The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction

BACKGROUND: Recent studies indicate that magnetic resonance imaging (MRI) after the administration of contrast material can be used to distinguish between reversible and irreversible myocardial ischemic injury regardless of the extent of wall motion or the age of the infarct. We hypothesized that the results of contrast-enhanced MRI can be used to predict whether regions of abnormal ventricular contraction will improve after revascularization in patients with coronary artery disease. METHODS: Gadolinium-enhanced MRI was performed in 50 patients with ventricular dysfunction before they underwent surgical or percutaneous revascularization. The transmural extent of hyperenhanced regions was postulated to represent the transmural extent of nonviable myocardium. The extent of regional contractility at the same locations was determined by cine MRI before and after revascularization in 41 patients. RESULTS: Contrast-enhanced MRI showed hyperenhancement of myocardial tissue in 40 of 50 patients before revascularization. In all patients with hyperenhancement the difference in image intensity between hyperenhanced regions and regions without hyperenhancement was more than 6 SD. Before revascularization, 804 of the 2093 myocardial segments analyzed (38 percent) had abnormal contractility, and 694 segments (33 percent) had some areas of hyperenhancement. In an analysis of all 804 dysfunctional segments, the likelihood of improvement in regional contractility after revascularization decreased progressively as the transmural extent of hyperenhancement before revascularization increased (P<0.001). For instance, contractility increased in 256 of 329 segments (78 percent) with no hyperenhancement before revascularization, but in only 1 of 58 segments with hyperenhancement of more than 75 percent of tissue. The percentage of the left ventricle that was both dysfunctional and not hyperenhanced before revascularization was strongly related to the degree of improvement in the global mean wall-motion score (P<0.001) and the ejection fraction (P<0.001) after revascularization. CONCLUSIONS: Reversible myocardial dysfunction can be identified by contrast-enhanced MRI before coronary revascularization.     

Impact of delayed reperfusion of myocardial hibernation on myocardial ultrastructure and function and their recoveries after reperfusion in a pig model of myocardial hibernation.

This study examined the effect of delayed reperfusion of myocardial hibernation from 24 hours to 7 days on myocardial ultrastructural and functional changes and their recoveries after reperfusion. Background: We have previously shown in pigs that after reperfusion the functional and structural alterations in short-term myocardial hibernation which was reperfused in 24 hours can recover in 7 days. The effect of delayed reperfusion of hibernating myocardium on the extent and severity of cellular and extracellular structural changes of hibernating myocardium, and their recoveries after reperfusion is not known. Methods and Results: A severe LAD stenosis was created in 27 pigs, reducing resting flow by 30-40% immediately after placement of the stenosis and producing acute ischemia as evidenced by regional lactate production, a decrease in regional coronary venous pH, reduced regional wall thickening (from 38.5 +/- 5.1% to 10.4 +/- 8.0%) and a 33% reduction of regional oxygen consumption. The stenosis was maintained either for 24 hours in 9 pigs (group 1) with LAD flow of 0.65 +/- 0.13 ml/min/g (38% reduction), or for 7 days in 17 pigs (group 2) with LAD flow of 0.67 +/- 0.14 ml/min/g (36% reduction). There were no differences (p = NS) in the reduction of wall thickening, rate-pressure product, lactate production, or regional oxygen consumption between group 1 and group 2. Quantitative morphometric evaluation of the ultrastructure on electromicrographs revealed a greater decrease in sarcomere volume and a higher incidence of myocytes with reduced sarcomere volume in 7-day than in 24-hour hibernating regions (53 +/- 19% versus 33 +/- 14%, p < 0.05). Patchy myocardial necrosis with replacement fibrosis was common, but 6 of the 18 pigs had no myocardial necrosis or replacement fibrosis in the 7-day hibernating group, and 4 of 9 pigs had no patchy myocyte necrosis in the 24 hour hibernating group. In 6 pigs in group 1 in which the stenosis was then released and hibernating myocardium reperfused in 24 hours, regional wall thickening recovered to 30 +/- 6% (p = NS compared to baseline) after one week of reperfusion. In 12 pigs in group 2 in which the stenosis was released and hibernating myocardium reperfused in 7 days, regional wall thickening recovered slowly, from 10.1 +/- 7.2% to 18.1 +/- 8.3% at one week (n = 5) and to 28.0 +/- 3.6% at 3-4 weeks of reperfusion (n = 7, p < 0.05 compared to baseline). Similarly, the sarcomere volume or myofilament recovered significantly (p < 0.01) and was not different compared to the normal region (p = NS) in the 24-hour hibernating region of group 1, but the recovery was much slower and was incomplete at 4 weeks (p < 0.01) compared to baseline in the 7-day hibernating region of group 2. Recovery of regional wall thickening correlated with ultrstructural recovery (p < 0.01). By multivariate stepwise regression analysis, the degree of LAD flow reduction, the extent of fibrosis, and myofilament loss were independent predictors of the extent of functional recovery. Conclusions: In a porcine model of myocardial hibernation with myocardial hypoperfusion, systolic dysfunction, and metabolic adaptations, a longer period of myocardial hibernation with delayed reperfusion was associated with more severe abnormalities of myocytes. an increasing interstitial fibrosis, and more protracted myofibrillar and functional recoveries after reperfusion. The extent of functional recovery is related to the degree of coronary flow reduction, the severity of the ultrastructural changes, and the extent of interstitial fibrosis.     

