Risk-stratified treatment recommendations facilitate treatment decision-making that balances patient-specific risks and preferences. It is unclear if and how such recommendations are developed in clinical practice guidelines (CPGs). Our aim was to assess if and how CPGs develop risk-stratified treatment recommendations for the prevention or treatment of common chronic diseases.We searched the United States National Guideline Clearinghouse for US, Canadian and National Institute for Health and Clinical Excellence (United Kingdom) CPGs for heart disease, stroke, cancer, chronic obstructive pulmonary disease and diabetes that make risk-stratified treatment recommendations. We included only those CPGs that made risk-stratified treatment recommendations based on risk assessment tools. Two reviewers independently identified CPGs and extracted information on recommended risk assessment tools; type of evidence about treatment benefits and harms; methods for linking risk estimates to treatment evidence and for developing treatment thresholds; and consideration of patient preferences.We identified 20 CPGs that made risk-stratified treatment recommendations out of 133 CPGs that made any type of treatment recommendations for the chronic diseases considered in this study. Of the included 20 CPGs, 16 (80%) used evidence about treatment benefits from randomized controlled trials, meta-analyses or other guidelines, and the source of evidence was unclear in the remaining four (20%) CPGs. Nine CPGs (45%) used evidence on harms from randomized controlled trials or observational studies, while 11 CPGs (55%) did not clearly refer to harms. Nine CPGs (45%) explained how risk prediction and evidence about treatments effects were linked , but only one CPG (5%) assessed benefit and harm quantitatively and three CPGs (15%) explicitly reported consideration of patient preferences.Only a small proportion of CPGs for chronic diseases make risk-stratified treatment recommendations with a focus on heart disease and stroke prevention, diabetes and breast cancer. For most CPGs it is unclear how risk-stratified treatment recommendations were developed. As a consequence, it is uncertain if CPGs support patients and physicians in finding an acceptable benefit- harm balance that reflects both profile-specific outcome risks and preferences. An important goal of evidence-based health care is to maximize benefits and minimize harms from medical treatments. To achieve an optimal balance, patients' individual profiles and preferences need to be considered . For exaRisk-stratified treatment recommendations are potentially useful to support personalized medicine. Personalized medicine aims at optimizing the benefit-harm balance by considering patient profiles (combination of characteristics) and preferences . For theRisk-stratified treatment recommendations only serve their purpose of supporting personalized medicine if valid methods were used to develop them. Because it is not known what proportion of clinical practice guidelines (CPGs) make risk-stratified treatment recommendations and what methods were used to develop them, our aim was to assess the methods CPGs applied in developing risk-stratified treatment recommendations for the prevention or treatment of selected common chronic diseases.We started by forming a framework for developing risk-stratified treatment recommendations. Figure We performed an environmental scan of CPGs, which included a limited literature search (described below) but not a comprehensive, systematic review of all CPGs. We focused on CPGs for major chronic diseases and from the United States (US), Canada, or the United Kingdom (UK) National Institute for Health and Clinical Excellence (NICE). The completed PRISMA checklist is available as Additional file We searched the US National Guideline Clearinghouse (NGC) database on February 5 2011 for CPGs with treatment recommendations for five major chronic diseases. The top five chronic diseases in the US are heart disease, cancer, stroke, COPD and diabetes, accounting for more than two-thirds of all deaths . In the Cardiovascular Diseases section of the database (n = 442) and considered CPGs specific for primary prevention of heart disease and stroke, that is, the prevention of an event in persons free of established cardiovascular diseases. For cancer, we chose to examine three types of cancer with the highest mortality rates in the US  [Lung Neoplasms (n = 53), Prostatic Neoplasms (n = 26) and Breast Neoplasms (n = 52) sections, respectively. For COPD, we considered CPGs specific for COPD within the Respiratory Tract Diseases section (n = 102). For diabetes mellitus, we considered CPGs for type II diabetes within the Diabetes Mellitus, Type 2 section (n = 44).For heart disease and stroke, we performed our search within the  cancer) . We searet al. in prostate cancer guidelines [We included CPGs that recommended using risk assessment tools to inform treatment decisions. Risk assessment tools are tools to calculate the probability of developing an event or a disease based on a prediction model (binary outcome), or tools that make projections about the course of disease measured by patient-reported or other continuous outcomes . We excluded CPGs if they were not from the US, Canada or NICE (UK); focused on childhood diseases; made recommendations on screening, genetic counseling or diagnostic work-up alone; or did not use any risk assessment tools to inform risk-stratified treatment decisions. This latter excluded category involved guidelines that recommended treatments according to diagnostic criteria, as for example based on pathological staging, rather than according to prognostic information .Guideline Summary section of each CPG on the NGC website to assess its potential eligibility. We excluded the CPGs labeled ineligible by both reviewers. For the other CPGs, we retrieved and examined the full text and resolved any discrepancies in eligibility through discussion or arbitration by a third reviewer (MP).Two reviewers (TY and DV) independently reviewed the We developed a standardized form to extract data from the included CPGs and the background documents detailing the methods used in developing CPGs when available. We extracted general items such as guideline title, bibliographic source, date released and guideline developer. We then extracted information related to five key components for developing risk-stratified treatment recommendations Figure . We extrMost CPGs that we excluded Figure  were on A large proportion of CPGs  were on type II diabetes or on primary prevention of heart disease and stroke ,18-32, aOf the 16 CPGs for type II diabetes and primary prevention of heart disease and stroke, nine (56%) suggested specific target lipid levels for each risk category when making recommendations about lifestyle management or pharmacotherapy  ,26-29,31Sixteen (80%) of the 20 CPGs reported using evidence on treatment benefits from RCTs or meta-analyses or other guidelines -32,35,36In reviewing how CPGs made the link between risk prediction and treatment effects, we found fewer than half of the CPGs  explicitly or implicitly stated that they applied evidence of relative risk reductions from RCTs and/or meta-analyses to different absolute risks ,23-27,32Only a small proportion  of CThree (15%) of the 20 CPGs qualitatively weighed the treatment benefits and harms ,29,32. NWe found a rather small proportion of CPGs for heart disease, cancer, stroke, COPD and diabetes that made risk-stratified treatment recommendations using risk assessment tools. Most of these CPGs recommend risk assessment tools that had been shown to accurately predict outcome risk in the target population of the CPGs and most of the treatment evidence is based on RCTs and meta-analyses. For the majority of the CPGs, however, it was not explicitly explained how treatment effects on benefit and harm outcomes were estimated for patients at different risks. Perhaps most importantly, it was unclear for all but one CPG how treatment thresholds were determined to generate risk-stratified treatment recommendations.We formed a framework for the development of risk-stratified treatment recommendations Figure  to systeWe discovered a number of major limitations in how CPGs develop risk-stratified treatment recommendations. It should be noted that some limitations propagated from single, prominent CPG  to other CPGs that adopted the approach or even the recommendations. For example, it was often unclear how the benefit and harm outcomes were estimated for different risk profiles. Some CPGs applied estimates on relative risk reduction to absolute risks. This approach relies on the assumption of constant (relative) effects across the risk spectrum. This assumption of constant relative treatment effects may be justifiable in many instances but it is usually difficult to verify. No alternative approaches for linking the absolute risk with treatment evidence were used. Additional sensitivity analyses may sometimes be appropriate to explore the assumption of relative treatment effects. For example, one could obtain risk-specific treatment estimates from large trials using individual patient data . Or, oneIn our view, the greatest limitation of current CPGs is that it is unclear how treatment thresholds were developed for most of them. Some CPGs stated that the thresholds were determined by experts. The USPSTF guideline on aspirin  was the Treatment thresholds are important because medical decision-making is discrete (to treat the patient or not). It is challenging to determine thresholds because clear cuts on the (commonly) continuous benefit-harm scale may not exist. In addition, there may often be substantial uncertainty about harms and heterogeneity of treatment effects as a consequence of poor reporting or a lack of evidence from primary studies. However, this should, in our view, not prevent CPG developers from making risk-stratified recommendations because health care providers need evidence-based guidance nevertheless and because variability in delivering health care may be unacceptably high in the absence of guidance. Quanstrum and Hayward  recentlyOne may criticize the approach used by the USPSTF, assigning equal weight to benefit and harm outcomes to calculate events expected per 1,000 people treated over 10 years, because empirical evidence suggests that patients, on average, assign different importance to myocardial infarction, major gastrointestinal bleeding and major stroke, the major drivers of the benefit-harm balance of aspirin . NeverthThe framework for developing risk-stratified treatment recommendation we proposed may be useful for those developing CPGs and to stimulate further research. While much research has been done on how to select and appraise evidence on treatment benefits and harms ,44 and hOur study has some weaknesses. We selected guidelines from five major disease categories and from one database and focused on CPGs from the US, Canada and NICE (UK). Thus our results may not be generalizable, but provide an optimistic assessment of CPGs because we included some of the most prominent guidelines in medicine. For the fields of cardiovascular medicine and diabetes, guideline developers have a long tradition of making risk-stratified treatment recommendations. We relied on published reports, which may not reflect the true underlying development process for CPGs. We considered all background documents that were openly accessible but we may have missed some information on the development of risk-stratified treatment recommendations.We found that the methods for linking risk prediction with treatment evidence are often not reported and that it was unclear for all but one CPG how treatment thresholds were developed. Therefore, current CPGs for major chronic diseases may not support patients and physicians in finding an acceptable benefit-harm balance that reflects profile-specific outcome risks and preferences.COPD: chronic obstructive pulmonary disease; CPG: clinical practice guideline; NGC: National Guideline Clearinghouse; NICE: National Institute for Health and Clinical Excellence; RCT: randomized controlled trial; USPSTF: U.S. Preventive Services Task Force.The authors declare that they have no competing interests.All authors contributed to the conception of the study; TY, DV and MP collected and analyzed the data; all authors interpreted the data; TY and MP drafted the article; all authors revised it critically for important intellectual content; and all authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/11/7/prepubPRISMA checklist. The additional file shows the completed PRISMA checklist and shows where the checklist items are reported.Click here for file


