One Health” approach, public health education, and some measures that can be taken to prevent zoonotic bacterial infections are discussed.An infectious disease that is transmitted from animals to humans, sometimes by a vector, is called zoonosis. The focus of this review article is on the most common emerging and re-emerging bacterial zoonotic diseases. The role of “Key points:A zoonotic bacterial disease is a disease that can be very commonly transmitted between animals and humans. Global climate changes, overuse of antimicrobials in medicine, more intensified farm settings, and closer interactions with animals facilitate emergence or re-emergence of bacterial zoonotic infections.One Health” approach, which requires interdisciplinary collaborations and communications in all aspects of health care for humans, animals, and the environment, will support public health in general.The global “New strategies for continuous dissemination of multidisciplinary research findings related to zoonotic bacterial diseases are hence needed. One Health” approach, which dates back to ancient times of Hippocrates  TheBacterial zoonotic infections are one of the zoonotic diseases, which can, in particular, re-emerge after they are considered to be eradicated or under control. The development of antimicrobial resistance due to over-/misuse of antibiotics is also a globally increasing public health problem. These diseases have a negative impact on travel, commerce, and economies worldwide. In most industrialized countries, antibiotic resistant zoonotic bacterial diseases are of particular importance for at-risk groups such as young, old, pregnant, and immune-compromised individuals .Almost 100 years ago, prior to application of hygiene rules and discovery of neither vaccines nor antibiotics, some bacterial zoonotic diseases such as bovine tuberculosis, bubonic plague, and glanders caused millions of human deaths. The spread and importance of some bacterial zoonoses are currently globally increasing. That is precisely why most of the developing countries are sparing more resources for a better screening of animal products and bacterial reservoirs or vectors for an optimal preventative public health service .Improvements in surveillance and diagnostics have caused increased recognition of emerging zoonotic diseases. Herein, changes in our lifestyles and closer contacts with animals have escalated or caused the re-emergence of some bacterial infections. Some studies lately have revealed that people have never been exposed to bacterial zoonotic infection risks as high as this before . It is pPeople who have closer contact with large numbers of animals such as farmers, abattoir workers, zoo/pet-shop workers, and veterinarians are at a higher risk of contracting a zoonotic disease. Members of the wider community are also at risk from those zoonoses that can be transmitted by family pets.The immune-suppressed people are especially at high risk for infection with zoonotic bacterial diseases. People can be either temporarily immuno-suppressed owing to pregnancy, infant age, or long-term immuno-suppressed as a result of cancer treatment or organ transplant, diabetes, alcoholism or an infectious disease .This manuscript reviews the most common bacterial zoonoses and practical control measures against them.Companion animals are increasingly treated as family members, and pets have many bacteria that may infect their owners. The human population of the European Union (EU) was approximately 500 millionPasteurella sp. , alpha-hemolytic Streptococcus (46%), Staphylococcus (46%), Neisseria (32%), and Corynebacterium (12%). However, following anaerobic bacteria are also isolated from infected wounds: Fusobacterium nucleatum (16%), Prevotella heparinolytica (14%), Propionibacterium acnes (14%), Prevotella intermedia (8%), and Peptostreptococcus anaerobius (8%)  .Normal human skin bacteria or other environmental microorganisms are scarcely isolated from infected wounds in bitten person –24. UsuaBartonella henselae, which was transmitted by cat scratches and bites, was only identified in 1992  and psittaciformes  are a small fraction of adopted pets, they are widely popular in Europe and they are potential carriers of zoonotic diseases . Some ofo humans , 40. TheStaphylococcus aureus (MRSA) or extended-spectrum beta-lactamases (ESBL) producing Enterobacteriaceae, which are known as nosocomial infections have been frequently isolated in companion animals  living on farms in Europe (see text footnote 1). It has been demonstrated that farm animals are reservoirs of many zoonotic pathogens to humans , 43. HowSalmonella, Campylobacter, Shigella, Yersinia, Listeria, and Enterococcus genera, as well as the E. coli species. These zoonotic bacterial organisms are propagated primarily among animals and subsequently infect people  has been identified worldwide. Thanks to decades of disease control measures that the occurrence of the infection has been greatly reduced. But there are still hundreds of new cases of human tuberculosis reported in the USA   . The inf (<5 km) .In the EU, many vector-borne zoonotic diseases are considered as emerging infectious diseases, which either appear in a population for the first time or may have existed previously but spreading rapidly. The ecology of vector-borne zoonotic bacterial diseases is complex where climate and weather may influence the transmission cycles. Milder winters, earlier start of spring or long intervals between winters cause extended seasonal tick activity and hence pathogen transmission between hosts in new regions of the world , 73. ManRickettsiae spp., Anaplasma phagocytophilum, Borrelia burgdorferi, Bartonella spp., and Francisella tularensis  and Lyme disease (Borrelia burgdorferi) have emerged as an important vector-borne zoonotic disease since 1980s , which is usually used to obtain a better cosmetic result might be needed to remove biofilm formed bite infections. This mechanical debridement is essential in the eradication of a wound biofilm. Antimicrobials may be more effective in the treatment of the wound after debridement in the prevention of biofilm reformation. Despite the use of currently optimal culturing methods, approximately 7% of infected wounds yield no bacterial growth. In such cases, some other fastidious pathogens, i.e., Chlamydia spp., Mycoplasma spp., and even viruses should be investigated. New advanced molecular diagnostic techniques are needed. Prevention strategies for animal bites include close supervision of child–animal interactions, stronger animal control laws, better reporting of animal bites, and public education for better ownership of pets. Regular nail trimming, routine oral examinations under annual health checks and comprehensive dental treatments of the companion animals  by veterinarians will reduce the bacterial mass exposure to humans in case of direct contacts or animal bites.Animal bite injuries in daily human-animal contact are not surprising, especially for the school-aged children. Most of these wounds are medicated by patients as first aid and not registered in health systems. In more developed countries, most of the victims with moderate to severe bite injuries will seek professional medical treatment. Regardless, all bites should be treated as serious, especially if the skin is broken. Prompt diagnostic and treatment can prevent wound complications. The possibility to form biofilms by previously mentioned wound microorganisms is quite high, may cause severe tissue damage and protect the bacteria from innate-immune response and antimicrobials. The most of the commercial topical agents and wound dressings are ineffective against the biofilm matrix. Surgical repair  rather than antibiotics solely. Herein, pet specific auto-immune vaccines against allergens and auto-Lactobacillales  as dietary supplements can also be more frequently administered within the preventative veterinary practice measures. Owners should be encouraged to insure their family animals to afford such costly veterinary services contradictory to the cheaper and sometimes life-long medical  treatment demanding options. Veterinarians should also spear more time to educate the pet owners under consultations to handle infected-antimicrobial treated animals with precaution due to irreversible consequences of the antimicrobial resistance development and its spread in households. Proper hand washing and use of gloves are strictly recommended while handling antimicrobial in veterinary clinics. Veterinarians should prescribe broad spectrum and synthetic antimicrobials preferably after culturing with extreme precautions . Reduced antibiotic use will hinder the development of antibiotic resistance in animal microbiota which might cause zoonotic infections in humans , 52.One Health.” Herein, control of the production stress especially in intensive livestock industry, with the development of better animal health management routines  and the increased animal welfare programs, will contribute eventually to an optimal production of animal health. Increased antimicrobial resistance among emerging and re-emerging farm-borne bacterial pathogens in crowded settings  is a growing problem. Restrictive antimicrobial choice with better animal welfare managements are needed to control the spread of antibiotic resistance elements.Food-borne zoonoses are an important public health concern worldwide and every year a large number of people affected by diseases due to contaminated animal originated food consumption. Food hygiene education of the consumers is an important competent of food-borne diseases prevention. However, main prevention of food-borne zoonoses must begin at the farm level with in the concept of “In the EU, the use of avoparcin was banned in 1997 and the use of spiramycin, tylosin, and virginiamycin for growth promotion were banned in 1998. All other growth promoters used in feeding of food producing animals were banned from January 1, 2006 after a few national bans the years aheadVector-borne and zoonotic bacterial pathogens are a major source of emerging diseases, and since the time of Hippocrates, weather and climate are linked to the incidence of such infectious diseases. Complexity of epidemiology and adoptive capacity of microorganisms and the arthropods make the vector-borne disease almost impossible to eradicate. Insect repellants, routine tick checks after outdoor activity in risk regions, prompt-proper tick removal, use of long sleeves and trousers (light-colored), and routine insecticide treatment of pets are recommended as general preventative measures . Herein,One Health” approach, which demands combined efforts of physicians, veterinarians, epidemiologists, public health workers, and urban planners. Collaborative international routine surveillance strategies, prompt – reliable agent identification techniques, and optimization of the treatment regiments will ensure the prevention and management of such infections.Identification and control of emergent zoonotic bacterial diseases require a “Leon Cantas defined the review theme, manuscript design, established the coordination and the collaborations, designed the manuscript, contributed to the data collection, data analysis, and drafting, writing and editing of the manuscript. Kaya Suer contributed to drafting and editing of the manuscript. All authors have seen, and approved the 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.


