Missing values were replaced by mean scale scores if respondents filled in at least 2/3 of the items of a scale. Scores thus ranged from 1 to 5, with higher scores indicating the patients’ perception of greater involvement in self-management and receipt of chronic care counseling .t-tests. Two-sided significance tests were conducted for differences between groups in background characteristics . We were also unable to determine whether improvements in quality of care delivery were caused by the DMPs or other factors, such as the implemented parallel policies that target specific elements of the chronic-care continuum in the Netherlands. A longitudinal study is necessary to establish whether implementation of a DMP leads to improved care for COPD patients on top of implementation of the COPD care standard or implementation of other innovations, such as self-management programmes or electronic patient record devices  . In addiOur results suggest that DMPs for COPD as currently established in primary-care settings in the Netherlands may significantly improve care. Patients recognised the changes in daily practice induced by the DMPs as care that was more structured and reflected the core elements of the CCM to a greater extent than regular care. The differences in patients’ perceptions may influence clinical and economic outcomes , since iStephen Abbott, Research Fellow, Division of Health Services Management and Research, School of Health Sciences, City University London, Northampton Square, London EC1V 0HB, UKBirthe Dinesen, Associate Professor, PhD, Master in Administration, SMI, Department of Health Science and Technology, Aalborg University, DenmarkDiego A. Rodríguez, MD, Respiratory Medicine Specialist, Barcelona, SpainNina Szczygiel, PhD Candidate, GOVCOPP-DEGEI, University of Aveiro, Portugal


Anti-dementia drugs may improve gait performance. No comparison between acetylcholinesterase inhibitors (CEIs) and memantine-related changes in gait variability has been reported. The objectives of this study were to 1) quantify and compare the mean values and coefficients of variation (CoV) of stride time in demented patients with Alzheimer’s disease and related disorders (ADRD) before and after the use of CEIs or memantine, and in age- and gender-matched controls patients with ADRD using no anti-dementia drugs; and 2) to determine whether changes in CoV of stride time differed between CEIs or memantine.A total of 120 demented patients with mild-to-moderate ADRD were prospectively included in this pre-post quasi-experimental study with two intervention groups  and a control group (36 age- and gender matched patients without any anti-dementia drugs). CoV of stride time and walking speed were measured with GAITRite® system while usual walking at steady state. Age, gender, number of drugs daily taken, use of psychoactive drugs, body mass index and time between the two visits were also recorded.There was no difference between groups for the time between baseline and follow-up assessments . Patients with memantine had a lower  CoV of stride time at follow-up assessment compared to those with CEIs . Patients with memantine had a greater decrease in CoV of stride time compared to those with CEIs  and mixed-effects linear regressions showed that this decrease was specifically explained by memantine (P = 0.028).NCT01315704).Our results showed that patients with ADRD and treated with memantine, but not those with CEIs, decreased their gait variability, and thus improved their gait safety (Trial registration number:  The ueceptors ,2. The oBetween June 2011 and December 2012, 84 demented patients with mild-to-moderate ADRD  with CEIs (n = 43) and memantine (n = 41), and 36 age- and gender-matched controlled demented patients with mild-to-moderate ADRD without treatment  were prospectively and consecutively included in this quasi-experimental study . The assignment in both intervention groups  was not randomized and it was an open label study. The choice of the anti-dementia drug was based on the severity of the cognitive decline , contraindications and side effects of CEIs and memantine. The age (plus or minus 2 years) and gender matching were performed only on the control group . Inclusion criteria were outpatients visiting the memory clinic with a de novo diagnosis of mild-to-moderate ADRD and at least one follow-up visit with two gait analyses separated by at least 6 months in the memory clinic of Angers University Hospital, France. At baseline assessment, all participants had no anti-dementia drugs. In addition, those receiving an anti-dementia drug during the follow-up  had an effective daily dose  for at least 3 months. Participants with co-prescription of cerebral vasodilatators, renal failure, extrapyramidal rigidity of the upper limbs  , as well2) was calculated. The diagnoses of ADRD were made during multidisciplinary meetings involving geriatricians, neurologists and neuropsychologists. The diagnosis of ADRD followed the Diagnostic and Statistical Manual of Mental Disorders, 4th edition and the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria [Participants included in the study underwent neurological examination, neuropsychological testing, and brain imaging. In addition, age, gender, number of drugs daily taken, use of psychoactive drugs , height (cm), weight (kg) and time (day) between the two visits were recorded. The body mass index . The entire study protocol was approved by the local Ethical Committee of Angers (France). Written informed consent for participation in the study was obtained from all participants.The participants’ baseline characteristics were summarized using