The impact of HIV on maternal mortality and more broadly on the health of women, remains poorly documented and understood. Two recent reports attempt to address the conceptual and methodological challenges that arise in estimating HIV-related maternal mortality and trends. This paper presents and compares the methods and discusses how they affect estimates at global and regional levels. Country examples of likely patterns of mortality among women of reproductive age are provided to illustrate the critical interactions between HIV and complications of pregnancy in high-HIV-burden countries. The implications for collaboration between HIV and reproductive health programmes are discussed, in support of accelerated action to reach the Millennium Development Goals and improve the health of women. While recent reports indicate declining trends in maternal mortality , 2, at tThe contribution of HIV to maternal mortality has been recognized for over a decade , 5, but This paper aims to enhance the understanding of the methods used to estimate HIV-associated maternal deaths and how they affect global, regional, and country estimates. Country examples of likely patterns of mortality among women of reproductive age are provided to illustrate the critical interactions between HIV and maternal mortality in high-HIV-burden countries.direct obstetric deaths resulting from obstetric complications of the pregnant state , from interventions, omissions, incorrect treatment, or from a chain of events resulting from any of the above, or indirect deaths resulting from previous existing disease or disease that developed during pregnancy, such as anaemia and malaria, which was aggravated by physiological effects of pregnancy. In some instances, deaths during pregnancy or the postpartum period might be due to causes that are incidental to pregnancy, such as accidents and violence. These are defined in ICD as pregnancy-related deaths, but are not included as part of maternal deaths. Pregnancy-related deaths comprise maternal deaths due to direct and indirect causes and also deaths due to accidental or incidental events that occur when a woman is pregnant. In the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, 1992 (ICD-10), WHO defines maternal death as the death of a woman while pregnant or within 42 days of termination of pregnancy, irrespective of the duration and site of the pregnancy, from any cause related to or aggravated by the pregnancy or its management but not from accidental or incidental causes . MaternaSome of the deaths of pregnant women with HIV are incidental deaths due to an AIDS-defining condition, without any obvious association with pregnancy. These deaths are therefore classified as pregnancy-related deaths, but not maternal deaths. In practice, the distinction between incidental and indirect causes of death is difficult to make, especially in the case of HIV. The effect of pregnancy on HIV disease progression is uncertain –9, but HIn the real world, identifying maternal deaths and determining their causes, in order to differentiate deaths due to direct or indirect causes, or to incidental causes, poses many challenges. Most developing countries do not have civil registration systems to record the death of a woman of reproductive age, and identification of maternal deaths usually requires special methods of investigation, such as household surveys. In addition, there are well-documented problems with regard to the identification of cause of death in general and maternal death in particular, which are exacerbated in the context of HIV –14. IdeaIn the run-up to the 2015 deadline to achieve the Millennium Development Goals, increased efforts are being made to track progress in reducing maternal mortality. In 2010, two major reports provided estimates of maternal mortality trends at global, regional, and country levels [http://www.who.int/gho/maternal_health/mortality/maternal/en/index.html). In summary, IHME's multivariate model included HIV prevalence as one of several covariates to estimate total maternal deaths, including what the authors call “HIV-related maternal deaths.” To distinguish the HIV-related deaths among the total number of maternal deaths, IHME conducted a counterfactual analysis that explored the effect on maternal mortality of reducing HIV prevalence to zero, by setting the HIV covariates of the estimated model to zero values. The difference between the two outputs produced the number of HIV-related maternal deaths. The primary source of data used in many countries was surveys or censuses, which do not exclude incidental deaths in pregnant women. Therefore, the numbers reported by IHME in those countries relate to our definition of pregnancy-related HIV death, including both HIV-associated maternal deaths and HIV deaths that are incidental to the pregnancy. Hogan and colleagues indicate that this approach would tend to bias the maternal mortality estimates upward, but note that there is no evidence-based analytical strategy to identify the proportion of pregnancy-related deaths that are incidental. Hogan and colleagues, at the Institute for Health Metrics and Evaluation (IHME) and other academic institutions, estimated levels and trends in maternal mortality for 181 countries between 1980 and 2008 and assessed the impact of HIV on these estimates. Details on the IHME methodological approach can be found in the published report , and modThe UN-affiliated Maternal Mortality Estimation Inter-Agency Group (MMEIG), together with academics from the University of California at Berkeley, developed estimates of indirect maternal deaths due to HIV as part of a larger effort to estimate country, regional, and global maternal mortality levels and trends between 1990 and 2008 . The inthttp://www.who.int/gho/maternal_health/mortality/maternal/en/index.html). First, a statistical model estimated the fraction of HIV deaths in women of reproductive age occurring during pregnancy or within 42 days of termination of pregnancy. The calculations required assumptions about the relative risk of dying from HIV of a pregnant versus a nonpregnant woman . This latter parameter was developed through a combination of expert opinion and tests of model fitness to reach a value of 0.4, which was applied to all countries. These deaths were removed from the computation of maternal deaths due to direct obstetric causes or to indirect causes other than HIV. Then a constant fraction of these deaths, counted as indirect maternal deaths, was added back to calculate total maternal deaths. For the estimation of these HIV-related indirect maternal deaths, it was assumed that half of the total pregnancy-related deaths among HIV-infected women were indirect maternal deaths, the other half being incidental to the pregnancy. This value was chosen to minimize distribution errors given the scarcity of appropriate data for estimating correct proportion of HIV deaths that are incidental (which can vary over time and place).The steps in this process were as follows , or 6% of the worldwide total of 358,000 maternal deaths in 2008. For the same year, the IHME calculated that 61,400 fewer maternal deaths (18%) would have occurred in the absence of HIV , of an estimated total of 342,900 maternal deaths. As noted above, the interagency model computed pregnancy-related HIV deaths and assumed that half of those were indirect maternal deaths. Direct maternal deaths in which HIV was present, and possibly a contributing factor, were not counted. The other model computed primarily pregnancy-related HIV deaths. Should the IHME model have used the interagency assumption about the proportion of pregnancy-related HIV deaths that are truly maternal, their estimated numbers of HIV-associated maternal death and total number of maternal deaths would have been reduced accordingly.Both models show that the vast majority of HIV-associated maternal deaths occur in sub-Saharan Africa (86% in the interagency model and 92% in the IHME model) . As a frThe ranking of countries with the highest number of HIV-related maternal deaths varies substantially by model . NigeriaThe countries with the highest fraction of HIV-related maternal deaths are shown in We examined some of the challenges in defining and counting HIV-associated maternal deaths and reviewed two recent methodological approaches for their estimation.  Both aThere are major differences in the way each model identifies pregnancy-related HIV deaths and examines the association of HIV with maternal deaths. The IHME model produces somewhat higher results, with the number of HIV-associated maternal deaths  about three times higher than the interagency estimates. In part because the IHME model has a lower overall number of maternal deaths, the fraction of maternal deaths associated with HIV is substantially higher when compared to the interagency model. Regional estimates of both numbers and affected fraction follow a similar pattern between models. At the country level, the models produce similar rankings in terms of the most affected countries, although the estimated numbers and affected fractions vary. These comparisons should be made with caution, partly because of the different model approaches and in how the results are presented. The interagency estimate distinguishes between incidental pregnancy-related HIV deaths and indirect HIV-related maternal deaths, to keep strictly to the ICD-10 definition of maternal death, without being able to fully delineate the differences between the two. The IHME model notes that the evidence to identify the proportion of pregnancy-related deaths that are incidental is scant, and its estimates are based on total numbers of pregnancy-related deaths in which HIV was present, while recognizing that this strategy biases the estimates upwards. Despite these differences, estimates using the different methods clearly reinforce that the HIV epidemic is having a profound influence on maternal mortality and, more broadly, pregnancy-related mortality. Worldwide estimates of the fraction of maternal deaths due to HIV range between 6 and 18%, with the majority of HIV-associated maternal deaths in the sub-Saharan region, where the affected fraction is between 9–32%. Country rankings between models are similar and provide a general but not precise estimate of the HIV epidemic's contribution to maternal mortality. More detailed examination at country level of the impact of HIV on maternal and pregnancy-related deaths shows diverse patterns. National estimates are usually based on few data points and are subject to all the caveats mentioned earlier about the identification of pregnancy-related deaths and the classification of cause of death. Nonetheless, they give an idea of the severe adverse effect of the HIV epidemic on women's health in high-burden countries.Despite methodological challenges, assessments of trends in maternal mortality clearly indicate that HIV has become a leading cause of death during pregnancy and the postpartum period in countries with high HIV prevalence and that the HIV epidemic has slowed down progress in improving maternal health.Improved knowledge of the contribution of HIV to maternal and pregnancy-related mortality should help to direct scarce resources to appropriate policy and programmatic responses and spur better collaboration between HIV and reproductive health services , 17. We It would be useful to distinguish between maternal HIV-associated death due to direct obstetric causes or indirect HIV-related causes and incidental pregnancy-related HIV deaths. The new ICD-10 amendment introducing a new code for an “indirect maternal death” is a step forward. However, this is likely to continue to remain a source of misclassification, given the ongoing clinical uncertainty around the relationship between HIV and other causes of maternal death. Further discussion among experts in ICD-compliant death certification and coding is needed to help clarify how best such interrelated causes of deaths should be classified. Adoption of a common terminology among researchers and health service providers would be a further benefit. There is also an urgent need to carry out systematic reviews of existing studies on the key parameters that underpin the estimates. These include studies on the relative risk of maternal death in HIV-infected versus uninfected pregnant women and the relative risk of dying from HIV disease of a pregnant versus a nonpregnant woman. More studies are also needed to elucidate the mechanisms by which HIV can contribute to direct or indirect maternal deaths. both improved HIV treatment and care and improved reproductive health services [Nonetheless, given the close, almost inextricable interactions between HIV and other causes of death during and around pregnancy and inadequate systems for civil registration in most countries, it will remain difficult to quantify the precise impact of HIV on maternal mortality in the foreseeable future. This should not serve as an excuse for inaction. Urgent measures are required to provide the many girls and young women who face the dual risks of HIV infection and pregnancy with the services that they need. In settings with a high HIV burden and continuing high maternal mortality ratios, especially in sub-Saharan Africa, this means scaling up comprehensive and integrated programmes that include services .


