PET Imaging of Post-infarct Myocardial Inflammation.

Funder: Department of HealthPurpose of reviewTo examine the use of positron emission tomography (PET) for imaging post-infarct myocardial inflammation and repair.Recent findingsDysregulated immune responses after myocardial infarction are associated with adverse cardiac remodelling and an increased likelihood of ischaemic heart failure. PET imaging utilising novel tracers can be applied to visualise different components of the post-infarction inflammatory and repair processes. This approach could offer unique pathophysiological insights that could prove useful for the identification and risk-stratification of individuals who would ultimately benefit most from emerging immune-modulating therapies. PET imaging could also bridge the clinical translational gap as a surrogate measure of drug efficacy in early-stage clinical trials in patients with myocardial infarction. The use of hybrid PET/MR imaging, in particular, offers the additional advantage of simultaneous in vivo molecular imaging and detailed assessment of myocardial function, viability and tissue characterisation. Further research is needed to realise the true clinical translational value of PET imaging after myocardial infarction

Novel Positron Emission Tomography Tracers for Imaging Vascular Inflammation

Abstract: Purpose of Review: To provide a focused update on recent advances in positron emission tomography (PET) imaging in vascular inflammatory diseases and consider future directions in the field. Recent Findings: While PET imaging with 18F-fluorodeoxyglucose (FDG) can provide a useful marker of disease activity in several vascular inflammatory diseases, including atherosclerosis and large-vessel vasculitis, this tracer lacks inflammatory cell specificity and is not a practical solution for imaging the coronary vasculature because of avid background myocardial signal. To overcome these limitations, research is ongoing to identify novel PET tracers that can more accurately track individual components of vascular immune responses. Use of these novel PET tracers could lead to a better understanding of underlying disease mechanisms and help inform the identification and stratification of patients for newly emerging immune-modulatory therapies. Summary: Future research is needed to realise the true clinical translational value of PET imaging in vascular inflammatory diseases

Pericoronary and periaortic adipose tissue density are associated with inflammatory disease activity in Takayasu arteritis and atherosclerosis.

AimsTo examine pericoronary adipose tissue (PCAT) and periaortic adipose tissue (PAAT) density on coronary computed tomography angiography for assessing arterial inflammation in Takayasu arteritis (TAK) and atherosclerosis.Methods and resultsPCAT and PAAT density was measured in coronary (n = 1016) and aortic (n = 108) segments from 108 subjects [TAK + coronary artery disease (CAD), n = 36; TAK, n = 18; atherosclerotic CAD, n = 32; matched controls, n = 22]. Median PCAT and PAAT densities varied between groups (mPCAT: P P = 0.0002). PCAT density was 7.01 ± standard error of the mean (SEM) 1.78 Hounsfield Unit (HU) higher in coronary segments from TAK + CAD patients than stable CAD patients (P = 0.0002), and 8.20 ± SEM 2.04 HU higher in TAK patients without CAD than controls (P = 0.0001). mPCAT density was correlated with Indian Takayasu Clinical Activity Score (r = 0.43, P = 0.001) and C-reactive protein (r = 0.41, P P = 0.002). mPCAT density above -74 HU had 100% sensitivity and 95% specificity for differentiating active TAK from controls [area under the curve = 0.99 (95% confidence interval 0.97-1)]. The association of PCAT density and coronary arterial inflammation measured by 68Ga-DOTATATE positron emission tomography (PET) equated to an increase of 2.44 ± SEM 0.77 HU in PCAT density for each unit increase in 68Ga-DOTATATE maximum tissue-to-blood ratio (P = 0.002). These findings remained in multivariable sensitivity analyses adjusted for potential confounders.ConclusionsPCAT and PAAT density are higher in TAK than atherosclerotic CAD or controls and are associated with clinical, biochemical, and PET markers of inflammation. Owing to excellent diagnostic accuracy, PCAT density could be useful as a clinical adjunct for assessing disease activity in TAK

Synthesis of liposoluble carboxylic acid ascorbyl esters catalyzed by immobilized lipases