The mechanisms for the emergence and transmission of synchronized oscillations in Parkinson's disease, which are potentially causal to motor deficits, remain debated. Aside from the motor cortex and the subthalamic nucleus, the external globus pallidus (GPe) has been shown to be essential for the maintenance of these oscillations and plays a major role in sculpting neural network activity in the basal ganglia (BG). While neural activity of the healthy GPe shows almost no correlations between pairs of neurons, prominent synchronization in the β frequency band arises after dopamine depletion. Several studies have proposed that this shift is due to network interactions between the different BG nuclei, including the GPe. However, recent studies demonstrate an important role for the properties of neurons within the GPe. In this review, we will discuss these intrinsic GPe properties and review proposed mechanisms for activity decorrelation within the dopamine-intact GPe. Failure of the GPe to desynchronize correlated inputs can be a possible explanation for synchronization in the whole BG. Potential triggers of synchronization involve the enhancement of GPe-GPe inhibition and changes in ion channel function in GPe neurons. Neural activity in the basal ganglia (BG) of patients with idiopathic Parkinson's disease (PD) and animal models of PD commonly shows high levels of synchronization, bursting, and oscillations in low frequency bands such as θ (4–7 Hz) and β (15–30 Hz) frequencies  treatment, their emergence and reversal are both thought to be crucially dependent on dopamine levels, although possibly involving different mechanisms , small conductance calcium-activated potassium (SK), and fast, transient, voltage-dependent sodium (NaF) channels as well as general cellular heterogeneity have been proposed for desynchronization of the dopamine intact GPe.Intrinsic properties of GPe neurons are determined by more than 10 voltage-gated ion channel types  are better described and may share characteristics of GPe-GPe connections. In rat brain slices, GP-STN connections have been found to be sparse, but sufficiently powerful to inhibit and synchronize the autonomous activity of STN neurons (Baufreton et al., Miguelez et al.  showed tIt is still unclear how much and which influence inhibitory GPe-GPe coupling has on synchrony in parkinsonism. If their firing is periodic, coupling between GPe cells could either synchronize or desynchronize activity Wilson, . In the Highly heterogeneous synaptic coupling between GPe neurons could be a factor for their desynchronization. As heterogeneity on a cellular basis can act as a decorrelator, highly inhomogeneous coupling amongst neurons could lead to similar effects. Sadek et al.  describeAlthough changes in synaptic transmission within the rat GP after dopamine depletion have been measured (Miguelez et al., Several lines of evidence emphasize the importance of intrinsic GPe properties in abnormal synchronization in parkinsonism. This makes the GPe an attractive target for future therapies, potentially involving direct pharmacological targeting.Most of the evidence provided in this review is based on rodent studies, but the rodent GP may differ substantially from the human GPe in some aspects. Functionally, a lower average firing rate has been observed in the rodent GP compared to the primate GPe, while firing patterns were very similar (Benhamou et al., Though often assumed, it remains unclear whether increased synchronization in the BG causes motor impairments in PD patients (Quiroga-Varela et al., A comprehensive mechanism responsible for synchronization and desynchronization of the GPe that is dependent on dopamine levels, is still missing. However, loss of pacemaker function in GPe neurons and altered function of GPe-GPe synapses are important candidates Wilson, . AlthougAfter dopamine depletion, GP neurons undergo plastic changes in their synaptic and cellular structure (Chan et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


One of the major goals in cancer research is to find and evaluate the early presence of biomarkers in human fluids and tissues. To resolve the complex cell heterogeneity of a tumor mass, it will be useful to characterize the intricate biomolecular composition of tumor microenvironment , validating secreted proteins as early biomarkers of cancer initiation and progression. This approach is not broadly applicable because of the paucity of well validated and FDA-approved biomarkers and because most of the candidate biomarkers are mainly organ-specific rather than tumor-specific. For these reasons, there is an urgent need to identify and validate a panel of biomarker combinations for early detection of human tumors. This is especially important for breast cancer, the cancer spread most worldwide among women. It is well known that patients with early diagnosed breast cancer live longer, require less extensive treatment and fare better than patients with more aggressive and/or advanced disease.In the frame of searching breast cancer biomarkers , studies have highlighted an optimal combination of well-known biomarkers: uPA + PAI-1 + TF. When individually investigated they did not show perfect accuracy in predicting the presence of breast cancer, whereas the triple combination has been demonstrated to be highly predictive of pre-cancer and/or cancerous conditions, approaching 97-100% accuracy.Despite the heterogeneous composition of breast cancer and the difficulties to find specific breast cancer biomolecules, the noninvasive analysis of the nipple aspirate fluid secretome may significantly improve the discovery of promising biomarkers, helping also the differentiation among benign and invasive breast diseases, opening new frontiers in early oncoproteomics. Growing evidence suggests that human cancers develop via a non-linear multi-step process of cellular diversification and evolution. In particular, breast cancer initiation/progression from ductal/lobular system are dynamic processes of cell clonal adaptation to a fluctuating tumour microenvironment. During reiterative cycles of clonal expansion, genetic diversification and clonal selection within the adaptive landscapes of tissue ecosystems”[able to evolve as a cancer grows and repopulate the cancer when the bulk of the tumor is wiped out by anticancer drugs”[Recently, the classical hypothesis on the origin of human cancer known as clonal evolution  has beer drugs”).tumours as originating from immature cells”[a rare subpopulation of multipotent progenitor cells with self-renewal ability different from the bulk cells”[About 150 years after Virchow’s original theory of cancer cell biology (“k cells”), the efk cells”, brain[k cells”, and skik cells” mouse tuThrough different technologically innovative bio-molecular approaches, studies unequivocally demonstrated the cellular heterogeneity of tumors, composed of different set of cells , hierarchically organized and characterized by specific biomolecular and morphological profiles.It has been clearly demonstrated that cellular heterogeneity is closely related to stochastic transcriptional events, leading to variations in patterns of expression among genetically identical single cells. This ceConventional cancer diagnostic tools  are limited by the impossibility to discern the intra-tumour cancer cells heterogeneity. The low sensitivity and specificity of standard methods to detect cancer cells or their specific secreted biomolecules represent one of the major obstacle for cancer diagnosis. In factsingle-cell analysis it is now possible to identify, quantify, isolate, and characterize the heterogenous composition of a tumour mass with single-cell resolution, with high efficiency of cell viability and integrity for genomic, transcriptomic and metabolomic analyses downstream[Through the analytical technique of wnstream. This sywnstream.Besides the numerous differences detected among cancer cells within a tumour, cancer cell heterogeneity is also actively guided by the surrounding stroma and the components of the cancer microenvironment . In this respect, both cellular and non-cellular components  may actively modulate the tumour heterogeneity by exerting selective pressure on the evolving tumour and by dictating the genetic/epigenetic/phenotypic composition of the tumour. So, it The documented natural occurrence of heterogeneity in cancer cell populations within a tumor mass represents the major obstacle for finding both an early predictive biomarker and a successful therapeutic treatment.A recent debate in the literature sheds light on the use-misuse-disuse in laboratory and clinical medicine of several cancer biomarkers, pointing out their difficulties to reach the clinic, and the reasons of different failure-success rates-20.A biomarker  represents an indicator of a peculiar biological state that can objectively measure and compare normal biological and pathogenetic processes, or pharmacological responses to a therapeutic intervention. OriginaDespite the frenetic bio-medical progresses ” term, of which about 40% are “cancer biomarker”) and the substantial advances in the understanding of the molecular and bio-cellular basis of human diseases, a pauciThe recent literature debate about cancer biomarkers has focused attention to several crucial aspects and caveats: a) complexity and underestimation of the problem, b) missing data on cancer biology knowledge, c) funding limitations, d) inappropriate clinical setting, e) unpromising discovery and scarce/neglected validation, f) pre-analytical and methodological shortcomings, etc.-20.Starting from the evidence that cancer represents a cluster of multifaceted diseases involving alterations in both biomolecular pathways and multiple gene expression , the actual biological milestone of the cellular heterogeneity of tumors represenA parallel effort is needed to characterize the heterogeneous composition of cancer cells and the influence of cancer microenvironment at both biochemical and molecular level. It shall also be crucial to detect and validate biomolecules as biomarkers, to provide diagnostic, prognostic or predictive informations.It seems clear that not only intracellular proteins (the proteome), but also proteins secreted or shed into the tumor microenvironment (the secretome) may play crucial roles in driving the malignancy evolution of a tumor. In fact, the proteome reflects both the post-translational modifications and cellular pathways of a committed cancer cell; whereas improved secretome analyses provide insights into the mechanisms of cancer cells, the biology of tumor microenvironment, the cancer cell interactions and tumor progression.The analysis of the cancer secretome represents a very promising approach able to detect cancer-related proteins directly in body fluids mirroring the tissue-specific tumor microenvironment, such as Nipple Aspirate Fluid (NAF) for breast cancer,26.In fact, the secretome of NAF samples  alloBreast cancer is one of the leading causes of death among women around the world; due to its well known heterogeneity, encompaIn fact, screening programs, digital mammography, specialized care and the widespread use of therapeutic agents, have reduced mortality rates but the identification of molecular targets remains a primary long-term goal for the development of specific early interventions and individual therapeutic strategies.More than 10 million people are diagnosed with cancer every year, and it is estimated there will be over 15 million new cases/year by 2020. In partIn the past decade, there have been considerable improvements in the way