Chronic hibernating myocardium in sheep can occur without degenerating events and is reversed after revascularization

IntroductionOur goal was to show that blunting of myocardial flow reserve is mainly involved in adaptive chronic myocardial hibernation without apparent cardiomyocyte degeneration.Methods and resultsSheep chronically instrumented with critical multivessel stenosis and/or percutaneous transluminal coronary angioplasty (PTCA)-induced revascularization were allowed to run and feed in the open for 2 and 5 months, respectively. Regional myocardial blood flow (MBF) with colored microspheres, regional and global left ventricular function and dimensions (2D echocardiography), and myocardial structure were studied. In sheep with a critical stenosis, a progressive increase in left ventricular end-diastolic and end-systolic cavity area and a decrease in fractional area change were found. Fraction of wall thickness decreased in all left ventricular wall segments. MBF was slightly but not significantly decreased at rest at 2 months. Morphological quantification revealed a rather small but significant increase in diffusely distributed connective tissue, cardiomyocyte hypertrophy, and presence of viable myocardium of which almost 30 % of the myocytes showed depletion of sarcomeres and accumulation of glycogen. The extent of myolysis in the transmural layer correlated with the degree of left ventricular dilation. Structural degeneration of cardiomyocytes was not observed. Balloon dilatation (PTCA) of one of the coronary artery stenoses at 10 weeks revealed recovery of fraction of wall thickness and near normalization of global subcellular structure at 20 weeks.ConclusionThese data indicate that chronic reduction of coronary reserve by itself can induce ischemic cardiomyopathy characterized by left ventricular dilatation, depressed regional and global function, adaptive chronic myocardial hibernation, reactive fibrosis and cardiomyocyte hypertrophy in the absence of obvious degenerative phenomena.SummaryReduction of myocardial flow reserve due to chronic coronary artery stenosis in sheep induces adaptive myocardial hibernation without involvement of degenerative phenomena.     

可溶性晚期糖基化终末产物受体拮抗缺血/再灌注小鼠心肌纤维化

目的 探讨可溶性晚期糖基化终末产物受体（sRAGE）对缺血/再灌注小鼠心脏炎症的影响及其机制。 方法 利用6～8周龄雄性C57BL/6小鼠构建心肌缺血/再灌注损伤模型（左前降支结扎30 min,再灌注2周）,随机分为4组,每组5只C57BL/6小鼠。通过心脏超声检测心功能,HE染色观察炎症细胞浸润情况,马松和天狼星红染色检测心肌纤维化,免疫组织化学染色检测半乳糖凝集素3（galecti-3）表达。 结果 与假手术组相比,缺血/再灌注组小鼠的心功能减退,心肌组织间有大量炎症细胞浸润,心肌纤维化面积增加,同时,心脏组织中 galectin-3 的表达增多;而给予外源性sRAGE处理后,小鼠的心功能显著改善,炎症细胞浸润减少,纤维化程度减轻,心脏组织中galecti-3的表达也显著减少。 结论 心肌缺血/再灌注损伤时,sRAGE可能通过抑制galectin-3的表达,减少小鼠心脏炎症细胞浸润,从而减轻心肌纤维化。     

