Cardiac troponins T and I are considered highly sensitive and specific markersfor the diagnosis of acute myocardial infarction. Currently, a series ofnonprimary cardiac abnormalities may manifest as an elevation in high-sensitiveassays. The reduction in their detection limits has allowed earlier diagnosisand the use of evidence-based therapeutic measures; however, this characteristichas increased the spectrum of detectable noncoronary heart diseases, which poseschallenges for characterizing acute coronary syndromes and creates a new rolefor these tests in known disorders in intensive care units, especially sepsis.Management of patients through a greater understanding of how these markersbehave should be re-evaluated to ensure their correct interpretation. These molecules, calledhigh-sensitive or high-sensitivity cTnT (hsTnT) and cTnI (hsTnI), are detectedearlier and at extremely low levels, thereby reducing the "blind" detection intervalof fourth-generation cTn assays and aiding not only in diagnosticconfirmation(7) but also in detecting patients at high risk forcardiovascular events.(8) According to the guidelines for non-ST-segmentelevation AMI (NSTEMI) and unstable angina, these tests have resulted in a 20%relative increase in type 1 AMI detection (due to spontaneous atherosclerotic plaquefissuring and dissection) and a reduction in cases of unstable angina. However,these characteristics should be treated with caution, since these markers arepresent in myocardial damage of diverse etiologies, sometimes without theinvolvement of clinically evident myocardial necrosis ((9)Biochemical analysis of myocardial necrosis markers, especially cardiac troponins(cTns), gained attention in the early 1990s for the diagnosis and prognosticevaluation of patients with acute myocardial infarction (AMI). Today, cTns areconsidered fundamental for the management of acute coronary syndromes (ACSs) andconstitute a critical step for their definition together with clinical andelectrocardiographic criteria. In addition to their high accuracy for infarctiondetection, the use of these markers has brought great utility for the choice ofdifferent therapeutic strategies.necrosis . An eval(10) According to the guideline, thecriterion used for AMI is the demonstration of cTn levels above the99th percentile or a drop in the marker and at least onecriterion involving clinical or complementary signs, such aselectrocardiographic changes indicative of new ischemia  and thedemonstration of a new infarct area or segmental contractility disorders inimaging examinations. After percutaneous coronary intervention and myocardialrevascularization, values three times the upper reference limit (URL) in the99th percentile are accepted. Based on the clinicalcircumstances, spontaneous AMI due to atherosclerotic plaque rupture, erosion,fissuring, or dissection is classified as type 1, AMI due to increased oxygendemand of the myocardium is type 2, AMI related to sudden cardiac death is type3, AMI associated with a percutaneous procedure is type 4a, AMI associated withintracoronary stent thrombosis is type 4b, and AMI associated with myocardialrevascularization surgery is type 5. The high-sensitive test also has theutility of excluding the AMI diagnosis at the initial presentation, since thenegative predictive value of the test is 97 to 99%.(7) With new tests,elevations are more commonly found in patients with structural heart disease,including those with obstructive coronary disease, kidney disease, and stableangina.(11) In situations of stable angina, values in the99th percentile have been found in 37% of cases with plaquesconsidered vulnerable and in up to 2% of the general population in otherstudies.(14) The latterpopulation may have heart failure, renal failure, or left ventricularhypertrophy in addition to coronary disease. In patients with compensated heartfailure, hsTnT can also be found very close to the clinical decision limit(14ng/L).(13) The clinical context should be considered forthe correct interpretation of these markers. Thus, the management of a criticalpatient deserves a detailed analysis of preexisting conditions when abnormalcurves from cTn assays are evaluated. The recommended flowcharts for patientswith suspected ACS include a strategy that involves serial collection of thebiomarker within a few hours. The diagnosis is confirmed in most cases usingclinical and electrocardiographic criteria and values more than five times theURL. Serial changes are more accurate when below or near the 99thpercentile, and very high values and a lack of significant variation in theinitial presentation are generally indicative of chronic myocardial injury,which considerably reduces their potential for the diagnosis of AMI type 1((15) Each hsTnT andhsTnI assay has its specific cutoff points, and very low values from both testscan accurately rule out a clinical presentation within a fewhours.(9) However, diverse clinical situations and thenontypical presentation of ACS in the intensive care unit (ICU) setting impairanalysis of the cTn levels combined with clinical data. Moreover, no parameteris available to evaluate the kinetics of these markers starting from the alreadyvery high values in the critical patient. Rigorous hemodynamic control,electrocardiogram, bedside echocardiography, or an imaging examination, whichmay demonstrate loss of viability in a new segment of the left ventricle, shouldbe essential for the differential diagnosis and confirmation of AMI. Givenelevated cTns, a chronic condition can be assumed only after the exclusion ofsymptoms suggestive of ischemia, a normal electrocardiogram and echocardiogram,and the absence of a rising and/or falling marker curve.The document created by the European Society of Cardiology (ESC), AmericanCollege of Cardiology Foundation (ACCF), American Heart Association (AHA), andWorld Heart Federation (WHF) for the universal definition of AMI considers anelevation and/or drop in cTns according to the associated clinical situation tobe essential for diagnostic purposes.I type 1.(15) Eac(16) Lower values found in the initial evaluation ofpatients for acute coronary syndrome may not be related to type 1 AMI , and transient elevations can be detected withoutclinical evidence of AMI in some situations.(17) Substantialincreases followed by falls should be considered for diagnosis  and have obtained the best positivepredictive value (90%).(9) This situation is observed in clinical practiceand was detailed in the study by Apple et al., which demonstrated that patientswith ACS had lower cTn levels and an earlier decline in the presence of unstableangina or the absence of persistent ST-segment elevation.(18) Patients withpersistent ST-segment elevation or progression to "Q" AMI have higher biomarkerpeaks and a late decline (7-10 days). The first situation refers to thepredominance of ischemic cTn release and the second to necrotic release. Anintermediate cTn release behavior probably exists depending on the nature of theinsult, time to reperfusion therapy, clinical course, and the patient'streatment success.An important conceptual theory for the interpretation of these tests is theformation of blebs containing cTns, of which approximately 2 to 6% are free inthe cytosol; these blebs release their material into the extracellular mediumdue to the reduced oxygen supply. When the tissue damage becomes prolonged, theblebs increase and rupture, triggering cell death. Loss of the structuralcontent of myocardial cells is reflected in the prolonged cTn release curve inAMI. However, if reperfusion occurs or if the injury is transient, these blebsare reabsorbed or may leak their cytoplasmic contents into the circulation withthe cell membrane still intact. This short detection period represents a pointrelease of the cytoplasmic content, which corresponds to the half-life of thedetected substances .(16) Low(19) Proposed mechanisms for the release of cTns inthe presence of septic shock also include focal ischemia and the effect ofendotoxins, cytokines, and reactive oxygen species on cardiomyocytes. Tumornecrosis factor (TNF) may modulate the activation or biosynthesis of proteases;for example, calpains and caspases may participate in the degradation ofcontractile proteins, including cTns.(21)Sepsis and other systemic disorders may lead to myocardial depression and celldamage caused by increased consumption and/or a reduced supply of oxygen to theheart.(24) Typically, cardiacoutput is elevated, leading to increased cardiac work and oxygen demand. Thepresence of tachycardia with a decreased diastolic filling time also increasesoxygen consumption. The coronary reserve flow becomes limited, and ischemia mayoccur. Finally, treatment with high doses of inotropic agents to increase theoxygen supply may increase the incidence of cardiovascular complications andaffect the outcome unfavorably in patients with adequate fluid resuscitation.Prolonged resuscitation may elevate ischemic damage with increased fillingpressures, parietal strain, and additional cardiomyocyte injury during septicshock.(25)Experimental studies suggest that generalized microvascular dysfunction is aprominent sign of septic shock and may indicate relative ischemia due to themicrovascular shunt effect or secondary flow heterogeneity resulting fromendothelial dysfunction, capillary plugs, interstitial edema, and free radicalproduction. Some studies suggest areas of reversible mismatch due toredistribution of the microcirculation in response to metabolicchanges.(26) Although some studies have shown an associationbetween several types of tachycardia and elevations in cTns, other factors mayconfound this association, such as the presence of coronary artery disease(CAD), other associated clinical conditions, and hemodynamicchanges.(28) Speculation alsoexists that the tachycardia present in sepsis and septic shock may cause cTnrelease in the absence of structural heart disease, CAD, and myocardialdepressing factors (sepsis) and thus may only represent a manifestation of theimbalance between oxygen supply and demand (type 2 AMI).Tachycardia during the hyperdynamic state is a striking finding. Stretching ofthe myocardial fiber and an increase in parietal tension are probable mechanismsdue to the parallel increase in natriuretic peptide and cTns in several types oftachycardia.(29) However, TNF values were not correlated withelevations in cTns in healthy humans tested with endotoxin, suggesting thatother mechanisms must be involved. The interleukin 6 (IL-6) level alsocontributes to increased cell permeability; the level is elevated significantlyin patients with septic shock and positive for cTns compared to the level inthose negative for cTns.(30) Additionally, cTn-positive patients have ahigher level of histological changes. Necrosis with contraction bands(coagulative myocytolysis) and fibrillar rupture is more commonly associatedwith calcium overload and typically is associated with reperfusion injuries andthe use of catecholaminergic drugs.(31)Mediators, such as TNF, are also implicated in the increased permeability of thecardiomyocyte membrane. As previously reported, this phenomenon could explainthe presence of cTns in the absence of irreversible celldamage.