Renal replacement therapies (RRTs) represent a cornerstone in the management of severe acute kidney injury. This area of intensive care and nephrology has undergone significant improvement and evolution in recent years. Continuous RRTs have been a major focus of new technological and treatment strategies. RRT is being used increasingly in the intensive care unit, not only for renal indications but also for other organ-supportive strategies. Several aspects related to RRT are now well established, but others remain controversial. In this review, we review the available RRT modalities, covering technical and clinical aspects. We discuss several controversial issues, provide some practical recommendations, and where possible suggest a research agenda for the future. Acute kidney injury (AKI) is common in critically ill patients and is associated with high mortality and morbidity . In patiThe aim of this review is to present a multidimensional update of RRT in AKI with a focus on mechanisms and modalities, anticoagulation, and extended indications. The topics of plasmapheresis and RRT during extracorporeal membrane oxygenation will not be covered in this review.Current RRT machines present multiple integrated components, including four- to five-roller pumps, three to four integrated scales, four to five pressure pods, reliable air detection, integrated pumps for heparin or citrate/calcium infusion, ultrafiltration, and various safety alarms. Considerable effort has gone into providing a user-friendly interface, limited error ranges, and possibility for data download/integration to electronic health records. New machines are often more a platform for multiple techniques than a simple dialysis monitor.Extracorporeal therapies are now exclusively delivered through double-lumen venous catheters. With few exceptions, blood flow is ensured by a peristaltic roller pump. Circuit pressures are constantly monitored in every part of the circuit . Furthermore, pressure drop and transmembrane pressures are calculated by the machine in order to monitor the filter clotting process. The most important aspect of filter patency is the process of concentration polarization, which is the accumulation of particles (mostly of protein nature) in the inner part of the hollow fiber that leads to a progressive decrease in membrane permeability and performance ,4. PossiVascular access is a particularly important determinant of the quality of RRT . A largeHemofiltration (HF) is a process that parallels what occurs in the human glomerulus . The tubFluid overload is associated with adverse outcomes in critical illness  and ofteThe timing of initiation of RRT remains controversial. It is clear that derangements of, for example, potassium, acid–base balance, pronounced azotemia, and fluid overload , early post hoc analyses [a priori at what level of fluid gain RRT should be started or the net ultrafiltration rate that should be prescribed; these factors should be tailored according to individual patient requirements.Interestingly, fluid overload may be a major outcome determinant for critically ill patients with AKI at continuous renal replacement therapy (CRRT) start ; it is panalyses , so thatThere is an even greater paucity of data on when to stop CRRT. RRT can be stopped when there is sufficient improvement in renal function, but how this can be evaluated while the patient is still receiving RRT remains unclear. Current practice suggests measuring urine output and serum creatinine levels while on a constant dose of CRRT and calculating the endogenous creatinine clearance by using both the urine and serum concentrations of creatinine. Decisions to delay or stop the next RRT session may be easier for intermittent treatments. Observational studies have shown that the most significant predictor of successful termination of CRRT is urine output . A urineIntermittent hemodialysis (IHD) was originally conceived as a treatment for acute renal failure, and CRRT was introduced as an alternative when IHD was contraindicated. Subsequently, CRRT has become a routine therapy for AKI in many countries but may not be available in some resource-limited settings. Intermittent therapy has advantages in facilitating rehabilitation and other aspects of therapy for some patients. However, when applied correctly, both continuous and intermittent modalities can achieve a satisfactory degree of metabolic control in most patients, and randomized controlled trials (RCTs) and meta-analyses have not shown a difference between modalities in terms of patient survival rates. The reasons for this lack of evidence may still lie in the selection of patients for the study populations, with many of the most severely ill patients excluded. Importantly, a systematic analysis of RRT modality and its effect on renal recovery from dialysis dependence in critically ill patients found that CRRT was associated with a higher rate of renal recovery compared with IHD , suggestVarious ‘hybrid therapies’ ,36 or ‘pThe dose of RRT is equivalent to the normalized dose of therapy delivered to the patient. In the past, RRT was largely under-dosed in critically ill patients. However, since the milestone trial by the group of Vicenza in 2000 , a dose Two large multicenter RCTs, the Randomized Evaluation of Normal versus Augmented Level of Renal Replacement (RENAL) and ATN studies ,43, showIn patients who had higher day 1 concentrations of plasma inflammatory mediators, intensive RRT was associated with reduced levels over the first week but no significant effect on renal recovery or mortality . HoweverThe increased solute clearance achieved by CRRT may cause unwanted losses of amino acids, vitamins, catecholamines, and other compounds . Severe Sufficient anticoagulation, without excessive risk of bleeding, is generally required to maintain filter and circuit patency in RRT. Although the precise definition of adequate filter patency is a matter of debate, most available membranes will have significant protein concentration polarization and pore fouling after 20 to 24 hours. Point-of-care (POC) techniques of coagulation - for example, rotational thromboelastometry and thromboelastography - are increasingly being used for rapid specific testing of hemostatic function in critically ill patients and during anesthesia with important clinical benefits . NeverthUnfractionated heparin (UFH) is still the most widely used anticoagulant . The majLow-molecular-weight heparins (LMWHs) have several advantages over UFH, including a lower incidence of HIT, less affinity for antithrombin, less platelet (and polymorphonuclear cell) activation, less inactivation by platelet factor-4, greater and more consistent bioavailability, and no metabolic side effects . HoweverThe complications associated with systemic heparin administration stimulated interest in regional anticoagulation techniques and especially regional citrate anticoagulation (RCA) -64. SodiCompared with systemic heparin, RCA has been associated with less bleeding, increased filter lifespan, and reduced transfusion rates and need for antithrombin III/platelet supplementation -67. RCA Although KDIGO  guidelines suggest that citrate be used for all patients without contraindications and heparin for other patients , some prEarly and adequate antibiotic therapy is crucial in critically ill patients with signs and symptoms of infection. AKI alters antibiotic elimination, leading to drug accumulation , and theCytokines and other inflammatory mediators contribute to the pathogenesis of septic shock and sepsis-associated AKI . Howeverex vivo experiments, animal experiments, and preliminary clinical studies [Standard filtration or dialysis membranes - even when used with high-volume HF - have demonstrated only limited effectiveness in removing cytokines, the vast majority of which are water-soluble and of mid-range molecular weight (5 to 51 kDa) . This is studies ,87. More studies . This teIt has been suggested that by separating the plasma so that cells do not come into contact with the sorbent, a system would need to be less hemocompatible but could be more effective. Coupled plasma filtration and adsorption (CPFA) separates plasma from blood by means of a plasma filter. The plasma is then passed through a synthetic resin cartridge for adsorption and returned to the blood. Unlike standard RRT, adsorption is very effective in removing large solutes. Once the blood has been reconstituted, a second blood filter can be used to remove excess fluid and small-molecular-weight toxins. CPFA and CRRT then can operate in series. A pilot clinical study using CPFA in sepsis demonstrated a marked resolution of immunoparalysis with function of circulating leukocytes restored to normal . A recenPolymyxin B hemoperfusion has been shown to decrease macrophage and monocyte activity and to inactivate circulating pro-apoptotic factors potentially involved in the pathogenic mechanisms of sepsis-associated AKI ,92. A syPatients with cardiac failure have reduced cardiac output and arterial underfilling but also venous congestion. Both of these aspects may cause AKI by reducing renal perfusion pressure ,97. Mech2 removal techniques may help to re-establish acid–base homeostasis and reduce vasopressor demands as well as ventilation pressures. Though not as effective as extracorporeal membrane oxygenation, extracorporeal CO2 removal in series with CRRT may contribute to further reduce tidal volumes (ultraprotective ventilation) or even help to avoid intubation [Respiratory failure is frequently associated with impaired renal function. Reduced cardiac output because of increased thoracic pressure results in activation of volume regulation characterized by sodium and water retention as well as reduced renal blood flow . Fluid rtubation ,106.2 production and thus brain CO2 partial pressure, with cerebral vasodilation and risk of increased ICP.AKI occurs in 8% to 23% of patients with acute brain injury and is an independent predictor of poor outcome in these patients ,108. AKICRRT should be the first option in these patients because it is associated with less increase in ICP compared with intermittent therapies . CRRT isCritically ill patients often develop multiple organ dysfunction. New extracorporeal therapies are being designed to provide supportive treatment beyond the classic renal indications. In the near future, technical developments in extracorporeal devices will lead to the creation of multiple organ support therapies, so that comprehensive replacement or at least support can be provided to multiple organs simultaneously. New machines already include multiple platforms in which different circuits and filters can be used in combination to support renal, heart, liver, and lung function. Such machines ideally will be able to automatically detect both ‘traditional’ (urea) and ‘inflammatory’ (cytokines) solutes in plasma of critically ill patients in order to automatically  tailor the therapy toward the ‘perfect blood purification’ system Figure . Along w