The consequences of vestibular disorders on balance, oculomotor control, and self-motion perception have been extensively described in humans and animals. More recently, vestibular disorders have been related to cognitive deficits in spatial navigation and memory tasks. Less frequently, abnormal bodily perceptions have been described in patients with vestibular disorders. Altered forms of bodily self-consciousness include distorted body image and body schema, disembodied self-location (out-of-body experience), altered sense of agency, as well as more complex experiences of dissociation and detachment from the self . In this article, I suggest that vestibular disorders create sensory conflict or mismatch in multisensory brain regions, producing perceptual incoherence and abnormal body and self perceptions. This hypothesis is based on recent functional mapping of the human vestibular cortex, showing vestibular projections to the primary and secondary somatosensory cortex and in several multisensory areas found to be crucial for bodily self-consciousness. The consequences of vestibular disorders are dramatic as they incorporate a wide range of symptoms including vertigo, loss of balance, and blurred vision. It is accepted that vertigo results from the activation of the vestibulo-thalamo-cortical pathways, postural instability and falls from abnormal vestibulo-spinal reflexes, and blurred vision from impaired vestibulo-ocular reflexes . More reIn addition to these deficits, vestibular patients sometimes report abnormal bodily perceptions. The role of vestibular organs in bodily perceptions has captured the attention of pioneering researches on body representations such as those of Figure 1 and Table 1 for details).The neuroscientific framework to understand bodily disorders in vestibular patients is based on the multisensory nature of the vestibulo-thalamo-cortical pathways, a finding that was unknown from Bonnier and Schilder when they described the consequences of vertigo on body perception. A vestibulo-visuo-somatosensory convergence has been found in all vestibular relays, including vestibular nuclei, thalamus, and cerebral cortex (see sensory conflicts (or mismatch) leading to a perceptual incoherence. That is, abnormal vestibular signals would induce misinterpretation of tactile, proprioceptive and visual signals from the body and, as a consequence, distort bodily self-experience. In support of this view are recent data on self-motion perception showing that even in the case of large visual–vestibular conflicts, vestibular information is not disregarded and both signals are “mandatorily fused”  to describe distorted representations of the volume, shape, and position of the body and body segments  and galvanic (GVS) vestibular stimulation on the perceived shape and size of the body. Neuroimaging studies have revealed the implication of the posterior parietal cortex in body shape and size perception. In particular, the perception of the current position of body segments is thought to rely on the superior parietal lobule and intraparietal region , 2009. TVestibular patients may lose connection with their body and may be subject to an out-of-body experience (OBE). During an OBE, subjects localize their self outside their body, at a location that is often elevated , and experience seeing the environment from this disembodied location. Subjects may also experience seeing their own body , a double with which they strongly self-identify . Yet, clpartial disembodiment that is reminiscent of OBEs of neurological origin. Another indirect evidence of a vestibular contribution to embodied self-location comes from the observation that OBEs are more frequent in patients lying than sitting or standing upright  and physical body location . Lopez e upright . Accorditriple sensory misintegration, with conflicting vestibular, visual, and somatosensory signals, may occur in multisensory brain regions such as the temporo-parietal junction (A neurophysiological model by Blanke and colleagues posits that during OBEs a junction . This mojunction . In addijunction . Altogetjunction . Accordijunction . Interfejunction . Vertigosense of agency, the experience of being the agent of one’s own actions (The loss of self–body connection described above is also evident in the motor control domain. A minimal sense of selfhood has been related to the  actions , 2009. I actions . For exa actions . VestibuTo date, the role of vestibular signals in the sense of agency has not been measured experimentally. However, it has been showed that CVS evoked in healthy participants significantly stronger feeling of “not being in control of the self” than control stimulation . In additemporal mismatch between an action and the sensory feedback from this action. Interestingly, perception of time is altered in vestibular patients (Vestibular patients may report altered sense of agency because vestibular organs do not correctly encode the consequences of their actions. Patients tend to underestimate their body displacements and misinterpret the direction of body movements , revealipatients  and intrpatients . Neuroimpatients . This reMost of the bodily disturbances described in the previous sections are part of depersonalization, a dissociative disorder characterized by the loss of familiarity of the self and surrounding and by a detachment from the self, that may be experienced as unreal . Early iDiscrepancy between vestibular and other body-related signals may deteriorate the experience of the body and surroundings, leading to DD. In line with this view is the observation that various sensory dysfunctions increase the frequency of DD symptoms (vestibular, visual, auditory: self, mood, and personality. I am optimistic that these data will also impact on the multisensory models of self-consciousness currently developed by neuroscientists and philosophers and in which the contribution of the vestibular system is often neglected.A better understanding of cortical vestibular processing, as well as of how CVS and GVS influence body and self perceptions, has provided the basis for a neuroscientific account of a so far under-recognized type of vestibular symptom – alterations in bodily self-consciousness. I have summarized evidence showing that abnormal forms of bodily self-consciousness in vestibular disorders may result from sensory conflict or mismatch in multisensory brain regions. This hypothesis should now be put under scientific scrutiny by correlating changes in bodily self-consciousness (e.g., subjective reports using DD questionnaires and objective measures of altered sense of agency and self-location; The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Rapid change in food intake, physical activity, and tobacco use in recent decades have contributed to the soaring rates of obesity, type 2 diabetes and cardiovascular disease (CVD) in Aboriginal populations living in Canada. The nature and influence of contextual factors on Aboriginal health behaviours are not well characterized.To describe the contextual determinants of health behaviours associated with cardiovascular risk factors on the Six Nations reserve, including the built environment, access and affordability of healthy foods, and the use of tobacco.In this cross-sectional study, 63 adults from the Six Nations Reserve completed the modified Neighbourhood Environment Walkability Scale (NEWS), questionnaire assessing food access and availability, tobacco pricing and availability, and the Environmental Profile of Community Health (EPOCH) tool.The structured environment of Six Nations Reserve scored low for walkability, street connectivity, aesthetics, safety, and access to walking and cycling facilities. All participants purchased groceries off-reserve, although fresh fruits and vegetables were reported to be available and affordable both on and off-reserve. On average $151/week is spent on groceries per family. Ninety percent of individuals report tobacco use is a problem in the community. Tobacco is easily accessible for children and youth, and only three percent of community members would accept increased tobacco taxation as a strategy to reduce tobacco access.The built environment, access and affordability of healthy food and tobacco on the Six Nations Reserve are not perceived favourably. Modification of these contextual factors described here may reduce adverse health behaviours in the community. Aboriginal people suffer a higher risk of developing obesity, type 2 diabetes and cardiovascular disease (CVD) compared to the general population -3. A preThere is emerging evidence to support the influence of community level factors on health behaviors associated with CVD, such as diet, physical activity and tobacco use -12. The The Six Nations Reserve in Brant County, Ontario spans approximately 18,000 hectares of land, and is located 25 km from the major city of Hamilton, between Brantford, Caledonia and Hagersville. The reserve is home to the largest population of First Nations in Canada, with over 12,000 Six Nations people . UnderstUsing a cross-sectional design, information was collected from individuals residing in the community to characterize community level factors of built environment, healthy food access and availability, and tobacco use among individuals from the Six Nations Reserve. The Research Ethics Board of McMaster University and Band Council of the Six Nations approved the study protocol and all study participants provided written informed consent. This study was funded by a grant from the Heart and Stroke Foundation of Ontario (Grant #PEA6547).Sixty-three individuals from the Six Nations Reserve were included in the present study. Study participants were previously enrolled in the SHARE-AP ACTION household-based randomized trial . EligibiIndividuals completed questionnaires with a trained interviewer at the SHARE-AP research unit located on the reserve. Standardized tools were specifically tailored for the Aboriginal population living on the Six Nations Reserve to assess built environment, food availability, and tobacco availability, access and beliefs. A modified Neighbourhood Environment Walkability Scale (NEWS) was administered to assess built environment and individual perceptions of neighbourhood walkability. The scale is used to assess proximity and ease of access to community facilities, walking and cycling facilities, street connectivity, traffic and crime safety, aesthetics, and community satisfaction. Items are rated on a 4-point scale. NEWS has test-retest reliability, and has been validated against Geographic Information Systems, accelerometer and anthropometric measures in the United States -22. ThisStatistical analysis was conducted using SPSS v11.0 software. All study variables were analyzed descriptively by percentage and means. Due to the limited statistical power we did not test the association between perceptions of the contextual environment and individual health behaviours.Recruitment began in May 2008 and was completed in December 2008. Of the eighty-three participants approached from the previous SHARE-AP ACTION study, 75.9% (n=63) responded and were included in the study. Demographic characteristics of study participants are shown in Table Table Table Table Participants were also asked whether they noticed tobacco and anti-tobacco advertisements in their community. Table  Most repThis study highlights several potential barriers toward adoption of healthy behaviours that exist in the Six Nations community. Specifically the built environment was viewed as being unfavourable to walking, access to healthy foods on the reserve was limited, and easy access to tobacco products was seen as problematic for the community.While most respondents were satisfied living on the Reserve, participants identified the Reserve as being a difficult place in which to walk, having low street connectivity, poor aesthetics, and a higher potential for crime and traffic safety concerns. The ratings for neighbourhood walkability on the Six Nations reserve are very low in contrast to urban cities in Canada, where street connectivity, aesthetics, access to walking/cycling facilities and safety score above mid-point values on the NEWS questionnaire . The NEWAll participants purchased their groceries off of the Six Nations reserve, which is likely due to the greater availability and affordability of food. Six Nations