means and standard deviations or frequencies and percentages, as appropriate. The normality of the parameters’ distribution was verified with a Shapiro-Francia test before and after applying usual transformations to normalize non-Gaussian variables. Participants were separated into 3 groups: those without anti-dementia drugs, those using CEIs, and those using memantine. First, between-group comparisons were performed using analysis of variance the Kruskal-Wallis, Mann–Whitney or Chi-square tests, as appropriate. Second, anti-dementia drugs effect , time effect  and an anti-dementia drugs effect X time effect interaction were included as independent variables in a repeated analysis of covariance (ANCOVA) to analyze their respective influence on CoV of stride time (dependent variable), with and without adjustment on baseline characteristics of participants. Third, a mixed-effect linear regression model (with Stata "xtmixed" command) using the same variables was performed to specify which anti-dementia drugs explained the change in CoV of stride time. P-values <0.05 were considered statistically significant. All statistics were performed using SPSS  and Stata .There was no difference between groups for the time between baseline and follow-up assessments (P = 0.062) Table . BetweenBetween-group comparison of the change in CoV of stride time between baseline and at follow-up assessment was significant (P = 0.038) but only patients with memantine had a higher change compared to those with CEIs P = 0.010)  , is condCEIs: Acetylcholinesterase inhibitors; ADRD: Alzheimer’s disease and related disorders; ANCOVA: Analysis of covariance; CoV: Coefficient of variation; MMSE: Mini mental status examination; NMDA: N-methyl-D-aspartate.The study was financially supported by Lundbeck France pharmaceutical company. The sponsors had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript. All authors declare that they have no competing interests.OB, CL and CA participated in designing the study, writing and reviewing of the manuscript. GA, FRH, GW, KG participated in reviewing the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/13/184/prepub


Rituximab is a drug used for the treatment of B-cell non-Hodgkin's lymphoma, and its range of use has expanded to the treatment of collagen diseases such as idiopathic thrombocytopenic purpura and rheumatoid arthritis. One serious complication of rituximab use is the reactivation of dormant hepatitis B virus, and prevention of this phenomenon has become an urgent issue. This paper provides a general outline of the problem through an analysis of patient cases that we and other groups have experienced to date. Rituximab is a human-mouse chimeric monoclonal antibody that targets the B-cell CD20 cell surface protein and has become indispensible for the treatment of B-cell non-Hodgkin's lymphoma –3. howevAcute hepatitis caused by HBV is initially suppressed by cytokines secreted from NK and other types of cells. CD8-positive cells subsequently induce a CTL reaction which then eventually leads to hepatitis. Since hepatitis is triggered by CTLs, a time lag exists from initial infection to hepatitis onset , 39. HowWe have reported on reactivation of HBV and hepatitis during rituximab treatment alone or in combination with chemotherapy. Other groups have reported a rate of HBV reactivation of 20%~55% , 18–20. To date, various investigators have identified a number of risk factors for HBV reactivation which include being male, HBs antigen positivity, HBV-DNA level, presence of lymphoma, use of anthracyclines or steroids, second- and third-line anticancer drug treatment, and youth. A review of these factors by Yeo et al. showed that youth, being male, and liver function prior to chemotherapy were potential risk factors. Furthermore, Yeo et al. conducted an analysis on HBV reactivation in patients using rituximab, as there is a potential for risk factors to change in such cases. Including risk factors which had previously been reported, they list being male, lacking HBs antibodies, and using rituximab as additional risk factors. Further analyses on such risk factors are needed in order to enable the stratification of HBV-infected patients receiving rituximab in order to identify those that require preventive administration with nucleoside analogs , 47, 48.In HBsAg-positive patients, there have been reports of HBV reactivation during chemotherapy –20. IncrA report by Pelizzari et al. suggested that lamivudine administration may result in a lower likelihood of emergent drug resistance compared to treatments for conventional hepatitis B . HoweverAnti-HBc-positive cases indicate a prior history of HBV infection. These include window period cases as well as cases which are HBV-DNA positive and Anti-HBs negative or HBsAg negative (occult HBV infection) , 74–76. HBV reactivation-induced hepatitis has been reported in Anti-HBs-positive, Anti-HBc-positive, HBsAg-negative cases , 43, 45.From each group, treatment guidelines for prevention of HBV reactivation are shown in HBV reactivation during chemotherapy treatment is thought to occur from HBV amplification in hepatocytes as a result of immunosuppression caused by anticancer drugs, and subsequently from HBV-infected hepatocytes that are targeted by an immune response that becomes activated after removal of this immunosuppression . It is l


