Primary Health Care work processes are complexand present difficulties for conducting integrative care, especially for nursing,but humanizing practices have showed an important role towards the development ofpositive work environments, quality of care and people-centered care by promotingaccess and universal health coverage. nursing challenges for universal health coverage are related to education andtraining, to better working conditions and clear definition of nursing role inprimary health care. It is necessary to overcome difficulties such as fragmentedconcepts of health and care and invest in multidisciplinary teamwork, communityempowerment, professional-patient bond, user embracement, soft technologies, topromote quality of life, holistic care and universal health coverage. This agenda includes reducing maternal mortality, end preventable deathsof newborns and under five-year-old children, end the epidemics of AIDS, tuberculosis,malaria and Neglected Tropical Diseases (NTDs), and ensure universal access to healthcare services. All these objectives can be achieved using nurses and midwivesstrategically placed at the person-centered community-based level. The route to Universal Health Coverage (UHC) and the Post-2015 development agenda isthrough the health worker. Nurses and midwives are the largest category of health workforce, related to eightypercent of health services, and are also the frontline health workers. Nursing andmidwives using a career pathway model of skill mix could be utilized to deliver healthcare and improve outcomes. However, affordable approaches to boost the performance ofhealth workers are urgently required. The path towards UHC implies addressing the gapsin competency, quality, motivation, productivity and performance of healthworkforce. . Key practical steps proposed by WHO for Nursing and Midwifery are: increaseinterdisciplinary, multi-professional, nurse-led teams and leadership skills; empowernursing and midwifery workforce by clear role clarification, valid job description andprofessional recognition; implement positive work environments to improve motivation andretention. . This unique policy is guided by values such as autonomy and empowerment ofhealth users, responsibility among patients and health professionals, establishment ofsolidarity, the construction of cooperation networks and collective participation in themanagement process. The NHP operates the following devices: user embracement, uniquetherapeutic project or patient centred care, public health projects; qualified listeningof health users and workers; among others.One way towards these steps was the inclusion of the National Humanization of HealthCare and Health Care Management Policy, also known as the National Humanization Policy(NHP) and/or HumanizaSUS, in different nurses and midwives' workplaces. This u. Considering this relation, the objective of this study was to identifynursing challenges for UHC, based on the findings of a systematic review focused on thehealth workforce's understanding of the role of humanization practices in PHC.Primary Health Care (PHC) is the gateway to the health system and organizes the networkof services. Humanization permeates the work processes and the stakeholders of primarycare. Consid. A mixed research synthesis by integrated design was used in this study.This design allows grouping the findings of both types of primary studies into thematiccategories to reach meta-synthesis. This integrated design uses PICo to guide data collection, a specificguide to extract information and to classify the quality of findings. The purpose of a systematic review is to enable the translation of the best scientificevidence into policies, practices and decisions in the healthcare context. A mixeynthesis. This i.In November 2013, the search was conducted using the following databases: PubMed,CINAHL, Scielo, Web of Science, PsycInfo, SCOPUS, DEDALUS and Proquest. The referencesof the articles selected for this review served as a source of new inclusions in thereview process so-called reference of the reference.. In this review, Population was PHC Professionals, Phenomenon of Interestwas Experiences of humanization practices and Context was PHC Settings. Adjusting theobjectives of the study to PICo, the guiding research question of this systematic reviewwas "What is the understanding of healthcare professionals with regard to the role ofhumanization practices in PHC?"PICo was used to guide the systematic review question, these mnemonic identifies the keyaspects Population, Phenomenon of Interest and Context. In thi concepts of humanization are centered on core principles such as access,empathy, humanization of assistance, personal autonomy, holistic health and userembracement. Data collection used controlled search terms based on these concepts. Thefollowing keywords were used: Primary Health Care with others, separately: humanizationof assistance, holistic care/health, patient centred care, user embracement, personalautonomy, holism, and health personnel attitude. Brazilian NHP conceptResearch articles were found in English and Portuguese from 1999 to 2011. The inclusioncriteria for the study were: articles related to attitudes/beliefs of primary healthcare professionals regarding the use/practice of humanization practices. Articles wereexcluded if were about patients or students and/or studies done in hospital settings.The articles were organized using EndNote, which is an electronic reference manager.Each article received an identification number. The articles referring to the same studywere treated as one and given a single identification number.. Knafl & Sandelowski(11) tool provides guidance on how totransform raw data into data that can be systematically combined and analyzed. Two independent reviewers assessed the articles and the final selection was made byconsensus, based on a comparison of the evaluation of both reviewers. The analysisresults were organized using a modified version of the Data Extraction Guide forQuantitative and Qualitative Studies. Knafl . Based on these domains each study was analyzed and classified as Strong,Good, Weak and Noisy (when there was lack of information).Information was extracted from each report in the following domains: research purposesand questions, theoretical framework, method and design, sampling strategy, samplecomposition, data collection and analysis techniques, techniques to optimize validity orminimize bias, techniques to protect human subjects, findings, anddiscussion. Based , the quantitative findings were qualified. Findings were converted into aqualitative format in order to combine them, by themes. The data was organized intoempirical categories that emerged from the analysis. Two independent reviewers assessedthe categories in terms of their respective scope and definition, with disagreementsalso being resolved by consensus. As recommended for systematic reviews aimed at providing a metasynthesis by integratingthe results of qualitative and quantitative studies (Mixed researchsynthesis),13, t. The analysis of findings from the systematic review considered the quality and resultsof the studies. The Consolidated Criteria for Reporting Qualitative Research (COREQ)checklist was applied to improve the quality of the recommendations presented in thisreview. From potential 90 references, reduced to 53 non duplicated studies, 30 studies wereincluded and systematically reviewed: 29 qualitative and 1 quantitative as In total, studies included 1,179 PHC professionals from United States of America (A1)and Brazil (A2-30) as shown in Each study was analyzed by its quality and classified: 18 as Strong , 5 as Good , 2 as Weak  and 5 as Noisy .. The findings were aggregated in eight empirical categories: attitudes and beliefs;health care conceptions; barriers; facilitators; education and training;professional-patient bond; teamwork and provision of humanizing practices. In thisarticle we describe the categories: health care conceptions; barriers; facilitators;education and training about humanizing practices and provision. In another paper wedescribe the other three categories that were identified in the review. This category included perceptions of health care professionals about conceptions ofhealth and care related to humanization practices. This category was present in 17/30studies.Regarding the concept of health, more than 130 professionals reported the need toconsider the patient in a physical, psychological and spiritual perspective and theirsocial and cultural context, beyond the biological dimension .Regarding the concept of care, more than 60 workers mentioned the importance ofindividualization of care, recovery of light technologies, shared responsibility, userembracement, need to meet social problems and promote behavior changes .Professionals mentioned and it was observed that the escape of the traditional curativemodel occurs when professionals seek to put in place a comprehensive conception ofhealth, through the recovery of the essence of caring, accountability, sensitivity tolistening, integrative perspective, use of light technologies, rescue ofprofessional-patient bond, health practice that promotes behavior change and improvesquality of life .Professionals reported difficulties in meeting concepts of health and care related touniqueness, autonomy and co-responsibility due to a health activity marked byindividualism, complaint-conduct and fractionation of therapeutic acts .The search for productivity, lack of working conditions, inadequate conceptions of thehealth-disease, unjust social conditions of the community and workers' predeterminedconceptions about the health users were cited as barriers to the achievement ofuniversal care .This category included perceptions of health care professionals about difficulties,barriers and limitations related to humanizing practices. This category was present in23/30 studies. More than 700 workers reported factors related to: 1) Lack of feedback (A1); 2) Lack ofreference and counter-reference ; 3) Excess of demand,inadequate physical space, lack of materials and professionals ; 4) Lack of support,partnership and attention from the County Health Department and community participationin meetings promoted by healthcare units ; 5) Excessive bureaucraticwork and lack of time ; 6) Inflexible working hours ; 7) Vertical Management ; 8) Dissatisfaction of professionals withworking conditions ; 9) Lack of educational groups, mentalhealth professionals and other areas for referral ; 10) Inadequate attitude ofprofessionals and users about user embracement and humanization practices ; 11) Lack of teamwork and definition ofprofessional roles ; 12) Lack of user embracement and FamilyHealth Program teams ; 13) Problems related to unsatisfactory community socialconditions ; 14) Lack of knowledge and specific training about UnifiedHealth System and Family Health Program to work in Primary Health Care .This category included perceptions of health care professionals about facilitators andpromoting factors related to humanizing practices. This category was present in 18/30studies.More than 300 workers mentioned factors related to: 1) Commitment of teams andresponsibility with the community ; 2) Participative management,including Unified Health System network, Family Health Program coordinators, LocalHealth Council, professional associations and third sector ; 3)User embracement practice over 5 minutes (A5); 4) Permanent discussions between thestaff of the Health Unit to evaluate and reprocess user embracement ; 5)Favorable working conditions such as more time, fewer people to attend, better