(34)When restricted to sepsis cases, elevated levels have been shown to beassociated with the disease severity. Generally, these results are very similarto those showing increased levels indicating worse left ventricular function anda consequent unfavorable outcome.(35) The study by Røsjøet al. indicated that hsTnT was an important early marker of circulatorydysfunction in what was then termed severe sepsis but was not added to theSimplified Acute Physiology Score (SAPS II) for the prediction of hospitalmortality. In this situation, cardiovascular dysfunction may not be the onlyfactor responsible for mortality in sepsis. hsTnT was present in all initialcases of severe sepsis, whereas 60% of patients had positive fourth-generationcTnT. The authors concluded that an initial hsTnT level of less than 14ng/L(99th percentile) in early severe sepsis might indicate a lowprobability of progression to septic shock.(34) A meta-analysispublished in 2013 showed that both cTnT and cTnI were independent factors ofmortality regardless of the causes or comorbidities involved in their elevationand corrected for confounding biases, such as renal failure or heart diseasepresent prior to inclusion in the study.(35) The field of cardiology shares thesame hypothesis, because evidence suggests that mortality increases in patientsadmitted with hsTnT levels above the 99th percentile regardless ofthe causal agent of cTn elevation. The SWEDEHEART registry noted that patientsadmitted with suspected acute coronary syndrome and hsTnT levels above 14ng/Lshowed higher mortality rates, although only 18.2% of the patients actually hadtype 1 AMI.(36)The prognosis of sepsis depends on the severity of organ dysfunctions, especiallycardiovascular dysfunction. Many studies have discussed the fact that cTns areindependent parameters of the outcome, with no distinction between the causes ofelevation of these biomarkers.(37) With the use of the high-sensitivetests, this correlation reached 60% in some cohort analyses. When studiesevaluated serial changes in the biomarker, 60% of the patients had stable cTnlevels, and the rest had a 20% rise and fall pattern.(38) The latter patternmay be related to a coronary event (type 1 AMI) or myocardial injury secondaryto stroke. Acute changes in autonomic control with exaggerated catecholaminerelease may be a noncoronary consequence of increased cTns instroke.(39) The insula is an important region for autonomicregulation and is frequently affected by involvement of the anteriorcirculation, and an association between stroke in this cortical area and anincrease in cTn values has been demonstrated.(40) However, otherstudies have not demonstrated a correlation between the cTn values and thelocation or volume of the infarction.(41) We add that exposure to excessivecatecholaminergic stimulation and myocardial ischemia due to coronaryvasoconstriction or pre-existing CAD may occur in type 2 AMI. The frequency ofassociated type 1 AMI is uncertain, but after adjusting for age and sex,patients with ischemic stroke are less likely to have associated coronarylesions despite elevations of the cTn levels similar to cases of NSTEMI;moreover, half of the patients in one study had no coronary lesions on theangiogram.(42) Hospital mortality is higher in patients withintracranial hemorrhage than in those with ischemic stroke, and the riskassociated with cTn elevation is higher in ischemic stroke than in hemorrhagicstroke.(43)After introduction of the sensitive myocardial necrosis markers, the associationbetween cTns and stroke was demonstrated extensively. A systematic review of 15studies prior to the use of high-sensitive cTns showed that 18.1% of patientshad elevated levels during the event.Thus, in patients with stroke and elevated cTns, an initial assessment of whetheran acute increase in the biomarker has occurred or whether it is elevated butstable is reasonable. Then, a careful assessment whether an associated ACSexists is essential. Once a high but stable value is detected, we should lookfor comorbidities associated with cTn elevation that may benefit from moreaggressive long-term management. A frequent situation is encountering abnormalcTn levels in stroke patients with a recent ACS or dilated cardiomyopathycomplicated by atrial fibrillation preceding the event.(44) However, because heart failure is a complexsyndrome, single biomarker assessment may not reflect all of itscharacteristics. The accumulated evidence emphasizes that cTns can addinformation to natriuretic peptides. After that description, subsequent studiescorrelated cTn levels with the disease severity. The cTn levels do not allow theetiology to be diagnosed but may reflect the increase in the left ventricularmass and provide data on the ejection fraction and diastolicdysfunction.(45) Elevation in the cTn levels was associated withthe symptom severity, increased need for supportive therapy with vasopressorsand inotropes, and worsening of the outcome at 30 days.(44)Biomarkers in the context of acutely decompensated heart failure have becomeimportant for diagnostic and prognostic assessments and are currently part ofthe standard clinical evaluation. Current recommendations indicate the use ofnatriuretic peptides.(46) These findingsalso apply to high-sensitive tests. Serial changes in the cTn concentrations arealso important, because the persistence of elevated cTn levels during or afterhospitalization is related to worse outcomes, whereas decreasing or stablevalues are associated with lower adverse outcome rates.(47) Despite thisfinding, the clinical usefulness is uncertain. The challenge persists in thedifferentiation between ACS-mediated release and noncoronary release. A Class Irecommendation with Level of Evidence C is included in the European guidelinesfor the use of cTns in acute heart failure.(44) However, the cTnconcentrations should be interpreted broadly. A careful evaluation with imagingand coronary angiography should be part of the investigation, especially incases of recent-onset heart failure, positive cTns, and high clinical suspicionof ischemia of coronary origin.A meta-analysis based on 77,297 patients concluded that detecting cTns in heartfailure patients increased their 1-year mortality and readmission rates,demonstrating a hazard ratio of 2.3 (95%CI 1.8 - 3.0).Epicardial involvement may be a striking finding in acute pericarditis, and cTnsare elevated in approximately 30 to 49% of cases. When they reflect myocardialinjury, the finding of cTns together with other findings compatible with globalor regional left ventricular dysfunction may indicate myopericarditis.(19)Elevation of the biomarker does not seem to be related to the prognosis ofmyopericarditis and is considered a weak marker of the extent of myocardialinvolvement.(48) The marker concentrations in that study showeddifferent behavior according to the clinical presentation. Patients presentingsymptoms for more than 13 days had substantially lower values. In contrast toother clinical conditions, cTn concentrations in myocarditis do not imply anadverse prognosis. Increased cTn levels were not useful to predict complicationsduring follow-up of 486 patients with acute pericarditis or myopericarditis, anda systematic review including eight studies concluded that cTns were not able topredict adverse events during clinical follow-up.(50) Nevertheless, the reduced rate of eventsand the small sample size in these studies should be considered.Although they appear to be useful for myocarditis diagnosis, cTns have limitedsensitivity, at least in studies using less sensitive markers. Better accuracywas gained with hsTnT in one study  with a sensitivity of 83% and specificity of 80% achieved using a cutoffof 50ng/L.(51)Takotsubo cardiomyopathy, which is also called stress-induced cardiomyopathy orapical ballooning syndrome, is reported in approximately 0.7 to 2.5% ofsuspected ACS cases.(52)Although we observe Takotsubo cardiomyopathy most commonly in women withemotional or physiological stress with a presentation of cardiomyopathy, it mayoccur in a broader clinical spectrum, including presentation in younger men andin those without a triggering event.(53) This elevation is disproportionate to thefinding of regional left ventricular dysfunction on imagingtests.(54)Most patients have a mild to moderate cTn increase within 24 hours ofpresentation.Some studies have attempted to differentiate patients with Takotsubocardiomyopathy from those with ACS using biomarker behavior, since diagnosticconfirmation is often performed only after finding no obstructive lesions oncoronary angiography and normal ventriculography. A prospective analysis of themagnitude of the elevations in cTnT and cTnI found that cases with the formerbelow 6ng/mL and the latter below 15ng/mL showed little probability of beingTakotsubo cardiomyopathy.(55)Because the presentation more closely involves regional left ventricular changesthan loss of viability due to necrosis, the ratio between markers has beenstudied at ACS patient admission. The ratio that best differentiated Takotsuboand ST-segment elevation AMI (STEMI) was the ratio between peaks of theN-terminal prohormone of brain natriuretic peptide (NT-proBNP) in ng/L to cTnTin µg/L. A cutoff value of 2,889 was able to distinguish Takotsubocardiomyopathy and STEMI (91% sensitivity and 95% specificity), and a ratio of5,000 was able to discriminate Takotsubo cardiomyopathy and NSTEMI (83%sensitivity and 95% specificity).(56)The incidence of myocardial contusion in patients with closed chest trauma rangesfrom 3% to 56% of cases depending on the diagnostic criteria used. The lack ofspecific signs and symptoms and the broad spectrum of clinical presentation makeits evaluation difficult.(57)Both cTnT and cTnI have an equivalent sensitivity profile and greater accuracyfor myocardial contusion detection. These indicators aid in the selection ofpatients who must remain under intensive cardiacmonitoring.(58) Patients with ECG changes,elevated cTn, or both must remain under observation in the ICU for at least 24hours, during which time most complications of myocardial contusiondevelop.(56)A study identified that patients with brain injury, thoracic injury, closed chesttrauma, and shock more frequently had higher cTnI values. In the same analysis,sustained (greater than 36 hours) and significant cTnI release (cTnI peak≥ 2µg/L) was more frequently associated with thoracic trauma (82%)and the presence of electrocardiographic changes. Based on electrocardiographicabnormalities, the sensitivity, specificity, and positive and negativepredictive values of cTnI release were 63%, 98%, 40%, and 98%, respectively.Mortality could not be discriminated according to the marker values, butpatients with a normal electrocardiogram and cTnI level 8 hours after chesttrauma had an almost null probability of complicated myocardial contusion andrequired no additional evaluation.(59) Intermediate-risk patients are consideredthose with signs of right ventricular dysfunction who are hemodynamically stableand cTn positive. Kucher et al. concluded that a normal echocardiogram andnegative cTns were useful for identifying patients with a lower risk of earlymortality.