MTTP gene resulting in the loss of its lipid transfer activity. Now it is known that it also plays a role in the biosynthesis of CD1, glycolipid presenting molecules, as well as in the regulation of cholesterol ester biosynthesis. In this review, we will provide a historical perspective about the identification, purification and characterization of MTP, describe methods used to measure its lipid transfer activity, and discuss tissue expression and function. Finally, we will review the role MTP plays in the assembly of apoB-lipoprotein, the regulation of cholesterol ester synthesis, biosynthesis of CD1 proteins and propagation of hepatitis C virus. We will also provide a brief overview about the clinical potentials of MTP inhibition.Microsomal triglyceride transfer protein (MTP) was first identified as a major cellular protein capable of transferring neutral lipids between membrane vesicles. Its role as an essential chaperone for the biosynthesis of apolipoprotein B (apoB)-containing triglyceride-rich lipoproteins was established after the realization that abetalipoproteinemia patients carry mutations in the  Evidence for an intracellular protein in the lumen of mammalian liver microsomes that transfers neutral lipids, triglycerides and cholesterol esters between phospholipid vesicles was first provided by Wetterau and Zilversmit ,2. The p4 and KSCN, and non-denaturing detergents, octyl β-glucoside Triolein absorption studies revealed that these mice absorb ~63% less triglyceride in 2 h. These studies showed that partial ablation of MTP gene also has significant effect on acute lipid absorption.Iqbal et al.  obtain pfl(exon1)/fl(exon1) mice with α-myosin heavy chain-Cre transgenic mice to generate cardiac myocytes specific ablation of the MTP gene. Heart specific MTP ablation (H-MTP-/-) increased triglycerides in cardiac myocytes in fasting mice. They did not report changes in MTP activity in these mice. Further, they showed that MTP inhibitors reduce secretion of apoB-containing triglyceride-rich lipoproteins by these cells. On the other hand, Bartels et al. . The review, ,74. Inhi review, . This su review, ,77 as we review, . Thus, bDrosophila ortholog of MTP that transfers phospholipids, but not triglycerides [Drosophila MTP was shown to rescue apoB secretion despite lacking triglyceride transfer activity [Drosophila MTP also responds to oleic acid supplementation and increases apoB secretion in cells [Drosophila MTP was found to be ~50% as efficient as the human MTP in promoting apoB-lipoprotein assembly and secretion. These studies have now been extended to mice. Khatun et al. [Drosophila MTP can assemble apoB-lipoproteins in mouse livers. They found that Drosophila MTP assists in the assembly of triglyceride-poor apoB100- and apoB48-VLDL and phospholipid rich apoB48-containing HDL size particles. Hence, the phospholipid transfer activity of MTP is sufficient for the assembly and secretion of primordial lipoprotein particles. The presence of triglyceride transfer activity along with the phospholipid transfer activity, as in the human MTP, increases the number of particles assembled as well as the amounts of neutral lipids associated with them.Although MTP is classically identified for its ability to transfer neutral lipids, it also transfers phospholipids. Identification of a ycerides ,68,70,71n et al.  have shoin vivo for lipoprotein assembly are apoB48 and apoB100, C-terminally truncated forms of apoB have been used to decipher initial steps involved in the molecular assembly of apoB-containing lipoproteins and the role of MTP in their lipidation. The N-terminal βα1 domain (amino acids 1-731) of apoB is critical in lipoprotein assembly, as its deletion does not result in lipoprotein formation [Though the major forms of apoB used ormation ,80. Thisormation ,82. Furtormation ,84.Drosophila MTP [Secretion studies using various C-terminally truncated forms of apoB revealed that N-terminal fragments of apoB, up to apoB25 (1134 amino acids), are secreted independent of MTP ,86. Analhila MTP . In the Earlier studies using MTP inhibitors indicated that secretion of apoB100 is more sensitive than apoB48 secretion . SimilarMttp gene deletion increases free cholesterol [A physiological ratio of free cholesterol/phospholipids in the cellular membrane is necessary to maintain membrane fluidity and excess cellular free cholesterol is toxic to cells . Hence, lesterol . They shlesterol . Microsoin vitro using hepatic microsomes isolated from MTP deficient mice and observed significant reductions. Interestingly, supplementation of these microsomes with purified MTP restored cholesterol ester biosynthesis without affecting triglyceride and phospholipid biosynthesis. They also studied acute effects of MTP and ACAT inhibition using specific inhibitors in intestinal and hepatic cells. Individually, both inhibitors reduced cellular cholesterol esterification to similar extents and in combination they exhibited an additive effect. These studies indicated that MTP and ACAT affect different pathways in cholesterol ester biosynthesis.To understand why MTP inhibition/deficiency leads to free cholesterol accumulation, they studied cholesterol ester biosynthesis in vitro using liver microsomes, purified MTP, and LDL. Enrichment of microsomes with cholesterol esters reduced cholesterol ester biosynthesis indicating that product accumulation inhibits this process. This inhibition was avoided when purified MTP and LDL was included in the reaction mixture. These studies suggest that MTP circumvents product inhibition by removing cholesterol esters and depositing them into apoB-lipoproteins.To identify two different steps necessary for optimal cholesterol esterification, MTP and ACAT were expressed in cells that do not express these genes. Expression of ACAT increased cholesterol esterification; however, expression of MTP reduced cholesterol ester synthesis. Further studies showed that increased synthesis of cholesterol esters also requires apoB; expression of MTP and apoB48 in ACAT expressing cells increased cholesterol ester synthesis and secretion. Therefore, cholesterol ester synthesis and lipoprotein biogenesis act in concert to maximize cholesterol ester biosynthesis. To delineate further how these pathways coordinate in optimal cholesterol ester synthesis and to identify molecular steps involved in this process, they reconstituted cholesterol ester synthesis Based on these studies, the role of MTP in cholesterol ester biosynthesis and consequences of MTP and/or ACAT deficiency on cellular cholesterol homeostasis can be explained as follows. Under normal conditions, ACAT synthesizes cholesteryl esters and MTP transfers both free and esterified cholesterol to apoB-lipoproteins Figure . When MTThe main function of CD1 proteins is to present microbial, viral and parasite lipids to restricted populations of T lymphocytes that affect both the innate and adaptive immune response. These proteins present both endogenous and foreign lipids, glycolipids and lipopeptides, to iNKT and CD1-restricted T cells and elicit cytokine release -115. TheCD1 molecules are transmembrane, major histocompatibility complex like glycoproteins that form heterodimers with β2-microglobulin ,110. TheCD1 molecules are synthesized with a signal sequence that directs them to the ER Figure  where thMttp gene increases peri-nuclear retention of CD1d while reducing their cell surface expression. A functional consequence of reduced CD1 expression is that these MTP deficient hepatocytes are less efficient in eliciting secretion of IL-2 by NKT cells in the presence of α-galactosylceramide, a ligand that occupies the hydrophobic domain on the CD1d surface. Intestinal cells also respond to α- galactosylceramide and induce secretion of IL-2 by NKT cells and MTP knockdown reduces this response. Further, oxazolone-induced colitis and associated weight loss is suppressed in MTP-deficient mice. These studies suggested that MTP transiently associates with CD1d and regulates CD1d-mediated antigen presentation in hepatic and intestinal cells.Several studies have shown that MTP plays a critical role in the loading of endogenous lipids onto newly synthesized CD1 molecules in the ER Figure . BrozoviSubsequently, evidence that MTP plays a role during CD1d antigen presentation in various antigen presenting cells was provided by Dougan et al. . They shSagiv et al.  studied Besides NKT cell activation, CD1d is also critical for the selection and development of NKT cells in thymocytes ,111. DouLater, Kaser et al.  studied As discussed before, MTP deficiency results in abetalipoproteinemia characterized by the absence of apoB-containing lipoproteins. Zeissig et al.  studied They also studied the amounts of CD1 molecules present on the cell surface in abetalipoproteinemia dendritic cells. Cell surface expression of group 1 molecules was significantly reduced in abetalipoproteinemia patients. Expression of group 1 CD1 molecules could be increased when cells were incubated with proteasomal inhibitors indicating that in the absence of MTP these molecules undergo proteasomal degradation similar to that shown for apoB. Despite reductions in iNKT cell activation, cell surface expression of group 2 CD1d was not diminished in abetalipoproteinemia monocyte-derived dendritic cells. Further, incubation of these cells with proteasomal inhibitors did not increase CD1d cell surface expression. This is in contrast to observations made in mice hepatocytes  