that human breast tumours are identified and characterized, uncovering biomolecular alterations by using different technologies . In this respect, appropriate development of potential early detection and diagnostic tests, especially in the breast microenvironment, will be necessary prior to their clinical application, with special attention to their specificity and sensitivity to avoid over/under-diagnosis and/or clinical misuse,27.The relevant biological role of breast microenvironment during cancer initiation and progression has been widely and continuously analyzed but unfortunately up-to-now not completely understood-35.The microenvironment of the human mammary gland is composed of epithelial cells surrounded by intricate stroma . Through autocrine/paracrine mechanisms, physical and hormonal interactions result which are crucial for breast normal development and physiologic functions,37. Howesolid tumors are not masses of equivalent cells, but instead contain cancer stem cells that support tumor maintenance)[Recently, the cell heterogeneity of a tumor mass and the interactions between tumor and microenvironment have been demonstrated ,29. Moretenance),40.The intraductal noninvasive approach of NAF secretome analyses may provide a panel of candidate biomarkers strengthening the armoury against BC,28. All Structural, cellular, functional and genetic alterations of stromal and epithelial cells may influence cell growth, morphogenesis and plasticity and contribute to the development of the tumorigenic phenotype.Numerous studies have analyzed the expression of selected candidate biomarkers (both genes and proteins) in normal and neoplastic primary human breast tissues, up-reguThese alterations can be monitored at the protein level and the protein signatures in the breast cancer microenvironment provide valuable information that may be an aid to more effective diagnosis, prognosis, and response to therapy, finally opening novel avenues for cancer-related biomarker discovery,45.Knowledge about the breast and breast cancer microenvironments,36,37 isClinicians usually prefer to over-treat some BC patients, instead of using prognostic biomarkers with less than perfect prediction”[Many studies have found candidate biomarkers for early diagnosis and/or as possible reliable prognostic or predictive parameters, but in some cases contradictory results are reported,49. The diction”.Urokinase-dependent plasminogen activator system (uPA), Plasinogen activator inhibitor (PAI) and the Thomsen-Friedenreich antigen (TF).Among candidate biomarkers for human BC considerable attention has been focused recently on the combination of the The serine proteinase urokinase-type plasminogen activator  and its specific inhibitors , are involved in the control of extracellular matrix turnover, tissue remodeling, cell adhesion and migration during physiopathological processes, including breast cancer,51.Altered expression of the plasminogen activation system (uPA-PAI-uPA receptor) was found to be correlated with tumor malignancy. It is believed that the tissue degradation following plasminogen activation facilitates cancer cell invasion contributing to metastasis. Data accumulating over the past 20 years have shown that the uPA system shows multifunctional roles in healthy and neoplastic conditions. In partTo date, these molecules are the only prognostic markers that have reached the highest level of evidence (LOE-1) in multi-centered clinical trials. UnfortuThe Thomsen–Friedenreich antigen (TF or CD 176), represents O-linked mucin type glycan found in about 90% of all human cancer and defined since 1920’s as pancarcinoma antigen,55.Although the mechanism of increased TF expression occurrence in cancer is still not completely understood, its increasing expression on the cancer cell surface as the disease progresses may be mainly related to an active unmasking procedure linked to altered glycosylation mechanisms.Although TF antigen roles in cancer are not completely understood (mainly due to different glycosylation patterns in different types of cancers), the pancarcinoma expression may have clinical utility as a potential immunotherapy target, leaving a possible glimmer of hope against recurrence of advanced BC.On the basis of the well known evidence that BC: 1) arises from the epithelial cells lining the ductal/lobular system, 2) is characterized by elevated cell heterogeneity, and 3) there is not currently a validated and FDA-approved BC combination of biomarkers; the secretome analyses of NAF fluids  may revStarting from the first evidence of the clinical utility of NAF analyses dating back to 1950s, growingNAF samples thus represent the reservoir of biochemical and hormonal components secreted by the ductal tree appearing as the mirror of all metabolic changes occurring within the breast gland; whereas, plasma samples represent only the surrogate source which reflects only in part the tissue-specific metabolic changes. On these basis, the “intraductal approach” of the NAF secretome is more accurate, specific and timely for early breast cancer detection.Due to the ever growing interest of molecular medicine moving from genomics to proteomics and metabolomics, the secretome of NAF represents a suitable method to discover BC specific biomarkers. So, NAF fluids represent protein-rich bioarchives highlighting what occurs within the microenvironment of the breast ductal system during all stages of the female breast life.BMC Cancer[In the frame of searching cancer biomarkers in breast microenvironment,27, a reMC Cancer reports Some previous studies have demonstrated that TF antigen was an independent predictor of disease only in post-menopasual women, correctly classifying cancer and atypia with a ROC value for disease prediction of 83%,67. It hAlthough these biomolecules appeared individually not perfectly accurate in predicting the presence of BC during different menopausal status, Sauter’s research team demonstrated the innovative biomarker combination in NAF: 1) uPA Starting from the importance to simultaneously investigate multiple biomarkers in different breast diseases (like atypia and cancer) to avoid pitfalls, shortcomings and false discovery of candidate biomarkers,20, the Viribus unitis” (lat. "With united forces"): the intraductal noninvasive approach of NAF secretome analysis confirms the importance of considering biomarkers in the breast microenvironment not individually but in well validated combinations, to provide more informative diagnostic/prognostic tests and limiting the biomarkers included in the “niche unmet needs”[“t needs”.Breast cancer, the major cause of death among women around the world, is characterized by a high complexity and not completely understood biological and clinical heterogeneity. Also byMoreover, the altered paracrine/autocrine mechanisms, physical, biomolecular and hormonal networks in the breast microenvironment lead to the development and progression of human BC, includiThe cell heterogeneity of BC reflects the complexity of the secretome , revealing the enormous difficulty to find useful and specific biomolecules as candidate cancer biomarker(s).Improving technological methods  to enablHowever, to effectively translate candidate biomarkers studies into the clinical setting, crucial factors have to be regarded ,24.In this respect, the analysis of the breast cancer microenvironment, mirrored by NAF, allows the detection of alterations in biochemical, morphological and molecular pathways promoting cancer initiation, progression, invasion and metastasis, taking into account also the different stem/non-stem cell composition and interactions in the human breast microenvironment.Therefore, analyzing NAF breast fluid proteins and proteinases  we could obtain useful insights about mechanisms making breast ductal cells more prone to morphological and biomolecular alterations .Biomarker studies  may help the comprehension of disease initiation and progression, stem repopulation of cancer, prediction of patient population characteristics, finally improving also the critical points of drug development, drug efficacy and drug-induced adverse reactions.It has been biologically and clinically demonstrated that individual biomarkers cannot predict or monitor cancer development/progression. To be highly effective in diagnostic/prognostic/clinical approaches it is crucial to combine specific biomolecules to obtain an optimal panel of biomarkers, which, through a comprehensive biomarker study registry, may significantly reduce false positives and hopefully identify promising cancer tests.BMC Cancer on TF, uPA and PAI in NAF samples[In this respect, the study recently published in  samples represenFuture developments in onco-single-cell-omics will potBC: Breast cancer; uPA: urokinase-type plasminogen activator; uPAR: urokinase-type plasminogen activator receptor; PAI: Plasminogen activator inhibitor; ECM: Extracellular matrix; TF: Thomsen-Friedenreich carbohydrate antigen; CSC: Cancer stem cells; NAF: Nipple aspirate fluid.Both authors declare that they have no competing interests.FM performed statistical analyses, drafted the manuscript and critically reviewed the final manuscript. DL performed database searches, drafted the manuscript and elaborated the figure. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/13/344/prepub


Vascularized composite tissue allotransplantation is a rapidly evolving area that has brought technological advances to the forefront of plastic surgery, hand surgery, and transplant biology. Composite tissue allografts (CTAs) may have profound functional, esthetic, and psychological benefits, but carry with them the risks of life-long immunosuppression and the inadequate abilities to monitor and prevent rejection. Allografts may suffer from additional insults further weakening their overall benefits. Changes in local blood flow, lack of fully restored neurologic function, infection, inflammation with subsequent dysregulated regenerative activity, and paucity of appropriate growth factors may all be involved in reducing the potential of CTAs and therefore serve as new therapeutic targets to improve outcomes. Strategies involving minimized immunosuppression and pro-regenerative therapy may provide a greater path to optimizing long-term CTA function. One such strategy may include mesenchymal stem cells (MSCs), which can provide unique anti-inflammatory and pro-regenerative effects. Insights gained from new studies with MSCs on composite allografts, advances in tissue regeneration reported in other MSC-based clinical studies, as well as consideration of newly described capacities of MSCs, may provide new regenerative based strategies for the care of CTAs. Patients receiving life-saving solid organ transplants directly contrast with those considered for vascularized composite tissue allotransplantation (VCTA). In general, VCTA recipients are physically healthy individuals except for the tissue defect; tissue transplantation is not considered life-saving or life-prolonging . The benSince the first successful hand transplantation by Dubernard in 1998, over 70 hand composite tissue allotransplantations (HCTAs) ranging from wrist level to shoulder level have been performed around the world . The devIn terms of long-term success, there are other, less well-characterized variables which play a role. While cerebral plasticity allows adaptation to use of the hands, it does not predict psychological acceptance . Such acThe first partial face allotransplantation was achieved in 2005 by Dubernard in Amiens, France, and the first full face allotransplantation, containing soft tissue and bony structures, was performed in 2010 by Barret in Barcelona, Spain . To dateThe face plays a major role in an individual’s interaction with the outside environment. The face represents sense-of-self and identity. In addition to the senses , it conveys emotion  and plays a major role in basic physical functions  . Facial Like hand transplant, neurologic sensory function precedes motor function. Reestablishing sensation and motion for speech, swallow, and mimicry through coaptation of the sensory and motor nerves  remain challenging. Near