(60) However, the reason for the increase in thesemarkers in pulmonary thromboembolism is still unclear. In one study, 63% ofcases with right ventricular dilatation had elevated cTns, whereas 29% of caseswith positive cTns had a normal end-diastolic diameter.(61) cTnI was alsoassociated with more segmental defects on ventilation/perfusion scintigraphy.However, hypoxia secondary to the decrease in the ventilation/perfusion ratio,hypoperfusion due to shock and coronary flow decrease, and systemic vein tocoronary artery embolism by patent foramen ovale can also be considered originsof the cTn elevation. Transmural right ventricular infarction despite normalcoronary arteries has also been found in cases of massive pulmonarythromboembolism.(62) When evaluating kinetics, some studies haveconcluded that the cTnT peak is lower and shorter than that ofAMI.(63) Although this behavior suggests that cTns arereleased from the cytosolic pool during ischemia, given such release kinetics,this hypothesis still requires testing. A meta-analysis of 20 studies with 1,985participants demonstrated that cTn elevation was significantly associated withincreased short-term mortality resulting from thromboembolism, includingsituations with a preserved hemodynamic status.(64) Another recentmeta-analysis of 1,366 patients identified a four-fold greater risk ofshort-term death in 55 patients.(65)Pulmonary thromboembolism patients with signs of shock and hypotension presenthigh mortality. After careful risk assessment, the use of thrombolytics in thesepatients is generally accepted.(10)The pathophysiological mechanism by which the cTn levels are elevated in chronicrenal failure (CRF) remains uncertain. The most investigated associations arethe presence of diffuse obstructive CAD with microinfarcts and left ventricularhypertrophy. A strong association exists between the cTnT level and the presenceof multivessel CAD in patients with asymptomatic CRF undergoing coronaryangiography.th percentile derived from the healthy general population as acutoff. In contrast to patients with preserved renal function, those with CRFmore commonly have baseline cTn above the 99th percentile,particularly when the assay is highly sensitive.(66) Therefore, aserial cTn analysis with a relative increase of approximately 20%, asrecommended by the guidelines, should be performed in the appropriate clinicalcontext for the diagnosis of AMI.(9) Both cTnT and cTnI can be used, and there isno consensus in the guidelines on the advantages of cTnI over cTnT for AMIdiagnosis in patients with CRF.(10) Importantly, both cTns are markers ofdiagnostic choice, and no substitutes are acceptable, such as the MB fraction ofcreatine kinase, with the prerogative of loss of cTn specificity in thiscontext.A study underscored the challenges in interpreting AMI in CRF using the99th percentile of the URL,resulting in a sensitivity of 94% and specificity of 86%. However, this changemay adversely change the sensitivity of the assay, and use of the URL providedby the manufacturer and/or institution for the exclusion or confirmation of AMIis advisable in these cases.(11) The diagnostic accuracy of high-sensitivityassays is also compromised in hemodialysis patients, since almost all patientshave baseline levels above the 99th percentile. In a series of 670hemodialysis patients evaluated for dyspnea or chest pain, the receiveroperating characteristic (ROC) curve for the hsTnT test was only 0.68 butsignificantly improved to 0.9 with serial evaluation over 3 hours. The mostfavorable cutoff point for the relative variation was 24%.(67) However, clinicaljudgment is a critical component for assessing chest pain in hemodialysispatients. Although the dynamic changes in markers improve the specificity forthe diagnosis of AMI in patients with CRF, relying on this parameter alone maybe associated with a loss of up to 12% of STEMI cases.(68)A study suggested that URL elevation occurred in this group of patients. In ananalysis of 75 patients with CRF, hsTnT was used with high accuracy for thediagnosis of AMI at a level twice the 99(70)During evaluation of a patient with CRF, a baseline cTnT or cTnI value shouldnever be interpreted as part of the loss in glomerular filtration alone. Evenwithout the association with AMI, elevated levels indicate a worse prognosis andshould be valued.(71) The involvement of the cardiac musculaturemanifests transiently with falls in the systolic and diastolic functions; thisphenomenon is called "heart fatigue".(72)Cardiac troponins may be elevated immediately after strenuous physical exercise,which is a phenomenon that has been studied in long-distancerunners.(73) In fact, these assays may be elevated duringshort periods of exercise in both cardiopathic and noncardiopathicpatients.(74) Several studieshave demonstrated that transient elevations do not indicate myocardial damage,since the levels normalize within 24 to 48 hours.(19) These data alsoreinforce the theory of cTn release in the cytosol and not from the structuralcontent of the myocytes.High-sensitive cTns are detected in approximately 80-86% of marathon runnersafter exercise.(75)In a meta-analysis of 1,120 individuals, Shave et al. found that the exerciseduration was related to increased cTnT levels without correlation with theparticipants' ages. With the use of high-sensitive assays, a negativecorrelation was also found between the cTn levels and performance, and anonsignificant correlation was found with age. This finding can help theclinician evaluate symptomatic patients after competitive exercises inpractice.(76)Interestingly, transient alterations in right ventricular function were found inhigh-intensity athletes. However, this finding has not added prognosticinformation to date.(19)The clinical impact of exercise-induced cTn elevations is still unclear. Symptomsduring exercise are relatively common, and marathoners presenting withdizziness, chest pain, and sometimes circulatory collapse may pose a challengefor diagnosis in the presence of elevated cTns. Currently, there are no data todiscourage athletes from competitive activity due to elevation in cTns afterexertion. Moreover, D-dimers and natriuretic peptides as well as cTns may beelevated after exercise.Lack of attention to compatible findings after high-intensity efforts, includingbiomarker elevations and transient right ventricular dysfunction in the absenceof clinical signs indicative of ACS, heart failure, or pulmonary embolism, cantrigger a costly, invasive, and unnecessary investigation. Treating the patientand not the clinical assay is still a fundamental precept.(77) Similarly, anotherstudy reported that ST-segment elevation was present in 16% of obstructive CADand 11% of nonobstructive CAD cases, respectively.(78) The recommendationis that coronary angiography should be used as an investigation if nounequivocal factor is the cause of type 2 AMI, such as known hemorrhagic shockin CAD.(79)Since the last AMI definition, diagnostic choice markers have emerged to supportclinical and electrocardiographic data. However, one of the major challenges inthe ICU environment is the differentiation between increases in cTns due tohemodynamic instability, sepsis, and other disorders and type 1 AMI.Electrocardiographic abnormalities may not provide diagnostic help, since thepresence of ST-segment elevation can occur in cases of type 2 AMI. Spatz et al.found that ST-segment elevation was present in 17% or 15% of type 2 AMI caseswhere obstructive CAD was present or absent, respectively.th percentile, ina clinical situation consistent with myocardial ischemia, and in cases with anevident imbalance between oxygen supply and demand without atheroscleroticplaque rupture and with one more criterion according to the universaldefinition. (79)The absence of spontaneous rupture and dissection of atherosclerotic plaques is apurely clinical analysis and increases the ambiguity of the AMI diagnosis due toimbalance between oxygen supply and demand, contributing to disparities in itsincidence (1.6% to 26%). The highest incidence was obtained with morerestrictive criteria. In addition, several studies did not place supply ordemand thresholds for oxygen, since several anatomical and pathophysiologicalfactors could be blamed. Patients with sepsis are also sometimes included inanalyses with those with type 2 AMI. Sepsis and septic shock share other factorsbesides the imbalance in oxygen demand and supply in their pathophysiology. Type2 AMI is diagnosed when there is evidence of necrosis due to increased anddecreased cTns with at least one value above the 99(79)Since the term was created in 2007, no practical guidelines have been availablefor management of type 2 AMI. Observational studies show that such patients aremanaged less frequently with revascularization, beta-blockers,angiotensin-converting enzyme inhibitors, statins, and antiplatelet agents, evenwhen significant CAD is present.(80) However, for patients with type 2 AMI, therewas an increase in indications for specialized cardiovascular evaluation,echocardiograms, and coronary angiography, which had no impact on the treatmentor prognosis. No specific therapy was available in these cases, and a missedopportunity actually existed. In the acute phase, it is intuitive to carry outstrategies for adequate oxygen supply and reduced oxygen demand, includingvolemic state adjustment, pressure, and inotropic support, if necessary; the useof blood products; heart rate control; and ventilatory support with an activesearch for the causal factor. Depending on the clinical situation, coronaryangiography should be used to investigate the presence of CAD. If applicable,the guidelines should be followed. However, if obstructive CAD is absent,strategies for risk reduction are scarce. In general, despite the differentdefinitions used among studies, there is a very somber prognosis for type 2 AMI,with long-term mortality reaching 63% after 3 years offollow-up.(78) Studies have focused on all-cause mortality atthe expense of cardiovascular causes.Shah et al. examined the impact of lowering the threshold of a high-sensitivetroponin test based on the incidence, management, and outcomes of type 1 andtype 2 AMI and myocardial injury. These tests resulted in higher costs, greateruse of hospital resources, and a better prognosis for type 1AMI.With the advent of high-sensitive troponin assays, both the detection sensitivity ofacute myocardial infarction and the detection of elevated marker levels insituations unrelated to acute coronary syndromes have increased. The increase in theprevalence of noncoronary conditions, which are associated with increases in cardiactroponins, presents challenges for the diagnosis of acute myocardial infarction,especially in the elderly population, in which coronary and noncoronary heartdiseases are found. Several strategies for the use of these markers have beenstudied without a definitive opinion in the current guidelines. Considering elevatedcardiac troponin values at the initial presentation is important, since thepredictive value of the test increases for cardiovascular and noncardiovasculardiseases. The behavior of the serial test can also help identify several situations,including acute myocardial infarction. This evaluation, combined with a rigorousclinical analysis, should increase the use of earlier therapeutic strategies andexclude patients with greater safety.