Left ventricular non-compaction (LVNC) is a recently recognized rare disorder. Magnetic resonance imaging (MRI) may help to clarify the uncertainties related to this genetic cardiomyopathy. Despite the fact that many articles have been published concerning the use of MRI in the study of LVNC, there is a lack of data describing the disease in the North African population. The aim of our study is to clarify MRI findings of LVNC in North African patients.In our retrospective cohort, twelve patients  underwent MRI for suspected LVNC. Correlations were investigated between the number of non-compacted segments per patient and left ventricular ejection fraction (LVEF), then between the number of non-compacted segments and left ventricular end diastolic diameter. The presence or absence of late gadolinium enhancement (LGE) was qualitatively determined for each left ventricular myocardial segment.Non-compaction was more commonly observed at the apex, the anterior and the lateral walls, especially on their apical and mid-cavity segments. 83% of patients had impaired LVEF. There was no correlation between the number of non-compacted segments per patient and LVEF , nor between the number of non-compacted segments per patient and left ventricular end diastolic diameter . LGE was observed in 22 left ventricular segments. No association was found between the pattern of fibrosis and non-compaction distribution .The distribution of LVNC in North African patients does not differ from other populations. Ventricular dysfunction is independent from the number of non-compacted segments. Myocardial fibrosis is not limited to non-compacted areas but can extend to compacted segments. Left ventricular non-compaction (LVNC) is a rare form of cardiomyopathy characterized by excessive and prominent trabeculations associated with deep recesses that communicate with the ventricular cavity ,2. SinceMagnetic resonance imaging (MRI) is a non-invasive exploration increasingly being employed in the diagnosis of LVNC. Due to its high quality cardiac imaging, this examination method may help to characterize and understand this disease. Thus, several MRI studies have been published describing LVNC features -14, yet We retrospectively reviewed morphological cine magnetic resonance imaging findings of ventricular non-compaction in twelve patients between 2007 and 2010. Those patients had been referred for MRI examination in order to investigate suspected LVNC or dilated cardiomyopathy. Information regarding presenting symptoms and echocardiographic data were obtained from referring centers. Patients with associated coronary artery disease were ruled out of the study.MRI was performed using a 1.5-Tesla magnetic resonance scanner . An eight-element cardiac phased-array receiver surface coil, with breath- holding in expiration and electrocardiogram (ECG) gating, was used for signal reception. The MRI sequences were conducted as follows: echo planar cine true-fisp imaging; dark-blood turbo spin echo T1-weighted; dark-blood turbo spin echo T2-weighted; and dark-blood half-Fourier single shot turbo spin echo. Images were obtained in two-chamber, four-chamber, and short-axis (from the atrioventricular ring to the apex) planes. After baseline imaging, a bolus injection of gadolinium was administered. Ten minutes later, delayed enhancement MRI was performed using an inversion recovery-prepared gated fast gradient-echo pulse sequence. The late gadolinium enhancement (LGE) images were acquired in end-systole in the same views used for cine images.All examinations were transferred to a dedicated workstation. Cine images were analyzed using Argus post-processing software . The cine loops were reviewed and the end-diastolic and end-systolic frames were identified.Assessment of LVNC was performed on short and long axis slices. All left ventricular (LV) myocardial segments were visually screened for the presence of a two-layer structure, with a thin epicardial compacted layer and a thick non-compacted endocardial one, with excessive trabeculations and deep intertrabecular recesses that communicate with the ventricular cavity. The ratio of non-compacted to compacted (NC/C) myocardium was measured for each involved myocardial segment in diastole, on short axis slices. For each patient, we considered the minimal NC/C ratio for subsequent analysis. Non-compaction was defined as a ratio of NC/C myocardium > 2.3 at end-diastole . The disLV diameters, volumes and ejection fraction (EF) were measured using standard volumetric techniques with dedicated software . Left veFor each patient, correlations were investigated between the number of non-compacted segments and EF, then between the number of non-compacted segments and LV end diastolic diameter.The presence of late gadolinium enhancement (LGE), a surrogate of myocardial fibrosis, was qualitatively determined for each LV myocardial segment using the seventeen-segment cardiac model. All short and long axis contrasted-enhanced images were reviewed, with a particular focus on images with elevated signal intensity. Patterns of LGE were visually classified as sub-endocardial, sub-epicardial, mid-myocardial, or transmural .The data was assembled using the computer software "EXCEL" (Microsoft). All analyses were performed with SPSS (version 18.0), in collaboration with the Faculty of Medicine's Biostatistics Department at the University of Rabat. Continuous variables are expressed as the mean and the standard deviation, and nominal variables as numbers and percentages. Univariate and multivariate analyses were made with the binary logistic regression model. Pearson correlation analyses were used for univariate correlations. A two-tailed p value of < 0.05 was considered statistically significant.Because this study was done retrospectively, no ethics committee approval was required.A total of twelve n = 12) cases of LVNC were included in our study. The mean age was 53 ± 8 years. Seven (58%) patients were male; two 2 (17%) were of sub-Saharan descent. Most patients (92%) were symptomatic. Six patients presented with dyspnea and four with palpitations. One patient had both dyspnea and chest pain. In seven patients, LVNC had been previously suspected on echocardiography. Four cases had been labeled as dilated cardiomyopathy. One case has the diagnosis of LVNC been made by echocardiography.  