physicalspace, more resources ; 6) Community commitment andpositive recognition verbalized by patients ; 7) Dialogue,professional-patient bond and better knowledge of community needs by a work processcalled ascription of the community ; 8) Understanding and acceptance ofuser embracement process by professionals and health users, patient availability of"giving vacancy to another patient more serious" (A15); 9) Presence of teamwork,performance evaluation and adequate division of activities between professionals ; 10) Continue education and training of health workforceprofessionals ; 11) Use of protocols and record data of userembracement ; 12) Flexibility for scheduling consultation times and lessbureaucratic practice (A18); 13) Organization of programmatic groups, support groups andprovision of other professional services ; 14) Realization of public contractsto contribute to retention of professionals in enrolled areas, preventing turnover ofpersonnel (A19).This category included perceptions of health care professionals regarding the influenceof training in the context of humanizing practices, including considerations regardinggraduation courses and continuing education. This category was present in 7/30studies.More than 60 professionals, including managers, reported a need for more training andgreater awareness of humanizing practices . From these, nine nurseshighlighted the need for training related to conformation and operation ofmultidisciplinary teams to deploy user embracement (A15).Studies have reported difficulties with training human resources to work in PrimaryHealth Care and with humanizing practices . Professionals fromsix healthcare units reported non-operation of the orientation training or that onlysome professionals can participate, highlighting the lack of training for dentists andnursing assistants (A30).Professionals reported experiences of training/workshops about user embracement at workand humanization of care ; nurse auxiliaries and community health agentsmentioned frequent participation in health training and activities (A30). A FamilyHealth Program team has Permanent Education project to train and qualify professionalsin accordance with the principles of humanization policy (A17).This category included perceptions of health care professionals about provision ofhumanizing practices, how this is organized, who practices them and their consequences.This category was present in 26/30 studies. Professionals reported the implementation of humanizing practices in PHC, such as userembracement, integrality, access, bond, universality, patient-centered practice andextended clinic .Regarding user embracement, from its implementation and consequent reorganization of thework process, in a health care unit, changes were observed in accessibility to services,demonstrated through the extraordinary increase of general care delivery by the Unitover one year. Data on the unit show that efficiency increased by 600% [production/hoursworked], related to the extraordinary increase in the yield by nurses, social workersand nursing assistants with the deployment of user embracement and the workreorganization process (A10).In ten health care units it was observed that the actions related to the process of userembracement were to identify the patient's problem and propose an answer; refer patientsto other services such as first aid, medical consultation, etc.; perform anamnesistowards the complaint; perform screening for immediate or mediate referral, according topre-established number of consultations and severity of the complaint; perform physicalexamination and check vital signs, focus on the complaint; supervise the nursingassistant when it performs user embracement; oversee the station entrance door;distribute tickets to attend; perform medical or nursing consultation; change drugprescriptions; realize health guidelines orientation; take care of wounds; administermedications; perform qualified listening to meet patient needs; provide support topeople seeking the service (A9).The offer of humanizing practices changed the organization and division of labor betweenthe teams of PHC, especially due to the implementation of user embracement .User embracement resulted in increased workload and teams performance withreorganization of the work process . In some healthcare units userembracement was offered by all staff , in others it was in charge of thenursing team  and in some units doctors were in the rear of userembracement . User embracement brought changes in the work process of thenursing team, re-meaning care for nursing assistants .In some consultations and in some units was observed that user embracement was practicedby the nursing assistant, carefully, showing availability, interest, involvement andresponse to health user needs (A5). Seventeen nurses reported that all employeesdynamicalle and continuously performed user embracement at any time and place (A6). In ten health care units it was observed that, with respect to the professionals whodeploy user embracement, in general, this activity is the responsibility of nurses andnursing assistants, with the rear of the medical professional; in some units, thecommunity health worker was responsible for user embracement, It was observed that, eachday, an average of forty user embracement practices took place, which lasted from threeto fifteen minutes each (A9). Among fifteen workers, most confirmed doing userembracement, only two doctors said not to do it (A11). In nine health care units, thereis great diversity in the composition of the work teams that have deployed userembracement: nursing assistants were at the frontline of this practice with theparticipation of nurses as technical reference; physicians act as support for unsolvedcases, limited to 12 vacancies for consultation per physician, without bonding andaccountability for this practice (A15).Primary healthcare teams had doubts in implementing humanizing practices, especially inthe organization of services and work teams related to user embracement ; being common to this practice to end in medical consultations,without changing staff practices or the management of the unit .Workers and managers reported and it was also observed in some healthcare units thatthey did not offer humanizing practices, resulting in restricted and limited patientaccess, work focused on consultations and medications, being exclusive to medicalspecialties of medium and high complexity, low resolution, lack of light technologies,user embracement primarily being applied as a technique of reception, screening andreferral, synonymous of emergency or waiting room; work processes focused on proceduresand techniques, as well as work process divided by each specialty; attachment to theprocedures and protocols; bureaucratic practice .Professionals' conception of health in relation to humanizing practices included thephysical, social, psychological and spiritual perspectives in search of wellbeing andquality of life through an integrative care. The conception of care included the use ofsoft technologies, individualization of care, patient empowerment, co-responsibility,access to services, user embracement, reference and counter-reference, teamwork,adequate professional behavior, changes in work process, the demand to attend socialproblems and to create life changes opportunities to patients.. As most of the studies included in this review were of Brazilianpractices, it was not surprising to find concepts of health and care that include theseproposals and practices.Since the late twentieth century, in the Brazilian context, different proposals, such asintegrative care, health promotion, humanization practices, have sought to overcometechnical, political and ethical impasses in health care. As mos.Health promotion is based on an expanded concept of health and disease and itsdeterminants. In this conception, health professionals and population are seen assubjects of the process and the focus of care is related to the way of life and workingconditions of individuals and social groups and their impact on the health-diseaseprocess.(-).Nursing theories also present expanded concepts of health and care, related to thebio-psycho-social-spiritual context, interpersonal relationships, holistic care,empowerment and health care needs. Just to present some examples: Florence Nightingaleshowed the relationship of the person and the environment to health, Martha Rogerscontinued to demonstrate this relationship and included the concept of holistic care,Rosemarie Parse increased the perception of a person including the spiritual domain,Madeleine Leininger included cultural aspects, Virginia Henderson the basic needs andself-care, Hildegard Peplau the importance of interpersonal relationships, Afaf Meleisthe concept of transitions, Jean Watson the concept of a critical event and humane careand Wanda Horta the concept of basic human needs-21.Therefore, in the health promotion approach, nursing theories and professionals in PHCpresent neither idealized nor fragmented conceptions of health and care in relation tohumanizing practices. Thus, nurses are encouraged to recognize and reaffirm the role ofnursing related to promoting quality of life for those who no longer have the ability tocare for themselves alone.However, professionals also cited barriers to work according to these conceptions ofhealth and care in order to deliver humanization practices. The barriers were not allpresent in a single practice, but were common at many units. It is a real challenge forteams, managers and health users to modify these barriers towards integral and universalcare.. Difficulties with access and referral put UHC in danger and also reflecton the health professional bond with health users and communities, especially inrelation to confidence in PHC services.One of the biggest current ethical challenges in the Unified Health System is to producetherapeutic linkages to ensure health users, family and community the possibility ofhealth care in adequate time. DifficOn the other hand, professionals cited many facilitators of humanizing practices. Thefacilitators were more common in units that had performed user embracement longer, thosewhich increased health user access to the unit and where meetings were held with allprofessionals to evaluate health care services.. These changes also include providing adequate working conditions to enablethe commitment of the teams and responsibility towards the community. Workers needspecific training, and participatory management is needed, including health services,Local Health Council, professional organizations and the third sector, to fosterunderstanding and promote the co-participation of professionals and health users.The complexity of the problems and the organization of services in PHC require changesin professionals and health users' attitudes and values. These .The complexity of PHC also requires new professional profiles to meet community needs.The growing challenge of educational institutions is to prepare professionals to work atdifferent levels of the health system, especially in PHC, in line with the system,teamwork, comprehensive health care, horizontal and more focused on the workprocess.Professionals, including health service managers, reported the need for more stafftraining. Professionals reported that they do not come prepared to work in the FamilyHealth Strategy nor to accomplish humanizing practices. According to the professionals,this unpreparedness was related with the lack of such contents in undergraduate andcontinuing education. To work with extended concepts of health and care in PHC, theconcepts of health