respondents travel off of the Reserve more than 5 times per month in order to obtain a variety of food items, and spend approximately $151 per week on groceries alone, in contrast to the average total food expense of $140 per week in Ontario households . In addiOverwhelmingly 90% of the community members reported tobacco use as being a problem in the Six Nations community especially among teenagers. Children and teenagers were perceived to have easy access to tobacco on the Reserve. Most participants are aware of smoking support programs, bans in public, advertisement laws, and health warnings on tobacco packaging. While most individuals indicated that bans on tobacco advertisements or increased law enforcement would be acceptable for reducing rates, only 3% were willing to tolerate increased taxation.Prior studies of the association between contextual factors and health behaviours in non-Aboriginal communities such as physical activity, dietary intake, BMI, and tobacco use have produced mixed results. A recent systematic review of studies in which community-based interventions were initiated to improve community levels of physical activity reported inconsistent results, and emphasized the need for well-designed intervention studies . Prior sCurrent literature regarding effective tobacco-related community interventions in Aboriginal communities is sparse. Our observation that advertisements promoting smoking and easy access to smoking for adults and children on the Six Nations reserve, together with the previous observation we reported of the high prevalence of cigarette smoking, makes it highly likely that the two characteristics are linked. However data from individual studies vary. For example, a community and school-based intervention among Native American children from 27 elementary schools and 5 states showed no influence of a community-based intervention including classroom lessons, media, and information sessions on rates of cigarette use . In a CoThere is strong evidence that increased taxation from a population perspective is associated with lower smoking rates, and it seems reasonable to assume that with increased taxation and decreased access to cigarettes, the rates of smoking on the Six Nations reserve would decline. The use of tobacco on the Six Nations reserve is complex. Registered Indians or bands on reserve are exempt from sales taxes for goods and services as outlined by section 87 of the Indian Act . AlthougThe World Health Organization and other health advocacy groups cite the aggressive global marketing of risky products and behaviors, particularly those targeting children and youth, as key factors in bringing tobacco, alcohol, and unhealthy processed foods into households worldwide . In our The small sample size of this study limited examination of direct associations between community level factors and individual behaviours. The evaluation tools we used may be too narrow to encompass all potential community level factors which impact on individuals health behaviours, as we relied on participants perception of their environment and not objective measures of the community. Other studies have shown that collection of both perception and objective measures of contextual factors enhances the ability to study influences of environment on health, and future studies should consider including both types of measures -51. FurtThis study highlights potential areas of interest for future study of contextual factors and community interventions. Our results suggest that interventions to improve reserve walkability, increase healthy food advertisements and nutrition education, and to reduce access and affordability of tobacco products may reduce the burden of chronic diseases faced by this community. Efforts should be made to find culturally appropriate community interventions that target health behaviours. Modifications to contextual factors have been attempted by other Aboriginal communities with successful intervention leading to increased access to fitness centers, use of walking trails, development of gardening programs, and improved food stores ,54.The present study characterizes the contextual determinants of key health behaviours associated with cardiovascular risk on the Six Nations reserve. This study provides preliminary information to assist in the design, implementation and evaluation of contextual studies and interventions to determine if they are effective in improving health behaviours. It is likely that multiple prevention strategies including individualized programs as well as community interventions are needed to improve the future health of this community.Authors declare that there are no competing interests.PJ, AB and AM assisted with the analysis, interpretation and drafting of the manuscript. HM, participated in data collection and provided comments of the manuscript drafts, CC assisted in the analysis of the EPOCH questionnaire data and provided comments on the manuscript drafts, RM helped to coordinate the study, and provided critical revisions on the manuscript drafts, SA conceived the study, and participated in analysis, interpretation and writing of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/12/952/prepub


Cardiac tumors represent a relatively rare, yet challenging diagnosis. Secondary tumors are far more frequent than primary tumors of the heart. The majority of primary cardiac tumors is benign in origin, with primary malignant tumors accounting for 25% of cases. Metastatic tumors usually arise from lung, breast, renal cancer, melanomas, and lymphomas. Clinical manifestations of cardiac tumors depend on the size and location of the mass and the infiltration of adjacent tissues rather than the type of the tumor itself. Echocardiography is the main diagnostic tool for the detection of a cardiac mass. Other imaging modalities  may offer further diagnostic information and the establishment of the diagnosis is made with histological examination. Management depends on the type of the tumor and the symptomatology of the patient. Cardiac tumors are a challenging and bizarre clinical situation. They are differentiated into primary and secondary (metastatic). The prevalence of primary cardiac tumors is 0.001–0.03% in autopsy series [Myxoma represents the most frequent benign tumor in adult population . It accoLipomas represent the second most frequent primary tumor, and they are usually located in the subepicardium, in the left ventricle, the right atrium, and the interatrial septum. Often they are asymptomatic; however, they may cause arrhythmias, conduction system disturbances, and symptoms of heart failure, especially in cases where they reach a large size . LipomatPapillary fibroelastoma is the most common tumor of the cardiac valves, accounting for 75% of valvular tumors. Papillary fibroelastoma usually affects the elderly (age range 60 ± 16) . Rhabdomyoma represents the most common cardiac tumor in children. Rhabdomyomas are usually multiple, and they affect the right and the left ventricle likewise. They may cause mechanical complications, such as obstruction of the right ventricular outflow tract. It is also common for rhabdomyomas to regress spontaneously after birth .Fibroma is the second most common cardiac tumor of childhood, although it may also affect the adult population. Fibromas are intramural tumors, located in the left ventricle, mainly in the intraventricular septum, and they are often mistaken for hypertrophic cardiomyopathy or apical thrombus.Angiomas, teratomas, and mesotheliomas are rare tumors (accounting for 7% of cardiac tumors), and they affect mainly children. Teratomas are located in the pericardium, and they may lead to constrictive pericarditis. Primary malignant tumors are relatively rare (accounting for 25% of primary cardiac tumors); they affect ages from 30 to 50 years old, and they are usually sarcomas . Most angiosarcomas are usually located in the right chambers of the heart , whereas Metastatic cardiac tumours are far more frequent (approximately from 30- to 40-fold) than primary tumors of the heart . They us The “carcinoid syndrome” leads to lesions usually in the right heart chambers. It affects mainly the cardiac valves with deposition of fibrous plaques, leading to thickening, shortening, and motion restraint of the tricuspid and/or the pulmonic valve and subsequent regurgitation or stenosis of these valves. Diagnosis and differential diagnosis of cardiac tumors often presents a challenge for the physician. Cardiac tumors, either benign or malignant, are difficult to be diagnosed due to their rarity, variety, and nonspecificity of the symptoms that they may cause. Patient's history, clinical examination, and blood tests rarely lead to an immediate diagnosis of the tumor; therefore, suspicion of this condition is critical for the correct and timely diagnosis of a cardiac tumor. Furthermore, beyond the performance of imaging techniques (discussed below), histological evaluation via biopsy is essential for the final diagnosis to be established. Clinical manifestations of cardiac tumors are differentiated in to four categories: systematic manifestations, embolic events, cardiac manifestations, and finally manifestations due to metastases.systematic symptoms and laboratory findings may resemble those of vasculitis and connective tissue diseases and may disorientate from the correct diagnosis. Fever may be present, as well as fatigue, arthralgia, rush, and the Raynaud phenomenon. The laboratory tests may reveal anemia, elevated white blood cell count and platelet count, thrombocytopenia, hypergammaglobulinemia, and elevated erythrocyte sedimentation rate (ESR). Systematic manifestations are attributed to secretion of various factors from the tumor cells .  The pulmonary embolism or peripheral embolism due to the embolism of tumor cells or thrombi formed on the tumor surface. Predisposition to embolic episodes depends mainly on the type of the tumor, its location , and the fragility of its surface. Small tumors with a friable appearance have a higher chance of embolization. Cardiac tumors may be the cause of cardiac manifestations, these depend mainly on the anatomic location, the size of the tumor, and the infiltration of adjacent tissues, rather than the histological type of the tumor. Cardiac manifestations may be caused by direct obstruction of cardiac or valve function, interruption of coronary flow, interpolation on the electrophysiology of myocardial contraction, and induction of pericardial effusion. Intramural tumors rarely produce symptoms, especially if their size is small. They may cause arrhythmias or disturbance of the conduction system, and in cases of large tumors, they may cause obstruction of the right or left outflow tract or compression of the cardiac chambers. Intracardiac tumors may exert severe clinical manifestations. Characteristically, myxomas of the left atrium may cause symptoms of mitral obstruction through prolapse via the mitral valve . Tumors located in the right chambers of the heart may cause signs and symptoms of right-sided heart failure. Regarding metastatic disease from other organs, these usually affect the pericardium  and less often the myocardium, the endocardium , and the venae cavae (obstruction). In general, the presentation of cardiac manifestation in a patient suffering from cancer is usually attributed either to cardiotoxicity because of chemotherapy [ Regarding cardiac manifestations due to otherapy  or occur Finally, primary cardiac tumors can cause symptoms through metastases to other organs. Most frequently, sarcomas metastases affect lungs, brain, and bones. The imaging techniques that are used when there is a suspicion for the occurrence of a cardiac tumor, as well as for the differential diagnosis of other cardiac masses like vegetations and thrombi, are mainly echocardiography, magnetic resonance imaging (MRI), and computed tomography (CT) of the heart. Chest X-ray can offer indirect findings from the enlargement of cardiac chambers, the occurrence of calcification, or pericardial effusion. Transthoracic echocardiography (TTE) can depict the shape, the size, the extent, and the mobility of the tumor, as well as, its location and its relation to adjacent cardiac structures, the width of adherence to the cardiac wall, and the hemodynamic consequences that it may confer to cardiac function [Transesophageal echocardiography (TEE) is superior to TTE, since one can avoid transducer contact with the thoracic wall and the lungs and achieve a better visualization and identification of small tumors (<5 mm) and tumors localized at the posterior cardiac segments [ Echocardiography represents a substantial imaging technique for the detection of cardiac tumors with a high sensitivity and specificity , and it can be easily performed at the patient's bedside . Transthfunction . Transessegments . It shouContrast echocardiography helps in the differential diagnosis between tumor and thrombus by examining tissue perfusion [ Of interest are newer echocardiographic techniques that may aid in the differential diagnosis of cardiac tumors from other cardiac masses. erfusion . In conterfusion .Three-dimensional echocardiography (3D Echo) contributes mainly to an improved assessment of the shape, the size, the mobility of a tumor and its relationship regarding adjacent structures, by making use of the wider imaging range that this technique provides [provides . Improve The use of cardiac magnetic resonance (C-MRI) with its wide imaging range allows for a better assessment of the tumor relation to adjacent structures, in order for a surgical resection technique to be designed. It also allows the detection of myocardial infiltration by the tumor or expansion of the mass to the pericardium or to adjacent structures . C-MRI m Cardiac computed tomography (C-CT) can also provide useful information, due to its high resolution and its ability to accurately depict cardiac morphology without limitations because of acoustic windows. Disadvantages of the method include the use of radioactivity and of nephrotoxic contrast mediums. C-CT provides less information regarding characterization of tissues in comparison to C-MRI; however, it can provide some information regarding the nature of the tumor by measuring X-ray attenuation and possible tumor expansion to adjacent tissues. Multidetector computed tomography (MDCT) is useful for the evaluation of calcification and fat content within a mass. Furthermore, the high spatial resolution of MDCT is beneficial to define small lesions, making this technique a useful tool for the staging of malignant tumors . The diagnosis of cardiac tumors and the estimation of their grade cannot be made with the use of imaging methods only, therefore histological confirmation is necessary. This can be achieved with minimally invasive techniques such as cytological examination of pericardial or pleural fluid or echocardiographically aided percutaneous or transvenous cardiac biopsy. In cases where diagnosis cannot be established, biopsy via thoracoscopy or even thoracotomy may be needed. Therapy of benign primary cardiac tumors is surgical resection, and the urgency to intervene is determined by the symptoms of the patient and the type of the tumor. Regarding myxomas, immediate surgical resection is indicated, regardless of symptoms, because of the high risk of embolic and cardiac complications. Surgical resection of myxomas confers good results (3% possibility of relapse) and is accompanied with small rates of periprocedural mortality (<5%). Papillary fibroelastomas are surgically removed in cases of large (>1 cm) and/or mobile tumors. In cases of small, immobile tumors in the left ventricles, conservative management and close follow-up may be advocated. However, because of their fragile nature, papillary fibroelastomas carry a high risk of embolic complications; therefore, most authors propose surgical management even in asymptomatic patients . Lipomas Regarding malignant primary cardiac tumors, their prognosis is dismal, since they tend to infiltrate the myocardium rapidly, cause obstruction of the cardiac chambers and produce metastases. Management of choice in sarcomas is surgical resection, with poor results and high rates of relapse . Chemoth Finally, regarding cardiac manifestations due to metastatic extracardiac cancer, priority is given to the management of the primary focus of the disease and the cardiovascular complications that are manifested .


Migration of cardiac neural crest cells into the pharyngeal arches and the pharyngeal and splanchnic mesoderm contributes to the development of the cardiac outflow tract. The adrenal cortex is derived from the splanchnic mesoderm. Neuroblastoma is more prevalent in patients with congenital heart disease than in the general population, because both originate from embryonal neural crest-derived cells. Similarly, and in light of recent embryological findings, abnormal development or migration of splanchnic mesoderm, possibly due to an underlying genetic defect, could contribute to the association of adrenocortical carcinoma and tetralogy of Fallot. We present the case of a cardiologically asymptomatic 49-year-old woman with total correction of tetralogy of Fallot in the first year of life. The conditions considered in the differential diagnosis of retroperitoneal masses include benign tumors , malignant neoplasms , pyogenic abscesses, hematomas, or the Budd–Chiari syndrome. Most primary retroperitoneal tumors arise from one or more of the mesenchymal tissues of the retroperitoneum, and others are derived from neuroectodermal elements or from remnants of the urogenital ridge. At present, adrenocortical carcinoma, a rare and heterogeneous malignancy, has a poor prognosis, and its pathology is incompletely understood .We present the case of a cardiologically asymptomatic 49-year-old woman with total correction of tetralogy of Fallot in the first year of life, to relieve the right ventricular outflow tract stenosis and repair the ventricular septal defect with a Gore-Tex patch. The patient had no cardiovascular risk factors and was not undergoing any cardiac treatment. She was treated with progesterone during the last 3 years because of menstrual disorders. During the last few months, she complained of pain in her right flank, which was associated with weight loss. The patient had no history of hypertension, headaches, palpitations, facial flushing, hirsutism, or Cushing’s syndrome.Abdominal ultrasonography and computed tomography  showed tExploratory laparotomy and biopsies of the adrenal tumor revealed an adrenocortical carcinoma , which sAn overriding aorta is a congenital malalignment defect, wherein the aorta fails to wedge between the mitral and tricuspid atrioventricular valves. In this situation, the aorta, which should receive all the blood from the left ventricle, overrides the ventricular septum to a greater (double-outlet right ventricle) or lesser  extent, thereby receiving a proportionate amount of blood from the right ventricle.There are several case reports of patients with coexisting neuroblastoma and congenital heart defects , 5-7, su


It is well acknowledged that the poor prognosis of gastrointestinal cancer is largely due to metastasis, which is the biological hallmark of malignant tumors. Metastasis is considered to be a multistep process in which malignant tumor cells spread inconsecutively from original site to distant organs. As for cancers of gastrointestinal tract, the common target site for metastasis is liver, lymph nodes, peritoneal, and, subsequently, lung and other sites of the body, which in single or as a whole, is the major cause of gastrointestinal cancer-related deaths.Therefore, the early diagnosis and effective treatment of gastrointestinal cancer metastasis is of vital importance, which may lead to substantial elongation of life expectancy of gastrointestinal cancer patients. In order to make further progressions in early diagnosis and intervention, the following three directions should be put due emphases on in future research. Firstly, the cellular and molecular mechanisms of gastrointestinal cancer metastasis should be clarified, such as the mechanisms of local angiogenesis, the heterogeneity of cancer cells, the cross-talk and cascade of signaling transduction systems, the decreased expression of cell adhesion molecules such as E-cadherin, and so on. To elucidate these mechanisms and to block relevant molecular pathways provides the most promising perspectives in the fight against gastrointestinal caner metastasis. And additionally, there are several interesting and enlightening hot points: the relationship between stromal microenvironment and metastatic destination; the role of cancer stem cells in metastasis; and how malignant cells get metastasis ability, inherent or acquired?The second direction is to find out specific and sensible biomarkers of gastrointestinal cancer metastasis and to predict the potential metastasis, to facilitate early diagnosis, which is up to now mainly dependent on insensitive and costly radiographic examinations. And the third one is the optimization of comprehensive treatment including surgical intervention.In this special issue, eight articles on gastrointestinal cancer metastasis are presented. One article discussed the advantages and disadvantages of repeated liver resection in patients with recurrent colorectal liver metastasis. One article reported that N-desulfated heparin is capable of suppressing the metastasis of gastric cancer through inhibiting tumor bFGF expression and tumor angiogenesis with no obvious anticoagulant activity. Yet another article is on the relevance between dietary salt intake and the risk of gastric cancer. The other five articles highlighted four kinds of potential biomarkers for gastrointestinal cancer screening and early diagnosis of metastasis, namely urine-free amino acid, ki-67 antigen, mir-21 and epidermal growth factor receptor (EGFR). J. Fan and his colleagues, through analyzing amino acids in urine samples of gastric cancer patients and healthy volunteers, figured out that urine-free amino acid profiling is of potential value for screening or diagnosing gastric cancer. D. Navarini and his colleagues, from Brazil, reviewed thirty-seven patients who underwent esophagectomy without presurgical chemotherapy or radiotherapy from 2000 to 2010, analyzed the level of EGFR expression and life span, and concluded that EGFR expression is related to higher TNM staging and shorter survival.Despite the obvious advancements made in the research of gastrointestinal cancer metastasis these years, the outcomes are far from final satisfaction, and thus it is still a field that deserves and calls for intensive and thorough research in the future.


Pinus sylvestris L.), and to study potential connections to tree ageing.The shortening of telomeres, the specific structures of repeated DNA sequence at the end of the eukaryotic chromosomes, has been connected with ageing and loss of cell replication or regeneration capacity. There is, however, only limited information available on telomeres of long-living trees. Physiological ageing, on the other hand, represents a serious problem for vegetative propagation of conifers, while in deciduous tree species ageing has no such a strict influence on regeneration ability. The aim of this study was, for the first time, to determine the variation in telomeric repeats in an economically important Nordic conifer, Scots pine  .In Scots pine samples, the size of telomeric repeats detected was variable, ranging from 0.9 kb up to 26 kb. Based on exonuclease treatment, high molecular weight repeats seem to be genuine telomeres at the ends of the chromosomes, while the low molecular weight signals probably originate at interstitial or centromeric positions. The Southern hybridisation was thus adjusted to show only high-molecular weight signals, and analyses were performed based on them.A decline in the average length of the telomeric repeats was observed with increasing level of tissue differentiation: immature and germinating embryos had the longest repeats, followed by cambium, elongating buds with tiny meristems and, finally, full-sized needles without meristems having the shortest repeats. When embryo samples were excluded from the data, the age of the tree had no significant effect on the length of telomeric repeats, although there was a tendency for telomere shortening with increasing age. In cambium samples, also the position of the tissue within tree (stem base versus top) affected the length of telomeric repeats, the telomeres shortening towards top of tree. The telomeric repeats also varied remarkably between tree individuals. Potential connections to regeneration ability are discussed.