patients had impaired LVEF (LVEF < 50%). Among the segments analyzed in our study, 120 (59%) were identified as non-compacted segments. The mean number of non-compacted segments per patient was 10 ± 2.7 and the mean NC/C ratio was 2.8 ± 0.5. , nor between the number of non-compacted segments per patient and LV end diastolic diameter  Figures .significant discrepancy between non-compacted and compacted segments concerning fibrosis involvement  [Figure A total of four (33%) patients showed LGE. LGE was mid-myocardial in two cases and sub-endocardial in the remaining patients Figure . OverallThe non-compaction of the LV myocardium is a congenital heart disease caused by an arrest of normal ventricular embryogenesis, which causes an excessive number of endomyocardial trabeculae, spaced out by deep recesses ,18. ReceOur study is one of the first series assessing MRI features of LVNC in the North African population. In only one instance was the diagnosis of LVNC confirmed by transthoracic echocardiography. In the others, the diagnosis has been given by MRI. Our findings are in agreement with prior research which asserts that even though LVNC diagnosis remains difficult , the useThe findings of our study are in agreement with those of previous reports: non-compacted segments are most commonly located at the apex and the lateral wall; the septal segments are rarely affected by LVNC ,25. It iIn our study, we tried to investigate the relationship between the extent of LVNC and LV impairment. Although 83% of patients had impaired LVEF, our analysis of the study group found no correlation between the number of non-compacted segments and LVEF. Previous reports have studied the contribution of non-compacted segments to LV dysfunction. Aras et al found that the number of LV segments affected by non-compaction is a major determinant of LV systolic dysfunction . LofiegoA distinct advantage of MRI is its capability of myocardial tissue characterization and its ability to demonstrate myocardial fibrosis with enhanced delayed imaging. Fibrosis is commonly found in association with LVNC, the diagnosis of which is unattainable with other non-invasive imaging modalities -7. In ouIn our patients, myocardial fibrosis was detected in not only involved segments but also morphologically normal ones, with a similar prevalence in both non-compacted and compacted zones. This result supports the hypothesis that non-compaction may be a diffuse disease process involving both non-compacted and compacted area ,30. The The major limitations of our study are its retrospective design and its small sample size, which can be explained by the high cost of MRI. Moreover, patients included in the study were referred for MRI from other centers. Thus, there was a selection bias in this population representing a group of mainly symptomatic patients, so the true severity of the disease was probably overestimated. In addition, pediatric cases were not included. Furthermore, we did not undertake family screening, nor were clinical data and follow up information available. Finally, we were unable to compare echocardiographic and MRI findings because echocardiographic examinations were not performed in the same institution.LVNC is an enigmatic cardiomyopathy that is still not widely known. Our study supports the hypothesis that LVNC diagnosis is not always clear and that MRI, with its high spatial resolution, seems to be able to improve the detection of this condition. Although our data refers to a small population, it suggests that the distribution of LVNC in North African patients does not differ from other populations. In addition, the extent of non-compaction appears to be unrelated to LV systolic dysfunction in this population. Furthermore, our findings indicate that myocardial scarring, which can be identified non-invasively by MRI, is not limited to the non-compacted myocardium, but can extend to morphologically normal areas. Finally, further studies of larger populations, including long-term follow up, are still needed in order to better clarify different facets of this cardiomyopathy. Accordingly, we propose the creation of a LVNC registry for North Africa.C: Compacted; CMR: Cardiac magnetic resonance; F: Female gender; LGE: Late gadolinium enhancement; LV: Left ventricular; LVD: Left ventricular end diastolic diameter; LVEF: Left ventricular ejection fraction; LVNC: Left ventricular non-compaction; LVSD: Left ventricular systolic dysfunction; M: Male gender; MRI: Magnetic resonance imaging; NC: Non compacted; TTE: Transthoracic echocardiography.The authors declare that they have no competing interests.The contributions of each author to this manuscript are as follows: AL and ND were involved in the design of the study, in cardiovascular magnetic resonance imaging and analyzing images, in acquisition, analysis and interpretation of the data, and in drafting of the manuscript. YE and OT were involved in cardiovascular magnetic resonance imaging. AB, LH, JZ, RC, IF, AA and IA were involved in echocardiography's examination of the patients. FE and AE were involved in analysis and interpretation of the data. MC was involved in the design of the study and in revising the manuscript. All authors have read and approved the final manuscript.