suggestiin vitro assay [The studies summarized above indicate that MTP is critical for the bioactivity of CD1 molecules. To understand how MTP plays a role in the biosynthesis of CD1 molecules, an ro assay  was devero assay ,84,124 tro assay ,42. In cIn short, it can be concluded that MTP plays a role in the proper lipidation of CD1 proteins in the ER. After this lipidation CD1 proteins are directed to the cell surface and then undergo endocytosis Figure . In the Hepatitis C virus (HCV) is the leading cause of chronic viral hepatitis. Patients who develop the disease have an increased risk of hepatic steatosis, cirrhosis, and hepatocellular carcinoma. HCV particles circulate as lipo-viral particles which are rich in triglycerides, but also contain apolipoprotein B, HCV RNA, and core proteins -127. Thecis and trans factors responsible for this response will undoubtedly further our understanding and medical treatment of this viral infection.Apart from the role of MTP in HCV propagation, experiments have been performed to study the effect of HCV on MTP. Using transgenic mice, Perlemuter et al.  showed tThus, these studies indicate that although the virus hijacks lipoprotein assembly for its secretion, high concentrations of virus inhibit lipoprotein assembly. There is no good explanation to rationalize these two incompatible observations. It is possible that at early stages of infection the virus hijacks lipoproteins for its propagation and transmission to other tissues . HoweverMTP has been a favorite target to lower plasma lipids and treat disorders characterized by higher production of apoB-containing lipoproteins such as atherosclerosis, metabolic syndrome, familial combined hyperlipidemia, homozygous and heterozygous familial hypercholesterolemia and hypertriglyceridemia ,133-140.To avoid hepatic lipid accumulation and plasma transaminase elevation, it has been proposed that intestine-specific MTP inhibition might be beneficial because of the inherent property of the intestine to self-renew. In fact, intestine-specific MTP inhibitor, JTT-130, has been shown to lower plasma triglyceride and LDL cholesterol in guinea pigs without increasing hepatic triglyceride . SimilarOther strategies to garner the full potentials of MTP therapy can also be explored. It might be possible to capitalize on natural compounds that have been shown to inhibit MTP activity, such as flavanoids (naringenin from grapefruits and hesperitin from oranges) , isoflavWe have discussed the role of MTP in apoB-lipoprotein assembly, cholesterol ester biosynthesis, and CD1 protein synthesis. Although significant information has been garnered about MTP structure and activity, very little is known about its biosynthesis and degradation. Similarly, mechanisms controlling different levels of MTP expression in different tissues and cells have not been explained. Furthermore, the function of MTP in different tissues and cells that do not express apoB and CD1 proteins, such as adipocytes, needs to be elucidated. We also discussed the emerging relationship between HCV and MTP. It is likely that MTP might also be involved in many yet unidentified biochemical, cellular and physiological processes.Because of its role in apoB-lipoprotein assembly, MTP has been targeted to reduce plasma lipids and their atherosclerotic potential. However, these drug therapies are associated with significant and worrisome changes in hepatophysiology ,144. If Significant investments have been made in the identification and evaluation of MTP inhibitors. But, much less time and money has been spent on explaining the molecular basis for adverse events associated with MTP therapy. For example, very little is known about the types of lipids accumulating in the liver after MTP inhibition and their role in the release of liver-specific transaminases. Because of its role in cholesterol ester biosynthesis, it is possible that adverse events associated with MTP inhibition might be related to free cholesterol accumulation. More studies are needed to establish a cause and relationship between the types of lipids that accumulate during MTP deficiency and their role in the release of liver enzymes. Several approaches to avoiding adverse events associated with MTP inhibition have been laid out above that can be experimentally evaluated.An area that needs more investigation relates to adverse events associated with intestinal MTP inhibition. Molecular basis for diarrhea and other intestinal complications are poorly explained. Another aspect of MTP therapy that has garnered little attention is its effect on heart and kidney functions. Although effects on these tissues may not be significant during acute treatments, they could be potentially consequential in long-term therapy.ACTA: Acyl-CoA:Cholesterol Acyltransferase; ApoB: apolipoprotein B; CD1: cluster of differentiation 1; ER: endoplasmic reticulum; MTP: microsomal triglyceride transfer protein; NBD: nitrobenzoaxadiazol; NK: natural killer; PDI: protein disulfide isomerase.The authors declare that they have no competing interests. This work was partially supported by NIH grants DK-46900 and HL-95924 MMH.MMH conceived the idea and wrote the manuscript. PR wrote sections (MTP expression in different tissues and MTP as the precursor to extracellular lipid transport systems), critically read and edited the final manuscript. MW furnished a draft on "Biosynthesis of CD1 proteins", critically read/edited and made Figure


The case of a patient with primary pulmonary Hodgkin Lymphoma simulating a mediastinal tumour is reported for its rarity and the diagnostic concerns encountered by us. Although the secondary infiltration of lung parenchyma by Hodgkin’s lymphoma (HL) may occur, pulmonary HL occurred as an isolated tumour  represents an uncommon observation.The patient was a 27-year-old non-smoker woman who kept under our attention because a mediastinal enlargement incidentally discovered by a standard thoracic radiography performed because of a vague pulmonary symptomatology, consisting of dry cough and mild dyspnoea on exertion. A comprehensive diagnostic work-up was performed. Routine laboratory analysis showed no abnormal findings, with the exception of a slight neutrophilic leukocytosis. Moreover, all common virus infections, including HIV, were ruled out by specific antibody tests. A computed tomography (CT) scan of the chest revealed a pulmonary mass (8 cm in diameter) in the middle lobe of right lung; this mass reached out to anterior-medium mediastinum, simulating a mediastinal neoplasm. No findings consistent with any pulmonary infiltrates or hilar and mediastinal lymph nodes involvement were detected . On the A comprehensive staging work up, including bone marrow trephine biopsy and a body CT scan, excluded any other extra-pulmonary disease localizations. No B symptoms were complained by the patient. So that a diagnosis of PPHL, stage IAE (L) according to the Ann-Arbor Staging System was made. The patient was treated with 6 courses of ABVD  regimen, achieving the complete disappearance of the pulmonary mass. Follow up at 1, 2 and 5 years showed a negative CT and Positron Emission Tomography scans, confirming the complete remission of the disease. To date, the patient is well; in the meantime, she had delivered two healthy baby boys.The case here reported is that of an unusual form of a PPHL which didn’t show the most common radiologic features described in other reported observations. Indeed, PPHL is usually characterized by multiple nodules, reticolonodular shadows or mass lesion;Therefore, our experience suggested that an integrated clinicopathologic and surgical approach can be necessary to make a diagnosis of PPHL, which should be included into the differential diagnosis of any suspicious mediastinal enlargement.


In Afriorldwide . Given torafenib  has becoorafenib . Thus, aorafenib . Therefo50 value of high affinity (below 100 nM). Recurrence after appropriate ATT is thus unlikely when tumor growth is dependent on the expression of the respective virus-derived proteins. To enhance the efficacy of ATT and to circumvent negative impact of the tumor microenvironment onto T cells, the transfer of redirected T cells can be accompanied with antibodies e.g. blocking immune regulatory PD-1 or Lag3 pathways. Additionally, the local expansion of adoptively transferred T-cells has to be increased to achieve higher T cell numbers. We have recently investigated this in detail and have found that changing the microenvironment in the liver by activation of toll-like receptors induced the transient existence of intrahepatic myeloid aggregates (iMATEs) which support T cell expansion e.g. enabling control of chronic hepatic viral infection after vaccination with DNA [For adoptive T cell therapy (ATT) two strategies to graft new specificities onto patients T cells are currently pursued and have already shown feasibility in preclinical trials and the clinic: (First) Genetic engineering of T cells with chimeric antigen receptors ,4 or  on T cell expansion, T cell mediated tumor cell killing and survival.Importantly, it has recently been shown that inflammation, as often accompanied with HCC in patients with chronic HBV or HCV infection, dynamically fine-tunes antigen sensitivity of CD8In conclusion, ATT is a highly auspicious strategy to treat HCC. Still, the most efficient modality for ATT for the various HCC subtypes has to be determined, before this approach might become successful in the clinic.