Alteromonadales and a higher relative abundance of marine representatives. However, the overall taxonomic structure of the saline layer was more similar to that of other snow layers and the atmosphere than to underlying sea ice and seawater. The expulsion of relatively nutrient-rich sea ice brine into basal snow might have stimulated the growth of copiotrophic psychro- and halotolerant snow members. Our study indicates that the size, composition and function of snowpack microbial communities over sea ice were influenced primarily by atmospheric deposition and inflow of sea ice brine and that they form a snow-specific assemblage reflecting the particular environmental conditions of the snowpack habitat.Sea ice and its snow cover are critical for global processes including climate regulation and biogeochemical cycles. Despite an increase in studies focused on snow microorganisms, the ecology of snow inhabitants remains unclear. In this study, we investigated sources and selection of a snowpack-specific microbial community by comparing metagenomes from samples collected in a Greenlandic fjord within a vertical profile including atmosphere, snowpack with four distinct layers of snow, sea ice brine and seawater. Microbial communities in all snow layers derived from mixed sources, both marine and terrestrial, and were more similar to atmospheric communities than to sea ice or seawater communities. The surface snow metagenomes were characterized by the occurrence of genes involved in photochemical stress resistance, primary production and metabolism of diverse carbon sources. The basal saline snow layer that was in direct contact with the sea ice surface harbored a higher abundance of cells than the overlying snow layers, with a predominance of  Snow and ice are not inert barriers, but active interfaces that mediate a range of physico-chemical and microbial reactions involved in global biogeochemical cycles4. Climate change, amplified in polar regions5, influences the extent and duration of the sea ice cover6, which in turn strongly affects climate regulation as well as marine ecosystems and global biogeochemical processes7.Sea ice, which forms, grows, melts at the ocean surface and is often overlain by snow can cover up to 22 million km8. Microbial abundance in snowpack generally ranges from 103 to 104 cells per ml of melted snow9. The atmosphere was proposed to be the main seeding source for microorganisms in snow based on several different observations. For example, the snowpacks on ice floes at three sites in the vicinity of the North Pole were shown to harbor similar microbial communities that largely differed from those in the underlying ice and seawater10. In a High Canadian Arctic study, the overlap in microbial community composition of air and snow samples with microbial mats in the region suggested the seeding of snow from adjacent cyanobacterial mats via local atmospheric transportation11. Dry deposition of long-range-transported atmospheric dust has also been described as a colonization process for non-polar glaciers and remote pristine Antarctica stations13. Another potential source for microorganisms in snowpacks over seawater is sea ice brine. Elevated microbial abundance has been observed in brine-wetted snow over arctic winter first-year sea ice, and the vast majority of the cells (up to 85%) were intact and functional, based on Live/Dead staining14. Upward brine expulsion from the ice matrix was considered to provide biomass to snow, despite potential retention of some microorganisms within the sea ice due to surface adhesion and ice-pore clogging17.Snowpacks are formed from accumulated layers of snowflakes that grow in the atmosphere around particles, including microorganisms, that act as ice nucleators leading to snow precipitation19. Because radiation and the concomitant hyper-oxidative environment are both deleterious to a wide range of biological molecules, these conditions should influence the composition and physiology of microorganisms inhabiting the snow. While numerous mechanisms for resistance to photo-oxidative stress have been characterized, such as detoxification via antioxidant production or enzymatic action21 and DNA and protein repair23, none of these traits has been described in snow microorganisms, with the exception of snow algae29. The snowpack is also considered to be a low nutrient environment30. When snow forms, it scavenges organic contaminants and persistent pollutants from anthropogenic sources32 that might act as carbon sources for snow microbial communities. Previous measurements of dissolved organic carbon (DOC) in non-saline snow over sea ice in the high Arctic have indicated that DOC concentrations are much lower in bulk melted snow (10X less) than in underlying sea ice brine (37.5 mg C L−1)33, where nutrients and microbial cells are concentrated within the ice matrix15. Capillary transport from sea ice brine into snow can bring organic material such as extracellular polymeric substances (EPS)14 along with high concentrations of salts34. The response to salt stress in a wide range of marine microorganisms involves the transport and metabolism of compatible solutes that are mainly derived from amino acid metabolism and act as osmolytes36. However, the occurrence of these mechanisms has not been evaluated in snow microbes.Within the snowpack, microbes are subjected to a range of physico-chemical conditions related to the specific structure and composition of snow. Snow is highly reactive to UV radiation and defined as a photochemical bioreactor45. These findings have contributed to snow microbial communities being considered as part of the cryo-biosphere47, but snowpack microbial ecology remains unclear. Previous suggestions have included that post-depositional processes might lead to the establishment of microbial communities specific to the snow ecosystem50, further challenging the hypothesis that microbes are simply trapped in a vegetative state in the snowpack before their release to other environments during snowmelt51. Our objective was to investigate how selection towards a snow-specific community occurs within snowpacks after deposition. To our knowledge, this study is the first to examine a complete vertical profile of microbial communities structure and potential functions, using high throughput shotgun sequencing, in an ice-covered Greenlandic fjord that includes atmosphere, snowpack, brine within sea ice and seawater. Metagenomes comparison was conducted to test the following hypotheses. First, the snow community would differ from the closely interacting and potential microbial sources: the atmosphere and underlying sea ice. Second, the differences in microbial community structure would relate to the selection of a snow-specific community harboring genetic traits linked to the conditions characteristic of the snowpack on sea ice: the potential to respond to photochemical and osmotic stress in surface and basal snow layer, respectively, as well as different trophic strategies depending on potential nutrient sources.Snowpack microbes have received growing attention in the last decade with studies showing that snow harbors numerous microorganisms that vary in terms of cell abundance, community composition and diversity depending on season, location, depth and other chemical parameters2 pristine snowfield with a homogeneous snow cover of 30 cm was selected for triplicate snow pit sampling. A vertical profile was sampled  with no close source of human activity (around 15 km). Due to logistical issues, air sampling was performed on the adjacent coast using a 0.1 μm filter mounted on a Swinnex connected to a remote downstream vacuum pump for the duration of the sampling on the fjord. A 10 m53. Libraries were purified using AMPure XP beads (New England Biolabs) and their concentration was normalized following Illumina Nextera XT protocol. Bioanalyzer and High Sensitivity DNA Kit (Agilent) were used to check the fragment size distribution of each library. Libraries were sequenced on an Illumina Miseq sequencer based at the Environmental Microbial Genomics group in Laboratoire Ampère  with 2 × 250 bp chemistry (MiSeq Reagent Kit v2).Filters and cells possibly detached from the filters were subjected to three successive rinsing/centrifugation steps using a phosphate buffer solution (PBS) to remove the RNAlater reagent. Total nucleic acids were extracted using the Power Water RNA isolation kit (Machery-Nagel), following manufacturer instructions, except that the DNAse treatment step was omitted . Libraries of total genomic DNA were prepared using Nextera XT preparation kit (Illumina) following the manufacturer’s instructions, except that we increased the number of PCR amplifications to 13 cycles as indicated for low DNA input (0.1 ng/µl in our case)54. Due to high variability in sequenced fragment size, forward and reverse reads were not paired and used as technical duplicates (marked with 0.1 or 0.2 at the end of sample name) to verify the congruity of annotation between the forward and reverse reads pools. Metagenome coverage was checked using NonPareil355 based on k-mer redundancy in the datasets and varied from 12% for seawater and up to 35% in surface snow. Quality-checked reads were aligned against the non-redundant (nr) protein reference database using Diamond BlastX algorithm56 and alignment outputs were filtered to an e-value threshold of 10e−5. Taxonomic composition and functional annotations were analyzed with MEGAN 557. Specifically, taxonomic assignment of each metagenomic read was based on last common ancestor (LCA) of all hits matching NCBI genome database as referenced in MEGAN GI accession number data release from March 2015. Reads with identified protein function  were assigned to hierarchical subsystems based on SEED58, KEGG59, and COG60 databases. For specific functions, such as melanin, scytonemin, mycosporine-like amino acids (MAAs) and mannitol biosynthesis, metagenomes were aligned against specific databases created from the NCBI protein database and retrieved using GERMLAB