Lymphocyte sub-populations and non-Langerhans' cell monocytoid cells in pulmonary Langerhans' cell histiocytosis

Pulmonary Langerhans' cell histiocytosis (PLCH) is a disease characterized by the occurrence of complex fibro-cellular interstitial lesions dominated by Langerhans' cells (LC), which occurs predominantly in young adult smokers. We undertook this retrospective study to better define the lymphohistiocytic cell populations in PLCH in order to obtain a greater insight into its pathogenesis. Formalin-fixed, paraffin-embedded, surgically excised, archival lung tissue from seven patients (two males, five females; average age 34.9 years) was immunostained with a panel of antibodies for lymphohistiocytic markers: CD1a, CD3, CD4, CD8, CD15, CD20, CD56, TIA-1, CD68-PGM1, Mac387, and mast cell tryptase. Double immunolabeling was performed with CD1a/Mac387. Leder cytochemical stain for chloroacetate esterase was also performed. A moderate number of lymphocytes, predominantly T lymphocytes, were scattered diffusely within the lesions. The mean CD4/CD8 ratio was 0.1/1. The CD3/CD8 ratio (1.18/1) substantiated the CD4/CD8 ratio. The CD8 subset was CD56-negative and TIA-1-positive, indicating a cytotoxic T lymphocyte phenotype. CD68-PGM1 was strongly positive in alveolar macrophages (AM) and weakly stained LC. Mac387, a marker of activated macrophages, weakly stained AM, while highlighting other interstitial cells. These interstitial cells appeared not to be LC (substantiated by CD1a/Mac387 dual labeling) or CD68-PGM-1-positive macrophages. Having excluded mast cells (positive with mast cell tryptase) and neutrophils (positive with CD15 and Leder stains), there appeared to be a residual population of non-Langerhans cell monocytoid cells (NLMC), which were Mac 387+, CD68-PGM1-, Mast cell tryptase-, CD15-, and CD1a-. Our results showed a predominance of CD8+, TIA-1+ cytotoxic T lymphocytes among the lymphocyte subsets which appear to interact with LC and AM in PLCH lesions. A small sub-population of NLMC was also present. Further studies are required to better define and to evaluate the role of cytotoxic T cells and NLMC in the pathogenesis of PLCH.     

T细胞介导的炎症反应在心肌纤维化中的"双刃剑"作用

心肌纤维化涉及到多种复杂的生物学机制.目前,对于免疫介导的心肌纤维化备受关注,而对于心肌损伤时T细胞介导的炎症反应在心肌纤维化中的作用尚存在争议.早期的炎症反应有利于心肌修复,但过度的炎症反应则促进纤维化发生.因此,详尽了解T细胞在心肌纤维化中的作用,有助于通过控制或干预过度的炎症反应来防治心肌纤维化发生,为心脏疾病提供新的治疗方法.     

Inhibition of mast cells by interleukin-10 gene transfer contributes to protection against acute myocarditis in rats

Progression of acute myocarditis involves a variety of inflammatory events. Mast cells have been implicated as the source of various cytokines, chemokines and histamine in acute inflammation and fibrosis. Interleukin (IL)-10 has well-known immunomodulatory actions that are exerted during the recovery phase of myocarditis. In this study, 9-week-old male Lewis rats were immunized with cardiac myosin. A plasmid vector expressing mouse IL-10 cDNA (800 mug per rat) was then transferred three times (7, 12 and 17 days after immunization) into the tibialis anterior muscles of the rats by electroporation. Microscopic examination of mast cells was carried out on toluidine blue-stained transverse sections of the mid ventricles. Mouse IL-10 gene transfer significantly reduced mast cell density, cardiac histamine concentration and mast cell growth, and prevented mast cell degranulation. Furthermore, improvement in both myocardial function and the overall condition of the rats was evident from the reduction in the heart weight-to-body weight ratio and inflammatory infiltration as well as improvement in hemodynamic and echocardiographic parameters. These findings suggest that IL-10 gene transfer by electroporation protected against myocarditis via mast cell inhibition.     