Alzheimer's disease (AD), the most common cause of dementia, is also associated with depression. Although the precise mechanisms that lead to depression in AD are unknown, the impairments in adult hippocampal neurogenesis observed in AD may play a role. Adult-born neurons play a critical role in regulating both cognition and mood, and reduced hippocampal neurogenesis is associated with depression in other neurological disorders. To assess the relationship between Alzheimer's disease, neurogenesis, and depression, we studied human amyloid precursor protein (hAPP) transgenic mice, a well-characterized model of AD. We report that reductions in hippocampal neurogenesis are evident early in disease progression in hAPP mice, but a mild depressive phenotype manifests only in later stages of disease. We found that hAPP mice exhibited a reduction in BrdU-positive cells in the subgranular zone of the dentate gyrus in the hippocampus, as well as a reduction in doublecortin-expressing cells, relative to nontransgenic controls at 5–7 months of age. These alterations in neurogenesis appeared to worsen with age, as the magnitude of reduction in doublecortin-expressing cells was greater in hAPP mice at 13–15 months of age. Only 13–15 month old hAPP mice exhibited depressive behavior in the tail suspension test. However, mice at both age groups exhibited deficits in spatial memory, which was observed in the Morris water maze test for hippocampus-dependent memory. These findings indicate that neurogenesis impairments are accompanied by cognitive deficits, but are not tightly linked to depressive behavior in hAPP mice. Alzheimer's disease (AD) is the most common form of dementia and is characterized by prominent impairments in memory Neurogenesis is also altered early in disease progression, prior to plaque deposition in AD mouse models, suggesting that it could play a role in early cognitive and/or psychiatric symptoms of AD Several studies have examined the implications of impaired neurogenesis for cognitive deficits in AD, but few have examined whether neurogenesis impairments are related to the increased incidence of depression observed in AD We investigated the relationship between impairments in neurogenesis and development of depressive behavior in transgenic mice that overexpress human amyloid precursor protein carrying AD-associated mutations (hAPP mice), a well-characterized model of AD. We assessed depressive behavior using the tail suspension test, and analyzed hippocampal neurogenesis using BrdU to label dividing cells as well as immunophenotyping to identify and count doublecortin-expressing cells. We examined hAPP mice at two ages, and found that aged hAPP transgenic mice exhibit both impaired neurogenesis and depressive behavior, but that deficits in neurogenesis develop well before depressive behavior is observed. Thus, impairments in hippocampal neurogenesis are not tightly linked to depressive behavior in hAPP transgenic mice.All animal work was performed with the approval of the Thomas Jefferson University Institutional Animal Care and Use Committee, under protocol #884A.hAPP transgenic line J20 heterozygously expresses hAPP carrying the Swedish  and Indiana (V717F) familial AD (FAD) mutations (hAPP770 numbering). Transgene expression in this line is directed by the platelet-derived growth factor β chain promoter . This line has been crossed for >10 generations onto a C57BL/6 background using nontransgenic (NTG) C57BL/6 mice from The Jackson Laboratory . hAPP mice are bred, maintained, and analyzed as heterozygous transgenic mice, and age-matched NTG littermates from the same line are used as controls. Before behavioral testing, mice were singly housed and allowed to acclimate for at least 4 days prior to testing. Age-matched hAPP and NTG mice were evaluated at 5–7 months of age  and 13–15 months of age . Cohorts of mixed sex  were used for depression and neurogenesis experiments, no sex differences were found. Two separate cohorts of male mice were used for water maze experiments. All behavioral experiments took place during the light phase. At least three days after behavioral studies were complete, mice were anesthetized and flush-perfused transcardially with PBS. Brains were fixed in 4% phosphate-buffered paraformaldehyde.BrdU  was dissolved in saline and administered intraperitoneally twice, spaced 2 hours apart. Mice were sacrificed two hours after the last BrdU injection. Brain sections were stained with rat-anti-BrdU antibody  followed by donkey-anti-rat secondary antibody conjugated to AlexaFluor-594 . Prolong Gold antifade mounting medium with DAPI (Invitrogen) was used to allow visualization of nuclei. Labeling was visualized with epifluorescence microscopy. BrdU-positive cells in the subgranular zone of the hippocampus were counted in every 10th coronal section throughout the dorsal-ventral extent of the hippocampus, and summed.Sliding microtome sections (30 µm) were avidin-biotin/immunoperoxidase stained using an anti-doublecortin antibody  followed by biotinylated goat anti-rabbit antibody . Diaminobenzidine was used as the chromagen. Doublecortin-immunoreactive neurons in the subgranular zone of the hippocampus were counted in every 10th coronal section throughout the dorsal-ventral extent of the hippocampus, and summed. Neuroblasts were distinguished from immature neurons on the basis of morphology Mice were suspended 53 cm above a cushioned pad, using tape to attach their tails to a horizontal pole above the pad . No mice exhibited notable floating or thigmotaxic behavior that affected performance. The experimenter was blinded to genotypes during testing.Immunohistochemical data were analyzed using two-tailed, unpaired Student's t-tests. A p-value of less than 0.05 was considered statistically significant. Behavioral data were analyzed with two-way repeated measures ANOVA with Bonferroni post hoc tests to compare the performance of hAPP mice relative to NTG controls in the Morris water maze, as well in minute-by-minute assessment for the tail suspension test. Probe trial performance was assessed using one-way ANOVA followed by Tukey post hoc tests for multiple comparisons. Two-way repeated measures ANOVA was used to compare performances of hAPP and NTG mice in the 24-hour trial of the tail suspension test relative to performance in the baseline trial. One-way ANOVA with Newman-Kuels post hoc tests were used for multiple comparisons tests on the same data.We examined doublecortin expression in the dentate gyrus of the hippocampus in coronal sections from hAPP mice at 5–7 months of age, when behavioral/cognitive deficits are robust, but before the development of extracellular plaques Because the maturation of adult-born neurons is impaired in hAPP mice To determine whether impairments in adult neurogenesis correspond with the appearance of depressive behavior in 5–7 month old hAPP mice, we assessed depressive behavior using the tail suspension test. hAPP and NTG controls (n = 24/genotype) were tested in a trial lasting six minutes. For each mouse, we measured the latency to the first bout of immobility as well as the total time spent immobile during the six minute trial. Reduced latency to immobility and increased total time spent immobile during the tail suspension test are indicative of a depressive phenotype We also examined the total immobility during only the first three minutes of the tail suspension test, because the minute-by-minute analysis in We then examined whether this difference would affect the measurement of learned helplessness in repeated testing. When we re-analyzed the data using only the first three minutes of the tail suspension test at both baseline and 24 hr trials, we confirmed that NTG mice exhibited increased total immobility time when tested 24 hours after a baseline trial, whereas hAPP mice did not . Two-wayAdult neurogenesis in the hippocampus is important for both cognition as well as mood We then examined doublecortin expression in coronal sections from 13–15 month old hAPP mice to assess neurogenesis later in disease progression, when both behavioral/cognitive deficits and extracellular plaques are evident in hAPP mice We also found that the degree of neurogenesis impairments in hAPP mice (relative to age-matched NTG controls) appeared to increase with age. We calculated the level of neuroblasts and immature neurons in hAPP mice as a percentage of age-matched NTG controls in each age group, and then compared the relative values of hAPP mice in the two age groups. The reduction in neuroblasts is greater in 13–15 month old hAPP mice compared to 5–7 month old hAPP mice , hAPP mice also already exhibit spatial memory deficits in the water maze. Together, these observations underscore the fact that whereas depression is a common symptom of AD, the most prominent symptom of AD is cognitive deficit, particularly related to learning and memory


Prodigious efforts and landmark discoveries have led toward significant advances in our understanding of atherosclerosis. Despite significant efforts, atherosclerosis continues globally to be a leading cause of mortality and reduced quality of life. With surges in the prevalence of obesity and diabetes, atherosclerosis is expected to have an even more pronounced impact upon the global burden of disease. It is imperative to develop strategies for the early detection of disease. Positron emission tomography (PET) imaging utilizing [18F]fluorodeoxyglucose (FDG) may provide a non-invasive means of characterizing inflammatory activity within atherosclerotic plaque, thus serving as a surrogate biomarker for detecting vulnerable plaque. The aim of this review is to explore the rationale for performing FDG imaging, provide an overview into the mechanism of action, and summarize findings from the early application of FDG PET imaging in the clinical setting to evaluate vascular disease. Alternative imaging biomarkers and approaches are briefly discussed. Vessels in the elderly restrict the transit of blood through thickening of the tunics.Leonardo da Vinci, 1452–1519.Leonardo da Vinci presented perhaps one of the first known descriptions of atherosclerosis. In his collection of notes from post-mortem observations of human anatomy and poorly understood pathology, da Vinci merged what were the distinct disciplines of art and science to describe and depict human development and physiology.18F]fluorodeoxyglucose (FDG) positron emission tomography (PET). We will discuss the role of FDG PET for the identification of the high-risk “vulnerable plaque” across the arterial tree and its potential for monitoring disease progression and response to therapy.Herein, we present a general introduction to advanced non-invasive imaging of atherosclerosis with particular emphasis upon FDG imaging. By the early 1980s, FDG was being used to distinguish between benign and malignant lesions, define metabolic activity of cancer cells and myocardium.“The prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar” . This pivotal discovery by Nobel Laureate Dr. Otto Heinrich Warburg in 1920s paved the way for future clinical application of [Active inflammation within plaque has been proposed as a major criterion to identify high-risk vulnerable plaque.Radiolabelled FDG is a glucose analog that is taken up by active cells to fuel in vivo metabolic processes.d-[3H]glucose (3H-DG) uptake is greatest in macrophage-rich regions assessed by macro- and micro-autoradiography in an experimental tumor-induced murine model. Moreover, cellular uptake studies also demonstrate that FDG uptake is almost three-fold greater in macrophages, as compared to tumor cells.Kubota et alFinally, pioneering work by Rudd et al,The relationship between carotid plaque composition and FDG uptake has been evaluated in several studies.FDG uptake in carotid vasculature has been shown to correlate with serum levels of C-reactive protein, a marker of systemic inflammation.There is also evidence that suggests that symptomatic carotid lesions tend to have greater FDG uptake when compared to asymptomatic lesions, although the extent of vascular stenosis is an important determinant.Possibly, the first clinical experience of imaging FDG uptake in large arterial vasculature was reported by Yun et al.Imaging of the coronary vasculature has proven more challenging due to the small size of these vessels. Confounders such as cardiac motion, myocardial FDG uptake and the spatial resolution of PET have impeded progress in imaging FDG uptake in coronary vessels. Despite such challenges, Dunphy et alIn order to suppress myocardial FDG uptake, Wykrzykowska et alThe interrelationship of atherosclerotic disease across arterial beds has also been evaluated using FDG imaging. Studies suggest that among different vascular beds, there is evidence for variable FDG uptake,In terms of identifying patients at greatest risk, older patients presenting with more cardiovascular risk factors tend to have more inflamed active and calcified inactive plaques.Serial FDG PET scanning has the potential to evaluate changes in inflammatory activity. Lifestyle modification induces a detectable reduction in FDG uptake within aortic and iliac vasculature.P = .01).More recently, 130 patients were randomized to either dalcetrapib (a novel HDL raising drug) or placebo to determine whether dalcetrapib modulates plaque progression and inflammation.Given that FDG imaging of vasculature is a relatively new area of science and investigation, it suffers from several limitations. Although FDG uptake is related to macrophage expression, direct evidence demonstrating that FDG is taken up directly into macrophage cells is still lacking. This may be achievable in the future with higher resolution imaging and amplified immunohistology. Imaging coronary vasculature with FDG continues to be hampered by myocardial motion and myocardial FDG uptake. Acquiring respiratory- and cardiac-gated images may reduce the impact of coronary vessel motion. Furthermore, as described, patient preparation and diets may lower myocardial FDG uptake.Serial imaging is required to accurately stage atherosclerosis as it matures, waxes, and wanes. PET and CT imaging requires exposure to radiation which currently precludes the feasibility of frequent serial imaging. Algorithms to reduce patient radiation exposure are under development and will eventually contribute toward enabling serial imaging. Hybrid PET/MRI and PET/CT imaging also require accurate image co-registration between both modalities, especially when evaluating small structures such as the internal carotid vasculature. Slight patient motion between image acquisitions can result in misalignment that can bias attenuation correction, precluding accurate co-localization, and image interpretation. The use of neck-braces and hybrid scanning systems can significantly reduce this.N,N′,N″,N9′′′-tetraacetic acid]-D-Phe1, Tyr3-octreotate (DOTATATE)  binds to hydroxyapatite molecules by replacing hydroxyl groups, and could, therefore, serve as a surrogate marker of active calcification within plaqueIn addition to inflammation, calcification of plaque may also contribute toward potentiating plaque vulnerability.These tracers are still very early in development and application. Further studies are required to establish and validate them prior to wider application in clinical research and potential future clinical application.Utilizing PET/CT imaging biomarkers, it may be possible to non-invasively stage lesions and assess different aspects of plaque progression. Among a cohort of 45 oncology patients, plaque was characterized for inflammation (FDG uptake), active mineral deposition (NaF uptake) and calcification (CT).One may speculate that in the early stages of advanced atherosclerosis, only FDG uptake would be detected as inflammation is predominant process present Figure . Active Considerable advancement has occurred in imaging atherosclerosis, with FDG PET/CT at the forefront for characterizing actively inflamed plaque. FDG uptake within plaque has transitioned from an incidental finding to a potential biomarker of vulnerable plaque that has even been implemented to evaluate the efficacy of vascular risk reduction therapy. Despite the proliferation of imaging research, significant progress is yet to be achieved in fully understanding the molecular biology of plaque progression and rupture. Recent pre-clinical developments may help in understanding how FDG and other novel tracers track inflammation in plaque.While FDG imaging has enhanced our understanding of the inflammatory processes that underlie atherosclerosis, further studies are needed to validate FDG uptake. It also remains to be determined whether FDG uptake within plaque could be a specific marker of activated, polarized M1 (pro-inflammatory) or M2 (anti-inflammatory) macrophages,While we have moved far beyond da Vinci’s initial gross observations 500 years ago to visualizing inherent processes within plaque, we still need to bridge the gap between translating imaging of atherosclerosis to accurately predicting life-threatening vascular events. At that point, we may begin to realize imaging-guided personalized care for patients with atherosclerosis.