normal sensory recovery of the early cases has been demonstrated between 3 and 8 months postoperatively by quantitative sensory tests . Motor rUnlike hand transplantation, facial transplantation must overcome the added hurdle of host responses directed against the transplanted mucosal barrier and associated microbiome , 20, 21.Pseudomonas aeruginosa infection on post-operative day 15 with destructive soft tissue infection, and subsequent death 65 days after transplant due to anoxic cardiac arrest from tracheostomy obstruction in the context of septic complications  and the death of the world’s first concomitant hand and FCTA patient (France). In 2009, Lantieri transplanted the upper 2/3 of face and bilateral hands to a 37-year-old recipient with significant burns. No acute rejection episodes occurred but the patient suffered multiresistant ications . This moications , 25 and ications .Original work involving cyclosporine A and successful rat hind-limb allotransplantation have paved the way for modern immunosuppressive therapy for composite tissue allotransplantation . ImmunosIn addition to triple therapy, some centers have attempted novel methods to reduce immunosuppression requirements. Devauchelle and Dubernard included bone marrow donor infusion in the first case, anticipating improved survival in recipients of solid organ transplant and donor hematopoietic stem cells , 30. HowDecreasing the risk profile of CTA requires eliminating or reducing the obligatory life-long immunosuppression component. Induction of donor-specific immunologic tolerance has been proposed in various clinical and animal models. The Pittsburg Hand Transplant Program has found early benefit with donor bone marrow transfusion at day 15, with reduction in immunosuppressive burden   though lProgressive steps in achieving stable mixed chimerism with a non-myeloproliferative conditioning regimen and donor hematopoietic stem cell infusion  have beeThere is already strong preclinical and clinical indication for the use of MSCs in solid organ transplantation suggesting this approach could be beneficial in VCTA. In preclinical models, MSCs have not only been shown to limit the extent of injury following renal ischemia-reperfusion  but also42in vivo transplantation of allogeneic MSCs. These more recent data question both the concept that MSCs are truly immune-privileged and the reality of non-crossmatched allogeneic MSC transplantation. While it is clear that further investigation is necessary to fully understand the immunogenicity of MSCs, the potential to utilize MSCs as an “off the shelf” therapeutic agent cannot be overlooked and may offer a significant advantage in the setting of VCTA.Another benefit to using MSCs is the opportunity to capitalize on the growing body of literature supporting the non-immunogenic properties of these cell populations. One key obstacle in solid organ transplantation is the need for a donor-recipient crossmatch. There is currently a large set of data suggesting that MSCs are non-immunogenic –47 thereBecause of increasing evidence to support beneficial effects of MSC, extension of MSC therapy from solid organ transplantation to VCTA is an appropriate next step for therapy in improving outcomes in CTAs. Beyond potential for facilitating immunotolerance, MSC application may potentiate therapeutic effects of repair and regeneration to those reported in acute and chronic wound models as VCTA contain skin elements, in contrast to solid organ allografts, which would benefit from accelerated closure, granulation, and angiogenesis.In VCTAs that include skin components, an effective progression through the phases of inflammation, tissue formation, and remodeling must occur since these are the overlapping phases of skin regeneration . NeutropTissue injury typically results in the secretion of several mediators of wound healing, such as platelet-derived growth factor, which attract and activate macrophages and fibroblasts . MSC-basThe perspective of the VCTA as a chronic wound is based on similarities seen in tissue dysregulation and potential pro-regenerative synergistic targets that may act as counteragents to retarded repair mechanisms in the setting of: (1) inflammation, (2) macrophage-mediated inflammatory processes, (3) impaired epithelialization and attenuated matrix deposition, and (4) endothelial injury and intimal hyperplasia. All of these processes serve as potential targets for MSC-based therapy, due to the effect of MSCs on cytokine signaling pathways regulating immune responses and inflammation.Mesenchymal stem cell-potentiated tissue regeneration and repair responses in chronic wound healing that may be paralleled and exploited in VCTA include: (1) MSC signaling with enhancement of cellular responses including cell survival, proliferation, migration, and gene expression; (2) MSC-conditioned media exhibiting paracrine activity as a chemoattractant recruiting macrophages and endothelial cells to the wound, including epidermal keratinocytes and dermal fibroblasts ; (3) dowFetal healing serves as an ideal model for wound repair. Pluripotent MSCs have been touted as the adult cellular proxy to reenact the tissue regenerative capacity seen early in development. Despite improved wound regeneration orchestrated by MSCs, there is no substantial evidence that MSCs promote “scarless” healing seen in fetal tissues mechanism due to MSC differentiation to replace damaged skin . Fetal wWhile a great deal of research has focused on immunosuppressive strategies following VCTA, very little has focused on promoting regeneration of the allograft components. Such a strategy, in combination with immunosuppressive regimens, may improve early function and reduce immunosuppressive requirements. Induction of MSC differentiation into many of the components of VCTAs, has been reported to induce significant regenerative effects on tissues . HoweverSince MSC-based regenerative properties are likely not due to terminal differentiation, with several studies have demonstrated that the number of MSCs administered could not numerically account for all the components of regenerating tissue –58 MSC-bMultiple strategies have been investigated to increase MSC presence at wounds, including the recruitment of endogenous MSCs as well as the direct application of MSCs to the wound. The total benefit derived from direct application of MSCs is additive with the potential for regeneration coming through both cellular engraftment and differentiation – exploiting MSC “stemness” – in addition to repair via paracrine signaling. Another strategy involves signaling endogenous MSCs to mobilize from the bone marrow and preferentially deposit in injured tissue over the surrounding, uninjured tissue –62. WhilWhile the risks of life-long immunosuppressive therapy serve as the impetus for finding alternative modulators of host immune responses in VCTA, MSCs may offer novel reparative and regenerative based strategies with application in these transplanted allografts. Components of tissue dysregulation involving the endothelial injury, delayed epithelialization, inappropriate inflammation, and paucity of appropriate growth factors may all be involved in reducing the overall benefit of CTAs and as a consequence, serve as novel therapeutic targets for MSCs to improve allograft outcomes.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Serous epithelial ovarian cancer (SEOC) is the most lethal gynecological cancer in the United States with disease recurrence being the major cause of morbidity and mortality. Despite recent advances in our understanding of the molecular mechanisms responsible for the development of SEOC, the survival rate for women with this disease has remained relatively unchanged in the last two decades. Preclinical mouse models of ovarian cancer, including xenograft, syngeneic, and genetically engineered mice, have been developed to provide a mechanism for studying the development and progression of SEOC. Such models strive to increase our understanding of the etiology and dissemination of ovarian cancer in order to overcome barriers to early detection and resistance to standard chemotherapy. Although there is not a single model that is most suitable for studying ovarian cancer, improvements have led to current models that more closely mimic human disease in their genotype and phenotype. Other advances in the field, such as live animal imaging techniques, allow effective monitoring of the microenvironment and therapeutic efficacy. New and improved preclinical mouse models, combined with technological advances to study such models, will undoubtedly render success of future human clinical trials for patients with SEOC. The continued high mortality associated with serous epithelial ovarian cancer (SEOC) underscores a need for tailored disease models and improved technology to study such models. Several recent advancements promise to facilitate the success of preclinical models in refining our understanding and treatment of SEOC. This mini-review will focus on the latest mouse models of ovarian cancer and improved technologies for using these models to study SEOC initiation, progression, relapse, and therapeutic response.Mouse models provide a wealth of information for understanding tumor biology. Through the validation of Ovarian cancer is the most common cause of gynecological mortality in the United States, accounting for more than 14,000 deaths annually , 3. Animde novo from the surface epithelium of the ovary or from the mucosa of the fallopian tube , into the abdominal cavity , or into the organ of origin (orthotopic) of an immune-compromised host. While intraperitoneal and orthotopic injections can mimic metastatic dissemination, subcutaneously injected cells are largely limited to tumor formation at the site of injection. The unique presence of a bursa, a sac encapsulating the ovaries and fallopian tubes, allows for intra-bursal injections in mice , 11. Thiin vivo with histology representative of the tumor of origin  strains lack both T and B cell responses. Because tumors can promote anti-tumor responses such as lymphocyte and macrophage infiltration, these models may not accurately represent disease progression and therapeutic response observed in otherwise immune-competent individuals –19. FurtAn alternative to traditional cell line-derived xenograft models involves the direct transfer of tumor fragments from individual patients. Minced fragments are delivered via orthotopic or intraperitoneal injection into immune-deficient mice to create “xenopatients” or tumor grafts , 20. Sucin vitro until transformation occurred, and subsequently injected back into the same strain  are immune-competent mice with genetic defects introduced using RNA interference, inducible gene expression, viruses, or DNA recombination techniques. GEMMs provide a means for investigating the role of genetic alterations in cancer development. These models allow researchers to control and direct gene expression, which can be limited to the tissue of interest using a tissue-specific promoter to introduce the desired genetic alteration, or expressed throughout the organism using germ-line mutations . FurtherTP53, C-MYC, K-RAS, AKT, and BRCA1 and BRCA2 , computed tomography (CT), positron emission tomography (PET), ultrasound] have been adapted for use in animals , 56. ThePositron emission tomography imaging is a standard diagnostic radiological technique commonly used to monitor drug action in cancer patients. This modality allows the measurement of metabolic activity in cancer cells and is especially useful in quantitative monitoring of tumor response to anti-cancer therapies . PET imaUltrasound imaging is another common tool used in small animal models and is often combined with other imaging techniques for a more comprehensive analysis . UltrasoMagnetic resonance imaging with gadolinium-based contrast agent permits high-resolution serial imaging with minimum scanning duration, allowing quantification of tumor volume over time. MRI data are comparable to caliper-based measurements taken at necropsy. This longitudinal imaging protocol is well suited for monitoring therapeutic response . MRI