免疫细胞在心肌重塑中的作用

心肌重塑几乎与所有类型的心脏疾病的发生发展相关,是一个重要的全球性健康问题.这种病理性重塑过程包括心室扩张、心肌炎症反应和心肌细胞肥大,最终导致心力衰竭的发生.在各种类型的心肌损伤后,心脏从纤维细胞转化为肌成纤维细胞,随后并沉积在细胞外基质中,这是心肌纤维化的重要病理机制.同时免疫细胞的激活及其介导的炎症反应也参与了心肌重塑的发生与发展,因而了解免疫细胞导致心肌重塑的可能病理机制可为临床防治和逆转心肌重塑提供新的靶点.     

Mac 387 antibody and detection of formalin resistant myelomonocytic L1 antigen.

The murine monoclonal antibody Mac 387 was raised against a purified protein fraction obtained from human monocytes. By immunoblotting experiments, Mac 387 was shown to react with a previously defined antigen called L1; this is a multichain myelomoncytic protein of about 36 Kd which shows sequence homology with the cystic fibrosis antigen. The L1 protein is present in the cytoplasm of virtually all resting peripheral neutrophils and monocytes; it is also variably expressed on the plasma membrane of these cells, possibly as a secretory product. Because the L1 antigen is resistant to denaturation by formalin, its tissue distribution can be studied in routinely processed biopsy material. In a wide variety of specimens Mac 387 was shown by immunohistochemical analysis, to produce a cytoplasmic staining pattern concordant with that of a well defined polyclonal antibody to the L1 antigen. Cytoplasmic reactivity was obtained with granulocytes and infiltrating macrophages but generally not with several categories of dendritic cells. In addition, squamous epithelium of mucous membranes was strongly positive, in contrast to normal epidermis.     

Drug-induced toxic epidermal necrolysis and pancytopenia: a puzzling association

The molecular mechanisms involved in the pathogenesis of toxic epidermal necrolysis (TEN) remain not fully understood. We report a unique case of antibiotic-induced TEN developed in a patient who also suffered from prolonged severe methotrexate-induced pancytopenia. The objective of the study was to explore the nature of the cutaneous inflammatory infiltrate and the density in dermal dendrocytes (DD). Immunohistochemistry was used to identify activated T lymphocytes (CD45R0), monocyte-macrophages (Mac 387, CD68), DD (Factor XIIIa), and Langerhans cells (CD1a). The proliferation marker (Ki67) and the antibody to Fas receptor (CD95R) were also used to assess the distribution of the germinative pool of keratinocytes and the FAS-related apoptotic process, respectively. Numerous Factor XIIIa+ DD were present in the papillary dermis with only sparce perivascular CD45RO+ T lymphocytes and scattered CD68+ or Mac 387+ macrophages. Double immunostainings revealed that a minority of Factor XIIIa+ DD co-expressed the CD68 glycoprotein (a marker of phagocytic activity). No cells co-expressed factor XIIIa and Mac 387 immunoreactivities. CD45RO+ T lymphocytes, CD68+ and Mac 387+ macrophages were absent in the epidermis. The expression of CD95R was present although restricted to the basal keratinocytes, while the L1-protein (Mac 387+) was diffusely present in the epidermis. Langerhans cells (CD1a+) were sparce, but normal in distribution. The presence of a great number of Factor XIIIa+ DD without any possible recent recruitment from bone marrow suggests that these cells differentiated from resident cells of the skin. Indeed, there was no co-expression of Factor XIIIa and L1-protein, thus showing the absence of recruitment from monocytes. The simultaneous over-expression of Factor XIIIa and CD68 in some DD indicates some phagocytic activity. In view of the absence of inflammatory cells in the epidermis, keratinocytes appeared responsible for their own destruction through CD95-mediated and/or calcium-dependent apoptotic pathways. This finding entails that TEN treatments should target the keratinocyte metabolism rather than the circulating inflammatory cells which presumably play a limited role, if any, in the epidermal destructive process.     