Since its introduction, ART has had profound impact on AIDS incidence and mortality in industrialized countries, and international collaboration, mainly through the Global Fund and the President’s Emergency Plan for AIDS Relief, has provided treatment to more than 4 million HIV-infected persons in low and middle income settings.2011 will mark the 30Despite these advances and much speculation, the full prevention benefits of ART still await clarification. Experience with mother-to-child transmission of HIV gave insight into the critical importance of HIV RNA as the dominant risk factor for HIV transmission, as well as proof of concept that ART reduced transmission rates through lowering viral load. Important studies published in 2010 include evidence that among couples discordantly infected with HIV, a 92% reduction in transmission occurred when the infected index was taking ART . The concept has arisen of community viral load as a risk factor for community-wide transmission , and ecologic evidence has been presented of ART scale-up correlating with reduced HIV incidence at the population level . These observations suggest more widespread ART among HIV-infected persons (“test and treat”) could provide substantial prevention benefit but data on such an approach are awaited, despite several mathematical models examining this.ART may provide prevention benefit when given as post-exposure prophylaxis and possibly as pre-exposure prophylaxis. The recent widely acclaimed study of a tenofovir-containing gel, associated with 39% protective efficacy against HIV acquisition in women on primary analysis , provides evidence of efficacy of pre-exposure prophylaxis as well as the feasibility of an efficacious microbicide. Results of trials of oral pre-exposure prophylaxis will become available in the near future.These developments occur in a global context of financial economic downturn, increased attention to the other health-related millennium development goals, and an emerging pandemic of non-communicable diseases. How to use ART most effectively and comprehensively for HIV prevention will challenge decision makers, even as evidence for individual approaches mounts.


ST-segment elevation myocardial infarction (STEMI) represents the most urgent condition for patients with coronary artery disease. Prompt diagnosis and therapy, mainly with primary angioplasty using stents, are important in improving not only acute survival but also long-term prognosis. Recent advances in angioplasty devices, including manual aspiration catheters and drug-eluting stents, and pharmacologic therapy, such as potent antiplatelet and anticoagulant agents, have significantly enhanced the acute outcome for these patients. Continuing efforts to educate the public and to decrease the door-to-balloon time are essential to further improve the outcome for these high-risk patients. Future research to normalize the left ventricular function by autologous stem cell therapy may also contribute to the quality of life and longevity of the patients surviving STEMI. ST-segment elevation myocardial infarction (STEMI) accounts for approximately 30–45% of an estimated 1.5 million hospitalizations for acute coronary syndromes annually in the USA . TherefoThe most important therapy for STEMI patients is the prompt reestablishment of antegrade flow. The earlier and the more complete the reperfusion, the greater the myocardial salvage and preservation of left ventricular function, the most important prognostic factor for long-term survival. There are pharmacologic and mechanical reperfusion therapies. Randomized trials have conclusively established primary angioplasty with stents as the optimal therapy for these patients, as primary percutaneous coronary intervention (PCI) provides >90% TIMI 3 flow in the infarct-related vessel compared with only approximately 50% with thrombolytic therapy, thereby improving myocardial salvage and survival, as well as preventing recurrent ischemia and reinfarction by definitively treating the severe stenosis that can result even after a successful thrombolysis . NeedlesP = 0.02) and reduced composite clinical endpoint of death, reinfarction, or stroke up to 6 months  versus thrombolytic therapy. Importantly, no emergency coronary artery bypass surgery was required for PCI-related complications. With the availability of stents to treat dissections effectively to maintain vessel patency and potent pharmacologic regimen even for thrombus burden, currently primary PCI is rarely associated with emergencies. Obviously, these centers without on-site cardiac surgery should have a working relationship with a tertiary center for emergency transfer should the patients experience complications not corrected by the interventional and pharmacologic therapies. Unfortunately the majority of patients with STEMI cannot be treated with primary PCI due to the unavailability of PCI-capable hospitals in remote areas. It is estimated that primary PCI is available in <25% of hospitals in the USA . On the But when these measures cannot guarantee acceptable D2B time or if there are no nearby PCI centers with high PCI volume or experienced interventional cardiologists, thrombolytic therapy despite its shortcomings is the preferred initial therapy, as some form of reperfusion therapy is more important than not providing any . In addiP = 0.004) [If primary PCI is not an option and thrombolysis is administered, there are many different strategies for further therapy following successful thrombolysis, as the latter alone can still be associated with high reocclusion rates and reinfarction due to the residual severe stenosis in the majority of patients . The imp= 0.004) . There w Since thrombolysis can provide successful reperfusion in only 50–60% of patients , rescue  An attractive option bridging the pharmacologic therapy and primary PCI is facilitated PCI, which refers to planned immediate PCI following an initial pharmacological regimen, usually thrombolytic therapy  . The hypThose patients presenting beyond the 12-hour window after symptom onset and thus less likely to obtain myocardial salvage with intervention have been a dilemma regarding the recanalization of the occluded infarct-related artery. It has been estimated that up to one-third of patients with STEMI may not receive reperfusion therapy due to this late presentation , 67. WhePlatelets play a major role in the initiation and propagation of the thrombus during STEMI following plaque rupture. Therefore, antiplatelet therapy has been shown to reduce ischemic complications following STEMI . ClopidoP < 0.001). The benefits were maintained up to 3 years following the initial procedure [Bivalirudin has been shown to provide effective anticoagulation during angioplasty with reduced bleeding complication compared with other options for both stable angina and low-risk acute coronary syndrome patients , 81. Thurocedure . One uneP = 0.051) and 1 year  as well as a significant reduction in major adverse cardiac events at 30 days compared with placebo  [ Glycoprotein IIb/IIIa inhibitors have been shown to be beneficial in STEMI patients, especially when these patients were not pretreated with oral antiplatelet agents . Recent = 0.043) .P = 0.048), with low one-year cardiac mortality  and 1-year incidence of definite and/or probable stent thrombosis  [Bare-metal stents have become the device of choice during primary PCI, mainly by reducing target vessel revascularization without improving survival or reinfarction , 97. How = 0.21) . AlthougSince STEMI patients are expected to have much thrombus burden and a high likelihood of distal embolization during primary PCI, it is logical to hypothesize that distal protection and thrombectomy devices would be beneficial. However, randomized trials have shown no benefit from distal protection during primary PCI . Distal P = 0.018) whereas mechanical thrombectomy resulted in higher mortality  compared with standard PCI [ Mechanical thrombectomy devices have not shown any benefit compared with no thrombectomy , 59. On dard PCI . Althougdard PCI , judicioIntra-aortic balloon counterpulsation (IABP) has been shown to improve outcomes in patients presenting with STEMI and cardiogenic shock and thus has been recommended in these patients undergoing reperfusion therapy , 103. NeHowever, it is not clear if STEMI patients without cardiogenic shock may also benefit from IABP therapy. Therefore, the CRISP AMI  trial randomized high-risk anterior STEMI patients  to primary PCI or prophylactic IABP before primary PCI and continued for at least 12 hours and measured infarct size assessed by cardiac magnetic resonance imaging 3 to 5 days after PCI . PatientDue to the intense anticoagulation and antiplatelet therapy during STEMI treatment, bleeding complication used to be common, especially at the vascular access site . TherefoMany patients with STEMI experience out-of-hospital cardiac arrest as their initial presentation  and whenNumerous studies have investigated the potential benefit of administration of bone marrow cells to improve left ventricular function in these STEMI patients, as even the most prompt reperfusion may not salvage all myocardium in jeopardy . There hOne of the unresolved issues regarding primary PCI has been the treatment of significant lesions in non-infarct-related vessel during STEMI. It has been estimated that approximately 50% of patients with STEMI present with multivessel coronary artery disease –125. TheSince drug-eluting stents may be associated with increased very late stent thrombosis risk versus bare-metal stents , novel sIt is accepted that the faster the revascularization after the symptom onset, the greater the likelihood of myocardial salvage and long-term outcome , 140. AlRecent advances in the management of STEMI patients  have res


Post-therapy scintigraphy showed no iodine uptake in the sellar region or bony metastases. Histology of the pituitary mass confirmed metastatic papillary thyroid cancer. Fifteen months later, she had a recurrence of pituitary metastases affecting her vision. This was resected and followed with external beam radiotherapy. Over 2 years, the pituitary metastases increased in size and required two further operations. Radioactive iodine was not considered due to poor response in the past. Progressively, she developed a left-sided III and IV cranial nerve palsy and permanent bitemporal hemianopia. There was a rapid decline in the patient's health with further imaging revealing new lung and bony metastases, and she eventually died 8 months later. To our knowledge, this is the first case of pituitary metastases from a radioiodine-resistant papillary thyroid cancer. Radioiodine-resistant metastatic thyroid cancer may exhibit rapid aggressive growth and remain poorly responsive to the currently available treatment.Metastases to the pituitary gland are an uncommon complication of thyroid cancer. They resemble pituitary neoplasms posing a diagnostic challenge. We present a case of an aggressive non-radioiodine avid papillary thyroid cancer with recurrent pituitary metastases and a review of the literature. A 70-year-old woman with a history of papillary thyroid cancer and bony metastases presented with symptoms of hypoadrenalism and peripheral vision loss. Magnetic resonance imaging showed a large pituitary mass impinging on the optic chiasm. She underwent transsphenoidal resection followed by Differentiated thyroid cancer (DTC) has an excellent prognosis with <5% of the cases presenting with distant metastases, usually to lung and bone.Metastasis to the pituitary is a rare complication of DTC.The diagnosis of pituitary insufficiency secondary to pituitary metastases from DTC may be delayed due to the non-specific systemic symptoms of underlying malignancy and TSH suppression therapy for thyroid cancer.The imaging characteristics of metastases to the pituitary may be similar to non-functioning pituitary adenoma.Radioiodine refractory metastatic thyroid cancer has significantly lower survival rates compared with radioactive iodine-avid metastases due to limited therapeutic options. Pituitary metastases are a rare complication of differentiated thyroid cancer (DTC) Here, we report a case of pituitary metastases from a radioiodine-resistant papillary thyroid cancer. This case report describes in detail the magnetic resonance imaging (MRI) characteristics and the histopathological findings of pituitary metastases from papillary thyroid cancer and provides an understanding of the natural history and prognosis of this rare disease.131I ablation, manubriumectomy in 2003 for a relapse of metastatic disease and radiotherapy to T1 vertebral metastases in 2007.A 70-year-old woman was under the endocrine unit since 2003 for the management and ongoing surveillance of metastatic papillary thyroid carcinoma. She initially presented in 1988 with a metastatic deposit of follicular variant of a papillary carcinoma of the thyroid in the manubrium that was iodine avid. She underwent a total thyroidectomy with partial resection of the manubrium followed by radioactive iodine ablation. Over a period of 15 years, she received a further five courses of 131I therapy. Unfortunately, her post-therapy scan and single-photon emission computed tomography (SPECT) did not show any activity in the pituitary fossa region or the thoracic spine, suggesting poor accumulation of iodine and thus 131I resistance. Her visual field defects improved following the surgery.In 2006, during an outpatient visit, she relayed a 12-week history of 7 kg weight loss, nausea and vomiting. She was admitted to hospital for investigation of these symptoms, including computerised tomography (CT) of the abdomen, gastroscopy and colonoscopy with no apparent cause found. Subsequently, on resolution of these symptoms after receiving an intra-articular steroid injection for shoulder pain, it was discovered that she was hypocortisolaemic with a morning cortisol of 133 nmol/l and an abnormal short synacthen test . FurtherFifteen months post surgery, she represented with headaches. Repeat computerised perimetry showed worsening bitemporal field defects. Repeat MRI scan of the pituitary  demonstrShe failed to achieve an adequate response from her radiotherapy, and over the next 3 years, the pituitary metastasis increased in its supra-sellar extent . ComputePituitary metastases are relatively uncommon, representing 1% of all sellar neoplasms from surgical and 5% in autopsy series Owing to a high prevalence of pituitary tumours, diagnosis of pituitary metastases can be challenging. Non-specific systemic symptoms  of underlying malignancy and TSH suppression therapy in case of thyroid cancer often delay the diagnosis of hypopituitarism caused by pituitary metastases et al. High-resolution CT and MRI are sensitive imaging modalities but lack specificity. The MRI of pituitary metastases demonstrates an iso-intense or hypo-intense mass on T1 with a hyper-intense signal on T2-weighted image Rapid aggressive tumour growth and infiltration of adjacent tissues favour the diagnosis of pituitary metastases. Pituitary metastases from thyroid cancer usually present with symptoms of mass effects like headache, visual loss or signs of other cranial nerve palsy due to supra-sellar extension with optic chiasm compression or cavernous sinus invasion respectively.Owing to the direct arterial supply, metastases to the posterior lobe of the pituitary gland are more common. The most common symptom reported in the literature is diabetes insipidus in up to 45% of the cases 131I resistant. Radioiodine refractory metastatic thyroid cancer can be managed with thyroid hormone suppression therapy, external beam radiotherapy or chemotherapy The overall 10-year disease-specific survival in DTC is 85% and it drops to 30–55% in radioactive iodine-avid metastases and 10–18% in non-radioactive iodine-avid metastatic disease Currently, there are a number of trials underway evaluating the role of therapies targeting specific molecules involved in the molecular and cellular pathogenesis of thyroid cancer. These therapies mainly target angiogenesis, tumour cell growth and apoptotic pathways, and oncogenic signalling pathways 131I ablation in non-radioiodine avid tumours has been well described in the literature and results from in vitro studies are promising; however, further studies are needed The role of various redifferentiating agents enhancing iodine uptake by modulating thyroid gene expression to improve the efficacy of In conclusion, pituitary metastases are a rare complication of metastatic DTC. These metastases are aggressive, invasive and large, causing mass symptoms and profound hypopituitarism. These secondary malignancies, when no longer iodine avid, pose a very poor prognosis. The efficacy of other treatment options including external irradiation and chemotherapy is low. Targeted therapies may hold promise to deliver better outcomes for non-radioiodine avid metastatic thyroid disease.The consent form has not been obtained because the patient is dead and the information provided in this report is unidentifiable.V Chikani was involved in the patient's care as a registrar and he prepared the manuscript and reviewed the literature. D Lambie reported the histopathology slides. A Russell was the physician responsible for the patient and he reviewed and edited the manuscript.