Cardiovascular magnetic resonance (CMR) imaging is unsurpassed in theevaluation of myocardial anatomy, function and mass. Myocardial perfusionpre- and post-stress, as well as late enhancement is increasingly used inthe work-up for ischaemic heart disease, especially in establishing thepresence of myocardial viability. Late enhancement patterns can contributesubstantially to the diagnosis of myocarditis and various cardiomyopathiesas well as infiltrative diseases and tumours. With their high incidence ofcardiovascular disease, patients on the African continent could potentiallybenefit enormously from the proper utilisation of this exciting, continuallyevolving and versatile technique, via thorough didactic and clinicaltraining as well as interdisciplinary co-operation. The quality of CMR imaging has consequently improved dramatically since the first MRimages of the human heart were described more than 20 years ago, and it is stilladvancing apace. CMR now represents one of the most versatile, non-invasive imagingmodalities available, offering high spatial resolution and image contrast along withtissue characterisation and haemodynamic assessment, without applying ionisingradiation, and with complete multiplanar coverage of the heart.Good communication between the referring physician and the CMR specialist isparamount to streamline the type and order of sequences required for each particularscenario. Although new sequences are constantly being developed, the basicprinciples of CMR remain unaltered, as follows.Each examination starts with a series of scout views performed on each patient toestablish the short- and long-axis views of the heart. These act as localisers inplanning the rest of the study. The pulse sequences used for scouting are based onsteady-state free-precession (SSFP). Typically, 27 scout images are acquired todefine the thoracic contents, including nine parallel images in each of the axial,coronal and sagittal planes.To assess anatomy and morphology, static images are required. Black-blood imaging isusually preferred because it allows clear distinguishing of the inner portion of thevessel or myocardium from blood. Half-Fourier single-shot fast-spin echo (HASTE) isa special variant of the fast-spin echo sequences, and ideal for delineation ofanatomy. Anatomical and morphological information is particularly important in thediagnosis of congenital abnormalities and cardiac tumours.Dynamic ciné CMR white blood imaging is used for global and regional left ventricular(LV) and right ventricular (RV) wall motion assessment as well as ventricularvolume, ejection fraction and mass measurements. It is now widely regarded as thegold standard.During perfusion scanning, a movie of the wash-in of gadolinium-based contrastthrough the myocardium is obtained . The gradientecho (GRE) pulse sequence is most commonly used nowadays to visualise perfusion ofthe myocardium at rest or during adenosine stress testing. Perfusion defects appearas dark regions surrounded by bright contrastenhanced, normally perfused myocardium.CMR perfusion is playing an increasingly important diagnostic role in ischaemicheart disease.Myocardial oedema is associated with prolonged magnetic resonance relaxation time onT2-weighted pulse sequences. Static dark blood images of the myocardium can beobtained, confirming the presence or absence of oedema, which manifests as brightareas among the normal darker myocardium.LGE images are acquired with an inversion recovery-prepared GRE or SSFP imaging pulsesequences, with images acquired 10–15 minutes following gadolinium (Gd) chelatecontrast administration. Gd circulates in the extracellular space and is excluded byintact myocardial cell membranes. They accumulate in areas of abnormal myocardium,resulting in T1 shortening manifesting as higher signal intensity on T1-weightedimages. Gd migrates through damaged myocitic membranes into the cells  or accumulates in the enlarged interstitialspace (in the case of scar tissue).The goal of LGE imaging is to create images with high contrast between thehyper-enhanced, damaged, fibrotic or non-viable tissue and the normal myocardium.LGE patterns play an important role in viability assessment during acute or chronicmyocardial infarction as well as in the setting of non-ischaemic cardiomyopathiesand cardiac tumours.Velocity-encoded (VENC) CMR imaging of blood flow is usually performed to measurevelocity in the arteries, veins and across valves or shunts. With VENC CMR, a cinéseries of greyscale images reflecting flow during the cardiac cycle is acquired. Thegrey level is proportional to the velocity of blood into or out of the measuredplane. VENC CMR allows quantification of valvular stenosis or regurgitation and isused in the assessment of valvular pathology.CMR plays an increasingly important role in cardiovascular pathology, as follows.In the event of an acute myocardial infarct, myocardial oedema can be seen on T2sequences as early as 30 minutes after the onset of ischaemia.2There is excellent correlation between the area at risk (AAR) measured by T2-weightedimaging and the angiographic APPROACH score, which is an anatomically andprognostically validated measure of the extent of myocardial jeopardy.7LGE plays an important diagnostic and prognostic role in patients with ischaemicheart disease.11et al.,13According to a recent study by Desjardins The absence of contrast enhancement during the first two minutes after contrastinjection in the centre of an area of infarction that may persist on the LGE imagespoints to microvascular obstruction, which is associated with a worse prognosis andoutcome.16Adenosine perfusion CMR has a high diagnostic accuracy in detecting coronary arterystenosis in patients with suspected coronary artery disease (CAD).20Adenosine perfusion CMR provides excellent risk stratification and intermediate-termprognostic value in patients with stable CAD.23Several different methods of assessing myocardial viability are available in thediagnostic armamentarium. Viability tests have become a crucial tool in evaluatingwhether patients with congestive cardiac failure related to CAD might benefit fromrevascularisation therapy.26et al.Allman • resting LV wall end-diastolic wall thickness (> 5 mm regarded asviable)28• low-dose dobutamine (LDD) stress assessment of contractile reserve29• LGE of non-viable scar tissue.30According to a recent meta-analysis, LGE CMR provides the highest sensitivity andnegative predictive value among the three methods. LDD CMR, however, has the highestspecificity and PPV.32Cardiovascular MRI provides a unique tool to assess multiple interrelated clinicalmarkers of viability in a single test.CMR is fast becoming an invaluable tool in the assessment of cardiomyopathies.Regional and global myocardial function can be assessed, and its unique capabilityto visualise the apex and lateral wall supersedes all other imaging modalities. Itis also unique in being able to perform tissue characterisation and to suppress fat,which, combined with LGE, assists in differentiating between various forms ofcardiomyopathy Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden death in youngpeople. The majority of HCM patients with sudden cardiac death have few or noclinical symptoms.34Circulation in 2010, MRIfindings now fall under the major and minor criteria.40According to a recent meta-analysis, the presence of LGE can predict a higher riskfor sudden cardiac death (SCD) and heart failure in patients with HCM, therebyidentifying patients who would benefit from ICD placement.Albeit non-specific, CMR findings in ARVD include fatty infiltration of the RV wall,dilatation of the RV, regional or global RV dyskinesis and patchy areas of LGE inthe RV wall mainly. CMR shows a characteristic pattern of global sub-endocardiallateenhancement as well as abnormal myocardial and blood-pool kinetics in patients withcardiac amyloidosis.43Endomyocardial biopsy (EMB) is considered to be the gold standard for the diagnosisof myocarditis. Recently, CMR has emerged as a promising non-invasive alternative.Three CMR techniques are applied in myocarditis:• LGE sequences for detection of myocardial necrosis/fibrosis• T2-weighted images for assessment of myocardial oedema44• T1-weighted sequences before and after contrast injection for the detectionof myocardial hyperaemia.The Lake Louise criteria for CMR diagnosis of myocarditis state that CMR findings areconsistent with myocarditis if two out of three of the above criteria are found tobe positive.46CMR is emerging as a most useful tool in the assessment of the pericardium. CMR,owing to its excellent resolution, can comprehensively assess pericardial anatomy.Through evaluation of regional myocardial deformation, ventricular interaction andvenous return, CMR can also assess the physiological consequences of pericardialconstriction. Owing to its combined anatomical and functional capabilities, CMR is aunique tool that enables one to distinguish between restrictive cardiomyopathy andconstrictive pericarditis.Echocardiography is the primary diagnostic tool for the assessment of congenitalheart disease but CMR can provide valuable information to confirm uncertaindiagnoses. The large field of view allows assessment of the anatomical relationshipsbetween cardiac and vascular structures.Although echocardiography remains the initial tool for assessing cardiac valves, CMRcan provide similar information in patients with sub-optimal or unsatisfactoryechocardiographic examination.The goal of CMR for assessing cardiac and paracardiac masses includes confirming orexcluding a mass suspected by X-ray or echocardiography, assessing its location,mobility and relationship to surrounding tissues, and imaging the degree ofvascularity; and distinguishing solid lesions from fluid and determining tissuecharacteristics as well as the specific nature of a mass. Owing to its excellentresolution, tissue characterisation and multiplanar approach, the extent of intra-or pericardial mass lesions can be clearly visualised. The additional administrationof gadolinium contrast agents can assess vascularity and help to differentiatetumour from thrombus.et al.49There has been continuous improvement in image quality and examination time incoronary artery imaging with CMR. Hamden Imaging speed is likely to continue to increase and larger and larger imaging volumeswill become accessible at any given spatial and temporal resolution. The ability toaccurately assess total scar burden via T1 mapping could provide a more objectivemethod of non-invasively quantifying diffuse myocardial fibrosis, as recent studieshave validated this method in various myocardial diseases.51Quantitative analysis of perfusion studies will become easier and more applicable inthe clinical setting. Myocardial tagging, enabling the CMR specialist to quantifydiastolic wall motion will probably move from the research environment into clinicalpractice. Although coronary artery imaging via CMR is still in its infancy, theimaging of carotid plaque composition looks promising, especially in evaluating theresponse to lipid-lowering drugs.CMR is a unique, versatile, rapidly evolving, non-invasive diagnostic tool offeringcomplete coverage of the heart, and is independent of chest wall anatomy. Owing toits excellent resolution, interstudy reproducibility, user independence and absenceof radiation exposure, it is bound to play an increasingly important role in cardiacimaging.CMR is regarded as the gold standard for evaluating ventricular function, because ofits reproducibility and validated assessment of ventricular size, function and massof both the left and right ventricles. CMR plays an increasingly important role inthe work-up of ischaemic heart disease as well as the non-ischaemiccardiomyopathies. Owing to the versatility and multitude of possible sequences, itis necessary to assemble lists of sequences into protocols that are specificallytailored to diagnostic questions or scenarios, in order to decrease scan time, andstreamline and simplify the technique.