A 62-year old man was referred to our institution in hemorrhagic shock after a laparoscopic cholecystectomy for acute cholecystitis, performed at an outside hospital. A chest X-ray revealed a right-sided massive pleural effusion. Urgent surgical exploration was performed through a video-assisted mini-thoracotomy which revealed active bleeding from a pleural adherence. Successful hemostasis was achieved intraoperatively and the patient had an uneventful recovery. In absence of intra-abdominal hemorrhage, a hemothorax should be considered as a potential source of major bleeding in patients who develop symptoms of hypovolemia after laparoscopic surgery. Although laparoscopic cholecistectomy (LC) is a well-established surgical procedure, a high index of suspicion should be maintained towards both surgical  and anaesthetic complications  . A case A 62-yrs old male patient was referred to our Institution due to massive right pleural effusion with severe hypovolemia at the end of VLC.2O and no increase of the pressure was needed. Intra-operative bleeding was about 300 cc because of a difficult isolation of the fellea from the liver, but it was easily controlled by argon beam coagulator. No impairment of respiratory parameters was observed by the anaesthesiologist.The procedure, planned for cholelithiasis, was performed in a peripheral hospital in about 2 hours and half, due to the presence of severe cholecistitis with empyema and massive intraperitoneal visceral adhesions. During the intervention pneumoperitoneum was kept constant at 12 cmHAt the end of procedure, before evacuation of pneumoperitoneum, the patient developed a hypotension which was initially responsive to fluid administration, but quickly deteriorated after the weaning resulting in severe hypovolemic shock with worsening of respiratory parameters .A chest X-ray performed in the operating theatre revealed a white right hemithorax, suggestive for massive peri-operative pleural effusion, that was soon confirmed by a contrast enhanced chest CT-scan Figure .th intercostal space. A total amount of 2400 of fluid and clotted blood was evacuated from pleural cavity, and active bleeding became evident from a vascularized adherence between parietal pleural and right diaphragm located nearby anterior costophrenic angle. After haemostasis with bipolar electrocautery, accurate inspection of pleural cavity did not reveal tears of parietal pleura, diaphragm, internal mammary and intercostals vessels nor rib fractures.Considering the clinical and radiological findings, we decided to perform urgent surgical exploration through right video-assisted muscle-sparing lateral mini-thoracotomy in the 7rd and 6th post-operative day, respectively.The post-operative course was uneventful with complete lung re-expansion Figure . Chest dThoracic bleeding is a rare complication of elective abdominal surgery, mainly resulting from not recognized, iatrogenic diaphragmatic tears. In this case, a pleural effusion usually appears post-operatively and progressively increases, but rarely this condition leads to severe hypovolemia and shock, unless a diaphragmatic artery has been injured.Non-surgical related cause of intrathoracic bleeding could be intra-operative pneumothorax, due to extraperitoneal gas insufflation or prolonged mechanical ventilation, with high peak pressures: lung collapse can produce tension and rupture of vascularised adherences between parietal and visceral pleura. However, in this case, worsening of respiratory parameters  always anticipates signs of hypovolemia , resulting in an haemo-pneumothorax.In this case, it has been supposed that laceration of the parieto-diaphragmatic adherence could have originated from diaphragmatic position change during pneumo-peritoneum, as it has been demonstrated in animal models . Video-aIntrathoracic bleeding is an extremely rare complication after abdominal surgery but it should be suspected and promptly diagnosed (through a chest X-Ray or Eco-fast) in case of worsening hemodynamic and respiratory failure in intra-operative or post-operative course. Medical supportive care only delays diagnosis leading to life-threatening conditions. Post-contrast TC is mandatory in order to exclude major vessels bleeding and thoraco-abdominal injury. We believe that a video-assisted mini-thoracotomy is a valid compromise even in these patients with hypovolemia because it allows rapid evacuation, inspection of pleural cavity and hemostasis, combining them with short and long-term benefits  .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.RC performed thoracic surgical procedure and wrote the paper, PM and RT participated in surgical procedure, TS and BF reviewed literature, BE and SG reviewed the paper. All Authors read and approved the final manuscript.