The insulin/insulin-like growth factor signaling (IIS) pathway is well-established as a critical regulator of growth and metabolic homeostasis across the animal kingdom. Insulin-like peptides (ILPs), the functional analogs of mammalian insulin, were initially discovered in the silkmoth Bombyx mori and subsequently identified in many other insect species. Initial research focused on the role of insulin signaling in metabolism, cell proliferation, development, reproduction and aging. More recently however, increasing attention has been given to the role of insulin in the regulation of neuronal function and behavior. Here we review the role of insulin signaling in two specific insect behaviors: feeding and locomotion. In both vertebrates and invertebrates, insulin is a key metabolic hormone that modulates carbohydrate and lipid metabolism in response to an organisms' nutritional state. Dysregulation of insulin production, release, or downstream signaling leads to metabolic disease, including diabetes and obesity   were originally discovered in the silkmoth Drosophila, the field of behavioral genetics began with the identification of the period gene as a critical regulator of rest:activity rhythms in the fly , reduces foraging motivation and food acquisition   and CYCLE (CYC), which drive the expression of the clock genes period (per) and timeless (tim). Eventually PER and TIM proteins re-enter the nucleus and inhibit the activity of CLK/CYC, thus preventing their own transcription. Ultimately the inhibition of CLK/CYC is relieved following the degradation of PER and TIM, allowing the cycle to begin again.Many insects, including nd Chung ]. This wnd Chung ]. BrieflDrosophila FOXO mutants and, by extension, perhaps elevated insulin signaling (which leads to the deactivation of FOXO), display increased sensitivity to oxidative stress. Thus, the metabolic state of the fly can influence the clock to affect behavioral rhythms.The anatomical and functional organization of the roughly 150 clock neurons in each hemisphere of the adult fly brain is well-established  activity , while the total distance traveled is similar for both sexes , identified a subset of neurons in the PI, henceforth called feminizing cells (FCs), capable of feminizing the locomotor activity pattern of male flies (Gatti et al., takeout, a putative JH binding protein and known circadian output gene, also display feminization of their locomotor activity (Meunier et al., Aspects of locomotor activity are sexually dimorphic in Drosophila melanogaster as well as other insect species provide researchers with a framework to begin to teasing apart the many different pathways and molecules that contribute to behavior. In this review we have described the progress that has been made with respect to the regulation of feeding and locomotion by insulin, however many questions still remain (Figure Given that behavior is so intricate, model organisms like n Figure . Future 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.


The evolution of the diverse flora in the Lower Volga Valley (LVV) (southwest Russia) is complex due to the composite geomorphology and tectonic history of the Caspian Sea and adjacent areas. In the absence of phylogenetic studies and temporal information, we implemented a maximum likelihood (ML) approach and stochastic character mapping reconstruction aiming at recovering historical signals from species occurrence data. A taxon-area matrix of 13 floristic areas and 1018 extant species was constructed and analyzed with RAxML and Mesquite. Additionally, we simulated scenarios with numbers of hypothetical extinct taxa from an unknown palaeoflora that occupied the areas before the dramatic transgression and regression events that have occurred from the Pleistocene to the present day. The flora occurring strictly along the river valley and delta appear to be younger than that of adjacent steppes and desert-like regions, regardless of the chronology of transgression and regression events that led to the geomorphological formation of the LVV. This result is also supported when hypothetical extinct taxa are included in the analyses. The history of each species was inferred by using a stochastic character mapping reconstruction method as implemented in Mesquite. Individual histories appear to be independent from one another and have been shaped by repeated dispersal and extinction events. These reconstructions provide testable hypotheses for more in-depth investigations of their population structure and dynamics. Biogeography as a synthetic discipline emerged because of the need to understand spatial patterns of biological diversity . From DaGiven all of the above, in many cases phylogenetic data are still very incomplete or completely lacking, although knowledge of the organisms living in an area and the history of the area is available. Therefore, in the absence of molecular phylogenies and temporal information, can we still generate testable hypotheses on the historical biogeography of an area and its organisms using modern approaches? We propose a study where species occurrence data in conjunction with well-known abiotic parameters may still inform the biogeographical history of an area and the individual taxa that inhabit it. Our approach is based on distribution data alone when this is the only available information that can be used in a biogeographic analysis, when the only alternative would be to perform no analyses. The information inherent to floristic data is clearly limited, but may still allow a first attempt to generate viable hypotheses on species history that can be further tested with more appropriate methods or when more data become available.The Volga is Europe's longest and largest river and an important feature in Russia's landscape, culture, and bio-diversity. It rises in the Valdai Hills, northwest of Moscow, and runs 3530 km across southeastern Russia to finally empty in the Caspian Sea, making it the largest river that does not drain into an ocean . The Cas14C dates generated by various studies  and were intercalated by regression events that include the current Novocaspian phase . Althoug studies . Overall studies , althougThe Astrakhan region comprises the Volga River's southern most part  with 13 Alopecurus, Althaea, Astragalus, Bromopsis, Carex, Corispermum, Elytrigia, Glyceria, Hierochloe, Lotus, Phalaris, Plantago, Poa, Polygonum, Rorippa, Salix, Senecio, Setaria, Simphytum, Thalictrum, Trapa, and Veronica among many others . This large number of taxa unknown to science was probably due to recent and rapid evolution in the LVV area, most likely caused by selective responses to the numerous Volga floods and more recent transgression processes that took place since the Pleistocene  and its several methodological variations . CladistOur original investigation of the LVV (including adjacent areas) based on floristic and abiotic data lasting 12 years, helped to define 13 distinct floristic regions (as summarized in Garden Place (BC), Kozinka (AH), and Carp Borough (XE) strictly represent the river valley; Three House Village (P) includes the narrowly defined river delta along with the small islands off the Caspian coastline; Blue-grey Hill (BK) and Lakeland (ZIB) are components of the more widely defined river delta and contain the chains of Baer knolls; the dry steppe and desert areas of Cabbage's Ravine (A), Ulmus Village (C), Dosang (VP), Jenotaevka (ZP), and Tambov Village (X) are immediately adjacent to the valley forming the extended LVV . The oldSpecies occurrence data was based on herbarium collections and fieldwork. Specimen data were collected from the herbaria of the following Institutions: Astrakhan State University (AGU), Saratov State University (SARAT), Volgograd State Pedagogical University (VOLG), Institute of Ecology of the Volga Basin, Russian Academy of Sciences (TLT), Biological and Geographical Departments of M. V. Lomonosov Moscow State University (MWG and MW), Main Botanical Garden of Russia (MHA), and Komarov Botanical Institute, Russian Academy of Sciences (LE). The complete floristic treatment of Mountain Bogdo and Lake Baskunchak areas has been the focus of Popov's recent studies  and is in its final stage of preparation. Therefore, for the purpose of our study we used his preliminary list of taxa.We recorded the occurrence of 1018 species see  across tNomenclature in this study follows k possible states (≥2) with no state considered plesiomorphic or apomorphic , we analyzed our data by selecting the G + I model to account for the presence of invariant sites and obtained the exact same results.As a comparison, MP analysis was also conducted with PAUP* 4.0b10 , using hAll analyses included an all-zero hypothetical artificial outgroup for rooting purpose . HoweverIn ML analyses of binary datasets character absences are equally informative as character presences; consequently, all-zero columns provide as much information as all-one columns. In the context of our approach, this means that we can estimate the history of floristic areas in the LVV based not only on extant species occurrence, but also on a hypothetical palaeoflora. Therefore, in addition to the analyses described above we generated a matrix that included various numbers of hypothetical extinct taxa . Essentially, we assumed that the dramatic transgression and regression events that occurred throughout the Pliocene and Pleistocene caused mass extinction but in the absence of essential knowledge about the past ancestral flora, we simulated a number of scenarios that featured 509, 1018, 1527, and 2036 extinct taxa. We created matrices that included: 509 extinct taxa  representing half the number of the species in the extant flora; 1018 extinct taxa  that assumed an equal number of ancestral species to the extant flora; 1527 extinct taxa  that assumed an ancestral flora larger by half the size of the extant flora; and 2036 extinct taxa  assuming an ancestral flora twice as big as the extant number of species. Matrices were analyzed using the same ML approach described above but with an all-zero hypothetical outgroup. In our specific scenarios, we assumed that the multiple transgression events may have likely led to the extinction of the ancestral flora; therefore, there is no contextual difference between the functional outgroup  and the extinct taxa. In other potential scenarios, all-zero columns could also represent failure to colonize an area.Individual taxon histories were recovered using stochastic character (species) mapping reconstruction . AlthougMP and ML analyses each generated a single tree . Within UPGMA analyses yielded a dendrogram with the clusters defined by soil type and overall ecosystem . Garden Matrices that included 509, 1018, 1527, and 2036 hypothetical extinct taxa generated topologies that are generally congruent with our previous results but differ in support values and relationships of some of the areas . Adding Crepis astrachanica, a narrow LVV endemic, using MP (5a) and stochastic mapping (5b), respectively. MP simply suggests that C. astrachanica is an endemic that may have evolved in the ancestral areas of Blue-grey Hill (BK), Lakeland (ZIB), and Carp Borough (XE). However, a closer look into stochastic mapping reconstruction shows that its presence at the base of the cladogram suggests that this taxon may have been present in the entire ancestral areas that include Three House Village (P), Blue-grey Hill (BK), Lakeland (ZIB), Carp Borough (XE), Kozinka (AH) and Garden Place (BC), and may have subsequently become extinct in a few of these. Similarly, for the nonendemic Suaeda salsa, parsimony reconstruction (Stochastic species mapping reconstructions for each of the 1018 species can be found in truction  suggeststruction . Given tThe numerous Caspian transgressions that occurred since the Miocene and throughout the Pleistocene are the main processes that led to the formation of the LVV and its adjacent areas . However(ZP) formed after Kapoostin Yar (A) and Ulmus Village (C), and are mostly the result of the sand, semi-sand substrates left over by the last regression of the Caspian Sea  and Garden Place (BC) not only is different from that of immediately adjacent areas (A and C) , UPGMA, Our findings are congruent with Fursajew's conclusions (1940). He suggested that the modern LVV flora formed only at the very end of the Khvalyn phase . The timSalix alba s. l.) and poplar (Populis nigra s. l.) forests and multiple floodplain meadows of the “low” and “middle” levels  as well as annuals .Interestingly, Tambov Village (X) and Kozinka (AH) appear to have no branch length . Branch ” levels . These tThe areas of Blue-grey Hill (BK) and Lakeland (ZIB), among the most recently formed in the LVV, are characterized by the presence of peculiar reliefs known as the Baer knolls chains . These aAreas BK and ZIB are remarkable in their floristic composition combining elements of swamp and steppe/semi-desert flora. The steppe flora of the Baer knolls seems very different from the flora in other steppe areas in the LVV and was formed mostly as the result of multiple dispersal events. Fourteen of the 23 endemic species are present in both of these areas, and a few others in either BK or ZIB. The formation of the Baer knolls may have contributed to high level of endemism of the areas BK and ZIB.Adding to the above scenario, we considered the occurrence of a hypothetical palaeo flora that became extinct due to those dramatic geological activities that led to the many transgression and regression events. In the absence of significant paleobotanical data, we performed analyses that included putatively different sizes of a paleoflora . All fouOur results show that regardless of the inclusion of hypothetical extinct taxa, we consistently recover a river valley and delta regions that harbored flora only after some of the adjacent areas were colonized. Incongruence is recovered only with regard to the relationships of Dosang (VP) and Jenotaevka (ZP), Cabbage's Ravine (A) and Ulmus Village (C) and their respective positions in the topology. However, there seems to be a general consensus for a flora that evolved first in Tambov Village (X), Dosang (VP) and Jenotaevka (ZP), following later in Cabbage's Ravine (A) and Ulmus Village (C), and finally all across the river valley and delta. The relationship of Tambov Village (X), Dosang (VP) and Jenotaevka (ZP) is also supported by the notion that these areas are largely desert steppes on mainly sand basalt substrates. Similarly, Cabbage's Ravine (A) and Ulmus Village (C) are characterized by similar dry habitats on mainly clay and silt substrates , UPGMA.Artemisia astrachanica, an endemic species currently found in extremely salty environments (BAC and BOG), on clay-silty substrates (A and C), along the swamps of the river valley (XE), and on the dry Baer knolls (ZIB and BK). The reconstruction also shows that this species was present in the ancestral areas of the LVV but never successfully established in mostly sandy and dry steppes environments , despite the ability of this species to grow on sandy, salty semi-meadow substrates, also known as limans .Given the complex scenarios characterized by a geologically dynamic active region, the history of the LVV flora clearly reflects the ramifications of these activities. We examined the ancestral reconstruction of each species along the branches and nodes of the taxon-area tree to generate testable hypotheses that may prompt future in-depth analyses on the population structure and dynamics of individual species. The current species distribution may harbor historical complexity that is likely tied to the geological activities in the Caspian Sea and LVV. s e. g., . ExtinctAstragalus baerii (b), Ceratophyllum kossinskyi (c), Corispermum filifolium (d);Onosma setosa (a), Potamogeton skvortsovii (b), Puccinellia vitalii (c)) or in a few others, dispersal has favored the expansion of species into adjacent areas with similar ecosystems, as in Melandrium astrachanicum . In time, these processes have led to the independent formation of the same plant community in two disjunct areas, clearly non-randomly.Individual stochastic mapping reconstructions can be used to synthesize the formation of entire plant communities. For example, the Given the complex geomorphological history of the LVV characterized by multiple tectonic events, including transgression and regression phases, the flora of the region has been shaped, often independently by its geomorphological history. Intuitively, we would have expected floristic elements to first occupy the northern areas that formed immediately after the last transgression phase. However, we found that geomorphologically older areas harbor floras that formed more recently. We recover a similar pattern by considering a hypothetical palaeoflora that may have been considerably smaller or larger than the extant flora. Our results show that the narrowly defined river valley and delta regions still harbor a more recent flora whilst adjacent drier habitats were the first to be colonized.Overall, when examining stochastic mapping reconstructions, current species distributions have been independently shaped by dispersal, extinction, and in some cases vicariance events due to ecological or physical barriers . Each species bears a unique history that may or not be under the direct influence of recent geological events, and may serve as the basis for further investigation on the evolution of local populations. Likewise, single species history can be used to synthesize the formation of whole plant communities and foster hypotheses on the ecological factors that provide stability and community structure.Finally, our study shows that in the absence of taxon phylogenies and temporal information, species occurrence data may still be informative and analyzed using modern approaches. The results we generated represent testable hypotheses on the history of an area and its inhabiting flora.


Streptococcus group B), treated or not treated during pregnancy or labor, may be cause of serious illness in the newborn. The aim of this study was to observe the evolution of infants exposed to certain risk factors, using the total blood count and the determination of C-reactive protein.Maternal infection is an important cause of morbidity and mortality in newborns. Rupture of membranes more than 18 hours before birth, fever during labor, urinary tract infections or vaginal infections  received prophylactic antibiotics at birth, however, registering changes in blood counts (leukocytosis/leukocytopenia) and/or increased levels of C-reactive protein in 10% of cases (resistance to antibiotics administered anterpartum/intrapartum?).All infants entered into the study were evaluated after at least 12 hours of life, determining the total blood count and C-reactive protein. There have been changes to these tests to a large number of subjects included in the study, and there have been cases in which, though the usual tests were within normal limits, infants developed symptoms, with no altered values of these laboratory tests (up to 72 hours). The infants exposed to certain risk factors (membranes ruptured more than 18 hours before birth and the presence of group B The result of common tests can be used to evaluate the newborn exposed to certain infectious factors, and to specify the correct therapeutic attitude, but in close relation with the clinical outcome, considering their non-specificity and potential false positive or negative results.


Mutagenicity refers to the induction of permanent changes in the DNA sequence of an organism, which may result in a heritable change in the characteristics of living systems. Antimutagenic agents are able to counteract the effects of mutagens. This group of agents includes both natural and synthetic compounds. Based on their mechanism of action among antimutagens, several classes of compounds may be distinguished. These are compounds with antioxidant activity; compounds that inhibit the activation of mutagens; blocking agents; as well as compounds characterized with several modes of action. It was reported previously that several antitumor compounds act through the antimutagenic mechanism. Hence, searching for antimutagenic compounds represents a rapidly expanding field of cancer research. It may be observed that, in recent years, many publications were focused on the screening of both natural and synthetic compounds for their beneficial muta/antimutagenicity profile. Thus, the present review attempts to give a brief outline on substances presenting antimutagenic potency and their possible mechanism of action. Additionally, in the present paper, a screening strategy for mutagenicity testing was presented and the characteristics of the most widely used antimutagenicity assays were described. The genomes of all living organisms are constantly subjected to damage by both external agents and endogenous processes, such as spontaneous DNA damage. Mutagenicity refers to the induction of permanent changes in the DNA sequence of an organism, which may result in a heritable change in the characteristics of living systems. Mutations may alter a single gene, a block of genes, or whole chromosomes. Point (gene) mutations affect only one nucleotide or a few nucleotides within a gene. Point mutations, which are the most common type of alteration in the DNA sequence, can be divided into three main types: a base pair substitution (the replacement of one base pair with another); a deletion (the loss of one or more base pairs); and an insertion (the addition of extra base pairs into the DNA sequence).The term “genotoxicity” is a broader concept than mutagenicity and describes the capacity of the compounds to affect the DNA structure or the cellular apparatus and topoisomerases, which are responsible for the genome fidelity. Genotoxic effects on DNA are not always related to mutations  and ethyl methanesulfonate (EMS) are able to react with DNA bases directly and transfer an alkyl group to form monoadducts in genetic material. Consequently, DNA strand breaks are produced, causing specific mispairing , affect genetic material directly, leading to structural damage; on the other hand, some compounds, including benzo[α]pyrene (BP), act on DNA in an indirect manner (indirect-acting mutagens) via the induction of the synthesis of different chemicals which influence DNA directly. During this process, the transformation of promutagen into the actual mutagen takes place. Table Many mutagenizing agents known as direct-acting mutagens. such as sodium azide , the removal of reactive molecules represents an important strategy in the process of antimutagenesis   against Salmonella typhimurium strains  -5-hydroxy-2(5H)-furanone (MX) was inactivated using various sulfhydryl compounds, such as cysteine  extracts displayed antimutagenic activity against direct-acting mutagenic agents through the rapid elimination of mutagenic compounds from the cells before the induction of genetic material damage , the extract of P. rimosus may affect the intercalation of mutagens to genetic material. The antimutagenic effect of the extract against indirect-acting mutagen BP may be partially ascribed to the inhibition of the mixed-function oxidase (MFO) system and also to the conjugation of the components of the extract with benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), being a BP-active mutagen. Moreover, the inhibition of 2-AF-induced mutagenesis might be related to the MFO inhibition or inactivation of the reactive carcinogenic ester of 2-AF, namely, 2-acetylaminofluorene-N-sulfate, which is capable of attacking guanine residues in nucleic acids. In case of both types of mutagens (direct and indirect), the extract of P. rimosus may remove free radical species generated by certain mutagens, such as DXN and BP.In another study, Ajith and Janardhanan  demonstrAcacia salicina display potent antioxidant and antimutagenic activities. Chloroform extract was antimutagenic against both direct- and indirect-acting mutagens, as the extract may serve as a blocking agent that is capable of influencing the activities of enzymes engaged in the metabolism of mutagens and carcinogens. Moreover, the tested extract displayed the ability to react directly with the mutagen’s electrophilic metabolites and was capable of protecting against oxidative DNA damage.Boubaker et al.  demonstrMangifera indica L. stem bark (MSBE) extract against DNA damage induced by ten different mutagenic agents in the Ames test. MSBE is a Cuban nutraceutical supplement rich in polyphenols. It was observed that MSBE protected against genetic material damage induced by all the tested mutagens, except for NaN3. This DNA protection may be due to the antioxidant activity of MSBE. In addition, the antimutagenic properties of the extract may be explained by the influence of MSBE upon the CYP subfamily. Pesarini et al. , it was proved that the attenuation of their unfavorable mutagenic effect might result from the influence on the DNA repair pathway, the stimulation of detoxifying enzymes, and the inhibition of enzymes that participate in the metabolic activation of