Microbes are vital to the functioning of multicellular organisms. This realisation has fuelled great interest in the effects of microbes on the health of plant –3 and anHyperparasitism or predation: Microbes can parasitise or predate upon the parasite [parasite .Interference competition: Microbes can produce toxic compounds, such as antibiotics or bacteriocins, that may either kill the parasite or reduce its growth rate [wth rate –42.Resource competition: Microbes can compete with parasites for host resources [esources ,42, usuaesources ,41.Host immune-mediation: Microbes can elicit a host immune response to which the parasite is not resistant [esistant ,42.Host tolerance-mediation: Microbes can increase the fitness of their host during infection without reducing the fitness of the parasite by enhancing host tolerance  [ repair) ,44.Despite the impact defensive microbes can have on host and parasite fitness, our current perspective of host–parasite evolution is largely based upon pairwise species interactions . By combMicrobes can be an evolvable component of host defence . Given tWolbachia in Streptomyces bacteria to ensure continued defence [Microbe-mediated defence is hypothesised to evolve from two sources of selection . Firstly defence . Alterna defence ,47  testing for signals of selection at the molecular level , (2) ide elegans , in whic elegans –21. In t defence ,19 is as defence , indicat defence . Consist defence .Given that defensive microbes protect hosts from parasite-induced fitness costs, they could reduce selection for costly immune-based or behavioural-based host defence mechanisms . Unless Trachymyrmex ant populations that harbour protective antibiotic-producing bacteria exhibit significantly reduced cleaning behaviour than populations without the bacteria [C. elegans [Drosophila melanogaster [Phylogenetic comparisons can be used to test the hypothesis that defensive microbes remove selection for host-based defences. Here, the innate resistance of host populations that harbour defensive microbes can be compared with those that do not. We can predict that host populations associating with defensive microbes should have a lower innate resistance to parasites. In support of this prediction, natural bacteria . The inn elegans  or Drosonogaster , would fParasite virulence is defined as the infection-induced decrease in host fitness  and is aThe extent to which defensive microbes might affect parasite virulence evolution is of concern in the application of microbe-mediated disease control strategies . If micrWolbachia are bacteria that live within the cells of 60%–70% of insect species and can spread vertically via manipulating host reproduction [Wolbachia strains isolated from Drosophila, wMelPop and wMel, have been found to reduce the infection load of a range of human parasites, including dengue virus, malaria, yellow fever, chikungunya, West Nile virus, and filarial nematodes, when introduced into the novel hosts Aedes aegypti and Anopheles gambiae [Wolbachia to halt disease transmission [Wolbachia within mosquitoes [Wolbachia combinations and over evolutionary time [Wolbachia-infected mosquitoes into natural populations have so far resulted in the successful spread of the wMel strain [oduction . Two Wol gambiae –68. Conssmission ,61. It hsquitoes ,69–71; hary time . Trial il strain ,74.Wolbachia as a disease control strategy [Wolbachia could constrain its evolution will indicate the potential for Wolbachia–parasite coevolution and so persistent disease control. Secondly, identifying the mechanism of protection will be vital in predicting whether Wolbachia will drive the evolution of mosquito dependence on microbe-mediated defence; if protection is indeed dominated by host immune mediation, Wolbachia may not remove the selection pressure for mosquito defences. Finally, characterising the mechanism(s) of Wolbachia-mediated defence will be important in predicting whether Wolbachia will select for changes in parasite virulence [More information will be critical to predicting the long-term efficacy of strategy . Specifiirulence .Research into the human microbiome has uncovered information regarding microbe-mediated host defence and has highlighted promising routes for disease control . TreatmeDespite growing interest in the manipulation of the human microbiome to prevent or cure infectious disease, the evolutionary implications have been largely overlooked. Recent theory has shown that microbiome engineering could lead to the evolution of increased parasite virulence . This prDefensive microbes are abundant in nature and have important fitness consequences for hosts and their parasites. By considering defensive microbes in the light of evolution, we can identify traits that enable their coevolution with parasites and reveal their impacts on the evolution of host-based resistance and parasite virulence. Such information will help us to choose defensive microbes for optimal disease control. Ultimately, by combining our understanding of defensive microbes at the mechanistic level with current evolutionary theory, we will be better able to predict the role of defensive microbes in driving host and parasite evolution in nature and in the context of disease control.


Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are increasingly common cause of chronic liver disease worldwide. The diagnosis of NASH is challenging as most affected patients are symptom-free and the role of routine screening is not clearly established. Most patients with severe obesity who undergo bariatric surgery have NAFLD, which is associated insulin resistance, type 2 diabetes mellitus (T2DM), hypertension, and obesity-related dyslipidemia. The effective treatment for NAFLD is weight reduction through lifestyle modifications, antiobesity medication, or bariatric surgery. Among these treatments, bariatric surgery is the most reliable method for achieving substantial, sustained weight loss. This procedure is safe when performed by a skilled surgeon, and the benefits include reduced weight, improved quality of life, decreased obesity-related comorbidities, and increased life expectancy. Further research is urgently needed to determine the best use of bariatric surgery with NAFLD patients at high risk of developing liver cirrhosis and its role in modulating complications of NAFLD, such as T2DM and cardiovascular disease. The current evidence suggests that bariatric surgery for patients with severe obesity decreases the grade of steatosis, hepatic inflammation, and fibrosis. However, further long-term studies are required to confirm the true effects before recommending bariatric surgery as a potential treatment for NASH. In recent years, the obese population has been rapidly increasing because of increases in diets rich in saturated fat and processed carbohydrates and sedentary lifestyles. The metabolic syndromes that are considered risk factors of arteriosclerotic diseases, such as abnormal glucose tolerance, hyperlipemia, and hypertension, have increased alongside obesity in the developed world . Non-alcNon-alcoholic fatty liver disease is the most common cause of liver dysfunction worldwide, and obesity is a well-documented risk factor for the disease. It is highest in populations with preexisting metabolic conditions, such as obesity, T2DM, and dyslipidemia . NASH isPerioperative liver biopsy in patients with severe obesity can result in complications, such as bleeding and sampling error, making exact diagnosis difficult to achieve. Among patients with severe obesity undergoing bariatric surgery, the prevalence of NAFLD can exceed 90%, and up to 5% of these patients may have unsuspected cirrhosis. Bariatric surgery can improve obesity-related diseases in addition to reducing body weight; as a result, it has more recently been termed “metabolic surgery.”We conducted a literature review using the Medline database. We identified studies conducted between 1995 and 2014 that examined the impact of bariatric surgery on NAFLD. This review evaluates the benefits and potential treatment option of bariatric surgical procedures for NAFLD as described in the literature.Past studies investigating lifestyle changes, such as diet, exercise, and behavior modification that resulted in weight loss of 5–10%, have shown that these changes can improve steatosis in some patients , 9. GreaAlthough no drugs are specifically licensed for the treatment of NAFLD, there is evidence to support the use of selected agents. Antiobesity medications such as orlistat, and drugs that augment insulin sensitivity and reduce plasma glucose concentrations and oxidative stress such as thiazolidinediones and metformin are among those that have been shown to improve liver histology in NAFLD –14. OrliIt is thought that GLP-1 receptor agonists work toward improvement of insulin resistance because not only can they improve the effect of insulin secretion but can also promote glucose uptake by the liver, adipose tissue, and skeletal muscle . Many stThe goal of bariatric surgery is not only to achieve satisfactory weight loss but also to obtain improvements in obesity-related comorbidities, including T2DM, obstructive sleep apnea syndrome, hyperlipidemia, and hypertension. However, no randomized controlled trials examining the effects of bariatric surgery on NAFLD were found in the literature search. Two meta-analyses evaluated the effect of bariatric surgery on the liver histology of patients with NAFLD , 23. MumBariatric surgery has a positive effect on obesity-related diseases in addition to reducing body weight. Because of this, it has been more recently termed metabolic surgery. Roux-en-Y gastric bypass (RYGB) has a reportedly greater positive effect on T2DM than restrictive procedures. This mechanism is not understood; however, two theories exist: the hindgut and foregut hypotheses. In the hindgut hypothesis, bypass of the upper small intestine diverts food directly to the lower small intestine, where glucagon-like peptide-1 (GLP-1) secretory cells promote GLP-1 secretion. In the foregut hypothesis, an unknown glucose-tolerance-complicating factor that inhibits GLP-1 secretion is discharged from the upper small intestine; because bypass surgery prevents food from passing through the upper small intestine, this factor is no longer secreted , 25. PosNo randomized clinical trials of bariatric surgery in NAFLD were found in the literature. Fourteen studies including reviews showed that RYGB has been associated with improvement in NAFLD , 30–42 . OverallRecent studies have shown that laparoscopic sleeve gastrectomy (LSG) is safe and effective, resulting in weight loss somewhere between the rates of laparoscopic RYGB and laparoscopic adjustable gastric banding (LAGB) , 44. AltBased on questionnaire survey results from 50 countries, Buchwald et al. reported that 340,768 bariatric surgeries were performed worldwide in 2011 , which iOnly four studies were found that utilized LAGB or LSG as a restrictive procedure to examine the effects on NAFLD –49 Tabl. Dixon eStudies of follow-up biopsies for NAFLD in LSG were not found in the literature review. Karcz et al. reported on the effect on NASH diagnosed at the time of LSG and NASH-related comorbidities using clinical and biological data at 1- and 3-year follow-ups. A significant improvement of AST, ALT, triglyceride, and HDL levels was shown in the 87 NASH patients .As a mechanism that improves NAFLD, GLP-1 plays an important role after LSG. It has been shown that GLP-1 receptor agonists may be an effective tool for the treatment of NASH. This is due to the continuous increase of serum GLP-1 levels and the reduction of hepatic glucose production, which are expected indirect actions of GLP-1 after LSG. However, a future study is required to confirm this. Umemura et al. reported that the mean weight reduction was 11 kg at 1 month after LSG for patients with severe obesity; the mean GLP-1 levels increased, while mean ghrelin levels decreased significantly . The resOnly two studies were found the biliopancreatic diversion procedures to evaluate the effects on NAFLD , 52. KesThe current hypothesis for the development of NAFLD is that obesity and insulin resistance increase the release of free fatty acids from adipocytes , and hepBile acids are important regulators of energy balance through the unclear receptor farmesoid X receptor (FXR) and the G-protein-coupled membrane receptor TGR5. Activation of FXR by bile acids after a meal induces synthesis of the intestinal peptide hormone FGF-19 and triggers a cascade that controls fed-fasted state metabolism. Bile acids could also