scripts. Microbial attributes were obtained from organisms with described features in NCBI database and referenced in MEGAN5. Trophic life styles were investigated using the ratio of COG functions characteristic of oligotrophy or copiotrophy determined by marine genomes and metagenomes in 2009 by Lauro et al.61. Statistical analyses were performed using STAMP62 and R-packages: ade4tkGui63, pvclust64, and vegan65.Raw sequencing data were filtered using the base quality upon read length with the fastX toolkit3 cells ml−1 of melted snow. Cell abundance was approximately ten times higher in the basal saline snow layer (SL3) (3.7 × 104 cells ml−1) than the surface layers and lower than that observed in the sea ice brine and seawater  in the upper two layers SL0, SL1) for bulk (melted) snow and increased with proximity to the sea ice from 1 ppt in the middle snow layer (SL2) to 10 ppt in the basal saline snow layer (SL3), and peaked in the sea ice brine at 54 ppt; seawater salinity was 34 ppt  and were mostly Bradyrhizobium. This taxon was also dominant in the surface snow layers (17% in SL0 and SL1). The surface snow samples  harbored a high relative abundance of Saccharomycota, Actinomycetales, Alteromonadales, Acidobacteriales. Cyanobacteria from the order of Nostocales were also observed with high relative abundance in some samples (up to 17% in SL1). Within the dominant groups, some families, such as Ktedonobacteraceae, Cytophagaceae and Pezizomycotina, co-occurred in surface snow samples  with significantly higher relative abundances than in the atmosphere, saline snow, sea ice brine and seawater samples . The structure of this order was very similar among all snow samples and dominated by Glaciecola (about 80%), whereas the atmosphere, sea ice brine and seawater samples harbored numerous other Alteromonadales representatives including Psychromonas, Colwellia, Shewanella and Pseudoalteromonas , Protists (Saprolegniaceae and Dictyosteliida) and algae  compared to all other samples , unclassified Proteobacteria , Thaumarchaeota (8%) and Euryarcheota (7%) were rarely observed in any of the snow layers  in seawater (approx. 2.5%) and in sea ice brine (approx. 5%), but were rarely detected in snow samples.The basal saline snow SL3) was dominated by nas Fig. . SL3 als was domiers Fig. . High abCyanobacteria, which were detected in high relative abundance in surface snow, or algae in saline snow, sea ice brine and seawater  of the relative abundance of functions (185 KEGG categories) produced four major groups related to sample type: seawater, brine, saline snow and a more dispersed group with surface snow samples  and atmosphere together Fig. . The moster Fig. . Major dter Fig. . Reads a61), microbial communities in our surface snow samples  were characterized as oligotrophic and in seawater as extremely oligotrophic, whereas microbial communities from the saline snow layer (SL3) and sea ice brine samples exhibited traits of copiotrophy  might prevent the selection towards microbes with specific genes involved in resistance to photochemical stress. DNA repair mechanisms, widespread among all kingdoms22, were detected with similar abundance in all samples, but genes for base excision repair, which is involved during indirect damage to DNA mediated by reactive oxygen species (ROS), were higher in surface snow. The mechanisms identified in our surface snow samples also included a wide range of specific enzymatic responses  and the production of non-enzymatic sunscreen and antioxidants in photosynthetic organisms  and non-photosynthetic organisms .Although UV extinction with snow and sea ice depth was not evaluated in our study, genes involved in resistance to photochemical stress were detected in higher relative abundance in the surface snow layers than in all other horizons and the atmosphere. Microorganisms are also subjected to high radiation in the atmosphere, and cloud microbes that were exposed to UV light in microcosms have been shown to remain metabolically active in the presence of OH radicals72. The mineralization of radiolabeled 2,4-dichlorophenoxyacetic acid was observed in surface ice cores of the Greenland ice sheet73, underlining the involvement of snow microbes in organic carbon contaminant cycling.Heterotrophic organisms dominated the microbial communities in all horizons sampled in our study. Surface snow layers exhibited genomic features associated with oligotrophy, even though a greater degree of oligotrophy was observed in the underlying seawater. Surface snow had a higher relative abundance of genes involved in lipid transport and metabolism, cyotochrome P450, and the biosynthesis, transport and catabolism of secondary metabolites. We also observed an increase in gene abundance for carbohydrate metabolic pathways, such as the degradation of starch, sucrose and some xenobiotic compounds, confirming the potential for metabolic versatility of snow microbial communities as highlighted in other studies. For example, microcosms of melted antarctic snow exhibited a higher rate of carbon uptake when amended with a combination of simple and complex carbon sourcesCyanobacteria in surface snow and eukaryotic algae in deeper layers . Diverse genes involved in primary production were identified in surface snow samples, although the carbon fixation pathway was less represented in surface snow sequences than in saline snow layer, brine and seawater. However, these processes may be underestimated in surface snow. Along with highly abundant Nostocales, numerous sequences were associated with uncharacterized Cyanobacteria that were difficult to annotate functionally. Based on our data and those of another study on microbial communities in late spring Greenland sea ice snow41, Cyanobacteria were the most abundant in the middle layer, which might be due to their development at a depth corresponding to optimum light levels. Distribution of Cyanobacteria as a function of snow depth has also been correlated with nitrogen availability in arctic terrestrial spring snow4. The distribution of Cyanobacteria is largely heterogeneous within the surface layer, where Nostocales represented up to 17% of reads in one of our biological replicates, suggesting their development in small patches. Some sequences of non-oxygenic primary producers were also detected , which is consistent with a previous report suggesting the occurrence of anaerobic niches in the highly porous terrestrial snowpacks50.Our study supports the hypothesis that primary producers occur within snowpack, composed mostly of Alteromonadaceae, Oceanospirillaceae, Shewanellaceae, and Pseudoalteromonadacea, include halotolerant marine representatives. In a concurrent study measuring 14C-labelled choline uptake, sea ice microbial communities were observed to transport and retain 14C-solutes as intracellular osmolytes when salinity was increased52. The rise in relative abundance of the genes involved in choline uptake and bioconversion to the osmoprotectant glycine betaine that we observed in the saline snow layer microbial community (compared to surface snow and even to sea ice brine and seawater) is consistent with the use of compatible solutes for osmoprotection. The most abundant genus in the saline snow, Glaciecola, lacks the catabolic pathway of sarcosine oxidase, and this pathway and general amino acid metabolism were underrepresented in the basal snow as compared to the brine and seawater. While the genes encoding choline uptake and bioconversion are widespread in halotolerant microorganisms, the capacity to further catabolize glycine betaine via sarcosine oxidase is rarer and may represent a long-term adaptation to the sea ice environment74.Although the microbial community we observed reflects a snow-specific assemblage that differed from sea ice brine and seawater, basal saline snow shared a critical environmental constraint with the underlying marine horizon: high salinity due to capillary transport from sea ice brine into the basal snow layer. Most of the microbial families detected in higher abundance in the saline snow layer relative to surface snow, such as Alteromonadales, might be at a competitive advantage to maintain elevated metabolic rates despite cold temperatures and high salinity. Numerous predominant taxa in sea ice brine samples, such as Rhodobacterales and its most represented genus Octadecabacter, were far less frequent in saline snow than in brine despite demonstrating many genomic features of adaptation to icy, saline and polar habitats76. Further studies are needed to decipher if the source of saline snow community is an enrichment of snow microbes, upward seeding from sea-ice brine or a combination of both.The microbial community in the saline basal snow layer exhibited numerous genetic features of copiotrophy, a higher microbial biomass levels (based on cell counts) relative to surface snow layers and an increase in representatives described as psychrophiles, as found in the sea ice brine microbial community. Although we did not measure DOC in our samples, we hypothesize that brine capillarity into the basal snow layer delivers not only salts but also nutrients that stimulate the growth of organisms already present in the snow and lead to their selection. In particular, halotolerant, copiotrophic, psychrophilic or psychrotolerant snow organisms, such as belonging to the group of 78. A parallel study carried out at our study site using epifluorescence microscopy confirmed elevated densities of viruses and high virus-to-bacteria ratios in both sea ice brine and seawater52. Virus-host interactions are thought to be a key feature of sea ice ecosystems, with a major role of viruses in the control of bacterial populations and nutrient turnover81. Our metagenomic results, however, did not provide evidence of the transport of viruses from sea ice brine into snow or of viral reproduction in the saline snow layer, leaving the importance of viruses in snow microbial ecology completely unknown.Sequences annotated as viruses were detected in high abundance in seawater and sea ice