HAAs  against acridine (AC) was explained by the fact that these derivatives are able to stop the production of DNA double-strand breaks or AC intercalating effects. In addition, the inhibition effects against ethyl methanesulfonate (EMS) may be related to the protection against DNA double-strand breaks or EMS alkylating action  was stated with recombinant yeast assay (RYA) and the Ames test . According to the results obtained, two of the tested xanthone derivatives presented beneficial antimutagenic potential. As for derivatives of pyrrolidine-2,5-dione, some of them had strong or moderate antimutagenic activity against NQNO. In general, one may speculate that the core structures of the test compounds may suggest their possible interactions with NQNO, thus preventing mutagenic activity, similarly to previously reported mechanisms of antimutagenic activities of caffeine and other methylxanthines  gene mutation assay, which identifies agents that cause gene mutations in the hprt gene of a suitable cell line, such as Chinese hamster cells  gene mutation assay, which detects compounds that induce forward gene mutations in the With reference to chromosomal abnormalities detection, both structural and numerical changes can be identified in vitro in metaphase-spread preparations from exposed mammalian cells. Common in vitro chromosomal damage tests include the mammalian chromosome aberration test and the micronucleus test. In the former assay, mammalian metaphase cells are analyzed for the presence of structural chromosome aberrations, and in the latter, micronuclei in the cytoplasm of cultured mammalian cells during interphase is detected. The micronucleus test is a procedure for the detection of both aneuploidy and clastogenicity in cultured mammalian cells , which detect single- and double-strand breaks, repair induced breaks and alkali-labile lesions; and the liver unscheduled DNA synthesis (UDS) test, which is useful for the measurement of the repair of DNA lesions  test; and chromosomal aberration tests. On the other hand, class 2 contains assays used for the identification of alterations in the offspring of exposed animals. These studies include i.a. testing for gene mutations in th ESTR assay; mouse visible specific locus test for detecting and quantifying the induction of heritable point mutations  in mammals; the biochemical specific locus test which allows the detection of mutations originating in the germ line of a mammalian species; and for chromosome or gene mutations in the dominant lethal test (Verhofstad et al. Usually, the antimutagenicity assay is done as the appropriate mutagenicity test, except that the tested cells are treated simultaneously with both the test compound and a standard mutagen. In the early evaluation of the antimutagenic effects of compounds, basic bacterial short-term assays are used. These assays have many advantages, including their simplicity, relatively low cost, sensitivity, and flexibility to different experimental settings (De Flora et al. Salmonella typhimurium/microsome assay (Maron and Ames his operon of genetically modified S. typhimurium strains (Maron and Ames Salmonella typhimurium mutagenicity and antimutagenicity test procedures can all be applicable to the Escherichia coli WP2 reverse mutation assay. The only assay difference is the addition of trace amounts of tryptophan instead of histidine to the top agar. This assay is primarily useful in the detection of A/T base pair damage (Mortelmans and Riccio The Ames test, also known as the Vibrio harveyi (Czyż et al. Vibrio harveyi strains. The bacterium is naturally sensitive to neomycin; however, antibiotic-resistant mutants can be separated. The frequency of appearance of mutants increases in the presence of mutagens in a dose–response manner, and this forms the basis of this assay.In the last several decades, several rapid bacterial mutagenicity/antimutagenicity tests have been developed and optimized, such as the assay based on a marine bacterium Escherichia coli PQ37 mutant strain and allows the assessment of DNA changes induced by various mutagens by the measurement of the expression of a reporter gene, β-galactosidase (Quillardet et al. Another vital tool in antimutagenicity assessment is the SOS chromotest (Quillardet and Hofnung Saccharomyces cerevisiae strains are equipped with endogenous cytochrome P450, and, therefore, can be very useful when testing promutagens (Zimmermann et al. Finally, the antimutagenicity assay on yeasts is also very popular in searching for new antimutagens. This is mainly due to the fact that yeasts as eukaryotes are characterized with chromosome structure and DNA repair processes similar to those in mammals. Furthermore, Mutagenic activity is one of the most important endpoints for the risk assessment of chemical compounds, including drug substances and drug candidates, as mutagens are capable of inducing various kinds of changes in the genetic material of a cell. On the other hand, the mutagenic effects of some chemicals may be partly modulated or reduced by the use of compounds presenting antimutagenic properties.Research over the past few years has revealed that mutation has a key role in carcinogenesis. Therefore, one may expect that searching for compounds with antimutagenic potency will remain in the focus of research in the near future. Research studies on antimutagenicity should be focused primarily on the understanding of the mode of action of the most active compounds. Furthermore, there is still much more research needed in order to clear up the exact links between the results of the short-term antimutagenicity studies and anticarcinogenicity experiments in animal models.


Long-acting injectable antipsychotics (LAIAs) may improve adherence to treatment and reduce the rate of relapse and rehospitalization in first-episode or recent-onset schizophrenia . However, despite their potential advantages, LAIAs are underutilised in clinical practice and the place of LAIAs in the early phases of schizophrenia is still a controversial clinical issue. For example, negative attitudes toward LAIAs in first-episode schizophrenia among psychiatrists are common, and the place of LAIAs for first-episode psychoses (FEPs) remains uncertain in the current clinical guidelines for the pharmacological treatment of schizophrenia. Moreover, a recent paper published in the New England Journal of Medicine by Rosenheck et al.  reportedThis special issue seeks to define the place of LAIAs in the treatment of first-episode or recent-onset schizophrenia.S. Zhornitsky and E. Stip present a systematic review examining the efficacy and tolerability of LAIAs versus their oral equivalents in randomized and naturalistic studies. In addition, they examine the impact of LAIAs on special populations at risk for treatment nonadherence such as patients with FEP, substance use disorders, and a history of violence or on involuntary outpatient commitment. Randomized studies suggest that not all LAIAs are the same in terms of side effects. They also suggest that LAIAs reduce risk of relapse versus oral antipsychotics in schizophrenia outpatients when combined with quality psychosocial interventions. Finally, large-scale naturalistic studies point to a larger magnitude of benefit for LAIAs, relative to their oral equivalent antipsychotics, especially among FEP patients.One of the original studies  reports a naturalistic, open-label study of 25 patients in the early phases of schizophrenia treated with RLAI and followed up at least 18 months. The authors found that patients receiving RLAI had a favourable global outcome.As already mentioned, although not found in all studies , there iThe paper published by R. Přikryl et al. in this special issue reviews the role of SG-LAIAs in treatment of first-episode schizophrenia patients and argues in favour of the use of LAIAs very convincingly in terms of clinical judgment. This paper also focuses on negative attitudes toward injectable medications among psychiatrists being one of the barriers that may explain the underutilization of LAIAs, especially in FEP patients, as reported by Heres et al. . Other bOne additional paper  reviews clinical trials, survey studies, and current international guidelines on the use of LAIAs in first-episode schizophrenia and considers the pros and cons of this treatment option. The paper presents a brief overview of a few preliminary naturalistic and randomized clinical studies primarily designed to evaluate SG-LAIAs in first-episode schizophrenia. Published clinical guidelines reflect uncertainties in the use of LAIAs in the critical early period of the illness. With some exceptions, the majority of treatment guidelines limit the use of LAIAs to multiple-episode patients and to openly nonadherent patients . ClearlyThe objective of the original research paper published by Ch. Asseburg et al. is to quantify changes in hospital resource use in a naturalistic clinical setting in schizophrenia patients in Finland following initiation of RLAI. Although not primarily focusing on FEP, the study found that consistent reductions in resource use are associated with the initiation to RLAI in Finland. These results agree with several recent studies exploring the issue of health resource utilization and cost-effectiveness , 9.Finally, we would like to outline three unmet research needs concerning LAIAs in FEP for the future.First, there is a need for better designed RCTs in FEP. There is an absence of long-term RCTs comparing LAIAs with oral medication after FEP regarding efficacy, tolerability, relapse prevention, and global outcomes. We also need studies examining patient preferences, acceptability, and attitudes toward LAIAs in early phases of the illness, as well as data about nonadherence rates of SG-LAIAs in early phases of the schizophrenia. There is also a lack of cost-effectiveness studies comparing LAIAs with oral antipsychotic treatments specifically focusing on first-episode schizophrenia patients.Second, the question of whether effective early intervention positively influences long-term outcome needs to be more effectively addressed. We need to know whether we are able to alter disease trajectory to clinical and neurological deterioration that mainly occurs within the first 3–5 years following the onset of the illness. Although there is some evidence to suggest a better global outcome using LAIAs as compared to oral antipsychotics with a reduced risk of relapse and rehospitalization , 11, it Third, we need increased availability of additional SG-LAIAs and to develop more reliable methods of antipsychotic delivery. Given the failure of the long-term oral treatments and keeping in mind that relapse can lead to serious consequences from all perspectives , the future of the schizophrenia pharmacotherapy will hopefully evolve to include better long-term delivery systems such as longer extended release injectable formulations, transdermal patches, subcutaneous implants of antipsychotics, and other long-acting devices like antipsychotic pumps to more effectively address the high risk of relapse due to nonadherence early in the course of illness. Antipsychotic release of skin implants containing risperidone and biodegradable polymers has been already assessed in vitro and in vivo in animal models , 16. SucTo summarize, considering that poor adherence to oral antipsychotic treatments and the very high relapse rates early in the illness due to nonadherence are the rule rather than an exception, from the clinical point of view, psychiatrists should think in terms of relapse prevention from the outset of the illness, identify and overcome local barriers to use LAIAs, and consider the option of SG-LAIAs to all patients with first-episode or recent-onset schizophrenia in a shared decision-making approach. The success of such pharmacological intervention would of course be enhanced by combining with appropriate psychosocial interventions within a relapse prevention program. In this sense, the current clinical guidelines regarding LAIA use in FEP are much too conservative and need to be updated. However, it needs to be remembered that there is still a need for more open-label or double-blind RCTs in early phases of schizophrenia, regarding the long-term efficacy, safety, global functional outcome, and cost-effectiveness of SG-LAIAs compared to oral antipsychotics in order to obtain a more robust clinical database for evidence-based medicine. Such studies will also define whether or not LAIAs introduced early in the course of the schizophrenia illness can alter the disease trajectory.