and care widespread trough graduation and training courses need to bereconsidered. . Teaching of humanizing practices also suffers from the influence ofscientific biomedicine. The rationalist, mechanistic and dualistic model of scientificrationality, dominant in health, prevents the recognition of other "truths" about healthcare, contrary to the reductionism of clinical pathology and mechanicalphysiology.It is worth noting the Flexnerian influence in the formation of health professionals,based on the mechanical, biological and technical aspect, and complain-conductpractice. Teachiysiology.. In relation to continuing education, a pedagogical intervention in two Health Centerswith themes about health system and humanizing practices showed that, after one year,there was an impact on management and work processes of some practices, with improvedaccess and better relationship between professionals and community. . This is the case of the skills related to nursing for universal healthcoverage. Moreover, there is a demand for training and continuing education, linkingtheory and practice, in order to build nurses and midwives' qualifications to becomeeffective leaders and managers, as proposed by the strategic directions for nursing andmidwifery education, training and career development.A health team needs technical, caring and management competence; demands beyond basictraining, other skills that involve extended listening, speaking andteamwork. This ielopment.Regarding the provision of humanizing practices, in some services, the entire healthteam or just some professionals were involved with user embracement in order to increaseaccess, bonding and accountability towards the community. In other units, userembracement was not deployed in order to reorganize the work process, but professionalswere seeking to improve the care process and the relationship with patients throughintegral and universal care and extended listening. Professionals reported problems in the provision of humanizing practices. Resultsindicated that, often, the outcome of user embracement when mistaken for Emergency Carewas medical consultation or medication, thus moving away from the goal of humanizingpractices, which is to increase professional-patient bonding and meet community needs bydelivering people-centered service. User embracement demands dialogue and qualifiedlistening to result in a positive work environment, empowerment and teamwork.Professionals reported that the provision of humanizing practices, especially theimplementation of user embracement, resulted in changes in teamwork. The resultsindicated that the nursing staff is often confronted with user embracement with thepresence of nursing technicians and auxiliaries. The user embracement team also includescommunity health agents, social service professionals and dentist auxiliaries. Nursesparticipate in the user embracement team and often play a role as rear to nursing teamand community health agents. Also at the rear are physicians and dentists, who deliversupport and advice to the user embracement team, however without presenting majorchanges in their work practice..Workers of a multidisciplinary team in general realize that health work is done bydifferent professionals in installments, but often do not realize that the absoluteautonomy of a professional in relation to other workers and users hinders theconstruction of shared work.This was the case reported by some professionals in relation to those physicians who haddifficulty participating in the user embracement and isolated their activities in PHC.But it was different from what was reported in relation to some members of the nursingstaff and other professionals who have managed to put on teamwork and expand theirshares in the unit through user embracement..Professionals reported that the implementation of user embracement brought importantchanges in the practice of non-medical professionals in PHC, especially for socialworkers and nursing professionals who broaden their actions regarding health care, thusmeeting a central idea of user embracement, which is to take the doctor's role as theonly protagonist of care and extend the clinic conducted by otherprofessionals.The Primary Health Care setting demands mutual responsabilization and integrated care,as well as understanding that user embracement is not screening and thatcomplaint-conduct should not be the goal of health care teams. Professionals who comeinto contact with the humanizing practices had enlarged conceptions of health and care.But this expansion has not always been enough to change the working logic in the unitsand achieve universal health coverage.. Universal health coverage is an aspirational concept. It establishes what is to beachieved but little about how to get there. The first step is building a healthworkforce that is both fit for the purpose and fit to practice.  can help and achieve universal health coverage. These are: strategiesdeveloped to encourage individuals, families and communities to play a more proactivepart in assessing health-care needs and the effectiveness of service provision;standards of practice for people-centered care incorporated into quality health servicedelivery; development and implementation of PHC models led by nurses and midwifes; toolsand models to improve the quality of practice, especially within PHC; research-basedchanges in nursing and midwifery practices to improve health services and outcomes;interprofessional and multisectoral collaboration strengthened to maximize thecontribution of nurses and midwifes to health and development goals.Some of the Strategic Directions for Strengthening Nursing and MidwiferyServices can helnt goals.. Results related to midwives were not identified in this systematic review. Midwiferypractice is also discussed in the Brazilian national policy towards Humanizationpractices; this scope is known as Child-birth Humanization and it defends respect forwomen's rights ;respectful treatment from providers; pain relief and prevention of iatrogenicpain.  that examined the impact of supplementary prenatal care delivered by nursesin a community-based population related this practice to positive health outcomes forpregnant women. Based on this study, overall skills, training and education requirements for universal healthcoverage could be identified. The overall skills were: holistic and universal approachthat acknowledges physical, emotional and spiritual elements of pregnancy; providesupport and address issues related to nutrition, lifestyle, food safety, psychosocialhealth and abuse, potential medical complications and exercise, multilingual andculturally appropriate care. Training and education requirements were community health,training in prenatal care and post natal follow-up, total person approach, humanisticperspective on learning, comprehensive pregnancy care, solution-focused counsellingapproach, community as partner approach, abuse screening and referral.A randomized controlled trial that exis study, overalA broad range of nursing services were presented in the findings of this systematicreview, such as nursing consultation, management of health units, orientation of nursingassistants, auxiliaries and community health agents, responsibilities related tovaccines, home visits, organization of therapeutic groups, participation in communityhealth councils. In order to deliver these services and achieve universal healthcoverage, a list of requirements is presented in Nursing challenges for universal health coverage, based on the requirements presented,are related to education and training, adequate working conditins in PHC and clear roleclarification. These challenges are intrinsically related, since it is education andtraining together with working conditions that help to define nursing role in PHC.Education and training considering expanded concepts of health and care, adequateworking conditions in PHC, with teamwork and positive environment, are fundamental torecognize and reaffirm the role of nursing related to quality of life promotion andpeople-centered care. Nursing role in PHC is beyond treating patients with a disease,the demand of care might be for guidance, personal autonomy and empowerment, forpatients to take care of themselves and their relatives. Among the studies included in the systematic review, a nurse in a health care unit thathad no humanizing practices reported that there was nothing else to do for a patientwith a terminal illness (A26). This is a demonstration of the nurse's mismatch with herprofessional role. Nursing goes beyond diagnosis, being a nurse is taking care ofsomeone who has no capacity to do so at every stage of life and death process.However, it is understood that the expanded concepts of health and care are contrary tothe fragmented and medical-focused conception currently present in many workplaces,presented in the media and taught in several health courses. Therefore, it is necessaryto invest in multidisciplinary teamwork, in deploying user embracement in the units,both for patients and professionals, privileging therapeutic areas and the use of softtechnologies, to promote moments of encounter that create bonds and improve recognitionof nursing by patients, community and other professionals.th Global Forumon Nursing and Midwifery. These are: policies that encapsulate the vision of UHC toensure integrated people-centered services; educational approach towards quality andrelevance of the nursing and midwifery workforce to meet the local and national changinghealth needs; interventions that lead to improved access to health care services andstrategies that support collaborative partnerships to minimize barriers to healthservices. Overall, the results from this systematic review are in accordance with some of thestrategies towards Universal Health Coverage proposed by the 6services. One limitation of the study is that the majority of the studies included in the revieware from Brazil. Nevertheless, results may be applied to different realities, especiallyto low and middle income countries and health systems facing critical health and socialchallenges, since these are the challenges of Brazilian primary health care. Humanizingpractices can enhance the care promoted by nursing and its responsiveness towards theimplementation of universal health coverage..Nursing as a social practice demands reflection on the complexity of social issues andhealth, in line with the plurality of current society. Nurses must combine, in dailywork, principles and values with competence, in an atmosphere of co-responsibility andcare.Nursing challenges for universal health coverage are related to education and training,adequate working conditions in PHC and clear role clarification in PHC. It is necessaryto overcome difficulties, such as fragmented concepts of health and care, and invest inmultidisciplinary work teams, community empowerment, professional-health user bond, userembracement, use of soft technologies, to promote quality of life, holistic care andimprove the recognition of nursing by patients and other professionals.The quality of the findings in this systematic review can be classified as low evidence,since most studies used interviews and focus groups as the primary method for collectingresults. Nevertheless, based on the perceived benefits presented by the professionals inrelation to humanizing practices into Primary Health Care, it is possible to make astrong recommendation towards this practice. Evidence suggests that nursing's frontlinerole in PHC for UHC can benefit from humanizing practices and from a more integrativeconception of health and care.