brine, representing up to 2.5 and 5% of the reads, respectively, while less than 0.1% in saline snow. Genes involved in DNA metabolism  were the most virally enriched auxiliary metabolic genes (acquired from host genomes) in sea ice brine and seawater datasets, as previously observed in temperate ocean metagenomesCyanobacteria, likely blooming in patches in surface snow, and of diatoms in saline snow, as well as some non-oxygenic producers, highlighted the potential for primary production. A high versatility in carbon source utilization within the predominant heterotrophic community was also observed. The saline snow layer, potentially fed with nutrients from the upward expulsion of sea ice brine, likely supported the growth of copiotrophic, psychro- and halotolerant snow members and could represent a unique niche with elevated microbial activity. Numerous questions remain as the spatial and time scales of snow microbial life cannot yet be compared to the high chemical and physical dynamics of Arctic snowpacks, limiting our understanding of snow microbial processes. A combination of microbiological data with detailed chemical profiles, measured in sufficient resolution to circumvent the highly variable structure of snowpack, will be necessary to further address the contributions of snow-specific microbial communities to large-scale geochemical cycles and evaluate the impact of their potential loss due to climate change.The Greenland fjord snow–ice microbial communities that we studied were strongly influenced by their atmospheric seeding sources, with organisms originating from terrestrial and marine environments as well as generalists retrieved ubiquitously. We inferred that post-depositional selection processes occurred in the snow to form a snow-specific microbial community Fig. . ComposeSupplementary Information


Evidence on the cellular role, developmental and cell-type expression profiles of these six diverse JME genes, point to their pathogenic variants driving the first steps of brain development when cell division, expansion, axial, and tangential migration of progenitor cells  sculpture subtle alterations in brain networks and microcircuits during development. These alterations may explain “microdysgenesis” neuropathology, impulsivity, executive dysfunctions, EEG polyspike waves, and awakening m-t-c convulsions observed in JME patients.Juvenile myoclonic epilepsy (JME), a lifelong disorder that starts during adolescence, is the most common of genetic generalized epilepsy syndromes. JME is characterized by awakening myoclonic jerks and myoclonic-tonic-clonic (m-t-c) grand mal convulsions. Unfortunately, one third of JME patients have drug refractory m-t-c convulsions and these recur in 70–80% who attempt to stop antiepileptic drugs (AEDs). Behavioral studies documented impulsivity, but also impairment of executive functions relying on organization and feedback, which points to prefrontal lobe dysfunction. Quantitative voxel-based morphometry (VBM) revealed abnormalities of gray matter (GM) volumes in cortical  and subcortical structures . Proton magnetic resonance spectroscopy (MRS) found evidence of dysfunction of thalamic neurons. White matter (WM) integrity was disrupted in corpus callosum and frontal WM tracts. Magnetic resonance imaging (MRI) further unveiled anomalies in both GM and WM structures that were already present at the time of seizure onset. Aberrant growth trajectories of brain development occurred during the first 2 years of JME diagnosis. Because of genetic origin, disease causing variants were sought, first by positional cloning, and most recently, by next generation sequencing. To date, only six genes harboring pathogenic variants  Genetic generalized epilepsies (GGEs), previously known as idiopathic generalized epilepsies, constitutes about 30% of all epilepsies. Based on the recent 2017 ILAE classification, GGEs mainly encompass four epilepsy syndromes: childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalized tonic-clonic seizures (GTCS) alone. Among these GGEs, JME represents the major part  and is lifelong with few antiepileptic drugs (AED) demonstrating good efficiency.In this manuscript, we will review the current knowledge about JME and discuss its pathophysiology. We will start by recalling the symptoms that define the JME syndrome. Next, we will describe the cognitive and behavioral phenotypes of JME patients and their siblings. Then, we will summarize the huge literature on the morphological, molecular, and functional neuroimaging of JME. Specific attention will be given to JME genes that harbor pathogenic variants in JME patients and that demonstrate Mendelian transmission and complex inheritance. We will explain what is known about the cellular roles of JME genes and describe the consequences of the mutations. Finally, we will review the cellular correlates of structural changes observed by MRI and will advance a hypothesis on how pathogenic variants of JME genes could interfere with brain development and produce the symptoms and signs of JME.Juvenile myoclonic epilepsy, called “Janz syndrome” in Europe and “Castels and Mendilaharsu Syndrome” in South America, was first described in 1854 by Delasiauve  and soon after by Herpin in 1867  . JME is sine qua non” to define the JME syndrome. MJs, during which full consciousness is retained, typically occur in the half hour that follows morning awakening or after an afternoon siesta. Brief, bilateral, and arrhythmic muscular contraction with variable repetition and amplitude, predominate in the upper limbs involving, in general, the dominant hand.Based on the ILAE definition , and a cIn 80–95% of patients, a longer cluster of MJs occurs with increasing amplitude and frequency, until MJs lead to the tonic phase of the tonic-clonic seizure [“myoclonic-tonic-clonic (m-t-c)” grand mal in the 2017 ILAE classification]. Typical absences seizures or “petit mal” , with miSeizures are often precipitated by lack of sleep (84%), stress (70%) or alcohol consumption (51%). Less frequently, various factors or behaviors such as hormonal shifts during menstruation, light stimulations, drug abuse, or praxis or action-programing activities trigger seizures. Response to antiepileptic drug treatment, mainly valproate, is reported as “good” but one third of JME patients are refractory and seizures recur in 80% of patients who attempt to stop antiepileptic drug treatment .Despite the fact that in its initial description, Although not defined as a psychiatric disorder, the prevalence of psychosocial dysfunctions in JME ranges between 22 and 75% . As repoSocial cognitive skills have also been examined in GGE patients. A first study reported impairment in recognition of facial emotions in GGE patients whereas both facial emotion recognition and facial identity recognition were impacted in patients with mesial TLE . AnotherThe origin or cause of these behavioral problems in JME is still being debated. On one hand, studies have suggested that personality disorders observed in epilepsies may be genetically determined. Others suggest that such behavioral problems are the consequences of the social life and relationship difficulties produced by seizure activity .Some research studies evaluated the contribution of anti-epileptic drug treatment, epilepsy duration or seizure control to the behavioral problems in JME patients. Broader impairments in cognitive functions and impulsive traits were observed in JME groups with treatment refractory seizures as compared to those for whom seizure control was effective . Some stBecause JME is of genetic origin (see section “Genes Associated With JME and Their Cellular Role”) and because seizure repetitions or antiepileptic medications may contribute to the neuropsychological profile of JME patients, the study of siblings has drawn particular attention. Iqbal was the first to compare JME patients and clinically unaffected siblings to a control group during a set of neuropsychological measures. This comparison pointed out that both JME patients and siblings performed worse than controls . JME patFor a long time, brain of JME patients were considered “normal” from a structural point of view. However, the development of more powerful MRI machine and of computational analysis allowing quantitative measurements of brain structures revealed several small differences in JMEs brains. Since the first paper published by Swartz in 1996 , a searcOnly in extremely rare occasions do autopsy brains of JME and GGE patients become available for postmortem studies. In 1985, the first opportunities in eight GGE patients (including three JME cases) provided Meencke and Janz from the Berlin school of epileptology enough evidence to propose the concept of “slight migration disturbances” which they called “microdysgenesis” in epilepsies. They associated “diffuse increase of single dystopic neurons in the stratum molecular and in the subcortical white matter (WM) in different areas of the brain” with idiopathic or primary generalized epilepsies . Lyon anBased on the data from Meencke and on electromyogram recordings showing that anterior horn cells of JME patients are altered suggesting a reduction of axon numbers , it is pIn conclusion, it is important to continue neuropathological studies of JME brains so that in the future, it will be possible to confirm/refute the existence of these microscopic structural abnormalities, and if confirmed, to refine their nature  and precise their location.Woermann and collaborators were the first to find an increase in mesiofrontal gray matter (GM) thickening in JME patients using voxel-based morphometry (VBM). Sometimes, such thickening increase is associated with abnormal cortical organization . VBM is in utero process  . All of Several studies also reported that the cerebellum was involved in JME. One study demonstrated a positive correlation between the cerebellar WM volume and the age of seizure onset . JME andIn order to better understand the neuropsychological profile of JME patients, one study assessed working memory using a