Disturbances in calcium handling play a central role in the disturbed contractile function in myocardial failure. Measurements of twitch tension in isolated left-ventricular strips from explanted cardiomyopathic hearts compared with non-failing hearts show flat or biphasic FFR, while it is up-sloping in normal hearts. Starting in 2003 we introduced the FFR measurement in the stress echo lab using the end-systolic pressure (ESP)/End-systolic volume index (ESVi) ratio (the Suga index) at increasing heart rates. We studied a total of 2,031 patients reported in peer-reviewed journals: 483 during exercise, 34 with pacing, 850 with dobutamine and 664 during dipyridamole stress echo. We demonstrated the feasibility of FFR in the stress echo lab, the clinical usefulness of FFR for diagnosing latent contractile dysfunction in apparently normal hearts, and residual contractile reserve in dilated idiopathic and ischemic cardiomyopathy. In 400 patients with left ventricular dysfunction (ejection fraction 30 ± 9%) with negative stress echocardiography results, event-free survival was higher (p < 0.001) in patients with ΔESPVR  ≥ 0.4 mmHg/mL/m2. The prognostic stratification of patients was better with FFR, beyond the standard LV ejection fraction evaluation, also in the particular settings of severe mitral regurgitation or diabetics without stress-induced ischemia. In the particular setting of selection of heart transplant donors, the stress echo FFR was able to correctly select 34 marginal donor hearts efficiently transplanted in emergency recipients. Starting in 2007, we introduced an operator-independent cutaneous sensor to monitor the FFR: the force is quantified as the sensed pre-ejection myocardial vibration amplitude. We demonstrated that the sensor-derived force changes at increasing heart rates are highly related with both max dP/dt in animal models, and with the stress echo FFR in 220 humans, opening a new window for pervasive cardiac heart failure monitoring in telemedicine systems.Up-regulation of Ca The assessment of left ventricular contractility  is an old dream for the cardiologist, but until recently it has also been a methodological nightmare. The pressure-volume relationship is a conceptually immaculate way to assess contractility and is extensively used in the experimental setting for animal studies, but only rarely in the clinical arena, and then only for research purposes in complex, technically demanding studies requiring invasive cardiac catheterization and maneuvers in the cath lab, with the attending risks of invasivity, contrast injection and radiation exposure. In the last 10 years, left ventricular contractility was brought into the noninvasive stress imaging lab, and particularly in the stress echo lab, where with minimal extra-computing time and virtually no extra-imaging time, left ventricular contractility can be measured at baseline and during stress with simple raw measurements of end-systolic pressure (by tonometry or cuff sphygmomanometer) and end-systolic volume . In this way, left ventricular contractility no longer “cuts the airy way” of pathophysiology but has entered the real world of clinical cardiology. This review will discuss the pathophysiological basis, experimental evidence, and clinical data supporting a more extensive use of contractile reserve in key diagnostic domains such as identification of coronary artery stenosis, myocardial viability and initial occult cardiomyopathy.2+ ions in the myocardial cytosol. Ca2+ ions enter through the calcium channel that opens in response to the wave of depolarization that travels along the sarcolemma. These Ca2+ ions “trigger” the release of more calcium from the sarcoplasmic reticulum (SR) and thereby initiate a contraction-relaxation cycle to the LV end-systolic volume indexed for body surface area. The ESPVR is determined at rest and at peak stress. The ΔESPVR  is calculated as the variation between rest and peak stress ESPVR. The rest ESPVR, the peak stress ESPVR and the ΔESPVR are built offline[The evaluation of LV contractility is potentially amenable to non-invasive assessment in the cardiac imaging lab, since cuff systolic pressure is a proxy of end-systolic pressure (in absence of aortic stenosis) and end-systolic volumes can be evaluated by radionuclide ventriculography or – wit offline-8,11. Th offline,13 , was the best predictor of future primary cardiovascular events   was also effective in stratifying the risk in the subgroups with progressively more severe baseline dysfunction  at increasing heart rates. We studied a total of 2,031 reported patients in peer-reviewed journals: 483 with exercise stress, 34 with pacing stress, 850 with dobutamine stress echo, 664 with dipyridamole stress echo,15-27. TIn patients with