Recently observed rapid climate changes have focused the attention of researchers and river managers on the possible effects of increased flooding frequency on the mobilization and redistribution of historical pollutants within some river systems. This text summarizes regularities in the flood-related transport, channel-to-floodplain transfer, and storage and remobilization of heavy metals, which are the most persistent environmental pollutants in river systems. Metal-dispersal processes are essentially much more variable in alluvia than in soils of non-inundated areas due to the effects of flood-sediment sorting and the mixing of pollutants with grains of different origins in a catchment, resulting in changes of one to two orders of magnitude in metal content over distances of centimetres. Furthermore, metal remobilization can be more intensive in alluvia than in soils as a result of bank erosion, prolonged floodplain inundation associated with reducing conditions alternating with oxygen-driven processes of dry periods and frequent water-table fluctuations, which affect the distribution of metals at low-lying strata. Moreover, metal storage and remobilization are controlled by river channelization, but their influence depends on the period and extent of the engineering works. Generally, artificial structures such as groynes, dams or cut-off channels performed before pollution periods favour the entrapment of polluted sediments, whereas the floodplains of lined river channels that adjust to new, post-channelization hydraulic conditions become a permanent sink for fine polluted sediments, which accumulate solely during overbank flows. Metal mobilization in such floodplains takes place only by slow leaching, and their sediments, which accrete at a moderate rate, are the best archives of the catchment pollution with heavy metals. Economic development, which has rapidly grown since the Industrial Revolution, has been accompanied by an increasing demand for heavy metals and substances containing metal compounds. Heavy metals escape during ore extraction and processing and are also widespread in industrial and municipal sewages; their sources have been extensively reviewed in earlier works  water-level changes in a dam have recently been described  has been proposed and is still used. However, it is not suitable to quantify most lithogenic elements suitable for geochemical normalization.Any analytical method can be used for pollution mapping if it is sufficiently productive. AAS, ICP MS or ICP OES and X-ray fluorescence spectroscopy (XRF) are currently the most popular methods, employed by many commercial laboratories. To enhance the analytical productivity at low costs, there is a tendency to replace methods that require time- and cost-demanding dissolution steps  by XRF with pressing or only pouring samples to measuring cells (Matys Grygar et al. Several types of portable instruments are suitable for direct pollution mapping (Gałuszka et al. Other methods for direct in situ mapping are less common. For radioactive pollution, gamma-activity mapping should be the method of the first choice (Martin et al. Floods play a crucial role in the remobilization of heavy metals from historically polluted deposits, whereas present-day pollutants are primarily transported during moderate and low flows. Moreover, floods, which normally represent only a small percentage of annual discharge, are a phenomenon that creates and reshapes the floodplain and is responsible for the transfer of metal pollutants from temporary sinks in the channel. In perennial rivers, metals in dissolved forms or associated with fine sediments can be transported over long distances depending on the flow competency, whereas sediments can be more persistently stored in a floodplain at overbank flows. For this reason, the length of the river and the degree of its modification, including structures such as groynes, weirs, dams, oxbow lakes or side channels, which are important traps for fine sediments, control the pollutant conveyance through the river system. The river damming and variety of engineering measures in floodplains suppress the effect of floods and limit overbank processes in most rivers.Floods control the distribution of sediment-associated heavy metals in alluvial channels by the creation of mezoforms, which are then modified during moderate and low flows and filled or infiltrated with polluted fines. Sediment sorting in a channel during both floods and lower discharges and in a floodplain during floods is a highly important mechanism responsible for rapid changes in heavy-metal concentrations in sedimentary sequences. The variable sorting overlaps the record of the historical changes of river pollution, and all reconstructions of heavy-metal pollution from those sequences must correct concentrations for grain-size effects.Proportions of flood-related physical and chemical metal mobilization from historically contaminated floodplains to rivers are hardly quantifiable because they are so site specific. However, both processes are most intensive during certain stages of floods. Typically, the physical remobilization of metals seems to dominate over leaching under high discharges in reaches where fine-grained alluvia are easily eroded. By contrast, floodplains constitute diffusive metal sources even in laterally stable reaches, particularly if polluted fines occur in a framework of coarse-grained sediments favouring the migration of dissolved metals. The relative contribution of physical and chemical metal mobilization depends not only on the rate of river erosion and the average grain size of alluvia but also on the depth and frequency of water-table fluctuations.Flood-related metal storage and remobilization are controlled by river channelization, but their influence depends on the timing and extent of the engineering works. Generally, the accretion of polluted sediments in groyne basins and in cut-off channels, performed not long before the pollution period, makes them hotspots of pollutants transported in enhanced amounts during high-water stages. Moreover, floodplains of lined river channels that adjust to new, post-channelization hydraulic conditions become the permanent sink for fine and polluted sediments, which accumulate solely during overbank flows. In such laterally stable river reaches, metal mobilization occurs only by slow leaching, and their sediments, which accrete at a moderate rate, are the best archives of the catchment pollution with heavy metals.


Epidermis is a stratified squamous epithelium that migrates from the edge of the wound on the underlying dermis to rebuild lost tissue. Peripheral neurons are elongated cells whose neurites are organized in bundles, within an endoneurium of connective tissue; they either die upon injury or undergo remodeling and axon regrowth. Skeletal muscle is characterized by elongated syncytial cells, i.e. muscle fibers, that can temporarily survive in broken pieces; satellite cells residing along the fibers form new fibers, which ultimately fuse with the old ones as well as with each other to restore the previous organization. Satellite cell asymmetrical division grants a reservoir of undifferentiated cells, while other stem cell populations of muscle and non-muscle origin participate in muscle renewal. Following damage, all the tissues analyzed here go through three phases: inflammation, regeneration and maturation. Another common feature is the occurrence of cellular de-differentiation and/or differentiation events, including gene transcription, which are typical of embryonic development. Nonetheless, various strategies are used by different tissues to replace their lost parts. The epidermis regenerates ex novo, whereas neurons restore their missing parts; muscle fibers use a mixed strategy, based on the regrowth of missing parts through reconstruction by means of newborn fibers. The choice of either strategy is influenced by the anatomical, physical and chemical features of the cells as well as by the extracellular matrix typical of a given tissue, which points to the existence of differential, evolutionary-based mechanisms for specific tissue regeneration. The shared, ordered sequence of steps that characterize the regeneration processes examined suggests it may be possible to model this extremely important phenomenon to reproduce multicellular organisms.In tissues characterized by a high turnover or following acute injury, regeneration replaces damaged cells and is involved in adaptation to external cues, leading to homeostasis of many tissues during adult life. An understanding of the mechanics underlying tissue regeneration is highly relevant to regenerative medicine-based interventions. In order to investigate the existence a  When talking of wound healing, a distinction is made by some authors between regeneration and repair. Regeneration is used to refer to the complete replacement of damaged tissue with new tissue not associated with scar tissue, while repair is used to refer to the re-establishment of tissue continuity . Regenerin situ guided tissue regeneration [Defects in wound repair constitute a severe health problem that frequently affects aged individuals, patients with diabetes or patients treated with immunosuppressants or chemotherapy . An earlneration .This review presents and compares the cellular aspects of regeneration in skin, nerve and muscle, three organs characterized by differences not only in anatomical and functional organization, but also in the number and location of stem cell niches and populations, which ultimately result in varying regenerative potential. By discussing the common traits and the specific features of regeneration in three model tissues, we propose general models of regeneration and highlight various strategies adopted to cope with damage and repair in mammals. The mechanisms of cell differentiation underlying normal homeostasis of tissue characterized by a high turnover, due to short cell life or significant cell loss, do not fall within the scope of this review. We will focus, instead, on regeneration following acute injury.sensu lato consists, in most tissues, of three phases: inflammation, repair and maturation. Following injury, cells are either quickly repaired or undergo necrosis, i.e. cell death characterized by rupture of the cell membrane and release of intracellular factors. The latter induce inflammation, which is required for the subsequent phase of regeneration. Examples of factors released by disrupted cells are: factor VIII, released by the endothelium [Regeneration othelium ; Wnt, reothelium ; cell meothelium . Acute iothelium . A clearothelium , which iothelium . The latothelium . Cell miothelium –15. Adulothelium , which uothelium . A similothelium , 19.The subpopulation of stem cells that undergo differentiation is directly responsible for tissue regeneration. Typically, differentiation is driven by master genes that progressively lead to the acquisition of the tissue-specific phenotype , 21. NotMaturation, which is the last phase of regeneration, consists in the consolidation of a terminally differentiated phenotype. The tissue architecture does not change significantly in this phase, but the cells acquire a functionally mature phenotype. For instance, although sarcomerogenesis occurs upon differentiation, the original, embryonic isoforms of the contractile proteins expressed by newborn fibers are subsequently replaced by other isoforms that are typical of adult tissue .Inflammation, differentiation and maturation differ from tissue to tissue in terms of the kinetics, mechanisms and final morphology of the newborn tissue. Details of the three model tissues described in this review are presented below.de novo production of ECM proteins, such as vitronectin and thrombospondins, and soon also harbors fibroblasts and immune cells. The latter, in turn, stimulate keratinocyte proliferation and migration; the importance of populations of neutrophils, leukocytes and mast cells has been partially highlighted in transgenic animal models, but remains a matter of debate [Following injury, inflammatory cell-derived proteinases degrade the blood clot, while the release of mitogens and chemoattractants by degranulating platelets stimulates migration and hyperproliferation of keratinocytes at the wound edge. Keratinocytes move between the blood clot and the underlying dermis as a monolayer sheet that subsequently undergoes multilayered stratification . The shif debate –29. The f debate , a serieFollowing hyperproliferation and migration, keratinocytes differentiate, as recently reported by Simpson . A subseStem cells are located in three different areas of the skin: hair follicle bulges, inter-follicular areas of the surface epidermis and sebaceous glands; although the relative contribution to skin wound healing of each of these stem cell populations is still poorly characterized, the involvement of different stem cell populations in cutaneous wound healing appears feasible, at least in animal models , 36.Owing to the significant length of neurons, a nerve transection most often cuts the axon, generating two cell fragments: the cell fragment that is distal to the injury site undergoes Wallerian (anterograde) degeneration, which is needed to create a microenvironment that favours axonal regrowth; the proximal cell fragment, consisting of part of the axon and the cell body, undergoes morphological changes (chromatolysis) that mirror metabolic changes and prepare regeneration and axonal elongation. The connective tissue (endoneurium) and the Schwann cells that surround individual axons in a peripheral nerve in most cases survive focal injury, with important consequences on the nerve regeneration mechanisms (discussed below). Varying neuron survival rates are observed following nerve avulsion or transection in different body districts , 38. Con+ appears to define the resealing site, since the Na+ influx from the lesion site diffuses along the transected axon but returns to normal resting values thanks to the action of Na+-K+ ATPase, thereby establishing a spatial-temporal gradient of Na+ along the transected axon [2+ influx through voltage-dependent calcium channels activates calpain and phospholipase A2 (PLA2), which mediate membrane resealing [a) Disruption of the membrane integrity following injury transiently opens the axonal plasma membrane and causes rapid entry of extracellular ions, which results in axon depolarization, an event that is essential for the closure of the lesion sites in the peripheral nervous system (PNS) , 47. Na+ted axon , 48. In esealing , 50. In esealing .b) A prominent feature of a regeneration-incompetent retraction bulb is the disorganization of microtubules, which ultimately leads to dying-back away from the lesion site. Wallerian degeneration activates Schwann cells to produce growth factors and to clear the myelin debris  through 2+-dependent and requires activation of calpains, PLA2 and PKC [c) The formation of a regeneration-competent growth cone is Ca and PKC . Growth  and PKC , 57 have and PKC , 59. Fin and PKC . At the  and PKC , 62. Sin and PKC . Once it and PKC .Table 2Although the involvement of autologous neural stem cells (NSC) in nerve wound repair is still unclear, adult brain-derived NCS grafting has been proposed as a potential approach for nerve repair . Despitein vivo: they are abundant on the surface of myofibers and myogenic cells, and they bind to growth factors relevant to myogenesis.As an exhaustive monograph on skeletal muscle regeneration has recently been published , we willFiber necrosis is the most common form of muscle damage. Though believed to be implicated in human muscle diseases, apoptosis is not an established means of muscle fiber extinction –74. The in vitro[in vivo[Following proliferation and migration from neighboring fibers, the myoblasts fuse with each other to form strips of multinucleated myotubes, a phenomenon observed during myogenesis in vitro and durio[in vivo, 83. Theo[in vivo.Figure 4Regenerating myofiber behaves as if it were denervated until the regenerated segment with its newly formed endplate re-establishes normal nerve muscle contact, which in turns affects fiber physiology . Worthy Proteomic analysis and high throughput screening are providing a plethora of information on regenerating versus non-regenerating tissue, and will certainly help to clarify the events that might lead to the selection of one regenerative strategy rather than another, including cell signaling, transcription, metabolism and energetics, and cell protection, survival and cycle , 88. Allex novo that is so orchestrated and gradual that it would only be possible during embryogenesis or if mammals had conserved the epimorphic regeneration (in which a blastema of undifferentiated cells is formed) that is typical of other organisms and is capable of complete organ regeneration throughout adult life. The evolutionary and anatomical aspects of regeneration have recently been discussed; in this regard, it has been noted that “the complexity of mammalian tissues/organs seems to go in parallel with high heterogeneity in the distribution/features of stem cell compartments”, which are markedly different in perennial and labile tissues [One major issue concerns the overall amount of energy spared by choosing restoration rather than reconstruction to replace damaged tissues. Nutritional needs in metabolic disorders associated with severe wounds, such as cachexia , are cri tissues . This masensu lato: 1) a destruction phase, characterized by the rupture and ensuing necrosis of the cells, the formation of a hematoma and the inflammatory cell reaction (with phagocytosis of the necrotized tissue); 2) a repair phase, consisting in the restoration or the ex novo reconstruction of the original cell type, either with or without the production of a connective tissue scar (concomitantly with capillary ingrowth within the injured area); 3) a maturation phase, characterized by tissue remodeling, inducing a shift toward the definitive pattern of gene expression, which ultimately leads to the rescue of the original physiological function  [ex novo, neurons restore their missing parts; muscle fibers instead use a mixed strategy, based on the reconstruction of missing parts and on the generation of new fibers. These differential strategies are represented by the two terms used in the title to refer to different forms of regeneration: restoration, the attempt to re-establish the status quo ante, and reconstruction, a more radical response, characterized by ex novo cell colonization and tissue formation. The choice of either strategy is deeply influenced by the anatomy and the distribution/features of stem cell niches typical of a given organ. In addition, the energetic costs for either regenerative strategy are also likely to play an important role. The abstraction of divergences and analogies between different types of tissue regeneration might pave the way for the mathematical modeling of this process, thereby making a major contribution to both pathology and regenerative medicine.A damaged tissue whose cells cannot be repaired by intrinsic cellular mechanisms, such as membrane resealing, DNA repair, cell cycle arrest and cytoskeleton reorganization, undergoes three phases of tissue regeneration undings) . This cl


Experimental animal models are crucial in the study of biological behavior and pathological development of cancer, and evaluation of the efficacy of novel therapeutic or preventive agents. A variety of animal models that recapitulate human urothelial cell carcinoma have thus far been established and described, while models generated by novel techniques are emerging. At present a number of reviews on animal models of bladder cancer comprise the introduction of one type of method, as opposed to commenting on and comparing all classifications, with the merits of a certain method being explicit but the shortcomings not fully clarified. Thus the aim of the present study was to provide a summary of the currently available animal models of bladder cancer including transplantable , carcinogen-induced and genetically engineered models in order to introduce their materials and methods and compare their merits as well as focus on the weaknesses, difficulties in operation, associated problems and translational potential of the respective models. Findings of these models would provide information for authors and clinicians to select an appropriate model or to judge relevant preclinical study findings. Pertinent detection methods are therefore briefly introduced and compared. The remaining 20–30% of UCC are a high-grade, non-papillary, muscle-invasive form that are responsible for the majority of morbidity and mortality. These invasive tumors can penetrate deeply through the muscle wall of the bladder, demonstrating a high propensity for distant metastasis and resistance to currently available treatments -2-thiazolyl] formamide (FANFT) ,36, whilTransplantable syngeneic models and xenograft models are both time- and cost-effective, and reproducible, but exhibit phenotypic and genotypic drifts in continuous cell or animal passages. The application of the immunocompetent host in syngeneic models allows the study of intravesical BCG treatment or gene therapy ,40–45.The immunoregulator BCG is widely recognized as a potent agent in preventing tumor recurrence, more effectively than any other chemotherapeutic agent. However, ~20% of patients discontinue BCG due to local and systemic toxicity and >30% of patients show evidence of recurrence , which hCertain individuals argue that the tumors are of rodent and not human origin, and therefore inherent characteristics including tumor growth, latency, growth rate, invasion and metastasis may be different from their human counterparts, and therefore that the translational potential of syngeneic models is even lower than xenogeneic models, and is one step further from clinical applicability.Based on whether the inoculation site is in the target organ or not, xenogeneic and syngeneic models could be further divided into heterotopic and orthotopic models. Heterotopic indicates that the graft is not transplanted in the original site, but usually subcutaneously in the flank or hind leg of the animal. If the target organ is not convenient for inoculation such as the bladder, kidney or bowels, the subcutaneous model should be considered since it is technically simple and can be carried out by an operator with minimum training. Furthermore, the tumor can be easily and non-invasively detected, and the tumor evolution can be conveniently assessed by palpation of the skin and measured with a caliper. For these reasons, subcutaneous bladder tumor models have been widely used in assessing the efficacy of novel therapeutic agents .However, the alteration of the tumor microenvironment due to the inoculation site may significantly affect the biological behavior of tumor growth and metastasis, genetic expression or the