promote weight loss by increasing energy expenditure in brown adipose tissue via TGR5. Bile acids might be involved in bariatric surgery-induced changes in energy homeostasis through two mechanisms: increased secretion of bile acids with direct effects on energy balance and increased delivery to the distal intestine due to nutrient and bile re-routing, with increased stimulation of L-cell production and the release of hormones with attenuating effects on bariatric surgery . Patti eIn a recent systematic review, post-operative resolution or improvement of T2DM occurred in 73% of patients . PotentiThe mechanism of how bariatric surgery plays a role as a potential treatment for NAFLD is also complex and not fully understood. Bariatric surgery is likely to have potential benefits in ameliorating the factors such as insulin resistance, lipid profile, inflammation, weight loss, and adipokines that contribute in a marked way to the pathogenesis of NAFLD Figure .Currently, the only proven effective treatment for NAFLD is weight loss. Many reports have shown that when performed by a skilled surgeon, bariatric surgery is safe and effective for reducing weight, improving quality of life, decreasing obesity-related diseases, and increasing life expectancy. However, there is a lack of randomized controlled trials examining the effects of bariatric surgery on NAFLD; the only available studies are either retrospective or prospective cohort studies .The American Association for the Study of Liver Diseases (AASLD), American College of Gastroenterology (AGG), and American Gastroenterological Association (AGA) recommend that foregut bariatric surgery should not be contraindicated in otherwise eligible obese individuals with NAFLD or NASH. However, these organizations recognize that it is premature to consider foregut bariatric surgery as an established option to treat NASH .The current evidence suggests that bariatric surgery for patients with severe obesity decreases the grade of steatosis, hepatic inflammation, and fibrosis. However, the lack of randomized clinical trials demonstrating the beneficial effects of bariatric surgery procedures for treatment of NAFLD prevented us from reaching a scientifically sustained conclusion. Positive results have been observed in cohort studies; however, this research has a high risk of bias. The research also reported a potential risk for worsening fibrosis scores. Therefore, bariatric surgery must be assessed in randomized clinical trials.The mechanism of bariatric surgery’s role as a potential treatment for NASH is complex and not fully understood. Further long-term studies are required to confirm the true effects before recommending bariatric surgery as a treatment option for NASH.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 rodents, the hippocampus has been studied extensively as part of a brain system responsible for learning and memory, and the prefrontal cortex (PFC) participates in numerous cognitive functions including working memory, flexibility, decision making, and rewarding learning. The neuronal projections from the hippocampus, either directly or indirectly, to the PFC, referred to as the hippocampal-prefrontal cortex (Hip-PFC) circuit, play a critical role in cognitive and emotional regulation and memory consolidation. Although in certain psychiatric and neurodegenerative diseases, structural connectivity viewed by imaging techniques has been consistently found to be associated with clinical phenotype and disease severity, the focus has moved towards the investigation of connectivity correlates of molecular pathology and coupling of oscillation. Moreover, functional and structural connectivity measures have been emerging as potential intermediate biomarkers for neuronal disorders. In this review, we summarize progress on the anatomic, molecular, and electrophysiological characters of the Hip-PFC circuit in cognition and emotion processes with an emphasis on oscillation and functional connectivity, revealing a disrupted Hip-PFC connectivity and electrical activity in psychiatric and neurodegenerative disorders as a promising candidate of neural marker for neuronal disorders. The Hip-PFC pathway comprises the major efferent anatomical connection from hippocampal formation, through monosynaptic and/or polysynaptic projections, to PFC, implicating a critical role of the Hip-PFC circuit in the anatomical and functional coupling of the two regions. Interactions between the hippocampus and the PFC are of major interest in understanding the neurobiology of psychiatric and neurodegenerative disorders. There are both direct- and indirect-Hip-PFC pathways. The direct-Hip-PFC pathway manifests the remarkable monosynaptic unidirectional projection between these two areas  and playThe direct-Hip-PFC pathway originates from the CA1 region of hippocampus and subiculum , 6. In rIn addition to monosynaptic Hip-PFC projections, there are complex multisynaptic routes between the hippocampus and PFC. We focus here on those which have been shown to be critically involved in higher cognitive function and several major brain disorders.Though hippocampus receives direct projection from the ventral tegmental area (VTA), it innervates the VTA through a multisynaptic pathway involving the glutamatergic efferent innervating nucleus accumbens (NAc) , 17. To Within the vHip, neuroanatomical studies have shown that the ventral CA1 and the ventral subiculum project to not only the mPFC, but also the basolateral amygdala (BLA) . AlthougExcitatory inputs from BLA densely arborize within superficial layers of mPFC , 29 and The hippocampus and anterior thalamic nuclei form part of an interconnected network involved in memory formation which is the central pathway comprising the direct projections from the hippocampus to the anterior thalamic nuclei. Additional pathways involve the internal capsule, associating the dorsal subiculum with the anteromedial thalamic nucleus, as well as the postsubiculum to the anterodorsal thalamic nuclei in rat . The PFCIt has been proposed that the reciprocal projections between PFC and thalamic nuclei may initiate brain wave oscillations, associated with consciousness, attention, and executive control , 45.Though there is no direct-Hip-PFC projection, hippocampal activity can be affected by PFC via various relay structures. The nucleus reuniens (RE) is the main nucleus of thalamus that receives mPFC innervation and transmits processed information to the hippocampus by monosynaptic projection  46]. Pa. Pa46]. Both pyramidal and local GABAergic neurons in the mPFC are directly targeted by the thalamic  and hippThe Hip-PFC pathway demonstrates synaptic plasticity. Repetitive electrical stimulation in the ventral subiculum or CA1 induces LTP or long-term depression (LTD) in the PFC –53 and aWorking memory is a task that is used to evaluate the transient holding and processing of new and already stored information, an important process for reasoning, comprehension, learning, and memory updating. Rodent experiments involving asymmetric pathway disconnection methods have shown that both PFC and hippocampus functionally interact during working memory  especialAlthough both hippocampus and PFC are required for spatial learning, the hippocampus plays a vital role in rodent , while tOscillations across the frequency spectrum are evident and theorized to be relying on the strength and kinetics of excitatory and inhibitory synaptic interactions . When laHigher order cognitive processes such as working memory are strongly associated with theta and gamma oscillations in the PFC , 71. TheHippocampal LFP and mPFC spikes are phase-locked at a range of time shifts. Most mPFC spikes followed hippocampal theta instead of leading it suggesting an interaction of hippocampus and mPFC directionality . AlthougStudy on gamma oscillation modulation in the mPFC uncovered that during sleep spindles the cortex is functionally disconnected with its hippocampal inputs which is presumably modulated by the strong recruitment of inhibitory interneurons . The comHippocampal sharp waves (SPW) are associated with ripple pattern , 85 and Hippocampal SPWRs are well placed to emphasize location of the animals. During the SPWRs, place cell firing is stronger when animal is located inside the cell's place-field as compared to outside. There is a nonlinear increase of the location-specific SPWRs firing rate as compared with that during theta periods , which pB receptors upon blockade of GABAA receptors by GABAA receptor antagonist, bicuculline [B receptors promotes the transition from theta-gamma to SPWRs working mode in hippocampus [BR in SPWRs. It has also been shown that bicuculline augmented GABAB receptor mediated inhibitory postsynaptic potentials (IPSCs) leading to SPWRs reduction [BR in regulation of SPWRs remains to be elucidated.Switching between hippocampal theta and SPWRs may be reliant upon systemic administration of acetylcholine (ACh) , GABA 9, and noruculline , 92. A rpocampus  suggestieduction , 94. ThuBehavioral study shows that PFC and hippocampus exhibit time-related correlation during the slow-wave sleep (SWS) . In the During light SWS, the thalamocortical network oscillates falling in a waxing-and-waning pattern at about 7 to 14 Hz and lasting for 500 ms to 3 s, called spindles . Both SPUsing multisite neuronal recordings in mPFC, it has been shown that oscillatory responses of cortical cells differ due to different cell types and cortical layers during sleep spindles . SuperfiPatients suffering from psychiatric and neurodegenerative diseases show cognitive impairment and emotional dysregulation as well as abnormalities of morphological, electrophysiological, and molecular properties in the Hip-PFC pathway. It is likely that disruption of the Hip-PFC functional connectivity might be a shared element of pathophysiology in the above disorders. We will discuss stress, depression, autism, and Alzheimer's disease in this review.Posttraumatic stress disorder (PTSD) patients usually show abnormally small hippocampus, amygdala . NeuroimGlucocorticoid (GR) and mineralocorticoid receptors (MR) not only display a different affinity for corticosterone, but also are heavily expressed in hippocampus, mPFC, and amygdala –109. ConMajor depression is a mental disorder characterized by a pervasive and persistent low mood that is accompanied by low self-esteem and a loss of interest or pleasure in normally enjoyable activities , 112. De NPY mRNA species: a “long” and a “short” variant [ NPY mRNAs, while only the “short” NPY mRNA was demonstrated to be downregulated in depression-like states in rat [The mature neuropeptide Y (NPY) is a 36-amino acid peptide, which is widely distributed in the nervous system , 120 and variant . Both fu variant , 123, ins in rat .Autism spectrum disorder (ASD) is a series of neurodevelopmental disorders defined by core deficits in repetitive behaviors and restrictive interests .A [B [More recent results suggest that impaired glutamate N-methyl-D-aspartate receptor (NMDAR) dysfunction in the PL mPFC and hippocampus may contribute to impaired synaptic response associated with psychiatric illness . Social A  and GABAA [B  receptorA [B , in postA [B .Neuroimaging studies have suggested that cortical interconnectivity is dysfunctional in ASD . An aberβ) plaques and intracellular neurofibrillary tangles (NFTs) and selective synaptic and neuronal loss [AD is a progressive neurodegenerative disorder that causes deterioration of memory, judgment, and reasoning in the elderly. AD brain is characterized by accumulation of extracellular insoluble beta amyloid (Anal loss .β and NFTs impair hippocampal and cortical function [Both Afunction . The corfunction , 136. Lofunction . These ffunction , 139 andfunction  and/or bIt has been shown that reduced Nav1.1 levels of PV cell underlie abnormal memory and gamma oscillation in the cerebral cortex of AD mouse model and AD patient . RestoriMolecular biology, anatomy, electrophysiology, and fMRI analysis in rodent and human strongly implicate that the Hip-PFC circuit plays an important role in fundamental cognitive processes, emotion regulation, and memory consolidation. Disruption in the Hip-PFC pathway, anatomically or functionally, might be a common element of pathogenesis in neuronal disorders and therefore underlies the curious overlap of symptoms among these otherwise disparate diseased conditions. Thus, study of the physiology and pathophysiology within the Hip-PFC circuit may be a key for understanding these highly debilitating and prevalent psychiatric and neurodegenerative disorders.