verbal and visuo-spatial fMRI paradigm. No difference on activation patterns was found between JME patients and controls . With a 1H-MRS) detected a specific decrease of N-acetyl aspartate (NAA) in the prefrontal cortex and frontal lobe of JME patients (18Fluoro-DeoxyGlucose (18FDG) uptake was increased in the thalamus of JME subjects and was positively correlated with the amount of generalized spike-wave (GSW)  . When 18xibility .The above imaging data were obtained using cross sectional studies (studies at one-time point) conducted mostly on patients suffering from recurrent seizures and/or that were under medication for many years. To decipher the origin of these differences in brain imaging and neuropsychologic findings, longitudinal experiments were designed to answer the following questions: do the brain imaging abnormalities and neuropsychologic impulsivity and executive dysfunction result from developmental variations preceding the first seizures or are they consequences of epilepsy-related factors i.e., chronic seizures and/or antiepileptic medication?When patients were evaluated within their first year of epilepsy, a smaller thalamic volume, more frontal cerebrospinal fluid (CSF) and executive dysfunctions were already detected in JME children but not in subjects suffering from benign childhood epilepsy with centrotemporal spikes . On the Two studies concentrated on the dynamic changes over time in the same individuals in relation to JME development. In the first study, children diagnosed with JME within the past 12 months and a control group were followed for 2 years . SignifiGREM1 (a member of the DAN family of bone morphogenic protein antagonist), OR10S1 (a member of the Olfactory receptor family), PPEF2 (serine/threonine phosphatase with an EF-hand domain), CHD1 (a member of a family of protein containing a chromo and a helicase domain), and PSME2 (subunit 2 of proteasome activator complex). Another more recent GWAS identified ultra-rare genetic variations in genes encoding GABAA receptor subunits in GGE patients  have been identified. All pathogenic variants with the exception of BRD2, are autosomal dominant traits. These genetic variations underlying JME cover only a small proportion of the JME world population. Only EFHC1 and ICK have been replicated in a sizable percentage of at least two separate countries of specific ancestral origin. We review their roles in the order of their discovery.The studies performed by Lennox on relatives and twins were the first to reveal the importance of genetics in epilepsies . These fpatients . AlthougA receptor GABRA1 gene in one large French-Canadian family from Quebec. It was the first mutation to be identified in autosomal dominant JME  in the alpha 1 subunit of the GABAnant JME . Since trequency .A receptors  was initially identified as a susceptibility allele for both JME and genetic epilepsy with febrile seizure plus (GEFS+). Two different missense mutations were reported, one in the GEFS + family (E177A) and another (R220H) in the JME patients (GABRD mutations have been reported in JME.The gene encoding the delta subunit of the GABAA receptor patients . No furtGabrd-KO mice has been shown to be more prone to seizures induced by pentylentetrazol (PTZ) and in the dentate gyrus, faster decay of evoked IPSPs was recorded (Both (E177A and R220H) mutations decreased current amplitude when expressed along with GABRA1 and GABRAB2 subunits in HEK cells . When threcorded .EFHC1 (EF-Hand containing-1) gene in chromosome 6p12 co-segregate in 21 affected members of six unrelated families from Belize and Mexico  experiments demonstrated that both shRNA and overexpression of pathological mutants, but not variants, impaired radial and tangential migration of neuroblasts when analysis is performed after 3 days at E17.5  gene  in the promoter region of the  2) gene . This SN 2) gene .Brd2-Het female mice exhibited spontaneous seizure  family of proteins. It is a transcriptional regulator that associates with transcription complexes and also acetylated histone H4 . It is p seizure . Under f seizure .CASR  gene co-segregates in affected members of a three-generation family and in 5 singleton individuals from south India  was the latest gene identified by linkage and whole exome sequencing with heterozygous pathogenic variants co-segregating with affected members of two large and 8 medium sized JME families from Mexico, Honduras, Belize, and Japan, indicating transmission of an autosomal dominant gene. A total of 21 pathogenic heterozygous missense mutations in 22 patients belonging to a cohort of 310 JME probands (7%) were reported  result (reported . When p.) result .Ick-KO mice died around birth probably because of respiratory failure but brain malformations were observed around E17.5 and ciliary defects were detected in the neural tube  for 6%, synapses for 6%, dendrites for 30% and non-myelinated axons for 29% . Of courde novo myelination. A fundamental emerging concept is that OLs do provide metabolic support to the axon they myelinate as, via their NMDA receptors, they sense axon energy demand . In the human brain, OPC represent 10–15% of glial cells . In the y demand .in vivo may not be directly related to the sole changes in number of axons or of their myelination. Progress is being made to fully characterize WM non-invasively, giving the hope that soon, we will be able to perform “in vivo histology of the human brain”  and their dynamics in different cell types with putative important consequences for various processes taking place during brain development such as cell division and migration of progenitors, neurite, and synaptic boutons formation. Beside its importance for division of progenitors, MT reorganization driven notably by a severing mechanism is essential for interneuron precursor migration, for dendrite/axons formation and also neuronal connectivity changes due to synapse rewiring as demonstrated in C. elegans . Presynaptic CaSR blocks the non-selective cation channel (NSCC)  . CaSR isrmed OLs  and affermed OLs . Finallyntiation .in vivo.Based on the cellular roles of proteins encoded by genes associated with JME, we hypothesize that, rather than pointing toward a single common mechanism, different and diverse but not necessarily overlapping developmental steps may be affected and may lead to, or favor, adolescent onset JME. However, much more work is needed to precisely identify the cellular and molecular details of the brain defects that are induced To summarize the above data: (1) Frontal lobe dysfunction, as evidence by impulsivity and dysexecutive cognitive traits, is present in JME patients and their clinically unaffected siblings; (2) MRI and PET investigations show morphological and functional differences in patients with JME compared to controls; (3) The thalamus, frontal cortex, SMA, corpus callosum and thalamocortical tracts are the most commonly impacted structures with varying changes reported in different JME patients; (4) Structural differences are already detected when seizures start during adolescence, suggesting these structural changes precede the symptomatology of JME; (5) Five Mendelian genes  and one complex inheritance gene (BRD2) that statistically associate with JME more than by chance, fulfill various roles in cellular function. Some of these JME genes are expressed not only by neurons but also by OLs.post-mortem brains revealed different cytoarchitectural defects such as alteration of neuronal densities, heterotopias or poorly defined neuronal layers but these are not detected by present brain imaging methods  might reveal a “better picture” of the morphological and functional abnormalities that are present in JME. In recent years, for example, we have come to realize many cases of surgically resected focal epilepsy result from MRI negative microscopic FCD. These type I cortical dysplasia can be undetectable by current 3 Tesla MRI inspection but are found by histopathological analysis, to be very similar to what was originally described as “microdysgenesis.” In autism, a similar experience has been reported. Cortical neuropathology on  methods .In conclusion, based on present evidentiary data, JME does not result from the simplistic concept of an endogenous imbalance between excitation and inhibition thresholds of a neuron or a group of neuron(s) in an otherwise histologically normal brain. Rather, evidence points to alterations in the first steps of brain development when cell division, expansion and migration of progenitor cells, including interneuron cortical progenitors, driven by pathogenic variants of diverse JME genes, sculpture subtle alterations in brain networks/microcircuits structure, and dynamics that in turn subserve the psychosocial, cognitive and seizure phenotypes of JME. Now, we have to explain how these networks and microcircuits imbalances ignite into the symptomatology of explosive awakening myoclonias and grand mal m-t-c convulsions that are triggered by sleep deprivation, hormonal shifts and fatigue.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


To evaluate the consequences of the decline in mtDNA content associated with aging we have created an inducible mouse model expressing, in the polymerase domain of POLG1, a dominant-negative mutation that induces depletion of mtDNA. We utilized this inducible mouse model to modulate mitochondrial function by depleting and repleting the mtDNA content. We demonstrate that, in mice, ubiquitous expression of dominant-negative mutant POLG1 leads to 1) reduction of mtDNA content in skin, 2) skin wrinkles, and 3) hair loss. By turning off the mutant POLG1 transgene expression in the whole animal, the skin and hair phenotypes revert to normal after repletion of mtDNA. Thus, we have developed whole-animal mtDNA depleter-repleter mice. These mice present evidence that mtDNA homeostasis is involved in skin aging phenotype and loss of hair and provide an unprecedented opportunity to create tissue-specific mitochondrial modulation to determine the role of the mitochondria in a particular tissue.