U okviru ove teze, ispitana je mogućnost efikasne i ekonomične proizvodnje askorbil-estara karboksilnih kiselina katalizovane imobilisanim lipazama. Testiran je veći broj lipaza, donora acil-ostatka i organskih rastvarača. Kao pogodni reakcioni medijumi su se pokazali polarni organski rastvarači u kojima je vitamin C rastvorljiv (t-butanol i aceton). Utvrđeno je da je lipaza tipa B producenta Candida antarctica (CAL B) najaktivniji katalizator u reakciji esterifikacije, kao i da je njen afinitet prema zasićenim karboksilnim kiselinama kratke i srednje dužine lanca i mono- i polinezasićenim masnim kiselinama dugog lanca veći nego prema zasićenim masnim kiselinama dugog lanca. Upravo ovi askorbil-estri pokazali su i najjače antioksidativno dejstvo. Optimizacija najznačajnijih reakcionih parametara vršena je statističkim planiranjem eksperimenata i primenom metode odzivnih površina u sintezi askorbil-oleata. Kao odzivna veličina je odabran specifični prinos koji predstavlja količinu proizvedenog estra po masi utrošene imobilisane lipaze, čime je ostvaren uvid u ekonomičnost enzimskog procesa. Na taj način je na 60°C, sa 0,135 M vitamina C, 0,2 %(w/v) lipaze, oleinskom kiselinom u višku (8:1) i pri početnom sadržaju vode od 0,018 %(v/v) postignut maksimalni specifični prinos od 16,7 mmol g-1. Dalje povećanje efikasnosti procesa ostvareno je dodavanjem molekulskih sita u cilju uklanjanja viška vode, upotrebom katalizatora u konsekutivnim reakcionim ciklusima i reaktivacijom delimično inaktivirane lipaze. Kinetička studija je pokazala da se početne brzine reakcije mogu modelovati ping-pong bi-bi mehanizmom sa inhibicijom vitaminom C. Finalnim modelom, u koji je uključen i efekat povratne reakcije hidrolize, dobro su fitovani i eksperimentalni podaci u dugim reakcionim vremenima. S obzirom na to da je visoka cena korišćenog komercijalnog imobilisanog preparata (Novozym® 435) jedna od najvećih prepreka komercijalizaciji postupaka enzimske sinteze askorbil-estara, u sledećem delu disertacije ispitani su različiti nosači i metode za imobilizaciju CAL B u cilju dobijanja aktivnijih i/ili jeftinijih biokatalizatora. Najveću esterifikacionu aktivnost, sličnu Novozym®-u 435, pokazala je CAL B imobilisana na makroporozni hidrofobni nosač Purolite® MN102 na bazi stiren-divinilbenzena sa...In this thesis, possibility of efficient and economical production of carboxylic acid ascorbyl esters catalyzed by immobilized lipases was examined. Vast number of lipases, acyl donors, and organic solvents was tested. Suitable reaction mediums were polar organic solvents in which vitamin C was soluble (t-butanol and acetone). It was determined that lipase B from Candida antarctica (CAL B) was the most active catalyst in the esterification and that its affinity towards saturated short- and medium-chain carboxylic acids and unsaturated longchain fatty acids was higher comparing to saturated long-chain fatty acids. Antioxidant activity of these esters was higher, as well. Optimization of crucial reaction parameters was performed by using statistically designed experimental plan and response surface methodology for the synthesis of ascorbyl oleate. As a response, specific yield, which represents amount of ester produced per mass of utilized immobilized lipase, was chosen, since it gave insight in cost effectiveness of enzymatic process. In that way, at 60 °C, with 0.135 M of vitamin C, 0.2 %(w/v) of lipase, oleic acid in excess (8:1), and at initial water content of 0.018 %(v/v), maximum specific ester yield of 16.7 mmol g-1 was accomplished. Process efficiency was additionally enhanced by adding molecular sieves in order to remove excessive amount of water, by reusing biocatalyst in consecutive reaction cycles, and by reactivating partially inactivated lipase. Kinetic study revealed that initial reaction rates could be modeled by ping-pong bi-bi mechanism with inhibition by vitamin C. By including reverse reaction of hydrolysis in final model, experimental data at long reaction times were properly fitted, as well. Considering the fact that high price of commercial immobilized preparation (Novozym® 435) that was used is one of the largest obstacles for commercialization of the enzymecatalyzed ascorbyl ester synthesis processes, within subsequent part of dissertation different carriers and methods for the immobilization of CAL B were tested, in order to obtain more active and/or cheaper biocatalysts. Highest esterifying activity, similar to Novozym® 435, was demonstrated by CAL B immobilized onto styrene-divinylbenzene based macroporous hydrophobic carrier with tertiary amino groups, Purolite® MN102, but its production costs..