The detection of pathogen-derived molecules as foreign particles by adaptive immune cells triggers T and B lymphocytes to mount protective cellular and humoral responses, respectively. Recent immunological advances elucidated that proteins and some lipids are the principle biological molecules that induce protective T cell responses during microbial infections. Polysaccharides are important components of microbial pathogens and many vaccines. However, research concerning the activation of the adaptive immune system by polysaccharides gained interest only recently. Traditionally, polysaccharides were considered to be T cell-independent antigens that did not directly activate T cells or induce protective immune responses. Here, we review several recent advances in “carbohydrate immunobiology”. A group of bacterial polysaccharides that are known as “zwitterionic polysaccharides (ZPSs)” were recently identified as potent immune modulators. The immunomodulatory effect of ZPSs required antigen processing and presentation by antigen presenting cells, the activation of CD4 T cells and subpopulations of CD8 T cells and the modulation of host cytokine responses. In this review, we also discuss the potential use of these unique immunomodulatory ZPSs in new vaccination strategies against chronic inflammatory conditions, autoimmunity, infectious diseases, allergies and asthmatic conditions. The primary role of the immune system is to protect the host from microbial invasions and infections. While nonspecific, innate immune mechanisms mediate the first stage of transient protection against the invading pathogens, more advanced adaptive immune mechanisms prevent microbial invasions and infections by activating antigen-specific T and B cells. Adaptive immune responses are superior to innate immunity because they provide pathogen specificity and immunological memory, which effectively prevents future reinfections of the host by the same pathogens . γδT cells . Furthermore, ZPS administration generates CD4 memory T cells with proinflammatory Th1 and Th17 phenotypes [While the subcutaneous vaccination and intra-abdominal abscess induction studies identified interesting immunomodulatory aspects of ZPSs, it is important to note that ZPSs are continuously presented to the immune system. ZPSs are components of the commensal bacterial flora, such as ards Th2 . B. fragenotypes . Thus, ZB. fragilis is one of the most frequently isolated bacteria from abdominal abscesses [The first murine model that was used for ZPS studies assessed the impact of ZPSs on the formation of intra-abdominal abscesses. Abdominal abscess formation is a major complication associated with abdominal surgeries, endoscopic therapies and inflammatory pathologies that involve mucosal barrier deficiencies, such as inflammatory bowel disease (ulcerative colitis and Crohn's disease) or diverticulitis. bscesses , 79. Besbscesses , 56. TheIn EAE, the murine model for human multiple sclerosis (MS), pathogenesis is mediated by self-reactive T cells that target the myelin basic proteins of the central nervous system . IL-10 hB. fragilis prevented inflammatory bowel diseases (IBD) in mice [Crohn's disease is believed to be caused by T cell immunity abnormalities  . ZPSs ha in mice , 59. TheAnother widely discussed clinical implication of ZPS usage is in the prevention of allergies , and a 23-valent pneumococcal polysaccharide vaccine  . Pneumococcal polysaccharide vaccines are highly effective in adults, though not in children, suggesting that without conjugated proteins, carbohydrates alone can induce a protective immune response in adults. Interestingly, both the pneumococcal vaccines also contain the capsular polysaccharide from S. pneumoniae serotype 1, the strain which produce the ZPS Sp1 .A recent study reported that vaccines with synthetic ZPS motifs provided protection against group B streptococcus infections . This imAs the ZPS Sp1 is able to activate CD4 T cells of adaptive immune system, future studies can optimize ZPS concentrations in vaccines to prevent pneumococcal and related bacterial infections. Thus, the unusual immunomodulatory properties of ZPSs make them attractive candidates for the treatment of many disease conditions. However, ZPS-based vaccination strategies are still in early experimental stages. To optimize ZPSs as immunoregulatory/vaccine candidates, more research aimed at elucidating the mechanisms of immune modulation by ZPSs is needed.αβT cells. However, the thymic selection mechanisms underlying the in vivo generation of this ZPS-specific T cell clones are currently unknown. Development of specific TCR transgenic mouse models are required to understand the selection and development of ZPS-specific T cells. These cells may be more enriched in the mucosae as ZPS-producing bacteria such as B. fragilis and S. pneumoniae are contained within the commensal flora of the gut and upper respiratory track, respectively. Thus, these ZPS-specific T cells are in constant contact with ZPS presented by APCs of the mucosal immune system. Accordingly, the steady-state presentation of this unique immunomodulatory microbial antigen is beneficial to our immune system as it can play pivotal role in shaping a functionally competent, immune system. However, when ZPSs are accidently introduced into a sterile area, such as the peritoneal cavity during intra-abdominal surgical procedures when abdominal contents can spill into the peritoneal cavity, or by intraperitoneal inoculation with ZPS and a sterile cecal adjutant, a rapid recruitment of ZPS-specific, proinflammatory CD4 T cells may be induced. This recruitment of CD4 T cells together with other innate cells results in the generation of intra-abdominal abscess, a defensive mechanism of the body to contain the infection. Recent studies have shown that ZPS-mediated intra-abdominal abscess induction depends on ZPS processing and presentation on MHCII molecules by APCs for recognition and activation of CD4 T cells. However, future studies are needed to determine how ZPS molecules are bound to MHCII, a paradigm described so far only for protein antigens. Difficulties in crystallizing sugar molecules hamper the study of the structural aspects of ZPS-MHCII interactions as well as those of the TCR-ZPS-MHCII-complex. However, newer approaches such as molecular docking [Unlike negatively charged polysaccharides, bacterial polysaccharides with both positively and negatively charged sugar molecules are able to activate CD4 and CD8 T cells of the adaptive immune system. This phenomenon demonstrates that molecules other than proteinaceous antigens are capable of activation of conventional  docking  may be uThe unique immunomodulatory property of ZPS is its ability to prevent the intra-abdominal abscess development when the experimental models are subcutaneously immunized with ZPS prior to intraperitoneal inoculation. During subcutaneous inoculation, ZPSs induce anti-inflammatory, immunosuppressive T cells. This population includes both the regulatory CD4 and CD8 T cells, which secrete the immunosuppressive cytokine IL-10. Thus, the same immunogen can elicit both proinflammatory and anti-inflammatory responses dependent upon the route and mode of administration. While the induction of proinflammatory responses and abscess induction requires ZPS inoculation with sterile cecal content as an adjuvant, induction of immunosuppressive responses by ZPS does not require an adjuvant. Thus, besides the possible differences in antigen presentation by APCs in eliciting these opposing biological responses, the role mediated by adjuvant also needs to be studied in more detail. Moreover, further studies are required to understand the mechanisms of APC-independent activation of CD8 T regs upon subcutaneous ZPS immunization.Regardless of the unanswered questions, the accumulating data on ZPS is changing our understanding about carbohydrate immunology. We now know that endosome acidification by ZPS can enhance APC functions, such as the processing and presentation of antigens. This is in disagreement with the traditional view that carbohydrates accumulate in the lysosomes and inhibit antigen processing and presentation. ZPS studies have also shown that besides proteins, carbohydrates can also bind to MHCII, an observation that opens the door for further studies in the area of antigen processing and presentation. Moreover, this paves the way for the design of new carbohydrate vaccines against infectious organisms. Additionally, ZPS studies have revealed that some carbohydrates antigens can activate both the CD4 and CD8 T cells of the adaptive immune system and induce proinflammatory or immunosuppressive responses upon administration through different routes. The ability to induce the production of anti-inflammatory cytokines, such as IL-10, makes ZPSs an attractive molecule for the generation of vaccines that can potentially prevent bacterial infections, inflammatory bowel diseases, and autoimmune diseases, such as multiple sclerosis.