efficacy of anti-proliferative agents –54. DrugCompared with subcutaneous models, orthotopic tumors mimic human bladder cancer behavior more closely, since the microenvironment is closer to the natural condition. Therefore experimental results generated by the orthotopic model are expected to have higher relevance . HoweverDifferent methods of orthotopic model establishment have been reported, mostly by intravesical instillation of the tumor/cancer cell suspension following preconditioning of the urothelium. Tumor cells instilled into normal bladders did not result in tumor establishment. To damage the integrity of the urothelium, chemical denudation with HCl and subsequent neutralization with KOH or extensive washing with saline results in increased take rates ,57. OtheFollowing a period of one to two weeks, tumor growth is usually detectable ,63. Signet al, is a reliable non-invasive method, permitting inspection of the urethra and whole bladder surface, obtaining detailed appearance and accurate locations of early lesions (Ultrathin cystoscopy (diameter 0.75 mm), developed by Asanuma  lesions  with a s lesions . If enha lesions . CystoscQuantitative analyses are necessary for the confirmation of inoculation and serial assessment of tumor evolution. Intravesical ultrasonography is reported as a reliable and appropriate non-invasive method for evaluating tumor stage and size in an orthotopic model with the positive predictive ratio regarding tumor staging reaching 85% . HoweverAll of the imaging tests require anaesthesia and urethral catheterization. A certain percentage of the animals (≤20%), may die prior to the end of the study due to procedural mishaps . Thus moUrinary bladder carcinogenesis has been studied extensively ever since the report by the surgeon Dr Rehn suggesting an association between contact with aniline dye and the development of bladder cancer in 1895 . HistoriAlthough the induction period is relatively long, the application of these chemicals provided readily available reproducible models necessary for detailed studies of the biochemical, pathobiological and immunological mechanisms involved in the pathogenesis of bladder cancer . VariousOf the three organo-specific carcinogens, the usage of FANFT is not currently common as a result of concern for environmental pollution and personnel health in spite of the fact that the commonly used AY-27 and MBT-2 rodent UCC cell lines, which are applied in the aforementioned syngeneic models, were induced by feeding rodents with FANFT. Thus the focus is on BBN and MNU. Since the chemically-induced tumors grow intravesically, the detection methods are the same as those employed in the transplantable syngeneic models.Highly limited to the urinary bladder, BBN is probably the most commonly referenced experimental carcinogen. Rodent bladder tumors induced by BBN mirror their human counterparts histologically and genetically . A previPolyporus umbellatus Fries  use significantly prevented and reversed esophageal and colorectal cancer . Similarus Fries  and isotus Fries  have alsus Fries . StudiesBBN is a yellow oily liquid usually dissolved in drinking water at the concentration of 0.05% to feed the animals. Although convenient, this method exhibits problems when measuring the exact dose of BBN taken by each individual animal. Different individuals may consume different doses, and carcinogenesis may take a longer period of time in those that drink less water. Certain authors suggested gavage three times per week, solving the problem of dosing, but also requiring a far more manual operation. The incidence rate of tumor formation can be 100%, however, subsequent to feeding with BBN for 6–8 weeks, another 6–8 months are required for the development of papilloma and carcinoma in all the animals .With regard to the development of squamous cell carinoma, the percentage of squamous elements varied in different reports ,100. TheMNU is the only carcinogen recognized to act directly on the urothelium following spontaneous pH-dependent decomposition without requiring metabolic activation. Therefore the carcinogen can be administered directly in quantifiable pulse doses via intravesical instillation, possessing unique advantages for the experimental analysis of complete carcinogenesis. MNU is a fine yellowish crystalline powder that is intrinsically unstable. As a result, variations in carcinogenic potency were observed in early experiments. Initially introduced by Hicks and Wakefield in the 1970s , MNU wasIn BBN induction, the two genders of rats or mice could be used, and male rodents are used more often, perhaps since in the human population males have a much higher incidence of bladder cancer, and notably previous findings indicate androgen or androgen receptors may be a contributing factor in tumorigenesis and angiogenesis ,106. In The inherent inconvenience of the practice renders MNU less popular than BBN. However, findings are also generated using MNU-induced models, such as the chemopreventive effect of curcumin . Few stuSquamous tumors were also reported in MNU-induced models. Steinberg suggested adding antibiotics in the drinking water of rats when they are administered MNU intravesical instillation to minimize the inflammatory response in order to prevent the development of squamous tumors . The modThe transgenic mouse, or genetically engineered mouse (GEM), generated by ever-improving techniques to carry cloned oncogenes or lack tumor-suppressing genes, provides an ideal system for dissecting the roles of these molecular events, individually or in combination, in bladder tumorigenesis. In 1974, Rudolf Jaenisch created the first GEM by microinjecting a simian virus 40 DNA into an early-stage mouse blastocyst, which was subsequently transferred surgically to the uterine horns of a surrogate mother . During UPII gene, first identified in 1995 (A number of GEM models of UCC employed the uroplakin II (UPII) promoter, the 3.6 kb 5′-upstream sequence of the mouse  in 1995 . UPs are in 1995 ,115. CerBy then, clinical and pathological studies had already identified the low- and high-grade forms of UCC, arising from two separate pathways . GEM UCCet al demonstrated that, during the original cloning of this promoter, ~1,500 bp of the UPII promoter region was oppositely inserted between two SacI restriction enzyme sites (from −1262 to −2805 from exon 1)  . Using t disease ,115. ThiGEM models, however, have certain limitations. As a result of the inherent flaws of the mechanism, only a portion of the animals exhibit the desired genotypic traits, and occasionally it cannot be ascertained as to whether the trait is as required, as discussed above. A paucity of models representing the high-grade, muscle-invasive and metastatic form of bladder cancer remains. With target genes switched on or off, GEM is ideal for studying single or multiple gene functions, but any specific model may not fully mirror the genetic alterations in natural human tumorigenesis, which involves the deregulation of multiple signaling pathways. Cancer cells in these models, which have the same or similar origin, tend to be less heterogeneous than human bladder cancer. Therefore, the biological behavior of the cancer may be different from the human case. GEM is usually not applied in testing the efficacy of novel therapeutic or preventive agents. When translating the laboratory findings of certain therapeutic strategies using GEM models, caution is essentially required.In previous years, studies had applied BBN or MNU to GEM to test whether certain genes could facilitate the carcinogenesis process and shorten the long inducing period. P27 knock-out mice are more sensitive to MNU, while Stat3-transgenic mice, Fez1/Lzts1-deficient, Keap1 knock-out and FHIT knock-out mice are more susceptible to BBN ,124–127.Rats and mice, as important tools of study, were often used in setting up bladder cancer models. In a certain type of model, one of the animals may have preference over the other rodent. For studies of carcinogen-induced bladder cancer models, rats are more frequently used than mice, particularly when induced by MNU. By contrast, in studies of genetically modified animal models, the usage of rats is rare.The differences in pathologic structural characteristics between rats and mice have been previously identified . A numbeSince nude mice were identified as a potent tool for establishing xenograft models, mice began to gain more popularity compared to rats. This was aggravated by the emergence of GEM. Mice also have the inherent advantage of smaller size and faster breeding. However, the rat remains noteworthy in areas where its larger body size and physiological similarity to humans are important, including pharmacological studies which test the effects and toxicity of drugs. The genome sequencing study of the rat in 2004  revealedAll the models developed by scientists make an effort to maximize the approximation of reality. Since it is hard to meet with all the standards of an ideal animal model, the objective of the present critical review is not to focus on the weakness of each model, dissert the superiority of one model over another, or prove the insufficient validation of the findings reported by studies using these models, but to offer investigators more information to take into account and select the ideal model that suits the relevant question of interest. Although GEM cancer models have been developing rapidly and showing great potential, they cannot fully take the position of transplantable and carcinogen-induced models. A meta-analysis compared outcomes from autochthonous models and GEMs and revealed that carcinogen-induced tumors showed an improved association with clinical responses .Certain studies recruit more than one type of animal model to enhance its validity and translatability. In an investigation of the chemopreventive and chemotherapeutic effects of silibinin, the heterotopic xenograft and MNU induced models were employed . PerhapsAnimal models of bladder cancer have advanced the understanding of the disease, enabled the exploration of treatment regimens and, ultimately, the translation of preclinical knowledge to improved patient care. Further effort should be devoted to modifying and optimizing these models. Every protocol must be approved by the institutional ethics committee for the use of laboratory animals to protect the welfare of the animals.


Linear growth in the postnatal period is controlled by the production, secretion, and action of pituitary growth hormone and IGF-1. IGF-I and IGF-II production and signaling are also essential for fetal growth and neural development. But the control of IGF production in the fetus is largely independent of GH.Among the factors that control fetal IGF production, the availability and utilization of nutrients is most important. Since fetal nutrient supply ultimately derives from maternal nutrient stores, we can understand fetal growth only through analysis of the factors that control maternal nutrient utilization and transport to the fetus.I will argue that hormones produced by the placenta, including placental lactogen, placental growth hormone, and sex steroids regulate the intake, absorption, utilization and transfer of maternal nutrients to the fetus and modulate fetal and neonatal insulin production. Dysregulation of placental hormone production may be associated with fetal growth retardation or fetal overgrowth and may predispose in later life to glucose intolerance and type 2 diabetes.