canMeasurement of metabolites and their intermediates can illustrate the response of an organism to a genetic manipulation or therapy. Metabolites are small, low molecular weight analytes and include amino acids, oligopeptides, sugars, fatty acids, and various intermediates of biochemical pathways, in contrast to large proteins and nucleotides that are assessed using proteomics and genomics, respectively . NuclearCommonly used in human studies, , 67 thisThe cancer stem cell (CSC) or tumor-initiating cell (TIC) hypothesis suggests that a small population of chemoresistant cells reside in the tumor, capable of reconstituting the tumor. These cells share properties of normal stem cells, such as self-renewal and multi-potency. Given the high recurrence of ovarian cancer, the TIC hypothesis is an attractive model for explaining ovarian cancer relapse.Mouse models have been especially useful in evaluating TICs. When injected into mice, these cells must recapitulate the heterogeneity of the original tumor. Animal models are essential for defining TICs and for evaluating drugs and pathways important for eradicating these cells. Patient-derived xenografts might allow further characterization of the frequency of TICs in human tumors, and their relevant biomarkers.in vitro using low attachment culture plates and specialized serum-free media to enhance the formation of multicellular spheroids with stem-like features  and CTL antigen-4 (CTLA-4) signals silence the immune response in tumors. A syngeneic mouse model of ovarian cancer showed that simultaneously blocking these pathways enhanced T cell infiltration into the tumor and increased long-term survival . A relatGenetically modified T cells engineered to over-express receptors for tumor-associated antigens have shown great success in mouse models of ovarian cancer , 88. ThiDespite our progress in understanding ovarian cancer biology, there remains a high mortality associated with this disease. Exciting advances in reporter assays, live imaging, metabolomics, TICs, and immune therapies, provide new information about the tumor microenvironment and further our understanding of SEOC development, progression, and recurrence Figure . FurtherThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Recent advances in next-generation DNA sequencing enable rapid high-throughput quantitation of microbial community composition in human samples, opening up a new field of microbiomics. One of the promises of this field is linking abundances of microbial taxa to phenotypic and physiological states, which can inform development of new diagnostic, personalized medicine, and forensic modalities. Prior research has demonstrated the feasibility of applying machine learning methods to perform body site and subject classification with microbiomic data. However, it is currently unknown which classifiers perform best among the many available alternatives for classification with microbiomic data.In this work, we performed a systematic comparison of 18 major classification methods, 5 feature selection methods, and 2 accuracy metrics using 8 datasets spanning 1,802 human samples and various classification tasks: body site and subject classification and diagnosis.We found that random forests, support vector machines, kernel ridge regression, and Bayesian logistic regression with Laplace priors are the most effective machine learning techniques for performing accurate classification from these microbiomic data. Advances in low-cost, high-throughput DNA sequencing technologies have enabled the studies of the composition of microbial communities at unprecedented throughput levels. Such studies are particularly interesting for biomedicine because for every human cell in the body there are about ten microbial cells in the gut alone . These mA typical microbiomic study relies on a marker gene (or a group of markers) that can be used for the identification and quantitation of the microbes present in a given specimen. A good marker gene needs to have three essential properties: (i) it must be present in all of the microbes that we try to identify, (ii) its sequences should be conserved in members of the same species, and (iii) the interspecies difference in the gene sequence should be sufficiently significant to allow for taxonomical discrimination. The 16S rRNA gene is commonly used in microbiomic studies as a marker gene to generate human microbiota surveys. For every sample in a dataset, a human microbiota survey contains hundreds of thousands or millions of DNA sequences from the underlying microbial community. Abundances of operational taxonomic units (OTUs), extracted from the high-throughput sequencing data using upstream bioinformatic processing pipelines, can serve as input features for machine learning algorithms.et al. took an excellent first step in this direction and established the feasibility of creating accurate models for classification of body sites and subject identification , served as input features for machine learning algorithms. The number of OTUs in each dataset is provided in Table , served The OTU tables and sample labels for all datasets used in the study are provided in Additional files We used 18 machine learning multicategory classification algorithms from the following seven algorithmic families: support vector machines, kernel ridge regression, regularized logistic regression, Bayesian logistic regression, random forests, k-nearest neighbors, and probabilistic neural networks. These machine learning methods were chosen because of their extensive and successful applications to many datasets from other genomic domains. Since all the classification tasks were multicategory  and most of the employed classifiers  are designed for binary classification problems , we adopted a one-versus-rest approach for the latter methods. Specifically, we trained separate binary classifiers for each class against the rest and then classified new samples by taking a vote of the binary classifiers and choosing the class with the ‘strongest’ vote. The one-versus-rest approach for classification is known to be among the best performing methods for multicategory classification for other types of data, including microarray gene expression ,4. RandoSupport vector machines (SVMs) are a class of machine learning algorithms that perform classification by separating the different classes in the data using a maximal margin hyperplane . For every algorithm P value associated with its statistical comparison against the nominally best performing classifier.Classification accuracy results of experiments without feature/OTU selection, averaged over eight datasets, are provided in Figure 2-regularized logistic regression and random forests with default parameters. However, when using RCI as a performance metric, the only classifiers which are statistically significantly worse than the nominally best performing classifier are the KNN-based methods, PNN and BLR with Gaussian priors. Therefore, several classifiers which are significantly worse when using the somewhat naive PCC metric are comparable when using the more descriptive RCI metric ; L2-LR: regularized logistic regression by an L2 penalty (machine learning method); OTU: operational taxonomic unit; PCC: proportion of correct classifications (classification accuracy metric); PNN: probabilistic neural networks (machine learning method); QIIME: Quantitative Insights Into Microbial Ecology; RCI: relative classifier information (classification accuracy metric); RF: random forests (machine learning method); SVM: support vector machine (machine learning method)BLR: Bayesian logistic regression (machine learning method); KNN: K-nearest neighbors (machine learning method); KRR: kernel ridge regression (machine learning method); L1-LR: regularized logistic regression by an LThe authors declare that they have no competing interests.AS and AVA conceived the research study and designed the methods and experiments. MH, VN, KK, ZL, LY prepared the data, implemented the methods and conducted all experiments and data analysis. AS, AVA, MH, KK, VN participated in the interpretation of the results. All authors have contributed to, read, and approved the final manuscript.Operational taxonomic unit table and sample labels for the CBH dataset.Click here for fileOperational taxonomic unit table and sample labels for the CS dataset.Click here for fileOperational taxonomic unit table and sample labels for the CSS dataset.Click here for fileOperational taxonomic unit table and sample labels for the FS dataset.Click here for fileOperational taxonomic unit table and sample labels for the FSH dataset.Click here for fileOperational taxonomic unit table and sample labels for the BP dataset.Click here for fileOperational taxonomic unit table and sample labels for the PBS dataset.Click here for fileOperational taxonomic unit table and sample labels for the PDX dataset.Click here for file


Macroautophagy is a cellular catabolic process that involves the sequestration of cytoplasmic constituents into double-membrane vesicles known as autophagosomes, which subsequently fuse with lysosomes, where they deliver their cargo for degradation. The main physiological role of autophagy is to recycle intracellular components, under conditions of nutrient deprivation, so as to supply cells with vital materials and energy. Selective autophagy also takes place in nutrient-rich conditions to rid the cell of damaged organelles or protein aggregates that would otherwise compromise cell viability. Mitophagy is a selective type of autophagy, whereby damaged or superfluous mitochondria are eliminated to maintain proper mitochondrial numbers and quality control. While mitophagy shares key regulatory factors with the general macroautophagy pathway, it also involves distinct steps, specific for mitochondrial elimination. Recent findings indicate that parkin and the phosphatase and tensin homolog-induced putative kinase protein 1 (PINK1), which have been implicated in the pathogenesis of neurodegenerative diseases such as Parkinson’s disease, also regulate mitophagy and function to maintain mitochondrial homeostasis. Here, we survey the molecular mechanisms that govern the process of mitophagy and discuss its involvement in the onset and progression of neurodegenerative diseases during aging. Macroautophagy (henceforth referred to as autophagy) is a high-regulated catabolic process responsible for the lysosomal degradation of cytoplasmic constituents. The main characteristic of the autophagic pathway is the formation of a double-membrane structure known as autophagosome, which engulfs cytoplasmic cargo and delivers it to lysosomes for degradation  . In direTable 1). While mitophagy shares key regulatory factors with the general autophagy pathway, it also involves distinct steps, specific for mitochondrial elimination. Studies in yeast identified specific genes that are required for mitophagy, but not for other types of autophagy -domain protein that is located in the outer mitochondrial membrane and is essential for the specific autophagic elimination of mitochondria upon nitrogen starvation or rapamycin treatment, without influencing general autophagy . Atg32 is the first protein shown to interact with the core autophagic machinery, and be required specifically for mitophagy. Interestingly, loss of Atg32 does not alter cellular reactive oxygen species (ROS) levels or growth on non-fermentable carbon sources . The mitochondrial fusion proteins mitofusin 1 and 2 have been identified as substrates of Parkin -induced kinase 1 (PINK1) have been shown to cause a recessive form of parkinsonism  . Howevertegrity  . In healtegrity  . Upon mitegrity  . Accumultegrity  . Followi Parkin  . Parkin  Parkin  . HoweverNix–/– mice retain mitochondria in erythrocytes and develop anemia because of decreased survival of these cells  and the GABA receptor-associated protein (GABARAP) in vivo and in vitro . Nevertheless, despite the requirement of Nix in erythrocyte differentiation, treatment of reticulocytes with uncoupling agents induces mitophagy upon mitochondrial depolarization in a Nix-independent manner . However, the signal that activates