The relation between viable segments and left ventricular ejection fraction improvement

For patients with coronary artery disease and left ventricular dysfunction who undergo revascularization, it is important to estimate the left ventricular ejection fraction (LVEF) improvement after revascularization, as this is a strong indicator of the long-term outcome. Identification of viable segments from echocardiography has been considered a predictive sign of LVEF improvement. However, a quantitative relation between segmental function recovery and global ejection fraction improvement has not been established. There is a clinical need to determine parameters that are predictive to LVEF improvement. A cylindrical left ventricular model is proposed to establish the relation between segmental myocardial function and LVEF based on a 12-segment echocardiograph model. Model results show that LVEF improvement is directly related to the contraction ratio in normal segments and a weighted sum of the number of viable segments that recover to normal or hypokinetic, which is equal to a weighted sum of the change in wall motion scores. This new combined parameter is a better predictor of the amount of LVEF improvement than the total number of viable segments or preoperative ejection fraction. The predictive value of the model was illustrated in a group of four patients with coronary artery disease who underwent revascularization.     

Squamous differentiation in primary urothelial carcinoma of the urinary tract as seen by MAC387 immunohistochemistry

Squamous differentiation (SqD) is variably present in urinary tract tumours, but its significance remains unclear. In this study, SqD was assessed by immunohistochemistry using the monoclonal antibody Mac387 in 145 urothelial tumours (bladder, n = 115; renal pelvis, n = 30). Mac387 detects the myelomonocytic L1 antigen; a member of the calgranulin family shared by epithelial cells and keratinocytes. L1 antigen was shown in SqD in urothelial carcinomas of the bladder or the renal pelvis, including 11 cases with focal SqD unrecognised by conventional analysis. SqD is more frequent in renal pelvic tumours (p = 0.027) and increases with grade/stage mainly in bladder carcinoma (grade, p = 0.05; stage, p = 0.005). Stage Ta/T1 bladder carcinomas with SqD recurred more (p = 0.021). In conclusion, Mac387 efficiently shows SqD in urothelial tumours.     

Renin: at the heart of the mast cell

Summary:  Cardiac mast cells proliferate in cardiovascular diseases. In myocardial ischemia, mast cell mediators contribute to coronary vasoconstriction, arrhythmias, leukocyte recruitment, and tissue injury and repair. Arrhythmic dysfunction, coronary vasoconstriction, and contractile failure are also characteristic of cardiac anaphylaxis. In coronary atherosclerosis, mast cell mediators facilitate cholesterol accumulation and plaque destabilization. In cardiac failure, mast cell chymase causes myocyte apoptosis and fibroblast proliferation, leading to ventricular dysfunction. Chymase and tryptase also contribute to fibrosis in cardiomyopathies and myocarditis. In addition, mast cell tumor necrosis factor-α promotes myocardial remodeling. Cardiac remodeling and hypertrophy in end-stage hypertension are also induced by mast cell mediators and proteases. We recently discovered that cardiac mast cells contain and release renin, which initiates local angiotensin formation. Angiotensin causes coronary vasoconstriction, arrhythmias, fibrosis, apoptosis, and endothelin release, all demonstrated mechanisms of mast-cell-associated cardiac disease. The effects of angiotensin are further amplified by the release of norepinephrine from cardiac sympathetic nerves. Our discovery of renin in cardiac mast cells and its release in pathophysiological conditions uncovers an important new pathway in the development of mast-cell-associated heart diseases. Several steps in this novel pathway may constitute future therapeutic targets.     