Cross-sectional and longitudinal studies exploring clinical, functional, and biological correlates of major depressive disorder are frequent. In this type of research, depression is most commonly defined as a categorical diagnosis based on studies using diagnostic instruments. Given the phenotypic and biological heterogeneity of depression, we chose to focus the phenotypic assessments on three cognitive dimensions of depression including (a) cognitive performance, (b) emotion processing, and (c) social cognitive functioning. Hence, the overall aim of the study is to investigate the long-term clinical course of these cognitive dimensions in depression and its functional  correlates. We also aim to identify biological “genomic” correlates of these three cognitive dimensions of depression. To address the above overall aim, we created the Cognition and Mood Study (CoFaMS) with the key objective to investigate the clinical, functional, and biological correlates of cognitive dimensions of depression by employing a prospective study design and including a healthy control group. The study commenced in April 2015, including patients with a primary diagnosis of a major depressive episode of major depressive disorder or bipolar disorder according to DSM-IV-TR criteria. The assessments cover the three cognitive dimensions of depression , cognitive function screening instrument, plus functional scales to assess general, work place, and psychosocial function, depression symptom scales, and clinical course of illness. Blood is collected for comprehensive genomic discovery analyses of biological correlates of cognitive dimensions of depression. The CoFaM-Study represents an innovative approach focusing on cognitive dimensions of depression and its functional and biological “genomic” correlates. The CoFaMS team welcomes collaborations with both national and international researchers. Diagnostics and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)   within the general population , 3 and i (DSM-5) , and the(ICD-10) , cogniti(ICD-10) , in depr(ICD-10) .Specifically, numerous clinical cross-sectional studies have established that a range of cognitive symptoms occur frequently during the acute state of depression . PatientHowever, cognitive impairment may not only affect the individual’s ability to function during acute episodes of the illness, as a large body of literature now suggests that cognitive dysfunction may continue into and after remission , 29, 30.In addition to the cognitive deficits during acute and remitted stages of major depression, deficits in psychosocial and overall functioning in MDD are well recognized and of clinical importance. A prospective study found that patients with MDD or bipolar depressive episodes had moderate to severe impairments in work and home functioning as well as mildly to moderately impaired relational functioning . While eOverall, the implications of poor cognitive function are far reaching. Research suggests that MDD patients with neuropsychological deficits tend to be less compliant with antidepressant treatment  and showThese cognitive dimensions of depression inherit a number of questions that are clinically important and remain unresolved, such as (A) the longitudinal course of cognitive deficits in MDD, (B) the relationship between cognitive deficits and general functioning, and (C) the question how social cognitive deficits relate to cognitive function deficits in domains, such as memory, attention, and executive function. To address these questions in more depth will help provide an understanding as to the clinical course and etiology of depression, identifying treatment targets of depression more clearly, and will contribute to clinical prevention.via neuroimaging  correlates. In addition, the study aims to identify biological “genomic” correlates of these cognitive dimensions of depression. By taking a prospective approach and by including a healthy control group, the study will increase the understanding of the cognitive dimensions of depression, its biological correlates, and its functional outcomes, etiology, pathophysiology, and state vs. trait characterization.To address the above overall aim, we created the Cognition and Mood Study (CoFaMS) with the key objective to investigate the clinical, functional, and biological correlates of cognitive dimensions of depression by employing a prospective study design and including a healthy control group.Hypothesis 1: Participants with mood disorders have poorer neuropsychological function in the cognitive dimensions of cognitive function, emotion processing, and social cognition compared to healthy matched controls.Hypothesis 2: Participants with mood disorders have poorer quality of life and poorer psychosocial functional outcomes that will correlate with the level of impairment in cognitive dimensions of depression.Hypothesis 3: Participants with mood disorders show a biological genomic “signature” that relates to cognitive dimensions of depression.The key hypotheses and aims of the project are:The outlined study design commenced in April 2015 and includes baseline and follow-up assessments at 6-weeks and 12-months post baseline. The design of the study is prospective in nature and includes a healthy control group. The naturalistic recruitment of patients aged 18 years or above occurs in inpatient and outpatient units through research clinics of the Department of Psychiatry, University of Adelaide and the Eastern, Western, and Northern Mental Health Networks in Adelaide, South Australia. Recruitment may also include the general community through advertisement. Healthy controls are recruited from the same population background as the patients.The inclusion criterion is a current or previous diagnosis of a major depressive episode according to the DSM-IV-TR . PrimaryThe study was approved by the Human Research Ethics Committees at the University of Adelaide  and the Royal Adelaide Hospital Human Research Ethics . Study participants were explained all study details in writing and in person before giving informed consent.All participants are screened for mood symptoms using the MINI600 Neuropsychiatric Diagnostic Interview. All sections of the MINI600 are administered, including Major Depressive Episodes, Manic and Hypomanic Episodes, Psychotic Disorders and Mood Disorders with Psychotic features, Panic Disorder, Alcohol Abuse and Dependence, and Substance Abuse and Dependence. The MINI600 is a well-validated measure with psychometrics showing good to excellent specificity and sensitivity concordance to both the Structured Clinical Interview for the American Psychiatric Association Diagnostic criteria (SCID) and the Composite International Diagnostic Interview (ICD-10) , 54. TheThe Structured Interview Guide of the Hamilton Anxiety and Depression Scale (SIGH-AD)  is adminA psychiatric history checklist is administered to assess information, such as age of onset of illness, number of lifetime episodes of mood disorders, number of hospitalizations, and family history of mental illness.The participants are administered a questionnaire assessing domains of activities in daily living, using the Functioning Assessment Short Test (FAST) , 57. TheA self-made employment questionnaire is administered to the participants. This questionnaire was developed to assess the impact of cognitive problems on employment status and work productivity in individuals suffering from mood disorders. The questionnaire is an interviewer-administered instrument. The studied time frame refers to the current employment status of the participant in the first section and their work productivity over the last 7 days in the second section. It is quick and easy to administer (on average it takes ~5 min) and provides a comprehensive assessment of the impact mood-related cognitive dysfunction has on occupational functioning.Participants are rated on their symptom severity using the Clinical Global Impression Severity Scale (CGI-S) and the Global Assessment of Functioning (GAF). The Clinical Global Impression scale (CGI) is frequently used in clinical research because of its face validity and practicability. The GAF combines the evaluation of symptoms as well as relational, social, and occupational functioning on a single axis. The scale runs from 1 to 100 and is divided into 10 equal parts providing defining characteristics, both symptoms and functioning, for each 10-point interval. A low rating reflects worse symptoms and a poorer level of functioning, whereas a high rating reflects less symptoms and a better level of functioning.The Lifetime Psychotropic Treatment Response scale (LPTR) is a modified scale from the Lithium Lifetime Treatment Response scale (LLTR) . The LPTParticipants will complete a battery of self-report questionnaires using standardized scales designed to assess aspects of emotion processing, stress and maltreatment exposure, perceptions of stress, coping strategies, quality of life, general capacity to function, health service utilization, and health beliefs. All components of the self-report measure are derived from well validated and widely used measures that are available in the public domain. Self-report measures include the Positive and Negative Affect Schedule (PANAS) –64, PercSome participants that will be recruited to the study will have a history of, or are suffering from depression with peripartum onset. These participants, due to their role as mothers of babies and very young children, face specific requirements of daily functioning, which are not well captured in the functioning scales used otherwise in the study. To address this potential gap, female participants with young children aged 0–5 are given the following questionnaires.r = 0.84) and is recommended as a tool for measuring parenting skill  is a self-report 10-item questionnaire that was developed to identify women who have post-partum depression (PPD). Generally, the EPDS  is used – The PEBL (Participants are administered series of computer-based game-like activities using the Psychology Experiment Building Language (PEBL), designed to assess memory and learning, attention, and working memory, executive function, and social cognition. All tests have been psychometrically validated and are used extensively in cognitive function research. The paper–pencil tests include the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) , the comThe PEBL , and theThe PEBL , 87.PEBL  (t (WCST)  is a neuCorsi Block Tapping Test  – has been added to the THINC-it assessment tool .Trail-Making Test B is a neuropsychological test of visual attention and task switching. Participants are instructed to connect a set of 18 dots as fast as possible while still maintaining accuracy. It can provide information about visual search speed, scanning, speed of processing, mental flexibility, as well as executive functioning.The WAIS ACS Social Cognition Test is an integrated test including facial affect, prosody, body language, and mental state interpretation. It has the advantage of a large normative sample of 800 subjects matched to the US census and has been validated with promising results against currently used facial affect recognition tasks in the setting of other psychiatric conditions. It comprised three subtests: affect naming, prosody-face matching, and prosody-pair matching. The subgroups each test a different aspect of social cognition , 87.For later genomic biomarker analyses , peripheral blood will be taken at each time-point of assessment for deriving DNA, RNA, serum, and plasma. The storage of biomaterials is split between