Synthesis of liposoluble carboxylic acid ascorbyl esters catalyzed by immobilized lipases

U okviru ove teze, ispitana je mogućnost efikasne i ekonomične proizvodnje askorbil-estara karboksilnih kiselina katalizovane imobilisanim lipazama. Testiran je veći broj lipaza, donora acil-ostatka i organskih rastvarača. Kao pogodni reakcioni medijumi su se pokazali polarni organski rastvarači u kojima je vitamin C rastvorljiv (t-butanol i aceton). Utvrđeno je da je lipaza tipa B producenta Candida antarctica (CAL B) najaktivniji katalizator u reakciji esterifikacije, kao i da je njen afinitet prema zasićenim karboksilnim kiselinama kratke i srednje dužine lanca i mono- i polinezasićenim masnim kiselinama dugog lanca veći nego prema zasićenim masnim kiselinama dugog lanca. Upravo ovi askorbil-estri pokazali su i najjače antioksidativno dejstvo. Optimizacija najznačajnijih reakcionih parametara vršena je statističkim planiranjem eksperimenata i primenom metode odzivnih površina u sintezi askorbil-oleata. Kao odzivna veličina je odabran specifični prinos koji predstavlja količinu proizvedenog estra po masi utrošene imobilisane lipaze, čime je ostvaren uvid u ekonomičnost enzimskog procesa. Na taj način je na 60°C, sa 0,135 M vitamina C, 0,2 %(w/v) lipaze, oleinskom kiselinom u višku (8:1) i pri početnom sadržaju vode od 0,018 %(v/v) postignut maksimalni specifični prinos od 16,7 mmol g-1. Dalje povećanje efikasnosti procesa ostvareno je dodavanjem molekulskih sita u cilju uklanjanja viška vode, upotrebom katalizatora u konsekutivnim reakcionim ciklusima i reaktivacijom delimično inaktivirane lipaze. Kinetička studija je pokazala da se početne brzine reakcije mogu modelovati ping-pong bi-bi mehanizmom sa inhibicijom vitaminom C. Finalnim modelom, u koji je uključen i efekat povratne reakcije hidrolize, dobro su fitovani i eksperimentalni podaci u dugim reakcionim vremenima. S obzirom na to da je visoka cena korišćenog komercijalnog imobilisanog preparata (Novozym® 435) jedna od najvećih prepreka komercijalizaciji postupaka enzimske sinteze askorbil-estara, u sledećem delu disertacije ispitani su različiti nosači i metode za imobilizaciju CAL B u cilju dobijanja aktivnijih i/ili jeftinijih biokatalizatora. Najveću esterifikacionu aktivnost, sličnu Novozym®-u 435, pokazala je CAL B imobilisana na makroporozni hidrofobni nosač Purolite® MN102 na bazi stiren-divinilbenzena sa...In this thesis, possibility of efficient and economical production of carboxylic acid ascorbyl esters catalyzed by immobilized lipases was examined. Vast number of lipases, acyl donors, and organic solvents was tested. Suitable reaction mediums were polar organic solvents in which vitamin C was soluble (t-butanol and acetone). It was determined that lipase B from Candida antarctica (CAL B) was the most active catalyst in the esterification and that its affinity towards saturated short- and medium-chain carboxylic acids and unsaturated longchain fatty acids was higher comparing to saturated long-chain fatty acids. Antioxidant activity of these esters was higher, as well. Optimization of crucial reaction parameters was performed by using statistically designed experimental plan and response surface methodology for the synthesis of ascorbyl oleate. As a response, specific yield, which represents amount of ester produced per mass of utilized immobilized lipase, was chosen, since it gave insight in cost effectiveness of enzymatic process. In that way, at 60 °C, with 0.135 M of vitamin C, 0.2 %(w/v) of lipase, oleic acid in excess (8:1), and at initial water content of 0.018 %(v/v), maximum specific ester yield of 16.7 mmol g-1 was accomplished. Process efficiency was additionally enhanced by adding molecular sieves in order to remove excessive amount of water, by reusing biocatalyst in consecutive reaction cycles, and by reactivating partially inactivated lipase. Kinetic study revealed that initial reaction rates could be modeled by ping-pong bi-bi mechanism with inhibition by vitamin C. By including reverse reaction of hydrolysis in final model, experimental data at long reaction times were properly fitted, as well. Considering the fact that high price of commercial immobilized preparation (Novozym® 435) that was used is one of the largest obstacles for commercialization of the enzymecatalyzed ascorbyl ester synthesis processes, within subsequent part of dissertation different carriers and methods for the immobilization of CAL B were tested, in order to obtain more active and/or cheaper biocatalysts. Highest esterifying activity, similar to Novozym® 435, was demonstrated by CAL B immobilized onto styrene-divinylbenzene based macroporous hydrophobic carrier with tertiary amino groups, Purolite® MN102, but its production costs..