mitophagy, to selectively eliminate sperm-derived mitochondria remains unknown.An additional important developmental role for mitophagy is the removal of paternal mitochondria in fertilized oocytes  . AlthougNeuronal cells typically require increased numbers of mitochondria, since most neuronal ATP is generated through oxidative phosphorylation. This high-energy demand is dictated by numerous neuronal processes, such as axonal transport of macromolecules and organelles, maintenance of membrane potential, loading and releasing neurotransmitters, and buffering cytosolic calcium. Therefore, neuronal survival and activity are critically dependent on mitochondrial integrity and functionality  . MitochoParkinson’s disease is caused by loss of dopaminergic neurons in the substantia nigra, a region important for motor control and coordination. Loss-of-function mutations in PINK1 and/or PARK2 genes have been linked with the early onset of hereditary forms of Parkinson’s disease. The PINK1/Parkin pathway has been shown to regulate the elimination of damaged mitochondria through mitophagy  , 2010. IAlzheimer’s disease is the most common age-associated neurodegenerative disorder, characterized by cognitive dysfunction and loss of memory, caused by neuronal cell death in cerebral cortex. Tissue sections from Alzheimer’s disease patient brains show distinctive intracellular neurofibrillary tangles and extracellular amyloid plaques composed of beta-amyloid derived from amyloid precursor protein (APP). While, the predominant hypothesis is that excess beta-amyloid leads to neuronal death, the mechanism that underlies pathogenesis is still unclear. Mitochondrial damage has been implicated in the development and progression of Alzheimer’s disease, since abnormalities in mitochondrial structure have been observed in afflicted individuals  . MoreoveHuntington’s disease is an autosomal dominant neurodegenerative disease caused by the abnormal expansion of the cytosine, adenine, and guanine (CAG) repeats within huntingtin (Htt) gene. The severity of pathology correlates with the number of CAG repeats, the length of expansion  . HuntingMitochondrial dysfunction has already been correlated with aging. Mitochondria are the primary source of ROS, such as nitroxides, hydrogen peroxide, and superoxide anions  . Aging pAlthough findings in diverse organisms indicate that the process of mitophagy requires the core autophagic machinery of cell, the initial signals that trigger and activate this selective type of autophagy, remain obscure. These signals appear to differ according to nutrient conditions, developmental processes, and damage-induced mitochondrial loss. Despite the fact that several proteins, such as ATG32, Nix, PINK1, Parkin have been identified as being critical for targeting mitochondria to autophagosomes, important information about the recruitment of these proteins to mitochondria and their interaction with the core autophagic machinery is lacking. Further investigation of the mechanisms mediating mitophagy will elucidate these key steps and shed light onto the link between mitophagy and aging. As a corollary, these studies are also likely to provide novel potential targets for therapeutic interventions against age-associated pathologies such as neurodegenerative disorders.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Although mercury concentrations have decreased about 20% in fish, fish-eating birds, and inland lake sediments across the Great Lakes region in recent decades, levels in top predator fish and wildlife are still dangerously high, and in some places concentrations in some fish and wildlife may now be increasing, according to a new report.Recent news reports bring fresh attention to a sweet ingredient for remediating solvent-laden soils: molasses.In late September 2011 Florida health officials received confirmation of the second case of locally acquired dengue fever in the Miami–Dade County area for 2011.in utero exposure has been linked to increased breast cancer risk in humans. BPA, an industrial chemical used to manufacture epoxy resins, polycarbonate plastics, and thermal paper, has not been linked to breast cancer in humans.A new study has found an association between prenatal exposure to low-dose bisphenol A (BPA) and development of mammary tumors in adult female mice.The National Institutes of Health recently announced a new research program to study human health impacts of climate change.


Alcohol use is common among people infected with HIV and may contribute to adverse consequences such as reduced adherence to treatment regimens and increased likelihood of risky sexual behaviors. Therefore, researchers and clinicians are looking for treatment approaches to reduce harmful alcohol consumption in this population. However, clinical trials of existing treatment models are scarce. A literature review identified only 11 studies that included HIV-infected patients with past or current risky alcohol use and which targeted alcohol use and other health behaviors. Four studies focusing on HIV-infected participants with alcohol problems found mixed effects on adherence and on alcohol use. Five clinical trials included at least 10 percent of HIV-infected subjects who use alcohol; of these, only one reported significant evidence of a favorable impact on alcohol consumption. Finally, two trials targeting alcohol users at high risk for HIV infection identified treatment effects that were not sustained. Taken together, these findings provide limited evidence of the benefit of behavioral interventions in this population. Nevertheless, these studies give some guidance for future interventions in HIV-infected patients with alcohol problems. Reduced adherence to medication regimens for treatment of HIV infection ;Lack of a health care provider for the HIV infection ;Delayed linkage to HIV medical care ;Increase in risky sexual behaviors ;Increased transmission of sexually transmitted infections ; andProgression of HIV disease .In the United States, people infected with the human immunodeficiency virus (HIV) drink more alcohol than people in the general population. Specifically, a higher proportion drink risky amountsGiven the spectrum of problems associated with such alcohol use among HIV-infected patients, one important avenue to improving the health of this population is to develop interventions that target alcohol use and its associated consequences. Accordingly, interventions have been designed to both decrease alcohol consumption and address the specific adverse health consequences.The concept that negative consequences of alcohol use can be reduced in patients with HIV infection is based on research demonstrating the impact of clinical interventions on alcohol consumption and associated negative consequences in patients without HIV infection . AlcoholFor alcohol-dependent patients, more extensive behavioral interventions  can be effective Given the strong evidence that alcohol consumption is an important health issue for many people with HIV infection, efforts to potentially ameliorate these problems by addressing alcohol use are of great interest. The studies in non–HIV-infected people reviewed above suggest that interventions among HIV-infected people with alcohol problems could be beneficial. However, the wide range of results in these intervention studies based on setting and disease severity argues for the need to carefully assess efforts to mitigate alcohol’s deleterious impact on health in HIV-infected patients. As an important step in this direction, this article summarizes the findings of a review of the clinical trial literature on interventions addressing alcohol consumption and its consequences among HIV-infected patients. After describing the design of the literature search and evaluation, the article reviews the findings of the studies identified and discusses the implications of those findings.HIV disease progression;Receipt of HIV treatment;HIV medication adherence;HIV risk behaviors;Acquisition of sexually transmitted infections; andAlcohol use.The literature review sought to identify clinical trials of interventions among HIV-infected people with past or current unhealthy alcohol use  that reTo be included in the review, the studies had to report alcohol-specific outcomes. Beyond that, the studies were classified into three categories of specificity. The most specific category comprised clinical trials that included only HIV-infected people with past or current unhealthy alcohol use. The second category comprised clinical trials that included only HIV-infected people but in which not all of the participants exhibited unhealthy alcohol use. For a study to be included in this category, at least 10 percent of participants had to report current alcohol use. The third category of studies comprised trials that were aimed at preventing alcohol use and sexual behaviors that put people at risk of HIV infection among alcohol-using people. Although these studies did not include HIV-infected participants or did not report the HIV status of the participants, they were reviewed because they may inform future research on people at risk of HIV transmission in the setting of alcohol use.Initially, the review intended to include only RCTs. However, very few studies were identified that met this criterion in the first two categories. Therefore, the search was expanded to include nonrandomized and non-controlled clinical intervention trials in categories 1 and 2.To identify relevant studies, the literature database MEDLINE was searched through September 30, 2009, using the search terms “HIV, alcohol, hazardous drinking, risky drinking, problem drinking, counseling, brief intervention, 12 step, pharmacotherapy, naltrexone, acamprosate, disulfiram, topiramate, and clinical trial.” For all articles identified using this approach, the reference lists also were scanned, as were related articles identified by the search engine for the MEDLINE data base to look for additional studies. Reference lists for articles that were closely related, but did not meet the criteria, also were reviewed. Finally, articles referenced in relevant review articles were examined. Titles of all articles were reviewed to determine if the articles met the selection criteria. If the nature of the study could not be discerned through the title, the abstract and/or full text of the article was retrieved and reviewed.For all studies that met the criteria for one of the three categories, information on the setting, study design, methodological quality, type of intervention, outcomes reported, period of follow-up, and results was extracted. The following sections summarize the findings of these analyses. They are presented as a descriptive narrative synthesis because studies were too few and heterogeneous to perform a standard meta-analysis.The search strategy described above identified 241 potentially relevant studies that were evaluated further. Of these, four studies including a total of 578 patients  met the These investigators conducted an RCT among 253 HIV-infected men who had had sex with men in the previous 3 months and who scored more than eight points on the AUDIT questionnaire . The intIn this pilot study, 31 HIV-infected primary-care patients with heavy alcohol use received one session of MI from a trained counselor, followed by daily telephone-based interactive voice response (IVR) assessments of drinking amounts and graphic feedback of changes in drinking at 30 and 60 days. This intervention resulted in a decrease in the number of drinks per day at 30 and 60 days (from 3.2 drinks per day at baseline to 1.7 drinks at 30 days and 1.2 drinks at 60 days). The IVR system was utilized; 77 percent of all possible daily calls were completed at 30 days. However, these improvements can not be attributed to the intervention with confidence because there was no control group.These investigators conducted an RCT among 143 HIV-infected people with “hazardous drinking” (defined as more than 16 standard drinks per week for men or more than 12 standard drinks per week for women), assessing treatment effects on HIV medication adherence and alcohol outcomes. The