different refrigerators, all of which were monitored by a central alert system 24 h/day 7 days/week.The primary goal of all quality assurance measures is to generate high quality data. The CoFaMS standard operations manual contains operating procedures for all CoFaMS interview and examination components. Prior to the beginning of CoFaMS-Baseline, the members of the study team underwent an initial training with follow-up quality checks. Performance is closely monitored and routinely assessed. Data management has been carried out in parallel with data collection, based on standardized and partly automated procedures for data processing and plausibility checking. Data backup routines are scheduled on a daily basis.The primary endpoints of COFaMS are the presence and severity of deficits of the cognitive dimensions of depression namely cognitive function, emotion processing, and social cognition and also include psychosocial and general function, genomic markers, and serum/plasma levels of biomarkers. Secondary outcomes include change in cognitive dimensions and psychosocial function over time and genomic markers and serum/plasma levels of biomarkers in peripheral blood.Depending on the outcome scale level  and time point of assessment (baseline vs. follow-up), the statistical methods comprise multivariable linear or logistic regression analyses, accounting for time-varying predictors and repeated outcome assessment. In addition, genomic marker analyses require specific software suitable for genetic analyses, gene expression analyses, network analyses, proteomics analyses, and other specialized analysis software packages.Depression is a mental disorder that is characterized by a recurrent course of illness in many cases, by clinical and biological heterogeneity contributes largest to the burden of disease. Specifically, depression reduces psychosocial function and work productivity. Among the symptom clusters of depression, cognitive dimensions are prominent and include emotion processing, cognitive function, and social cognition. These cognitive dimensions as key features of depression appear to be relevant for psychosocial function and present as targets of psychological treatment . The CoFaM Study aims to improve the understanding of the clinical, functional, and biological correlates of three cognitive dimensions of depression: emotion processing, cognitive function, and social cognition. Advances in the understanding of these cognitive dimensions are important to identify new treatment targets and to prevent decline in functional capacity. Recruitment of cases and controls of CoFaMS is ongoing. Study recruitment continues until December 2018.First, the CoFaM Study is suited to characterize three major cognitive dimensions of depression with an emphasis on cognitive function, social cognition, and emotion processing in depressed participants compared to healthy controls. The important trait-state characteristics of cognitive symptoms of depression will be addressed since this study includes patients with current, recurrent, and remitted depression cross-sectionally and prospectively. In addition, the included assessment of psychiatric comorbidity, such as anxiety disorders, will enable us to account for the impact of psychiatric comorbidity on cognitive dimensions of depression. A comparison to other mood disorders, such as bipolar disorder, extends this approach.Second, the often observed psychosocial and functional decline and inability to recover after an acute episode of depression to premorbid functioning requires a better understanding of the mediators of functional decline. The CoFaM Study will address this key question by investigating the mediating role of the three cognitive dimensions in functional impairment decline in depression. A possible outcome of this study might be a better understanding of this crucial relationship, and the research might provide new leads into improving psychosocial functioning in the future.Third, the biological correlates and genomic biomarker of depression specifically are lacking in the field. One of the reasons might be the heterogeneity of depression that inhibits a clearer correlation between symptoms of depression and biological correlates. By focusing on cognitive dimensions of depression, it is assumed that cognitive function might more closely correlate with biological markers  than a global syndrome of depression consisting of a variety of symptoms clusters. The CoFaM Study allows for the study of the molecular underpinnings of cognitive dimensions by collecting extensively specimen for genetic, gene expression, epigenomic, sequencing, and serum/plasma analyses.In conclusion, the CoFaM Study represents an innovative approach focusing on cognitive dimensions of depression and its functional and biological “genomic” correlates. The CoFaMS team welcomes collaborations with both national and international researchers.BB conceived the study, supervised its design, the coordination, and execution of the study. BB drafted the manuscript. TA provided specific knowledge to the execution of the study and made substantial contributions to the acquisition of the data. All authors read and approved the final manuscript.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.


In recent decades, thyroid ultrasonography has become one of the most important procedures performed in daily endocrinological practice. This convenient, fast, non-invasive and cheap procedure benefits in many aspects on determination of thyroid morphology.The advantages of thyroid US include measurement of thyroid volume, evaluation of its echogenicity with visualization of parenchyma vascularisation. Also, thyroid ultrasonography is necessary for selection of so-called suspicious features of potential malignancy among thyroid lesions. According to numerous studies, combination of some specific sonographic features indicate higher risk of malignancy, and indicate necessity for fine needle aspiration biopsy (FNAB).Sonographic features of the lesion, that rise the suspision of malignancy include: decreased echogenicity; irregular, diffused boarders; microcalcifications; local limphadenopathy; taller than wide orientation in parenchyma; increased vascular pattern in the center; documented, rapid growth of the lesion -3. Howev. Finally, we analyzed the data of 5439 thyroid lesions. Just like in the paper of Brito, we have revealed the usefulness of some sonographic features in selecting potential malignancies. Both studies revealed significant value of “taller than wide feature” with positive predictive value of 76%. Different, independent features of higher risk of malignancy included hyopoechogenicity, and the presence of microcalcifications. According to both metaanalyzes, the value of Doppler analysis of the nodule vascularisation in prediction of thyroid malignancy, seems doubtful.  . Thus, eRecently sonoelastography has been introduced in endocrinology practice, as an additional tool for ultrasonographic evaluation. This modern, non-invasive method, uses the acoustic radiation force in the assessment of the elasticity of examined tissue. Its value has been previously proven in the diagnosis of non-thyroidal oncologic conditions, such as breast cancer . The firIn 2010 Sebag et al., estimated the accuracy of shear wave elastography in non-invasive diagnosis of thyroid malignancies ,12.The potential of SWE in the diagnosis of thyroid malignancies had also been studied in detail in our center. The paper by Szczepanek-Parulska et al. included 122 patients with multinodular goiter (393 lesions) referred to our clinic prior total thyroidectomy . Before For the malignant lesions, the cut-off value of >50kPa was revealed as the most sensitive . (table) Also SWE was found to be highly effective in the diagnosis of malignant lesions, with the use of quantitative color scale. Other sonographic markers of malignancy appeared to be significantly less accurate. table Another problem in endocrine practice is the issue of the selection of nodules for FNAB in case of multinodular goiter where the amount of lesions can be high and it is not possible to puncture all nodules. Study performed in our department showed that SWE is also valuable tool in the selection of lesions for FNAB . All anaDespite many benefits and high diagnostic value in differentiation of benign and malignant thyroid lesions SWE is not free of limitations. Some features were described as interfering results of sonoelastographic examination and potentially leading to overestimation of the cancer risk. According to the study performed by Bhatia et al.  partialletc.). Also data about usefulness of SWE in case of some particular types of thyroid cancer – such as follicular and medullary TCs are very limited. Altogether, there is still a need for further techniques allowing for more reliable distinction between benign and malignant thyroid nodules as well as further studies on the available techniques.In conclusion, conventional sonographic markers of malignancy seem to be valuable for the preliminary assessment of thyroid nodules; however, these features do not benefit in satisfactory values of sensitivity and specificity. Elastography and particularly SWE seems to be important advance of conventional ultrasonography allowing for the more reliable distinction between benign and malignant thyroid nodules as well as better selection of lesions for FNAB in case of multinodular goiter. However, SWE can be not credible in case of some lesions (e.g. partially cystic, with calcifications,


Recently, compelling evidence reveals that stromal populations, especially the fibroblastic reticular cells (FRC), of the secondary lymphoid organs (SLO) not only serve as structure scaffold for organizing and maintaining the structure of the lymphoid tissues, but also possess crucial functions in immune regulation, including induction of T cell tolerance and the generation of regulator T cells. Interestingly, we and others recently reported that similar lymphoid-like fibroblastic reticular cells also exist within the tumor microenvironment (TME) that facilitates the organization of tumors, as well as the induction of immune tolerance. We showed that those stromal cells augmented the differentiation of myeloid cells, including myeloid derived suppressors (MDSCs). As chronic inflammation plays a vital role in tumor initiation, progression, and metastases, we hypothesized that the crucial functions of these lymphoid-like FRCs in the TME are to induce immunotolerance and promote chronic inflammation, thereby promoting tumor progression. In this study, we examined the cellular and molecular characteristics of these FRCs and revealed their heterogeneity both at cellular and molecular levels. Interestingly, some of their properties appear to be intrinsic, not easily altered by the milieu they reside. Functionally, these FRCs provide crucial signals for the survival, differentiation, and tolerogenic phenotype of myeloid cells, including MDSC, dendritic cells, and macrophages. We are currently in the process of elucidating the molecular mechanism by which these FRCs induce tolerogenic myeloid populations. Our better understanding of the immune modulatory function and specific mechanisms of these FRCs, both within the lymphoid tissues and TME, will provide valuable information for the development of novel immunotherapy regimens to improve therapeutic outcome by combining active immunotherapy and the ultimate reversal of tumor-induced immunotolerance.Supported by 01CA169133 from NCI/NIH and funds from GRU Cancer Center to YC.