Selenium is an essential trace element with potential anti-atherogenic and antioxidant effects. Experimental data suggest that selenium might be beneficial in the prevention of atherosclerosis and its complications, whereas human epidemiological studies have yielded conflicting results. Data on hair selenium status in hyperlipidemic patients are still lacking. Therefore, we analysed selenium concentrations by X-ray fluorescence in the hair of 81 statin-naïve patients with newly diagnosed Fredrickson-type IIa and IIb hyperlipoproteinemia and compared their data with 43 healthy volunteers. We also assessed the frequency of other classical risk factors of atherosclerosis. Hair selenium levels were found to be significantly higher in hyperlipidemic patients compared with volunteers with normal lipid levels. Also, a significantly increased number of traditional atherosclerosis risk factors were observed in hyperlipidemic patients with hair selenium concentrations above the median in contrast to those with below. Our results suggest that high hair selenium status might be associated with adverse blood lipid profile together with an increased number of traditional risk factors in a selenium-deplete population. These findings warrant further investigations to study the impact of selenium supplementation on the incidence of cardiovascular events. Selenium is an essential trace mineral that plays an important role in several redox, metabolic and inflammatory pathways in mammals. These processes are also involved in the development of atherosclerosis, in which selenium is suggested to be protective functioning as a selenocysteine incorporated into selenoproteins. To date, at least 25 selenoproteins have been identified . EpidemiAs it is reviewed elsewhere, previous animal-based studies have shown that—amongst other antioxidants—selenium might reduce oxidative stress and serve as a cytoprotective agent in harmful courses characterized by enhanced reactive oxygen species (ROS) production and/or inflammation, all of which are hallmarks of atherosclerosis –7. Of noThe majority of the above-mentioned studies have measured serum levels as a marker of selenium status, which one can interpret as a ‘snapshot’ of potential antioxidant capacity provided by this trace element. Other techniques, such as toenail or hair selenium levels might provide an assessment reflecting a longer interval of mineral status in the human body. However, literature employing these techniques specifically aimed to investigate correlations between selenium status and atherosclerotic complications or lipid profile is scarce: only a few studies have been performed on toenail selenium status –21 and iTo our knowledge, especially in our Central-Eastern European region, there is no literature published about the hair selenium status of hyperlipidemic patients. Also, data are lacking regarding the associations between hair selenium status and the prevalence of traditional risk factors of atherosclerosis. Therefore, we aimed to find out whether hair selenium levels of hyperlipidemic patients would differ from that of healthy individuals and whether hair selenium status would show a correlation with the lipid profile or with the presence of classical risk factors of atherosclerosis in hyperlipidemic patients.We enrolled 81 consecutive patients with newly diagnosed Fredrickson's type IIa or IIb hyperlipoproteinemia that were referred to our lipid clinic at the 1st Department of Internal Medicine, University of Debrecen Medical and Health Science Center, Hungary; and compared their data with 43 healthy volunteers recruited from our department. All participants provided their written informed consent. Study design, analyses and data collection were approved by the institutional ethic board. The study was carried out according to the World Medical Association Declaration of Helsinki. Individuals with active liver, kidney and dermatological scalp diseases, having a diagnosis of type 1 diabetes mellitus or secondary hypertension were excluded from the study. Also, we did not enrol individuals with positive history of CVD or taking lipid lowering drugs, vitamin supplements, selenium or iron containing drugs. None of the investigated participants used medicated shampoos, bleaches or dyes.Participants completed a physical examination and a questionnaire about their medical history. Metric body mass index (BMI) was calculated as the ratio of the weight measurements in kilogrammes to the square of the height measurements in metres. After a 10-min. rest, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured three times 2 min. apart in sitting position. Hypertension was defined as averages of SBP ≥ 140 and/or DBP ≥ 90 mmHg or currently receiving antihypertensive treatment. Patients with the diagnosis of type 2 diabetes mellitus and receiving any type of anti-diabetic treatment were classified as type 2 diabetic. Smoking was defined if the patients declared themselves as current smokers or had stopped <15 years ago. Patients were asked about the health status of their close relatives including their parents, grandparents, siblings, children and grandchildren; family history was considered to be positive for cardiovascular events if the participants had reported incidence any of ischaemic heart disease, acute coronary syndrome, stroke or peripheral arterial disease in their relatives.p-aminophenazone—CHOD-PAP; and glycerol phosphate oxidase-p-aminophenazone—GPO-PAP respectively; Modular P-800 Analyzer; Roche/Hitachi, Basel, Switzerland). High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were assessed by homogenous, enzymatic, colorimetric assays (HDL-C plus 3rd generation and LDL-C plus 2nd generation respectively). Apolipoprotein A-1 (Apo A-1) and apolipoprotein B (Apo B) examinations were performed by immunoturbidimetric assays (Tina-quant a Apolipoprotein A-1 ver. 2 and Tina-quant a Apolipoprotein B ver. 2 respectively). The tests were performed according to the recommendation of the manufacturer.After a 12-hr fast, blood was drawn from cubital veins and sera were prepared immediately. Reagents were purchased from Roche Diagnostics, Basel, Switzerland. Lipid fractions were measured by automated methods: serum cholesterol and triglyceride levels were measured by enzymatic, colorimetric tests  analysis with an automated X-ray emission analytical apparatus of energy resolution of 165 eV  as it is described elsewhere –26. The t-tests. Wald–Wolfowitz runs test was applied to analyse the association between log hair selenium and the presence of risk factors. P < 0.05 was considered statistically significant.Statistical analysis was performed by the SAS™  for Windows™ 8.2 computer software. As hair selenium and triglyceride levels showed a skewed distribution, we performed a logarithmic transformation on these variables. Comparisons between groups were analysed by unpaired P < 0.001). Serum triglyceride and hair selenium levels showed a skewed distribution with the majority of the values falling into the lower range; however, these lipid and trace mineral concentrations appeared to have a high inter-individual variability; therefore we performed a logarithmic transformation on these variables. As expected, log triglyceride was significantly higher in hyperlipidemic patients compared with healthy individuals (P = 0.006). Interestingly, however, log hair selenium was found to be significantly increased in hyperlipidemic patients in contrast to healthy individuals (P = 0.0013).The characteristics of the study population are shown in log hair selenium respectively  compared with those with low hair selenium concentration  , 36. Hyplog hair selenium levels, further assessment of the hyperlipidemic patients did not mirror significant differences in the lipid profile of individuals below or above the median of the trace mineral, indicating that lipid measurements might be affected by factors other than selenium exposure in these patients.Considering the monthly hair growth rate, hair samples being cut 1 cm away from the scalp represent the mineral status of the last 3 weeks, approximately, which can be a reliable biomarker of selenium status. Based on the median of Serum selenium level has been reported to be decreased in smoking individuals , whereasWe also found a significantly increased number of traditional atherosclerosis risk factors in hyperlipidemic patients with hair selenium concentrations above the median. Patients were slightly overweight and hyperlipidemic irrespectively of their hair selenium concentrations, which indicate the presence of other factors in the background of this result. Glutathione peroxidase (GPx) isoenzymes are known to be differently reactive to changes in selenium status  and erytOur findings provide new data regarding hair selenium status in hyperlipidemic patients with different risk factors in a selenium-deplete population and reassure previous results that high selenium levels—together with a higher frequency of traditional risk factors—might contribute to a development of adverse lipid profile and progression of atherosclerosis. Further information on hair selenium status in a prospective study design is of major importance to assess the risk of different cardiovascular outcome in hyperlipidemic patients with various selenium levels.