Every behaviour of an organism relies on an intricate and vastly diverse network of neurons whose identity and connectivity must be specified with extreme precision during development. Intrinsically, specification of neuronal identity depends heavily on the expression of powerful transcription factors that direct numerous features of neuronal identity, including especially properties of neuronal connectivity, such as dendritic morphology, axonal targeting or synaptic specificity, ultimately priming the neuron for incorporation into emerging circuitry. As the neuron's early connectivity is established, extrinsic signals from its pre- and postsynaptic partners feedback on the neuron to further refine its unique characteristics. As a result, disruption of one component of the circuitry during development can have vital consequences for the proper identity specification of its synaptic partners. Recent studies have begun to harness the power of various transcription factors that control neuronal cell fate, including those that specify a neuron's subtype-specific identity, seeking insight for future therapeutic strategies that aim to reconstitute damaged circuitry through neuronal reprogramming. For this diversity of subtypes to assemble into functional circuits, it is imperative that the identity of each neuron be properly specified during nervous system development. In this review, we consider a neuron's subtype as the constellation of molecularly, morphologically and physiologically distinct characteristics that allow it to be distinguished from other neurons, including one particularly unique and functionally significant component of its identity, its connectivity. How then, is an undifferentiated neuronal precursor ultimately instructed to achieve its distinct identity and integrate appropriately into the emerging circuitry? Fundamental in this complex process is the interplay between a neuron's intrinsic transcriptional milieu and the extrinsic cues it encounters as it enters the surrounding network.Internally, neuronal identity specification is controlled by an extensive hierarchy of transcription factors that act in concert to regulate neuronal development, many of which have been reviewed previously –6. FundaIt would be myopic to consider the internal effects of subtype-specifying transcription factors in isolation, however, as they also play a major role in determining a neuron's extracellular connectivity, dictating features such as dendritic morphology, axonal targeting and synaptic specificity. Once a neuron becomes incorporated into the surrounding circuitry, extrinsic signals from its pre- and postsynaptic partners then further refine its identity by regulating its transcription factor expression, neurotransmitter status, dendritic morphology or distinct synaptic protein profile. A neuron's connectivity thus lies at the intersection between the intrinsic and the extrinsic cues that together converge to determine a neuron's ultimate identity.Two prototypical examples of subtype-specifying transcription factors, for which much is known about both their ability to specify neuronal identity as well as impact neuronal connectivity, are Fezf2 and Ptf1a. Fezf2 is expressed in layer V cortical pyramidal cells and is crucial for specifying not only the identity but also the unique connectivity of corticofugal projection neurons (CFuPNs) –12. Ptf1In this review, we trace the process by which subtype-specifying transcription factor expression shapes neuronal connectivity and then provide examples of how early connectivity feeds back on neuronal identity. First, we survey how the subtype-specifying transcription factors begin to intrinsically establish neuronal identity, focusing primarily on Fezf2 and Ptf1a. We then outline studies that demonstrate how these factors prime a neuron's connectivity, identifying some known downstream mediators that assist in the process. We next discuss how early pre- and postsynaptic contacts of a developing neuron can refine its distinguishing properties, using well-characterized examples from neuromuscular and thalamocortical circuitry. Finally, we consider future applications of the subtype-specifying transcription factors in directing neuronal connectivity for circuit repair.3.Invertebrate research has been instrumental in demonstrating the dependence of neuronal identity specification on the internal transcriptional milieu. As development of a neuronal precursor proceeds, the progressive expression of lineage-specific transcription factors leads the precursor through a sequence of regulatory states, culminating in the specification of its terminal neuronal fate ,21. A neNrl mutant mice, rod precursors differentiate instead into cone-like photoreceptors, as determined by a shift to cone-like gene expression, morphology and electrophysiological properties [Xenopus retina is sufficient to increase the number of retinoblasts that differentiate into rods, at the expense of those that differentiate into cones [Tlx1/3 mutant spinal cords, dorsal inhibitory interneurons are overproduced at the expense of excitatory interneurons, as indicated by the expanded expression of inhibitory transcription factors and neurotransmitter markers and a concomitant reduction of excitatory neurotransmitter markers [In vertebrates, terminal neuronal fate is similarly governed by powerful transcription factors that act as selectors between related neuronal subtypes, inducing gene expression batteries that direct the acquisition of one terminal identity, while suppressing gene expression batteries of competing identities. For example, the basic motif-leucine zipper transcription factor Nrl acts in the retina to specify rod over cone photoreceptor identity. In operties ,25. Convto cones . As anot markers . Misexpr markers . Finally markers –30. Mise markers .Perhaps two of the most thoroughly investigated subtype-specifying transcription factors in the vertebrate nervous system, however, are Fezf2 and Ptf1a, and extensive research into their ability to direct aspects of neuronal identity and connectivity warrants a more comprehensive discussion of these examples. Like the examples described above, Fezf2 and Ptf1a are both necessary and sufficient for their respective neuronal subtypes, acting as a switch between developmentally related identities . KnockouPtf1a mutants, inhibitory interneuron precursors in the dorsal horn switch their fate to become excitatory precursors, upregulating excitatory transcription factors and glutamatergic markers at the expense of inhibitory transcription factors and GABAergic markers [Ptf1a mouse mutant, suppressing the molecular markers and neurotransmitter status of dorsal excitatory interneurons while promoting those of inhibitory interneurons [Xenopus or chick retina has a similar effect, inducing horizontal and amacrine fates over excitatory photoreceptor, bipolar and ganglionic neuronal fates [The subtype-specifying transcription factor Ptf1a is more broadly expressed than Fezf2, acting in multiple regions of the central nervous system (CNS) to induce a number of subtype-specific identities, depending on the region of its expression. For example, in the spinal cord of  markers . Similar markers ,16, and  markers ,17. Ptf1 markers . Not lim markers . The sufrneurons –37. Furtal fates ,39. Mostal fates . TogetheVglut1 and Gad1, activating the former and suppressing the latter [Beyond their endogenous function as an identity switch between developmentally related subtypes, another important property that attests to the potency of both Fezf2 and Ptf1a for neuronal subtype specification is their ability to cell-autonomously convert the identity of other neuron classes in distant regions of the CNS that normally exclude their expression figures . The swie latter . These re latter , as welle latter . Use of e latter  , suggesting its dependence on Ptf1a expression in GABApre neurons, which reside in this region of the spinal cord [Ptf1a has similar functions in priming a neuron's eventual circuit connectivity. As mentioned, misexpression of Ptf1a is sufficient to alter the dendritic projection pattern of cortical pyramidal cells, causing them to elaborate a more branched, radial array of neurites . Also, wnal cord .Together, these studies suggest that a major role of subtype-specifying transcription factors, such as Fezf2 and Ptf1a, is to predispose developing neurons to adopt characteristics that affect their later incorporation into circuitry. Among other properties, these transcription factors impact dendritic morphology, axonal targeting, electrophysiological output and synaptic specificity, helping to shape a neuron's circuit connectivity.5.Once the intrinsic transcriptional milieu helps to prime neuronal connectivity, consequent synaptic interactions of a developing neuron within its emerging neuronal network also provide critical extrinsic cues that further influence the neuron's acquisition of a particular identity. To this point, studies have demonstrated that the plasticity for reprogramming a postmitotic neuron via transcription factor misexpression diminishes after the first postnatal week ,33, leadXenopus muscle cells with spinal cord neurons, direct contact of the spinal neurons with target muscle cells suppresses the spinal neurons' ability to adopt a non-cholinergic neurotransmitter status [Many distinguishing properties of neuronal subtype depend on contact with the postsynaptic target. These interactions are distinct from the target-derived cues that function more generally to support neuronal growth and survival or to regulate the mechanics of synapse assembly . A wr status . These pr status ,53. Subtr status ,55. Morer status ,56. ThesPresynaptic to the developing neuron, afferent-derived influences on neuronal identity have been described for thalamocortical projections onto layer IV spiny stellate neurons in the somatosensory cortex. For example, the afferent-derived molecules neuritin-1 and VGF are expressed in the thalamic neurons that project to the cortex and help specify the complex dendritic morphology of their postsynaptic spiny stellate neuron targets . A recenMerging the concepts of post- and presynaptic influence on neuronal identity, the GABApre interneuron in the spinal cord affords an illustrative example of how one of its distinguishing characteristics, its synaptic protein profile, is modulated by both its postsynaptic target and its afferent input. The synaptic expression of the GABA-synthesizing enzyme GAD65 has been shown to distinguish the GABApre population from other populations of spinal interneurons ,59. Remo6.As the factors that control neuronal identity and connectivity have become better understood, much enthusiasm has been generated for harnessing these processes to repair neuronal circuits damaged by disease or injury. Central to this goal is the idea that neuronal identity is far more plastic than was once imagined. Originally, cellular differentiation was thought to descend through an ever-narrowing set of fate-specifying decisions until the cell reached its final identity. Waddington  originalin vitro and in vivo neuronal reprogramming. A variety of developmentally expressed transcription factors have begun to be explored for their ability to help generate specific neuronal subtypes, not only from other neurons, but also from closely related glia, or even more distant lineages, such as fibroblasts [Increasing awareness of the plasticity of cellular identity has spurred a torrent of current research into roblasts ,63–66. Oroblasts . When throblasts ,69. Otheroblasts ,70. Thesin vivo, may be ideal candidates to include in these studies. The ability of Fezf2 to reprogramme postmitotic neurons of other subtypes in vivo [in vivo would also eliminate the need for transplantation. Furthermore, it has been proposed that in vivo transdifferentiation of closely related neighbouring neurons might reduce barriers toward establishing the correct wiring, as they may already share similar features with the desired neuronal subtype, which could help ease the transformation [As promising strategies evolve to reprogramme neuronal identity, subtype-specifying transcription factors, such as Fezf2 and Ptf1a, which have been shown to cell-autonomously redirect neuronal subtype identity  in vivo ,33 is en in vivo ,70. Use However, as strategies for transcriptional neuronal reprogramming evolve, it is necessary to consider that the actions of any misexpressed transcription factor, including the subtype-specifying transcription factors, will be restricted by the epigenetic landscape of the neuron in which it is expressed. To this point, previous studies have demonstrated that the identity-specifying abilities of other transcription factors indeed rely on the cooperation of various mediators of chromatin modification. For example, the neurogenic transcription factor Pax6 associates with the chromatin remodelling Brg1-containing BAF complex to direct a neuronal over a glial fate . FurtherOnce the programming of a specific neuronal subtype becomes facile, the next major hurdle will be to ensure the proper connectivity of reprogrammed neurons. It is therefore convenient that a major downstream function of the subtype-specifying transcription factors is to prime aspects of a neuron's connectivity. Coupled with a better understanding of the extrinsic signals that shape identity, such as those imparted by the neuron's pre- and postsynaptic partners, our ever-improving ability to manipulate each of these variables will eventually allow us to control the subtleties of neuronal identity and connectivity with increasing precision. While the therapeutic uses of neuronal reprogramming to regenerate damaged microcircuitry are still in their infancy, there is no question that transcription factors that can cell-autonomously instruct neuronal subtype identity and connectivity will continue to play a fundamental role in the study of reprogramming for circuit repair.7.While a functional organism requires the proper development of each and every cell, the precise coordination of both identity specification and incorporation into the surrounding tissue is nowhere more essential than for neurons within the nervous system. Each of the innumerable neuronal subtypes must first be generated, and then each must wire appropriately with its synaptic partners, in order to establish a network capable of forming memories, planning and executing actions, or generating emotions. A critical event that regulates this process during early neuronal development is the expression of subtype-specifying transcription factors, such as Fezf2 or Ptf1a. These transcription factors are powerful regulators of many aspects of neuronal identity, and are both necessary and sufficient to cell-autonomously confer subtype-specific features to developing neurons. One major function of the subtype-specifying transcription factors is to prime various elements of a neuron's connectivity, such as its dendritic morphology, axonal targeting and synaptic specificity. As these features help the neuron become incorporated into early neuronal networks, synaptic contacts from pre- and postsynaptic partners help to refine its identity, by further regulating its molecular expression pattern, dendritic morphology, neurotransmitter status or synaptic protein profile. Replacing damaged microcircuits is one of the eventual therapeutic goals of studies that aim to use subtype-specifying transcription factors for neuronal reprogramming. As our understanding of the interplay between intrinsic transcriptional control and extrinsic network control over neuronal identity becomes more sophisticated, a future of successful circuit repair through neuronal reprogramming appears ever more within reach.