normal baseline left ventricular function and negative stress echo by standard wall motion criteria, the evaluation of contractile reserve provided additional diagnostic information. Lack of contractile reserve can identify minor forms of anatomically significant coronary artery disease (CAD) that are unable to give the absolute subendocardial underperfusion necessary to induce true regional ischemia and wall motion abnormalities. In patients with negative stress and significant (≥ 50%) obstructive CAD, the contractile reserve is attenuated in proportion to the severity of stenosis. A negatGalderisi et al. assessedIn an another paper by Jellis et al., in subcLimitations of this noninvasive study include that peak cuff systolic pressure was used as a surrogate marker of end-systolic pressure. However, there is a close relationship between these two variables, and any sampling error is duplicated between rest and stress values, thereby not affecting the overall ratio. CalciumIn recent years, the FFR has been transferred from the experimental lab to the clinical arena, and in particular within the clinical arena from the cardiac catheterization to the stress echo lab, with an obvious step-up in interest and applicability. Ideally, the non-invasive, imaging-independent, objective assessment of FFR would greatly further enhance its practical appeal Figure . A new cPatients with abnormal rest LVEF and negative stress echocardiography by conventional regional wall motion criteria may still experience an adverse outcome in the long-term follow-up, which can be identified by ΔESPVR, providing a prognostic stratification in addition to that given by regional wall motion abnormalities and LVEF. Despite exercise, pharmacological and pacing are different ischemic stressors in terms of cardiac, systemic and coronary hemodynamics, the same contractile reserve cut-off value of ΔESPVR stratifies patients equally well for non-ischemic events at follow-up. In this task, the contractility information complements clinical, coronary flow reserve (CFR), and therapeutic information, allowing stratification of the different “shades of white” of a negative response, with very benign prognosis in subjects with normal resting function, preserved resting LV function, normal (> 2.0) CFR on LAD, and normal test studied off-therapy, with hard events rate < 1% per year. At the other end of the spectrum are subjects with subclinical tests, undergoing therapy with impaired resting LV function, blunted contractile reserve, reduced CFR and hard-event rate > 3% Table . ContracBSA: Body surface area; CABG: Coronary artery by-pass grafting; CAD: Coronary artery disease; CFR: Coronary flow reserve; CHF: Chronic heart failure; CRT: Cardiac resynchronization therapy; DC: Dilated ischemic cardiomyopathy; DCM: Idiopathic dilated cardiomyopathy; DIP: Dipyridamole; DOB: Dobutamine; ΔESPVR (or simpler PVR pressure-volume relation): The difference between peak stress and rest ESPVR; EF: Ejection fraction; ESP: End-systolic pressure; ESPVR: End-systolic pressure-volume-ratio; EX: Exercise; FFR: Force-frequency relation; ICD: Implantable cardioverter defibrillator; LV: Left ventricle; LVESP: Left ventricular end-systolic pressure; MR: Mitral regurgitation; PM: Pace-maker; PVR: Pressure-volume relation; TX: Heart transplant; PCI: Percutaneous coronary intervention; 2-DE: Two-dimensional echo.The authors declare that they have no competing interests.TB conceived this review, performed the data analysis, and drafted the manuscript; MZ and TL are chief and coworker of the Scientific Visualization Unit Group; QC, LC, EA, LP, were responsible for data collection and revised the manuscript; SS performed the statistical analysis; EP contributed to the preparation of review design, data discussion, and critical revision of the manuscript. All authors read and approved the final manuscript.TB, Scientific Coordinator of the CCM project n. 48 “Aged Donor Heart Rescue by Stress Echo – ADONHERS” Institute of Clinical Physiology, National Research Council, Pisa, Italy. MZ, Director, Scientific Visualization Unit, Institute of Clinical Physiology, National Research Council, Pisa, Italy. QC, Division of Cardiology, Fatebenefratelli Hospital, Benevento, Italy. EA, Division of Noninvasive Cardiology, Cardiothoracic Department, San Raffaele Hospital, IRCCS, Milano, Italy. SS, PhD, Institute of Clinical Physiology, National Research Council, Pisa, Italy. TL, Scientific Visualization Unit, Institute of Clinical Physiology, National Research Council, Pisa, Italy. LP, Institute of Clinical Physiology, National Research Council, Pisa, Italy. EP, Acting Director Institute of Clinical Physiology, National Research Council, Pisa, Italy.Dilated Cardiomyopathy: A molecular view. Dilated