Organ failure can be defined as a relevant concept of functional-anatomical condition of body structural change. Anatomical, functional disorders of the body are the expression of structural remodeling. The process is complex, including the first functional cell mass reduction , and on the other hand the development of fibrosis process with a starting point at the extracellular matrix. Both mechanisms that take place are caused by etiological factors, enhanced, favoring the developer cytokines mediated by inflammatory processes such as premature death and functional constituent cells of the body; secondly the inflammation leads to fibrosis. The article review is a summary of the knowledge that exist at the level of the anatomical organ remodeling. Expressing serious disturbance in the function of the clinical plan of the anatomical organ failure translates the existence of a remodeling/ reshuffled architectonics organ expression conduct of at least two fundamental processes:  - Activation of functional cell death by apoptosis induced necrosis, or by similar processes; 1].  - Replacing damaged cells in the interstitial connective tissue, as a result to this hyperplasia [2]. The main actions developed by the active substances (cytokines and chemokines) which are released are designed to increase vascular permeability, cell adhesion and migration, to be recruited to lesion sites, cellular infiltrate  [3].  Progressive organ failure is the result of a dynamic process, which allows the recognition of the stages of induction and development, potentially reversible up to a point in disease progression. In the first step, after the damage caused by the etiologic agent, the installation of protoplasmic pH changes as an expression of the tendency to develop metabolic acidosis by altering cellular metabolic processes. The initiation and development of various morphological and functional disturbances in apoptotic cells are stimulated by the generation of the etiologic agent of the disease, but back activation of cytokines, produced either by stimulated cells in organ structure or by local migrated cells, which generally belong phagocyte system mononuclear. In a later stage, cytokines, through their autocrine, paracrine or metacrine action, stimulate the release of enzymes and proteolytic cell-destructive acts primarily as caspases and/ or dominant effect at the gap, as metalloproteinases  [4].  First, the degranulation recruits monocytes, bossing them, and then they are marginalized, so that the diapedesis and migration to reach the lesion focus chimiotactism and/ or electro-attraction. As a result of binding to apoptotic cells stimulated by TSP, monocytes become macrophages engaged in phagocytosis in the area of inflammation. At the launch, the purpose of phagocytosis is only to remove necrotic cells and those that have been partially destroyed, without the intention of developing inflammation. However, an inflammatory response occurs, leading to the initiation of the remodeling architectural conditions of the body, due to the capacity of the mononuclear cell free system, the local active functional products and/ or enzymes involved in inflammation. They will join those released from damaged cells of the body, empowering and mutually action [5].  The remodeling is focused in particular on the activation (proliferation and differentiation), fibroblasts are accomplished by the action developed by pro-inflammatory cytokines, such as PAI-1 (Plasminogen Activator Inhibitor-1), osteopontin, growth factors and prostaglandins. In parallel, some of them, such as PAI-1 exercise and control role, intervening matrix remodeling extracellular [6].The theory admits oxidative stress as a basic principle, excessive growth ROS7 production [8].  Destructive lesions cell activate as the level of extracellular matrix fibrosis recognizing a common cytotoxic mechanism, developed through self-healing by oxidative stress ; c. angiogenic factors like angiotensin II (Ag II);  b. proteolytic enzymes, acting primarily in the extracellular matrix, such as MMPs [4]. Ischemia occurs as the ultimate mechanism of fibrosis and fibrogenesis that compresses arteriolar lumen stenosis is produced, and path deviates by an excess quantity of collagen, where other proteins of the extracellular matrix are deposited. In such cases, ischemia is responsible for the imbalance between tissue blood flow and metabolic consumption, externalized by inducing alterations apparently free of new cells and discharge of proteolytic enzymes, activating local inflammatory and immune mechanisms, developer-fibrotic destructive effects; self-sustaining process [1].  The common characteristic of these factors is that the acts associated release, while stimulating and empowering themselves, self-sustaining deteriorative anatomic and functional processes of the body, the body reshaping. Functionally, the process becomes one fix clearing destructive one, because beyond cell death induced etiology, cellular inflammatory mechanisms, immune and last but not least, ischemic destruction occurs [10]. The way it was defined made fibrosis be still unclear, the results of experimental studies arguing on a direct anabolic fibroblast exercised by various active compounds synthesized locally or systemically.  Anatomically, it was recognized that the optimum performance of the functions of an organ assumes a proportional development not only in architectural and structural terms - functional cells but also of the intercellular matrix. The latter development reflects a balance between the production and the degradation of collagen; homeostasis is permanently regulated particularly on the synthesis process. Understanding the mechanisms of fibrogenesis is facilitated by defining its biochemical characteristics as the synthesis of extracellular matrix proteins in the basal membrane and/ or interstitium . Moreover, the actions developed through-corticoid receptor stimulation minerals and which reinforce each other, and several which developed by increasing oxidative stress on both apoptotic cells and on fibroblasts stimulated the injured body [13]. These intricate actions developed while clearly demonstrating the myocardium, allowing the use of antagonist minerals and hope-corticosteroid therapy in various forms of congestive heart failure, including those that occur after the myocardial infarction.  By binding to specific receptors, hormones, minerals and corticosteroids are involved not only in excessive production of ROS in vascular development, tissue inflammation, but also in the activation of fibrosis [ The results of experimental studies admit that Ag II acts in developing the two-stage fibrosis: 16].  A. In the first stage, the active angiotensin induces increased cytokine osteopontin expression, the protein responsible for the organization and stability of extracellular matrix due to its ability to bind to the various gap structures: collagen, fibronectin etc. [17].  B. In the second stage, the active angiotensin potentiates the pro-fibrotic developed by minerals and hormones, steroids, acting as a factor stimulating growth factors which regulate the expression and synthesis of collagen [20]. Due to the coupling of various ligands, Ras subfamily proteins specific membrane receptors are activated. In this form - Ras-GTP - acts as a transducer that initiates various cellular processes, including apoptosis. Although it is now widely accepted that inflammation precedes fibrosis, experimental studies have shown that fibrosis is not always in control of inflammation. As far as stimulation is concerned, the Ras protein induction develops and action/ development of inflammation and fibrosis is under the direct control of MMPs and their tissue inhibitors  [22]. Functionally, in terms of normal tissue metabolism, MMPs are inactive and in conditions of hypoxia-ischemia, oxidative stress or other factors, such as the Lezion action, are activated. The results of the experimental studies on animals have shown that the excess of MMPs leads to progressive tissue remodeling, while reducing the inhibition of MMPs. The duration and intensity of action developed by MMPs are modulated in at least three ways: the action of tissue inhibitors, the speed of the auto degradation and the endocytosis of selective [23].  In order to develop cellular effects, both hormones mentioned, just as various pro-fibrotic cytokines serve as ligands to cell membrane receptors and communicate with the nucleus and/ or cytoplasm of the cell by activating pathways in cytoplasmic signal carrier. Most of these pathways that transmit such signals are used as transducer protein Ras proteins attached to the internal face of the cellular membrane   - Interleukins IL-1, IL-4, IL-6 etc. [23]. - Growth factors - transformation: EGF, HGF, TGF-ß, etc. The presence of TGF-β in the extracellular matrix is an indirect factor reduction of body cell mass, which is functional as it acts as an inhibitor of the cellular proliferation [The difficulty in understanding the mechanisms of organ failure resulting from complexity, which includes various pathogens, such as inflammation, oxidative stress, neuro-hormonal activation, damage  of cells that migrated from the body or the local purpose defense. The functioning at an optimum capacity of the cellular signal is conditioned by the existence of a constant quantity of agents ROS/ RNS, the activation of oxidative stress leads to an exacerbation of ROS signaling, which is responsible for the genesis of structural alterations at the cellular and interstitial level.  Although there have been important advances in the knowledge of the mechanisms by which induced cell death and organ fibrosis are installed, there are still many unknown aspects, which justify the increasing interest of research to identify them, in the hope that they will be able to discover new therapeutic means, turning an irreversible process into a reversible one.