Understanding underlying pathological mechanisms is prerequisite for a sensible design of protective therapies against hearing loss. The triad of age-related, noise-generated, and drug-induced hearing loss displays intriguing similarities in some cellular responses of cochlear sensory cells such as a potential involvement of reactive oxygen species (ROS) and apoptotic and necrotic cell death. On the other hand, detailed studies have revealed that molecular pathways are considerably complex and, importantly, it has become clear that pharmacological protection successful against one form of hearing loss will not necessarily protect against another. This review will summarize pathological and pathophysiological features of age-related hearing impairment (ARHI) in human and animal models and address selected aspects of the commonality (or lack thereof) of cellular responses in ARHI to drugs and noise. Acquired hearing loss is the most common hearing impairment in modern societies. Not all of its causes, however, are of modern origin. Of the major contributing entities, presbycusis or age-related hearing impairment (ARHI) has been recognized by physicians and societies since ancient times. The environmental overload with damaging noise levels, beginning with the industrial revolution, and the introduction of ototoxic antibiotics and anti-cancer agents in the last century added to the spectrum of hazards to the auditory system and established the current triad of drug-induced, noise-induced and age-related hearing losses.Medical science and research over the last centuries have given us an excellent knowledge of inner ear pathologies and their functional consequences. Recent advances have added insights into molecular pathways, their physiological control mechanisms, and their modulation by environmental and genetic influences. Intriguing biochemical and molecular parallels began to surface, leading to speculation of a common underlying mechanism of acquired hearing loss and the prospect for a unified pharmacological protection. However, details about the individuality of cell death and homeostatic pathways and differentiated responses to attempted protection soon dispelled this notion. This review will focus on ARHI and compare its biochemical and molecular characteristics to ototoxic hair cell death and noise trauma. While the overall pattern of presbycusis is also shaped by changes in central auditory pathways, we will limit our considerations to the cochlea.ARHI is the most prevalent form of hearing loss in humans. It is characterized by decreased hearing sensitivity, decreased ability to understand speech in a noisy environment, slowed central processing of acoustic stimuli, and impaired sound localization  is affected in both genders by 60–69 years  gene at the ahl locus predisposing them to accelerated hearing loss, distinct from the late-life age-related changes in other mouse strains and in human. Indeed, no convincing evidence yet exists associating variants in human CDH23 with ARHI. For example, a recent study of 310 aging participants with poor hearing vs. 308 participants with good hearing found no association of a common CDH23 variant with presbycusis .Animal models that reflect a sensorineural ARHI with loss of outer and, later, inner hair cells include aging rats and mice. CBA/J mice as well as the CBA/CaJ and CAST strains present little evidence of hearing loss until 18 months of age, i.e., long into their lifespan, when they begin to show hair cell loss and elevated auditory thresholds , compound action potential and distortion-product otoacoustic emission  than in younger (15–38 years old) subjects  are produced in every cell by enzymatic reactions and mitochondrial respiratory mechanisms. However, only their excess—either via overproduction or insufficient detoxification—will create oxidative stress and potentially trigger cell death. A well-maintained redox balance is important for the cochlea as for any other tissue. Transgenic mice with deficiencies in antioxidant systems, lacking the enzyme copper/zinc superoxide dismutase, lost hair cells and auditory neurons to a greater extent than their normal littermates  for the 13 proteins that it encodes are more likely to occur and persist in a lifetime than mutations in nuclear DNA. As a consequence, mitochondrial function may be compromised and pathology can become evident, varying with cell type and the type of mutation  and old (18–26-month-old) CBA/J mice with hearing deficits. The middle-aged mice also bore nuclei with necrotic features, which were absent from old mice  are a family of kinases that include c-jun NH2-terminal kinases (JNK), p38 MAPKs, and other extracellular signal-regulated kinases. Immunohistochemical analyses in the cochlea of aging CBA/J mice demonstrated increased phosphorylation  of JNK and p38 MAPK in outer hair cells  for the last 3 years of their lives . To what extend these two effects can be distinguished is an interesting theoretical question but of no practical consequence. Diet is an easily modifiable factor and any delay in ARHI would have important implications for public health. Unfortunately, there is no simple remedy.2), magnesium, and lycopene (a carotenoid antioxidant). Similarly, an epidemiological study of 1,910 Korean subjects aged 50–80 years compared their hearing thresholds with self-reported intake of dietary supplements , and niacin (vitamin B3) positively correlated with better thresholds. A survey of a general population in the USA aged 20–69 years  likewise found that diets high in vitamin C, beta-carotene, and magnesium were correlated with better hearing  and vitamin B12  with low serum levels of folic acid  state are confounding factors that are capable of influencing the success of therapeutic interventions. Furthermore, subtle forms of auditory damage may escape simple audiometric tests and a final verdict on success or failure of protective strategies may have to await more sophisticated audiological assessments.There is another unresolved question. While a short-term administration of antioxidants or vitamins might be safe for drug and noise exposure, the hazards of a life-long regimen of nutritional supplements are unknown. Studies in animals as well as clinical trials have warned of a potentially increased risk of cancer and mortality associated with prolonged consumption of antioxidants or vitamins. Specifically, meta-analyses of clinical trials singled out beta-carotene, vitamin A, and vitamin E as associated with increased overall mortality (Miller et al., When we compare the mechanisms of drug, noise, and age-related hearing loss, there appear to be more similarities between drug- and noise-induced hearing loss than between those two and age Table . One of Looking ahead, regeneration of human hair cells seems decades away but other approaches may provide new directions. Some aspects of ARHI may relate to the phenomenon of cochlear synaptopathy, causing “hidden hearing loss” by the loss of auditory nerve fiber/hair cell connections (Kujawa and Liberman, 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.