Cardiomyopathy is a common heart disease that causes heart myofibers to pulse in a weakened way, which becomes particularly dangerous under stress, when heartbeat is accelerated. .Click here for fileDilated Cardiomyopathy: The sarcomere At each cycle of heartbeat, the heart cell contracts (shortens) at systole and relaxes at diastole. Under stress, both the speed and the intensity of the movement are increased. In the DCM heart, both the structure and the activity are impaired: the mitochondrion is enlarged, due to the excess ATP request, and the fibers are not as compact and aligned as in the healthy fiber. The relaxation phase is never complete, resulting in the typical ECG track. Under stress the situation is worsened: the heart fibers, unable to completely de-contract, try to compensate by even stronger contraction, in a forward loop that worsens with time, and can lead to heart failure. .Click here for fileDilated Cardiomyopathy: Ca2+ induced Ca2+ release (zoom to synaptic junction). The signal to initiate contraction is a brief depolarization of the membrane, which triggers a very rapid release of calcium from the sarcolemma. This is followed by more sustained release of Ca2+ from the ryanodine receptor on the T Tubules. In this way, the signal rapidly diffuses throughout the contractile fiber. When more blood is needed in the organism, the frequency of signal is increased, and more Ca2+ is released. However, all Ca2+ is removed from the fiber before the onset of next beat. The DCM heart is impaired in the re-uptake of Ca2+, resulting in a small amount of Calcium constantly present in the fiber. When more CA2+ is released because of higher demand, the problem of re-uptake worsens. .Click here for fileDilated Cardiomyopathy: Actin-myosin contraction. Contraction is the result a sliding of actin and myosin fibers, due to the activity of the myosin cycle: this cycle is active in the presence of Calcium, which mediates transmission of signal to both the actin and myosin fibers, via other accessory proteins. The activity requires energy, in the form of ATP (not shown). When Calcium has been removed, the myosin heads detach from the actin fibers and the muscle can relax. In the DCM heart calcium re-uptake is incomplete: this leads to a constant contraction which, on one hand requires more energy (hence the enlarged mitochondria) and on the other impedes full extension of the heart fibers during relaxation, thus limiting the amount of incoming blood. The problem is even worse under stress conditions. Note that due to the excess work and the lack of total relaxation, the actin and myosin fibers of the dilated heart are not regularly aligned and the overall structure of the myofiber is slightly disorganized. .Click here for fileDilated Cardiomyopathy: Calcium re-uptake. Clearing of intracellular Calcium is carried out by the Sarcoplasmic Reticulum Calcium Pump (known as SERCA), a very efficient protein capable of concentrating Calcium at a rate of two ions for one ATP. One of the molecular defects of the dilated heart is the reduced efficiency of this pump: this is physiologically counterbalanced by a higher expression (and more intense activation) of the Na+/Ca2+ exchanger of the plasma membrane. The problem is especially felt under stress: in this condition, with faster cycles, even more Calcium is released, aggravating the burden of re-uptake on the defective SERCA, not well-complemented by the activity of the plasma membrane exchanger. Since this pump is also inefficient, the final result is that blood circulation is not sustained to the required level. .Click here for fileForce-frequency curve with stress echo in a normal subject. Upper panel: On the left, systolic blood pressure by cuff sphygmomanometer ; left ventricular end-systolic volumes calculated with biplane Simpson method ; heart rate increase during stress ; in the lowest row, the force-frequency curve built off-line with the values recorded at baseline (second column), and at different steps  up to peak stress (sixth column). An increased heart rate is accompanied by an increased systolic pressure with smaller end-systolic volumes .Click here for fileForce-frequency curve with stress echo in a subject with dilated cardiomyopathy and depressed baseline left ventricular function (EF% = 30%). On the left: systolic blood pressure by cuff sphygmomanometer ; left ventricular end-systolic volumes calculated with biplane Simpson method ; heart rate increase during stress ; in the lowest row, the force-frequency relation built off-line with the values recorded at baseline (second column), and at different steps  up to peak stress (sixth column). An increased heart rate at peak exercise is accompanied by no changes in end-systolic volumes .Click here for file