intervention involved eight 1-hour individual sessions of MI and cognitive behavioral skills training over 3 months and was compared with a time- and content-equivalent control.This RCT included 151 HIV-infected patients on antiretroviral therapy (ART) who had a history of alcohol problems. The participants received either four nurse-delivered, 30- to 60-minute sessions focusing on HIV medication adherence and alcohol counseling, both in a clinic and at home, or no intervention. The study found no significant differences between groups upon examination of the following outcomes: 3-day medication adherence, 30-day adherence, CD4 cell count, viral load, drinks per day, percent reporting drinking, or percent reporting hazardous drinking. Study limitations were that not all participants were non-adherent to their HIV medication at baseline and a substantial percentage were not in the risky-drinking range of unhealthy alcohol use, the group most amenable to brief interventions.Five studies identified in the literature review fell into this category, and only one of these  demonstrIn a preliminary analysis of 3-month outcomes among 51 subjects randomized to four 1-hour motivational enhancement therapy sessions in an adolescent clinic, A study among HIV-infected youths compared the effects of 23 2-hour group sessions and usual care on risk behaviors . The invThe four other studies in this category did not demonstrate any significant effects of the interventions tested on alcohol use:Two informative RCTs have been conducted among alcohol drinkers at high risk for HIV infection. Another RCT  comparedGiven the high prevalence of unhealthy alcohol use among HIV-infected people and its associated adverse health consequences, development of clinical and public health interventions that seek to address alcohol use and improve health outcomes in this population is a priority. In recognition of this, NIAAA, as early as 1996, issued a request for applications entitled “Developing Alcohol-Related HIV Preventive Interventions (AA–97–03).” Since then, several studies have been published that describe clinical outcomes of interventions in this population. However, as this article has demonstrated, the literature on this important topic still is not extensive. A literature search revealed only four clinical intervention studies focusing exclusively on HIV-infected patients with current or past unhealthy alcohol use; five other clinical trials included and documented the alcohol use of some of their HIV-infected participants. Overall, the current state of research strongly suggests that although the problems related to alcohol in HIV-infected people are abundant, effective interventions are few and new ones are urgently needed. Hence, addressing alcohol problems remains an important issue in HIV research.Not only are studies among alcohol-abusing, HIV-infected patients scarce, but the existing studies also yielded mixed results. Two of the four studies that specifically targeted HIV-infected people with alcohol problems showed improvement in drinking outcomes. The other two clinical trials  among alA notable finding of this literature review was that as of 2009, no study of pharmacotherapy for alcohol dependence in HIV-infected patients had been published. This is surprising given that pharmacotherapy plays a major role in addressing the AIDS epidemic by improving outcomes of HIV-infected subjects. Moreover, some preclinical research has demonstrated that naltrexone, an effective medication for alcohol dependence, inhibits alcohol-mediated enhancement of HIV infection  and may Two of the studies reviewed here that included HIV-infected patients among whom at least 10 percent currently used alcohol, targeted risky sexual behaviors rather than alcohol consumption. Assessing treatment effects on sex risk factors is appropriate for studies among HIV-infected drinkers because several studies have demonstrated an association between alcohol use and risky sex . In bothThe dearth of studies focusing on alcohol consumption among HIV-infected people is understandable. Although the spectrum of unhealthy alcohol use ranging from risky use to alcohol dependence occurs in this population, other pressing health concerns  appropriately become the main focus of clinical trials that also may address alcohol consumption in their intervention arms. Developing interventions that target a specific behavior  at the time of alcohol use is a worthy pursuit, and understanding the importance of decreasing alcohol use in order to successfully achieve behavior change is crucial for developing future interventions.One interesting development noted in the studies reviewed here was the use of new technology  in two of the studies . These aWhen assessing the relevance of the studies reviewed here, particularly those conducted among HIV-infected patients with past or current unhealthy alcohol use, it is important to consider the methodological quality of the work . The report by Regarding their design, most, but not all, of these studies met important design criteria, such as random allocation of participants to treatment groups and intention-to-treat analysesThe outcome measures reported were not consistent across studies and not always meaningful, limiting the comparability of study outcomes. For example, What are the characteristics of interventions that mitigate the health consequences of alcohol use in HIV-infected people?How does the treatment setting impact the effectiveness of behavioral interventions?How can technology best be used to extend and enhance intervention effects?What characteristics of HIV-infected drinkers suggest greater challenges when attempting to improve clinical outcomes?How can individual, network, or community interventions in people with multiple overlapping problems, including alcohol use, optimally reduce unhealthy behaviors?How might combined pharma-cotherapy and behavioral therapy be utilized to address the spectrum of clinical consequences that accompany heavy alcohol consumption?In summary, as of 2009 the medical literature on clinical trials focused on people with HIV infection and unhealthy alcohol use is limited . Few of these studies were able to document improved outcomes, and any effects observed generally were modest and transitory. Based on these findings and current knowledge, the following questions need to be addressed:Obtaining answers to these questions is the key next step in the successful development of clinical and public health interventions to mitigate the adverse outcomes from alcohol use in HIV-infected patients.


Objective: There remains no general consensus in the neurosurgical oncology literature regarding the role of extent of glioma resection in improving patient outcome. Although the value of resection in establishing a diagnosis and alleviating mass effect is clear, there is less certainty in ascertaining the influence of extent of resection (EOR). Here, we review the recent literature to synthesize a comprehensive review of the value of extent of resection for gliomas in the modern neurosurgical era. Methods: We reviewed every major peer-reviewed clinical publication since 1990 on the role of EOR in glioma outcome. Results: Thirty-two high-grade glioma articles and 11 low-grade glioma articles were examined in terms of quality of evidence, expected EOR, and survival benefit. Conclusion: Despite limitations in the quality of data, mounting evidence suggests that more extensive surgical resection is associated with longer life expectancy for both low- and high-grade newly diagnosed gliomas. Gliomas are the most common primary malignant brain tumor in adults, yet outcomes from this aggressive neoplasm remain dismal. In the modern era, the multimodal management of these tumors begins with microsurgical resection whenever possible. Advances in intraoperative technique, including neuronavigation, intraoperative magnetic resonance imaging, intraoperative ultrasound, stimulation mapping techniques, and fluorescence-guided surgery, have all been developed to maximize tumor resection and minimize surgical morbidity for both low- and high-grade gliomas . Despite significant advances over the last two decades in brain tumor imaging and intraoperative technology, the actual impact of glioma resection in extending tumor-free progression, patient quality of life, and patient overall survival remains unclear. With this in mind, we have examined every major clinical publication from 1990 to 2012 that reports on the role of EOR in glioma outcome. Our objective is to synthesize a comprehensive assessment of EOR in the modern neurosurgical era, as well as to critically examine the quality of evidence in the published literature. Lastly, we aim to identify the magnitude of improvement in patient survival, if any, that can be achieved with the degree of EOR.A literature search of the PubMed database from January 1990 to June 2012 was conducted using the following key words: “high-grade glioma,” “low-grade glioma,” “astrocytoma,” “anaplastic astrocytoma,” “oligodendroglioma,” “oligoastrocytoma,” and “glioblastoma (GBM).”English-language series including adult patients with hemispheric gliomas were identified. Before analyzing the studies in detail, we conducted additional screening. Small series (<75 patients), or those with incomplete methodological data (such as specification of how EOR was assessed), were eliminated. Also excluded were those studies where EOR was recorded only as a volume of residual tumor, or those studies that only compared resection to biopsy. We excluded series that had both adult and pediatric patients if the adult patients had not been analyzed separately. Studies including pilocytic and gemistocytic astrocytomas, where data regarding patients with these tumors were not separated from other low-grade gliomas, were excluded. Based upon these criteria, we found 32 studies examining EOR for high-grade gliomas and 11 studies examining EOR for low-grade gliomas Tables .For these remaining studies, we considered the statistical analysis that affected interpretation of data. This assessment included the identification of potential methodological flaws and information that was omitted from the publication. The methodological parameters we evaluated included choice of statistical tests and adjustment for confounding variables. The specific information that we searched for consisted of discussion of possible sources of bias in selection of cases, number of events (deaths), length of follow-up for patients without events, i.e., survivors, hazard ratios, and confidence intervals. We sought to identify potential confounders underlying predictor variables. For example, it could be possible that all patients in whom a subtotal resection (STR) was achieved underwent adjuvant chemoradiation and that none of those in whom a total resection was achieved underwent such therapy. We also looked for a specific statement of how the multivariate analysis, if any, was conducted. Because none of these studies were prospective randomized trials, we looked for how many patients were in each of the analyzed subsets, to determine if studies were adequately powered to see statistically significant differences.Preoperative and postoperative tumor volumes, from which the EOR is calculated, have been considered as possible prognostic factors. We therefore identified publications to find studies that included evaluations of preoperative and residual tumor volumes on outcome. High-grade gliomas were in all series defined by the enhancing region on a T1-weighted MRI. For low-grade gliomas, tumor volume and EOR were calculated upon T2-weighted MR imaging. Tumor progression was defined by the radiographic progression of these MRI features. Studies using volumetric tumor analysis were evaluated separately, as this method can dramatically affect EOR calculations  demonstrated a significant survival benefit for increasing EOR  showed no patient benefit with increasing EOR, although one study did trend toward increased patient survival with increased EOR despite statistical non-significance  demonstrated a survival benefit associated with increased EOR using