EHP 120(6):885–892; Nazarenko et al.].The growing use of engineered nanomaterials in consumer products raises questions regarding potential adverse health effects of nano-material exposures. Although a considerable amount of research exists on the toxicity of pure nanomaterials, there is only limited information exposure to nano-materials combined with other ingredients in consumer products. A team of researchers now reports their observations on inhalation exposure through the use of nanotechnology-enabled and non-nanoenabled (“regular”) cosmetic powders [There are currently more than 1,300 documented nanoenabled consumer products . This figure represents only those products voluntarily reported by manufacturers. In a previous study, these investigators examined the potential for inhalation of nanoparticles through the use of nanoenabled and regular consumer spray products. This time, they analyzed particle size, shape, agglomeration (clustering), and distribution for three nanoenabled and three regular cosmetic powders. To simulate real-world exposures, they applied each powder to a life-size female mannequin head using its enclosed brush or pad. Then they measured the size distribution and concentration of particles that could be inhaled as a result of such application.All particles in the first sample of nanoenabled powder were in the nanoscale range. The second nanoenabled powder contained a wide range of agglomerated particles, with the majority being nanosized. Despite its label, the third nanoenabled powder contained no nanoscale particles. The researchers did find a number of nanoparticles agglomerated with larger particles in two regular powders, which were not marketed as nanoenabled. The third regular powder contained mostly particles measuring greater than 5 mm in diameter.Particles under 100 nm in diameter may travel all the way to the terminal alveoli, where air exchange takes place. However, the authors’ electron microscopy data and airborne particle measurements suggest that exposure to nano-particles would be largely through agglomerates of 5–10 mm and larger, which are likely to lodge in the tracheobronchial and head airway regions. But because these agglomerates have a combined surface area greater than that of solid particles of the same size, they may pose different health hazards than solid particles.The study offers a methodology that could be applied to future studies focusing on real-world inhalation exposures related to nanoenabled consumer products. Results from such studies can help guide estimates of exposures through the short- and long-term use of such products.


David Boulware discusses the challenges of diagnosing tuberculous meningitis and the implications of the study by Patel and colleagues using the Xpert MTB/RIF assay for diagnosis.Please see later in the article for the Editors' Summary PLOS Medicine:This Perspective discusses the following new study published in doi:10.1371/journal.pmed.1001536Patel VB, Theron G, Lenders L, Matinyenya B, Connolly C, et al. (2013) Diagnostic Accuracy of Quantitative PCR (Xpert MTB/RIF) for Tuberculous Meningitis in a High Burden Setting: A Prospective Study. PLoS Med 10(10): e1001536. Vinod Patel and colleagues evaluate the sensitivity and specificity of quantitative PCR using Xpert MTB/RIF for diagnosis of TB meningitis in the high-burden setting of South Africa.Mycobacterium tuberculosis. This combination creates a disease that is notoriously difficult to definitively diagnose. In this week's issue of PLOS Medicine, Patel and colleagues report the diagnostic performance of the GeneXpert system's Xpert MTB/RIF assay for the diagnosis of TBM in a cohort of 204 South African, predominantly HIV-infected, adults presenting with suspected meningitis of whom 59 had definitive TBM Tuberculous meningitis (TBM) is characterized by copious cerebrospinal fluid (CSF) inflammation and yet few M. tuberculosis DNA in approximately 2 hours with minimal hands-on time Clostridium difficile, methicillin-resistant Staphylococcus aureus).The GeneXpert System (Cepheid) is a single use cartridge-based real-time PCR fully automated system that performs sample decontamination, sonication, automated nucleic acid amplification, and fluorescence-based quantitative PCR There is a rapidly emerging literature regarding the performance of the Xpert MTB/RIF assay. Fundamentally, the sensitivity depends on the burden of organisms and thereby the target DNA present in the specimen. The published Xpert MTB/RIF detection threshold is approximately 100–130 colony forming units (cfu)/ml of sample The threshold of detection is a key principle. The Xpert MTB/RIF test performs better when there is a larger burden of infectious organisms present in the specimen being tested. Yet, TB meningitis is a paucibacillary condition with few organisms. More organisms are likely present when the host is immunocompromised, or when a larger input volume is used for the test. Thus specimen centrifugation can compensate and should improve diagnostic yield, as demonstrated by a 35% improvement in sensitivity in this study The prior data on Xpert MTB/RIF testing of CSF are limited. In India, the Xpert MTB/RIF assay detected two of seven culture-positive specimens using an input volume of ∼1 ml Although two commercial TB PCR tests previously existed Patel and colleagues modeled a clinical score to predict who had such high pretest probability of TBM that Xpert MTB/RIF was unnecessary to perform M. tuberculosis organisms, likely increasing the diagnostic yield of molecular testing. In the current study, the GeneXpert performed poorly among HIV-uninfected persons, and the performance in children is unknown. Third is the CSF profile. TBM is classically a lymphocytic meningitis , in a clinically stable patient treated presumptively for bacterial meningitis a repeated lumbar puncture in 48 hours is likely a better strategy than sub-optimal Xpert MTB/RIF testing using a limited volume. A repeat lumbar puncture can collect a sufficiently large volume as well as reassess CSF glucose. At 48 hours, the CSF glucose should have risen by >100% of the initial level in treated bacterial meningitis Xpert MTB/RIF appears to be a highly useful test to “rule in” the diagnosis of TBM, yet the clinical acumen of physicians remains a necessity for the wise use of any new diagnostic test. Careful application of these new diagnostic tools should improve clinicians' ability to deliver timely, cost-effective care to patients with suspected TBM throughout the world, an approach that future studies should systematically evaluate.