Major depressive disorder (MDD) is a common emotional cognitive disorder that seriously affects people’s physical and mental health and their quality of life. Due to its clinical and etiological heterogeneity, the molecular mechanisms underpinning MDD are complex and they are not fully understood. In addition, the effects of traditional drug therapy are not ideal. However, postmortem and animal studies have shown that overactivated microglia can inhibit neurogenesis in the hippocampus and induce depressive-like behaviors. Nonetheless, the molecular mechanisms by which microglia regulate nerve regeneration and determine depressive-like behaviors remain unclear. As the immune cells of the central nervous system (CNS), microglia could influence neurogenesis through the M1 and M2 subtypes, and these may promote depressive-like behaviors. Microglia may be divided into four main states or phenotypes. Under stress, microglial cells are induced into the M1 type, releasing inflammatory factors and causing neuroinflammatory responses. After the inflammation fades away, microglia shift into the alternative activated M2 phenotypes that play a role in neuroprotection. These activated M2 subtypes consist of M2a, M2b and M2c and their functions are different in the CNS. In this article, we mainly introduce the relationship between microglia and MDD. Importantly, this article elucidates a plausible mechanism by which microglia regulate inflammation and neurogenesis in ameliorating MDD. This could provide a reliable basis for the treatment of MDD in the future. Major depressive disorder (MDD) is a common neuropsychiatric disorder with multiple contributing factors—both genetic and environmental—that now affects approximately 350 million people worldwide , a potent activator of proinflammatory cytokines, was found to induce depressive-like behaviors  inflammasome and so on  Microglial cells respond to stress through neuroinflammation. This “cytokine hypothesis of depression” proposes that inflammatory cytokines play a key role in the crosswalk of the neurochemical, neuroendocrine, and neurotrophic systems of depressive disorder. It is supported by the evidence that the administration of proinflammatory cytokines in both plasma and CSF have been found to influence the progression and severity of MDD in different populations  The enteric-brain axis is a system involved in the activation of microglia. In depressed patients, antidepressant treatment has been associated with the dysregulation of the HPA axis  NLRP3 inflammasome activates microglial cells. Inflammatory processes have been implicated in both acute and chronic stress conditions. The molecular steps leading to IL-1β maturation and a caspase-activating complex take place in an intracellular complex termed the inflammasome  Glucocorticoids induce microglia activation. Most people with MDD showed elevated levels of inflammatory biomarkers. The HPA axis is a major endocrine system that regulates inflammatory responses. Although glucocorticoids are generally anti-inflammatory, they can promote inflammation under certain situations, especially when the brain homeostasis has been disrupted; in this case, glucocorticoids activated microglia respond to a range of immune challenges, including injury, trauma, or infection  The norepinephrine system is also thought to be a stressor of activated microglia. Both social and psychological stress cause the release of norepinephrine, and these signals are released by various immune cells, including microglia. Primary microglia expressed beta(2) adrenergic receptor (AR) and norepinephrine and isoproterenol upregulated the expression of receptor mFPR2, a mouse homolog of human formyl peptide receptor FPR2 that activated beta(2) AR in microglia. Furthermore, the activation of beta(2) AR on microglia induced the expression of an insulin-degrading enzyme and increased the degradation of Aβ42  Physiological stress may also trigger microglia activation directly by releasing damage-associated molecular patterns (DAMPs) in the brain. The DAMP acts on the toll-like receptor 4 (TLR4) receptor of microglia, producing dangerous signals that are further passed on and cause changes in microglia; specifically, acute stress induces the production of high mobility group box-1 protein (HMGB1) in the DAMP, which enables the microglia to secrete proinflammatory factors, leading to upregulate the gene expression of microglial matrix metal proteins  The activity of neurons causes the activation of microglia. Microglia are involved in synaptic pruning both in development and in the mature CNS. It is now known that, under certain conditions, microglia may adopt a proneurogenic phenotype, which involves the expression of neurotrophins and anti-inflammatory cytokines, such as insulin-like growth factor 1 (IGF-1), brain-derived neurotrophic factor (BDNF), and IL-4  microglia often release inflammatory mediators that severely result in the injured tissue . This activation of microglia by LPS was found to decrease adult neurogenesis, specifically by inhibiting the proliferation or the survival of the new cells  phenotype operates in both neuroprotection and reconstruction of neural networks in the brain. The M2 microglial cells are distinguished by the release anti-inflammatory mediators, such as IL-4, IL-10 and transforming growth factor-(TGF) ß  to alternative activated (M2) cells  and transcription factors (TFs) in microglia (Guedes et al., Microglial cells have multiple activation states, namely M1 and M2, that have different effects on modulating neurogenesis in normal and disease conditions. For some, clinical depression is caused by decreasing neurogenesis. Understanding whether the approaches are able to regulate key factors to transform the microglial phenotype for treating MDD is still a great challenge. Much work remains to be done, but it is possible that a deeper understanding of the interplay between different activations of microglia and adult hippocampal neurogenesis may help to develop future strategies to treat MDD.The review article elaborately discusses the fact that the activated microglia phenotypes are related to MDD and are helpful for precisely regulating microglia to explore the mechanism of treatment of MDD.The hypothesis of neurogenesis and inflammation, which complement the defects of monoamine hypothesis, gives us a better understanding of the pathogenesis of MDD. Changing the microglial structure and function may link the two hypotheses.The review further elucidates the relationship between inflammation–microglia and neurogenesis–depression symptoms. Such correlations might be of value in the development of a new generation of antidepressants.LZ collected the literature and wrote the manuscript. JZ drew the pictures and revised the article. ZY approved the manuscript and helped in obtaining financial support.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.


This review highlighted resistance training as an important training type for the brain. Most studies that use physical exercise for the prevention or treatment of neurodegenerative diseases have focused on aerobic physical exercise, revealing different behavioral, biochemical, and molecular effects. However, recent studies have shown that resistance training can also significantly contribute to the prevention of neurodegenerative diseases as well as to the maintenance, development, and recovery of brain activities through specific neurochemical adaptations induced by the training. In this scenario we observed the results of several studies published in different journals in the last 20 years, focusing on the effects of resistance training on three main neurological aspects: Neuroprotective mechanisms, oxidative stress, and cognition. Systematic database searches of PubMed, Web of Science, Scopus, and Medline were performed to identify peer-reviewed studies from the 2000s. Combinations of keywords related to brain disease, aerobic/resistance, or strength physical exercise were used. Other variables were not addressed in this review but should be considered for a complete understanding of the effects of training in the brain. Most studies suggest the use of physical exercise to decrease the risk of cardiovascular , pulmona2+/calmodulin-dependent protein kinase II (CaMKII), and fodfatidilinositol 3-quinase (PI3K)/protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) which act upon specific targets and modulate gene expression through transcription and translation processes [Despite aerobic exercise being more associated with neuroprotective mechanisms , recent rocesses . The effThe brain is susceptible to physical exercise by a change in the neuronal redox state. The acute response to physical exercise increases blood flow and enhances cell metabolism , adaptivAccording to Varendi and colleagues , the BDNThe effects of exercise on BDNF production could be systemic however, exercise mediated changes in BDNF levels in the central nervous system have been the most studied to date. BNDF acts on certain neurons in the central and peripheral nervous system, regulating existing neurons and stimulating the growth and differentiation of new ones . As one It has been reported that BDNF is involved in neural survival and differentiation  which coThe results of the effect of resistance training on BDNF levels are diverse. Studies in humans showed that no alterations ,36,37 orThe brain is highly sensitive to oxidative stress due to its high levels of phospholipids and polyunsaturated fatty acids . These mAerobic physical training has been used in different studies in humans ,55,56,57Although the cellular mechanisms involved in the regulation of brain oxidative stress by resistance exercise are not fully understood, it is possible to speculate that the adaptive changes induced by resistance training from muscle involve the up-regulation of antioxidant and brain redox regulation from different proteins and pathways, such as the mammalian target of rapamycin (mTOR), a serine/threonine kinase important for cell growth, proliferation, and survival of brain  as well BDNF release from muscle contraction reaches the brain and binds to Tropomyosin receptor kinase B (TrkB) to induce phosphorylation of different cascades of signaling pathways: PI3K/AKT/mTOR, Pi3K/AKT/CREB, Pi3k/ERK/CREB, and phospholipase Cγ (PLCγ)/CamKII/CREB. The activation of these different signaling pathways results in the additional secretion of the BDNF. In additional, it is possible that the brain mTOR and CREB signaling are also important targets of resistance exercise. These observations are supported partially by previous studies that showed PI3K/mTOR signaling  and elevS-transferase (GST), NAD(P)H: quinone oxidoreductase 1 (NQO1), and γ-glutamatecysteine ligase (GCL) [The BDNF leads to the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) , which rse (GCL) . This mePrevious studies have showed that strength training promotes the upregulation of Nrf2 in the central nervous system after experimental autoimmune encephalomyelitis (EAE) induction . SimilarThere is not much evidence regarding the effects of resistance training on higher brain functions such as cognition, executive function, and attention. The primary outcome of major clinical trials was muscle strength ,93,94, fCognition is the ability to process information through perception, knowledge acquired through experience and context, and personal characteristics that integrate all information to interact with the environment. Aging and many neurological diseases impair cognitive functions, from mild cognitive impairment to severe dementia with Alzheimer’s disease being the most prevalent dementia . Some muPreclinical experimental studies focused on the effects of resistance training in the hippocampus of adult male rats. Cassilhas and colleagues  demonstrClinical studies have also demonstrated the benefits of strength exercise in the executive function ,94,95, aCognitive inhibition is strongly associated with working memory. The core executive function of working memory involves storing information and mentally working with it ,103. AgiThe effects of resistance exercise on the brain are not yet fully understood due to the few studies available so far. Although promising, these studies do not allow for a definitive conclusion regarding the effects resistance exercise on the brain’s redox and cognitive mechanisms. In some cases, associations were speculative and further investigations are required. In this regard, future studies in animals and humans may fill these gaps and contribute to further understanding the effects of resistance exercise on the brain.