univariate or multivariate analyses  demonstrated no overall survival benefit associated with increased EOR using either univariate or multivariate analysis  have demonstrated a benefit to increasing EOR in univariate and/or in multivariate analysis  demonstrated a benefit with increasing EOR (Table N = 992) found no significant difference between gross total and subtotal resections in 5-year patient survival  should also be incorporated into future analyses. Also, it is unclear whether the correlation between EOR and survival holds true for both first-time and recurrent operations in either low- or high-grade patients. Lastly, the efficacy of emerging adjuvant therapies, such as bevacizumab, should also be studied in the context of EOR.Our review of all studies in the modern neurosurgical era for both low- and high-grade adult supratentorial gliomas highlights recent literature that associate more extensive microsurgical resection with improved life expectancy. In GBM, this level of evidence reaches Level 2b from retrospective analysis of randomized trial data; most evidence is Level 3 from retrospective case series. In addition to providing greater overall survival, more aggressive resections for low-grade gliomas may also impact the natural history of the disease, favorably altering its risk profile for malignant transformation. A prospective, randomized study using modern intraoperative techniques and standardized perioperative adjuncts remains the gold-standard in settling the controversy, but such a trial may never occur. For the time being, retrospective matched studies, retrospective reviews of randomized trials, or prospective observational trials remain the most practical solutions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Stress-related cardiomyopathies can be observed in the four following situations: Takotsubo cardiomyopathy or apical ballooning syndrome; acute left ventricular dysfunction associated with subarachnoid hemorrhage; acute left ventricular dysfunction associated with pheochromocytoma and exogenous catecholamine administration; acute left ventricular dysfunction in the critically ill. Cardiac toxicity was mediated more by catecholamines released directly into the heart via neural connection than by those reaching the heart via the bloodstream. The mechanisms underlying the association between this generalized autonomic storm secondary to a life-threatening stress and myocardial toxicity are widely discussed. Takotsubo cardiomyopathy has been reported all over the world and has been acknowledged by the American Heart Association as a form of reversible cardiomyopathy. Four "Mayo Clinic" diagnostic criteria are required for the diagnosis of Takotsubo cardiomyopathy: 1) transient left ventricular wall motion abnormalities involving the apical and/or midventricular myocardial segments with wall motion abnormalities extending beyond a single epicardial coronary artery distribution; 2) absence of obstructive epicardial coronary artery disease that could be responsible for the observed wall motion abnormality; 3) ECG abnormalities, such as transient ST-segment elevation and/or diffuse T wave inversion associated with a slight troponin elevation; and 4) the lack of proven pheochromocytoma and myocarditis. ECG changes and LV dysfunction occur frequently following subarachnoid hemorrhage and ischemic stroke. This entity, referred as neurocardiogenic stunning, was called neurogenic stress-related cardiomyopathy. Stress-related cardiomyopathy has been reported in patients with pheochromocytoma and in patients receiving intravenous exogenous catecholamine administration. The role of a huge increase in endogenous and/or exogenous catecholamine level in critically ill patients  to explain the onset of myocardial dysfunction was discussed. Further research is needed to understand this complex interaction between heart and brain and to identify risk factors and therapeutic and preventive strategies. Neurocardiology has many dimensions, namely divided in three categories: the heart's effects on the brain ; the brain's effects on the heart ; and neurocardiac syndromes, such as Friedreich disease . The preThe first description of suspected SRC was reported by W.B. Cannon in 1942 cited by Engel et al. [It is now widely admitted that this autonomic storm, which results from a life-threatening stressor, can be observed in the four following situations that induce left ventricle (LV) dysfunction :- Takotsubo cardiomyopathy or apical ballooning syndrome - Acute LV dysfunction associated with subarachnoid hemorrhage - Acute LV dysfunction associated with pheochromocytoma and exogenous catecholamine administration - Acute LV dysfunction in the critically ill Emotional and physical stress can induce an excitation of the limbic system. Amygdalus and hippocampus are, with the insula the principle brain areas, implicated in emotion and memory ,10. ThesWittstein et al. compared plasma catecholamine levels in patients with SRC to those observed in patients with Killip class III myocardial infarction . They reThe mechanisms underlying the association between this generalized autonomic storm secondary to a life-threatening stress and myocardial toxicity are widely discussed. Three mechanisms have been reported. Some authors have suggested that multivessel epicardial coronary artery spasm could supervene, but angiographic evidence of epicardial spasm was not reported by Wittstein et al. . CoronarJapanese authors reported in the nineties the first cases of reversible cardiomyopathy precipitated by acute and severe emotional stress in postmenopausal women ,17-20. TUsually seen in postmenopausal women, the clinical presentation of Takotsubo is similar to that of an acute coronary syndrome with typical chest pain and ECG abnormalities. Reported emotional stress included for example death of a family member, traffic road accidents, financial loss, and disasters, such as earthquakes ,23,24. ITypically, echocardiography showed apical and midventricular wall motion abnormalities and hyperkinesis of the basal myocardial segments . These wWhen performed, LV angiography confirmed these wall motion abnormalities Figure  with theMany morphological LV variants of Takotsubo have been reported: isolated midventricular and basal dysfunction with apical sparing, isolated basal hypokinesis, named inverse Takotsubo ,26. The Bybee and Prasad suggested four "Mayo Clinic" diagnostic criteria for Takotsubo: 1) transient LV wall motion abnormalities involving the apical and/or midventricular myocardial segments with wall motion abnormalities extending beyond a single epicardial coronary artery distribution; 2) absence of obstructive epicardial coronary artery disease that could be responsible for the observed wall motion abnormality; 3) ECG abnormalities, such as transient ST-segment elevation and/or diffuse T-wave inversion associated with a slight troponin elevation; and 4) the lack of proven pheochromocytoma and myocarditis [Patients with suspected and/or proved Takotsubo must be monitored in intensive care. Because massive catecholamine release was observed in Takotsubo-induced stunned myocardium, beta agonists and vasopressors might be avoided whenever possible even in acute circulatory failure and mechanical circulatory support preferred if necessary. Sympathetic activation suggested the use of beta blocker therapy as soon as LV failure was corrected. The presence of a dynamic obstruction in the LV outflow precluded the initiation of an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or diuretic treatment because of a possible potentiation. Anticoagulation with heparin was required to prevent left ventricle thrombus formation ,24,27.Echocardiographic examination will be regularly performed after hospital discharge to evaluate the resolution of LV dysfunction, which is complete in the majority of the patients after 1 to 3 months. A favorable prognosis has been widely reported in the more recent literature .ECG changes and LV dysfunction occur frequently after subarachnoid hemorrhage and ischemic stroke. This entity, referred as neurocardiogenic stunning, was called neurogenic SRC . Four inEchocardiography shows hypokinesis involving basal and midventricular portion of the left ventricle, i.e., inverse Takotusbo. These findings are more usual than those observed in patients suffering from Takotusbo. Bybee and Prasad have suggested an algorithm for the evaluation of patients with subarachnoid haemorrhage and LV dysfunction associated with ECG abnormalities . SimilarLV dysfunction has been reported in the case of endogenous or exogenous over production of catecholamines. Pheochromocytoma is a rare neuroendocrine tumor located in the adrenal medulla that secretes catecholamines and particularly norepinephrine. Many case reports have suggested the onset of reversible LV dysfunction mimicking neurogenic SRC and rarely Takotusbo ,26. ThisAcute LV failure occurs in approximately one-third to one-half of critically ill hospitalized patients. As reported by Chockalingam et al., determination as to whether the LV dysfunction is the cause, effect, or a coincidental finding has to be made and revisited periodically . One of If a previously undiagnosed dilated cardiomyopathy is excluded, global LV dysfunction can be partly explained by a relative contribution of direct catecholamine myocardial toxicity in the following situations: tachycardia-induced cardiomyopathy, hypertensive crisis, sepsis, multiorgan dysfunction, and postcardiac arrest syndrome. In these situations, a high incidence of myocardial injury assessed by cardiac troponin I levels was demonstrated despite the lack of acute coronary syndromes on admission to the intensive care unit ,32. QuenTachycardia-induced cardiomyopathy has been defined as a global systolic LV dysfunction secondary to atrial or ventricular tachyarrhythmias that reversed with rhythm control ,34. StudMild troponin elevations, ischemic ECG changes, and LV dysfunction can be observed in patients with uncontrolled hypertension, for example, in patients suffering from neuroendocrine tumors, such as pheochromocytoma. Rapid blood pressure lowering was required with vasodilators, i.e., nitroglycerin infusions and/or oral administration of ACE inhibitors and angiotensin receptor antagonists, to prevent the onset of acute LV dysfunction and cardiogenic shock ,35,36.Myocardial dysfunction, which is characterized by transient biventricular impairment of myocardial contractility, is commonly observed in patients suffering from severe sepsis and septic shock ,38. LV dBy contrast, some authors consider sepsis-induced myocardial depression an adaptative and at least partially protective process ,43. TheyThus, to keep adrenergic stimulation of the heart at the minimum level, some recently published papers suggested a place for beta-blockers to favor the enhancement of the decatecholaminization in septic critically ill patients ,43,46. OPrengel et al. reported that severe stress, such as that occurring with cardiac arrest and cardiopulmonary resuscitation, activates the sympathetic nervous system and causes a rise in plasma catecholamine concentrations, which could play a role in the onset of post cardiac arrest myocardial dysfunction . This po1-adrenergic actions [The time to recovery appeared to be between 24 and 48 hours and complete for a wide majority of the patients. Laurent et al. reported that cardiac arrest survivors have reduced cardiac output 4 to 8 hours later . Cardiac actions -52. ThisIn conclusion, SRC can occur after an acute physical or psychological stress, subarachnoid hemorrhage, pheochromocytoma crisis, acute medical illness, such as severe sepsis, and after the administration of exogenous catecholamine administration. The presence of contraction band necrosis in the myocardial biopsy specimen suggests a catecholamine-mediated mechanism even if other pathophysiological mechanisms have been suggested. Further research is needed to understand this complex interaction between heart and brain and to identify risk factors and therapeutic and preventive strategies.The author declares that they have no competing interests.