Stressors have been related to medically insufficiently explained or functional somatic symptoms (FSS). However, the underlying mechanism of this association is largely unclear. In the current study, we examined whether FSS are associated with different perceived stress and cardiac autonomic nervous system (ANS) levels during a standardized stressful situation, and whether these associations are symptom-specific.We examined 715 adolescents  from the Dutch cohort study Tracking Adolescents’ Individual Lives Sample during the Groningen Social Stress Test (GSST). FSS were assessed by the Youth Self-Report, and clustered into a cluster of overtiredness, dizziness and musculoskeletal pain and a cluster of headache and gastrointestinal symptoms. Perceived stress levels  were assessed by the Self-Assessment Manikin, and cardiac ANS activity by assessing heart rate variability (HRV-HF) and pre-ejection period (PEP). Perceived stress and cardiac ANS levels before, during, and after the GSST were studied as well as cardiac ANS reactivity. Linear regression analyses were used to examine the associations.Perceived arousal levels during  and after  the GSST, and perceived unpleasantness levels before  and during  the GSST were related to FSS during the past couple of months. The association between perceived stress and FSS was stronger for the FSS cluster of overtiredness, dizziness and musculoskeletal pain than for the cluster of headache and gastrointestinal symptoms. Neither ANS activity levels before, during, and after the GSST, nor maximal HF-HRV and PEP reactivity were related to FSS.This study suggests that perceived stress levels during social stress are related to FSS, whereas cardiac ANS activity and reactivity are not related to FSS. Functional somatic symptoms (FSS), like fatigue and chronic pain, are symptoms not fully explained by a conventional medical condition. They are common during adolescence and can have large impact on adolescents’ lives ,2. More The most commonly examined pathway is that stressors result in high perceived stress levels and that these high perceived stress levels lead to feelings of tiredness and other somatic discomfort. High perceived stress levels have repeatedly been associated with FSS in adolescents –9. MoreoApart from maladaptive psychological responses to stress, also maladaptive physiological responses have been thought proposed to play a role in the relationship between stressful experiences and development of FSS. Specifically, inadequate reactions of the cardiac autonomic nervous system (ANS) system are thought to explain part of the association between stressors and FSS . The carAnother remaining question is whether psychological or physiological stress levels are particularly related to specific clusters of FSS. Much debate is going on in the field of psychosomatic medicine about whether all FSS result from the same underlying etiology and can thus be examined together (the lumping approach) or whether each FSS has its own specific background and should be examined separately (the splitting approach). Taking both approaches will shed more light on these different points of view. Previous research suggests that the association between FSS and cortisol responses may be symptom-specific. For example, fatigue and musculoskeletal pain symptoms have been found to be specifically related to morning cortisol levels ,21, so tMost previous research on the association between cardiac ANS and FSS examined absolute ANS activity levels. However, the use of absolute ANS activity levels has been criticized, since using these absolute ANS levels does not allow taking interindividual cardiac differences, for instance cardiac preload and afterload, into account . TherefoN = 715) who participated in a social stress test.The aim of the current study is to examine whether perceived stress levels and ANS activity before, during, and after a standardized stressful situation are related to FSS in adolescents. We hypothesize that FSS are associated with high perceived stress levels, low PNS levels and high SNS levels before, during and after a standardized stressful situation and that these associations are symptom-specific. Further, we hypothesize that FSS are related to high cardiac ANS reactivity. Our hypotheses were tested in a large population-based sample of adolescents . In totThe experimental session consisted of a number of different challenges, i.e. a spatial orienting task, a gambling task, a startle reflex task, and a social stress test. The session was preceded and followed by a 40-minute period of rest . Before,The GSST was the last challenge of the experimental session. It involved a standardized protocol, inspired by  the Trier Social Stress Test . The par2. ICG data were assessed with a BIOPAC NICO100C Noninvasive Cardiac Output Module. The PEP reflects the time interval between the onset of the electromechanical systole (Q-wave onset) in the ECG and the opening of the aortic valves co-occurring with the B-point in the ICG. B-points were manually scored by extensively trained raters using the VU-AMS interactive software (www.vu-ams.nl), which graphically displays the large-scale ensemble averages ICG 39]). RegIn conclusion, the findings of this study suggest that perceived stress levels before, during, and after a stressful situation are related to FSS in the past couple of months. This was specifically true for symptoms of overtiredness, dizziness and musculoskeletal pain in contrast to headache and gastrointestinal symptoms. Cardiac ANS activity levels before, during and after a stressful situation were not related to FSS in our study, nor were HRV-HF and PEP reactivity.S1 Dataset(XLSX)Click here for additional data file.


Previous studies have shown a relationship between stressful war experiences and mental health symptoms in children and adolescents. To date, no comprehensive studies on the role of childhood adversities have been conducted with war-exposed adolescents living in post-war, low-resource settings in Sub-Saharan Africa.A cross-sectional study of 551 school-going adolescents aged 13-21 years old was undertaken four years post-war in northern Uganda. Participants completed self-administered questionnaires assessing demographics, stressful war experiences, childhood adversities, posttraumatic stress disorder (PTSD), depression, and anxiety symptoms.Our analyses revealed a main effect of gender on all mental health outcomes except avoidance symptoms, with girls reporting higher scores than boys. Stressful war experiences were associated with all mental health symptoms, after adjusting for potential confounders. Childhood adversity was independently associated with depression symptoms but not PTSD, anxiety, and PTSD cluster symptoms. However, in situations of high childhood adversity, our analyses showed that stressful war experiences were less associated with vulnerability to avoidance symptoms than in situations of low childhood adversity.Both stressful war experiences and childhood adversities are risk factors for mental health symptoms among war-affected adolescents. Adolescents with histories of high childhood adversities may be less likely to develop avoidance symptoms in situations of high stressful war experiences. Further exploration of the differential roles of childhood adversities and stressful war experiences is needed. Adolescents in Africa’s Great Lakes region continue to emerge from various armed conflicts that expose them to stressful war experiences and the risk of developing mental health symptoms e.g. PTSD, depression and anxiety -3. AdoleMore recently, some studies have explored the influence of childhood adversity and stressful war exposure on the mental health of children and adolescents following long-standing conflicts, such as in Uganda, Sri Lanka and Afghanistan -11. HoweThe direct correlation between the degree of trauma and the amount of mental health symptoms is consistent across a number of studies. Developmental theorists have postulated a stable association between childhood adversity and behavioral difficulties in later life , and somChildhood adversity and stressful war experiences may have independent effects on mental health symptoms , while cChildhood adversities have been proposed to modify later stress sensitivity and risk of mental health symptoms through stress sensitization (SS), stress amplification (SA), and stress inoculation (SI) models, wherein the interaction between childhood adversity and later stressful experiences determines risk for psychopathology . The SS Taken together, these findings show that there is no single overarching principle of how childhood adversities affect mental health symptoms following stressful events later in life. In this paper, first, we aimed to assess whether childhood adversity and stressful war experiences were independently associated with PTSD, depression and anxiety symptoms. Secondly, we explore the moderating role of childhood adversity in the association between stressful war experiences and mental health symptoms. We hypothesise that (1) both childhood adversity and stressful war experiences would be associated with all mental health symptoms, and (2) childhood adversity would moderate the association between stressful war experiences and mental health symptoms.As previously reported elsewhere ,26, the Self-report questionnaires were reviewed with local mental health staff and teachers and later pretested with non-participating adolescents to ensure local validity. All questionnaires were administered in English, the official language used in all Ugandan schools. A socio-demographic questionnaire was used to determine participants’ age, gender, ethnicity, living situation, marital status of parents and whether the adolescent’s parents were still alive or not.Childhood adversity was measured using a modified version of the Adverse Childhood Exposure (ACE) questionnaire used by Bruffaert and colleagues . Six conyes/no questions , each referring to a stressful war event typically encountered during active conflict in northern Uganda, such as “Did you experience death of close family or friends?” Because of our interest in the experience of exposure to war events prior to 2006, when the conflict in Northern Uganda was still intense, participants were asked to limit their responses to that specific period. Childhood adversities and stressful war experiences were modelled as continuous scores in our analyses.Stressful war experiences were measured using a Stressful War Events (SWE) questionnaire designed specifically for the study population . The SWEnot at all) to 4 (extremely). Cronbach’s alpha values demonstrated good reliability .PTSD symptoms were assessed with the Impact of Event Scale–Revised (IES-R) , a 22-itnever) to 4 , inquire about the severity of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) based symptoms. In this study, we use the subscales measuring symptoms of depression (15 items) and anxiety (10 items), both subscales showing good Cronbach’s alphas (respectively .83 and .78). For both IES-R and HSCL-37A, we used continuous scores for analyses to retain greater variability in the data.Depression and anxiety symptoms were assessed using the Hopkins Symptom Checklist-37 for Adolescents (HSCL-37A) , a self-Five separate hierarchical linear regression analyses for each mental health outcome were conducted. All necessary quality criteria for regression analyses were met. In the first step, demographic variables  were entered. In the second step, adverse childhood experiences (ACE) and stressful war events (SWE) were added, with both covariates mean centred. In the third step, the interaction term SWE x ACE was included, followed by simple slope analysis to further explore this relationship.Detailed baseline characteristics of the study population and gender differences in childhood adversities, stressful war experiences and mental health symptoms are presented in Table Hierarchical regression models revealed a main effect of gender on all mental health outcomes except avoidance symptoms, with girls reporting higher scores than boys Table . AnalyseThe present study aimed to examine the differential effects of childhood adversities and stressful war experiences on mental health symptoms and to explore the moderating role of childhood adversity in the relationship between stressful war experiences and mental health symptoms. There are three notable findings in this study. First, there was a main effect of gender on all mental health symptoms except avoidance symptoms, with females reporting higher scores than males. Females also reported higher scores of childhood adversities, stressful war experiences and PTSD, depression and anxiety symptoms than males. Although the findings may reflect a gender-specific exposure and response to particular traumas, suggesting that war is more harmful to females than males, the higher rates of exposure of females to both war-related and intra-familial experiences could have led to an elevation of symptom response .Second, in keeping with our hypothesis and the extant literature, stressful war experiences were risk factors for all mental health symptoms -4. ContrChildhood adversities were not associated with PTSD and anxiety symptoms in our study sample. This finding is inconsistent with that of other researchers who have found stressful war experiences to be less predictive of mental health symptoms than childhood adversities . AlthougLastly, in contrast to our hypothesis, childhood adversities did not moderate the association between stressful war experiences and all mental health symptoms, but it moderated the association between stressful war experiences and avoidance symptoms. Specifically, stressful war experiences were significantly less predictive of avoidance symptoms in situations of high levels of childhood adversity compared to situations of low levels of childhood adversity. This finding contradicts previous studies in which high childhood adversity was reported to increase vulnerability to the effects of stressful war experiences -17. Two We draw particular attention to the fact that childhood adversity did not moderate the relationship between stressful war experiences and the common mental health symptoms among adolescents post-war. Regardless of the level of childhood adversities, stressful war experiences remained predictive of depression, anxiety and PTSD symptoms, in keeping with the extant literature -3. PossiThe data were retrospective and self-reported, and consequently subject to recall and social desirability biases. Although recall bias is expected to be less extreme in a survey of adolescents than adults or younger children, recall bias is still a possibility in retrospective reports of childhood adversities and stressful war experiences. The cross-sectional design precludes both causal inference  and the longitudinal analysis of adjustment trajectories . The genThe above limitations notwithstanding, the data and analyses reported here add further to the literature on post-war adolescents by replicating and extending previous research on the mental health symptoms and the impact of exposure to both childhood adversity and stressful war experiences. Assessing and understanding the role of moderating influences of childhood adversity is important for identifying individual differences in the influence of stressful war experiences on mental health, and for targeting interventions that will hopefully improve mental health outcomes in conflict and post-conflicts situations. Our findings thus support the differential associations of childhood adversities and stressful war experiences with post-war mental health symptoms ,42. Alth