MARINE ACCIDENTS RESEARCHED THROUGH HUMAN FACTOR PRISMA

We are aware of a large number of marine accidents that result in numerous casualties and even deaths and substantial negative environmental effects. The objective of this paper is to indicate factors that contribute to human errors which is identified as the most frequent cause to marine accidents. Despite rapid technological development and safety legislation, this paper identifies the human factor as the waekest link in maritime safety system. This analysis could lead to decrease of vessel accidents. In addition, starting from the European Maritime Safety Agency data and by linear regression model application, we have obtained the trend of number of ships involved in marine accidents as well as the trend of lives lost in marine accidents  in and around European Union waters

MARINE ACCIDENTS RESEARCHED THROUGH HUMAN FACTOR PRISMA

We are aware of a large number of marine accidents that result in numerous casualties and even deaths and substantial negative environmental effects. The objective of this paper is to indicate factors that contribute to human errors which is identified as the most frequent cause to marine accidents. Despite rapid technological development and safety legislation, this paper identifies the human factor as the waekest link in maritime safety system. This analysis could lead to decrease of vessel accidents. In addition, starting from the European Maritime Safety Agency data and by linear regression model application, we have obtained the trend of number of ships involved in marine accidents as well as the trend of lives lost in marine accidents  in and around European Union waters.</em

Myocardial Amyloidosis: The Exemplar Interstitial Disease

Cardiac involvement drives prognosis and treatment choices in cardiac amyloidosis. Echocardiography is the first-line examination for patients presenting with heart failure, and it is the imaging modality that most often raises the suspicion of cardiac amyloidosis. Echocardiography can provide an assessment of the likelihood of cardiac amyloid infiltration versus other hypertrophic phenocopies and can assess the severity of cardiac involvement. Visualizing myocardial amyloid infiltration is challenging and, until recently, was restricted to the domain of the pathologist. Two tests are transforming this: cardiac magnetic resonance (CMR) imaging and bone scintigraphy. After the administration of contrast, CMR is highly sensitive and specific for the 2 main types of ventricular myocardial amyloidosis, light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR). CMR structural and functional assessment combined with tissue characterization can redefine cardiac involvement by tracking different disease processes, ranging from amyloid infiltration, to the myocardial response associated with amyloid deposition, through the visualization and quantification of myocardial edema and myocyte response. Bone scintigraphy (paired with exclusion of serum free light chains) is emerging as the technique of choice for distinguishing ATTR from light chain cardiac amyloidosis and other cardiomyopathies; it has transformed the diagnostic pathway for ATTR, allowing noninvasive diagnosis of ATTR without the need for a tissue biopsy in the majority of patients. CMR with tissue characterization and bone scintigraphy are rewriting disease understanding, classification, and definition, and leading to a change in patient care

Novel Positron Emission Tomography Tracers for Imaging Vascular Inflammation

Abstract: Purpose of Review: To provide a focused update on recent advances in positron emission tomography (PET) imaging in vascular inflammatory diseases and consider future directions in the field. Recent Findings: While PET imaging with 18F-fluorodeoxyglucose (FDG) can provide a useful marker of disease activity in several vascular inflammatory diseases, including atherosclerosis and large-vessel vasculitis, this tracer lacks inflammatory cell specificity and is not a practical solution for imaging the coronary vasculature because of avid background myocardial signal. To overcome these limitations, research is ongoing to identify novel PET tracers that can more accurately track individual components of vascular immune responses. Use of these novel PET tracers could lead to a better understanding of underlying disease mechanisms and help inform the identification and stratification of patients for newly emerging immune-modulatory therapies. Summary: Future research is needed to realise the true clinical translational value of PET imaging in vascular inflammatory diseases

Positron emission tomography imaging in cardiovascular disease.

Positron emission tomography (PET) imaging is useful in cardiovascular disease across several areas, from assessment of myocardial perfusion and viability, to highlighting atherosclerotic plaque activity and measuring the extent of cardiac innervation in heart failure. Other important roles of PET have emerged in prosthetic valve endocarditis, implanted device infection, infiltrative cardiomyopathies, aortic stenosis and cardio-oncology. Advances in scanner technology, including hybrid PET/MRI and total body PET imaging, as well as the development of novel PET tracers and cardiac-specific postprocessing techniques using artificial intelligence will undoubtedly continue to progress the field