Endothelial colony-forming cells (ECFCs), are circulating endothelial progenitor cells increasingly studied in various diseases because of their potential for clinical translation. Experimental procedures for their ex vivo culture still lack standardization. In particular two different extracellular matrix proteins, either fibronectin or collagen, are commonly used by different Authors for coating plastic plates, both allowing to obtain cells that have all the features of ECFCs. However, possible differences in the impact of each substrate on ECFCs have not been analysed, so far. Therefore, in this study we investigated whether fibronectin and collagen may differentially affect ECFC cultures.ECFCs were isolated and cultured from peripheral blood mononuclear cells of healthy donors. The impact of fibronectin compared with collagen as the only variable of the experimental procedure was analysed separately in the phase of isolation of ECFC colonies and in the following phase of cell expansion. In the isolation phase, although similar frequencies of colonies were obtained on the two substrates, ECFC colonies appeared some days earlier when mononuclear cells were seeded on fibronectin rather than collagen. In the expansion phase, ECFCs cultured on collagen showed a longer lifespan and higher cell yields compared with ECFCs cultured on fibronectin, possibly related to the higher levels of IL-6 and IL-8 measured in their supernatants. ECFCs cultured on both substrates showed similar immunophenotype and ability for in vitro tube formation.Overall, the results of this study indicate that, although both fibronectin and collagen efficiently sustain ECFC cultures, each of them brings some advantages within individual steps of the entire process. We suggest that colony isolation performed on fibronectin followed by cell expansion performed on collagen may represent a novel and the most efficient strategy to obtain ECFCs from adult peripheral blood samples. Endothelial progenitor cells (EPCs) are bone marrow-derived cells playing a critical role in adult vasculogenesis and endothelial homeostasis Circulating EPCs can be studied following two main approaches Among populations of putative EPCs that can be isolated and cultured from adult blood, only endothelial colony-forming cells (ECFCs), also called late-EPCs or outgrowth endothelial cells, are considered the true EPCs. In fact, they have all the characteristics of true endothelial progenitors, as they possess clonal proliferative potential and they express endothelial but not hematopoietic cell surface antigens. Most important, unlike other putative EPCs that are endowed with proangiogenic activity but fail to display vasculogenic activity, ECFCs have the unique ability to display in vivo vasculogenic activity when implanted into immunodeficient mice Procedures for ECFC isolation and propagation strictly depend on coating the culture surface with extracellular matrix protein that promotes cell adhesion and growth Ethics approval was obtained from the Institutional Review Board of Istituto Clinico Humanitas, Rozzano, Milan, Italy, and written informed consent was provided by study participants.6 cells/well) precoated with either human fibronectin  or type I rat-tail collagen , as indicated. After one day of culture, nonadherent cells and debris were aspirated, adherent cells were washed with EGM-2 medium, and EGM-2 medium was added to each well. Medium was changed every 2 days until the first passage. The initial appearance of visible colonies, identified as well circumscribed monolayers of cobblestone-like cells, was determined by daily culture observation using an inverted microscope, and the first day of ECFC colony emergence was recorded. Colony size was determined by measuring colony diameters 3 days after colony appearance. The frequency of ECFC colonies was determined by measuring the number of colonies in the primary culture on day 30, as no ECFC colony emerged at a later time point. ECFC colonies were released from the original tissue culture plates by trypsinization (trypsin 0.25%) , resuspended in EGM-2 medium, and plated onto 6-well tissue culture plates precoated with fibronectin or collagen, as indicated. Subconfluent cells were further subpassaged in flasks and expanded until cell senescence, as determined by morphology changes, decrease in proliferation and positive staining for senescence-associated ß-galactosidase  ECFCs were isolated and cultured from peripheral blood mononuclear cells (PBMCs) of healthy donors according to methods previously described Cell proliferation of ECFCs was assessed as described elsewhere The amount of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), IL-6 and IL-8 in culture supernatants were determined by DuoSet ELISA kits from R&D Systems. All individual steps were performed according to the manufacturer’s instructions.Immunophenotyping of ECFCs was performed as previously described The uptake of Dil-acetylated low-density lipoprotein (Dil-ac-LDL) by ECFCs and their staining for Ulex Europaeus Agglutinin-1 (UEA-1) were assessed as previously described 4 cells per well, and incubated at 37°C. Cells were observed during the following 12–72 hours with inverted microscopy for capillary-like formation.Matrigel assays were performed as previously described Data were shown as mean ± standard error of the mean (SEM). Comparisons of samples to establish the statistical significance of difference were determined by the Mann-Whitney U-test or Wilcoxon signed-rank test, as indicated. All statistical analyses assumed a 2-sided significance level of 0.05. Data analyses were performed with Openstat software.6 PBMCs vs collagen: 66.8±6.6, p = ns). As expected, colonies with cobblestone-like morphology appeared on both extracellular matrix protein substrates. At least one colony was obtained in 7 of 9 donors in both conditions, and similar frequencies of ECFC colonies were obtained on the two substrates . However, ECFC colonies from donors whose PBMCs were seeded on fibronectin appeared some days earlier than those seeded on collagen  . PBMCs from 9 donors were then seeded on fibronectin-coated plates and PBMCs from the other 9 donors were seeded on collagen-coated plates. A similar number of PBMCs was seeded in each condition (fibronectin: 69.2±9.5×10= 0.009) .6 PBMCs were seeded in each condition. Also in these paired experiments, no difference was observed in the quantity of ECFC colonies obtained with the two substrates. In fact, at least one colony was obtained from all donors in both conditions, and the frequency of ECFC colonies did not differ between substrates . Similarly to what we observed in the unpaired experiments, also in these paired experiments ECFC colonies appeared few days earlier when PBMCs were seeded on fibronectin rather than collagen  . PBMCs from the same donor were divided into portions, with half of them seeded on fibronectin-coated plates and the rest seeded on collagen-coated plates. A mean of 75.0±9.2×10= 0.009) . Once es8 cells vs 2.5×108, p = 0.037)  .To investigate the mechanisms possibly involved in sustaining the higher cell yield observed when ECFCs were cultured on collagen rather than fibronectin, we analysed in our cultures the main proangiogenic cytokines secreted by endothelial progenitor cells To further assess whether IL-6 and IL-8 were responsible indeed for the difference in ECFC expansion observed on different substrates, we investigated whether addition of these cytokines to ECFCs cultured on fibronectin could recapitulate the behaviour of ECFCs cultured on collagen. To this aim we analysed the effects of IL-6 and IL-8, added at concentrations similar to those measured in culture supernatants, on ECFC proliferation. Cell proliferation was assessed by the colorimetric CV assay, and expressed as optical density (OD). As shown in We then asked whether coating of culture plates with fibronectin rather collagen as an extracellular matrix protein may differently affect the immunophenotype or functional properties of the expanded cells. To this aim, we compared early passaged (3–5) ECFCs expanded on fibronectin with equally passaged ECFCs expanded on collagen. As shown in As shown in In this study, we provide evidence that fibronectin and collagen used for culture surface coating differently affect the efficiency of ECFC isolation and expansion. This is an important issue. In fact, although ECFCs are increasingly being studied in various diseases because of their potential for clinical translation, yet experimental procedures for their ex vivo culture still lack standardization. In particular, either fibronectin or collagen are commonly used as coating substrates to obtain cells that have all the features needed to be defined ECFCs The results obtained in the first step of the process indicated that fibronectin sustained the isolation of ECFC colonies more efficiently than collagen. In fact, maintaining constant all the other experimental variables, PBMCs seeded on fibronectin gave rise to ECFC colonies almost one week earlier than PBMCs seeded on collagen. Notably, this advantage of fibronectin-coating was confirmed in the experiments where the comparison between substrates was performed within the same subject, thus overcoming differences possibly due to interindividual variability. We suggest that the shorter time of initial cluster appearance supported by fibronectin may be advantageous, as it may help reduce time-and reagent-consuming procedures in the lab and may allow getting results faster.On the other hand, the results obtained in the second step of the process indicated that collagen sustained more efficiently than fibronectin the cell propagation of ECFCs. In fact, the comparison of parallel cell cultures, started from the same colony and performed in identical experimental conditions apart from the substrate used for plastic coating, demonstrated that higher cell yields were obtained when ECFCs were cultured on collagen, likely related to the longer survival of cell cultures and the higher cell proliferation observed on this substrate. Notably, the supernatants obtained from ECFCs cultured on collagen contained higher levels of IL-6 and IL-8, angiogenic cytokines that have been demonstrated to directly promote the survival of endothelial cells, as well We conclude from this study that, although both fibronectin and collagen are appropriate to sustain the entire process of ECFC culture, colony isolation on fibronectin followed by cell expansion on collagen may represent the most efficient strategy to obtain ECFCs from adult peripheral blood samples.


Inflammatory myofibroblastic tumor is currently considered to be a low-grade neoplasm, and it rarely involves the heart. We reported a rare case of a 59-year-old female who received cardiac surgery for complete resection of inflammatory myofibroblastic tumor in the left atrium. Five months after surgery, the patient presented with acute cardiogenic pulmonary edema and subsequent sudden death due to a left atrial tumor which protruded into the left ventricle through mitral annulus during diastole. The recurrence of inflammatory myofibroblastic tumor in the left atrium was strongly suggested clinically. Dear Editor,Inflammatory myofibroblastic tumor (IMT) occurs mostly in children and young adults  and usuaA 59-year-old Chinese female was hospitalized because of exertional dyspnea for 2 weeks. Transthoracic echocardiography showed a left atrial mass Figure A. CoronaUp to now, the pathogenesis of IMT remains unclear, although it is thought to be an abnormal and exaggerated immunologic response by proliferated spindle cells and primary myofibroblasts to injury, inflammation, and infection. The diagnosis of IMT can be difficult due to the wide morphological spectrum. Coffin et al. have classified the histological findings of extrapulmonary IMT into three patterns: (a) spindle cells in a myxoid background with a vascular and inflammatory component resembling nodular fasciitis (myxoid/vascular pattern); (b) compact spindle cells with intermingled inflammatory cells resembling fibrous histiocytoma (compact spindle cells pattern); and (c) dense plate-like collagen resembling a desmoid or scar (hypocellular fibrosis pattern) . In the IMT is considered a low-grade neoplasm. The recent classification of the World Health Organization recognized the uncertainty of its biological nature, that is, its clinical features might resemble malignant neoplasia. Whenever feasible, complete surgical resection remains the mainstay of treatment. Up to now, the recurrence rate of pulmonary IMT is low. However, local recurrence rate of extrapulmonary IMT is up to 25 % . To the IMT = inflammatory myofibroblastic tumor.YX collected data and drafted the manuscript. XC carried out the literature research. LM was helpful in literature review. WY conceived the study and critically revised the manuscript.The authors declare that they have no competing interests.