Mast cell tryptase may modulate endothelial cell phenotype in healing myocardial infarcts

Mast cells and macrophages infiltrate healing myocardial infarcts and may play an important role in regulating fibrous tissue deposition and extracellular matrix remodelling. This study examined the time-course of macrophage and mast cell accumulation in healing infarcts and studied the histological characteristics and protease expression profile of mast cells in a canine model of experimental infarction. Although macrophages were more numerous than mast cells in infarct granulation tissue, macrophage density decreased during maturation of the scar, whereas mast cell numbers remained persistently elevated. During the inflammatory phase of infarction, newly recruited leucocytes infiltrated the injured myocardium and appeared to be clustered in close proximity to degranulating cardiac mast cells. During the proliferative phase of healing, mast cells had decreased granular content and were localized close to infarct neovessels. In contrast, macrophages showed no selective localization. Mast cells in healing canine infarcts were alcian blue/safranin-positive cells that expressed both tryptase and chymase. In order to explain the pro-inflammatory and angiogenic actions of tryptase--the major secretory protein of mast cells--its effects on endothelial chemokine expression were examined. Chemokines are chemotactic cytokines that play an important role in leucocyte trafficking and angiogenesis and are highly induced in infarcts. Tryptase, a proteinase-activated receptor (PAR)-2 agonist, induced endothelial expression of the angiogenic chemokines CCL2/MCP-1 and CXCL8/IL-8, but not the angiostatic chemokine CXCL10/IP-10. Endothelial PAR-2 stimulation with the agonist peptide SLIGKV induced a similar chemokine expression profile. Mast cell tryptase may exert its angiogenic effects in part through selective stimulation of angiogenic chemokines.     

Recovery of cardiac function mediated by MSC and interleukin-10 plasmid functionalised scaffold

Stem cell transplantation has been suggested as a treatment for myocardial infarction, but clinical studies have yet to demonstrate conclusive, positive effects. This may be related to poor survival of the transplanted stem cells due to the inflammatory response following myocardial infarction. To address this, a scaffold-based stem cell delivery system was functionalised with anti-inflammatory plasmids (interleukin-10) to improve stem cell retention and recovery of cardiac function. Myocardial infarction was induced and these functionalised scaffolds were applied over the infarcted myocardium. Four weeks later, stem cell retention, cardiac function, remodelling and inflammation were quantified. Interleukin-10 gene transfer improved stem cell retention by more than five-fold and the hearts treated with scaffold, stem cells and interleukin-10 had significant functional recovery compared to the scaffold control (scaffold: −10 ± 7%, scaffold, interleukin-10 and stem cells: +7 ± 6%). This improved function was associated with increased infarcted wall thickness and increased ratios of collagen type III/type I, decreased cell death, and a change in macrophage markers from mainly cytotoxic in the scaffold group to mainly regulatory in scaffold, stem cells and interleukin-10 group. Thus, treatment of myocardial infarction with stem cells and interleukin-10 gene transfer significantly improved stem cell retention and ultimately improved overall cardiac function.     

Distribution of non-lymphoid, inflammatory cells in chronic HBV infection

Non-lymphoid cells play a key role in the initiation and maintenance of cellular immune responses. Using in-situ immunohistochemical techniques and a panel of monoclonal antibodies (mcabs) reactive with B5-fixed, paraffin-embedded liver biopsies, we analysed the non-lymphoid cell component in inflammatory infiltrates in 20 cases of chronic hepatitis B virus (HBV) infection. In addition, lymphocyte subsets and HLA-DR antigens were studied. Mcab KP1 labelled scattered Kupffer cells, which variably expressed HLA-DR antigens. Their random distribution and lack of significant topographical association with lymphocytes suggest that classical Kupffer cells do not play a major role in cell-mediated immune reactions. On the other hand, mcab Mac387 was unreactive with normal liver tissue but labelled HLA-DR+ dendritic cells in areas of intralobular inflammation. On (immuno)electron microscopy, these Mac387+ dendritic cells were situated in the Disse space, where they formed close contacts with lymphocytes. Similar dendritic cells were situated at the edge of portal tracts in cases of chronic active, but not chronic persistent hepatitis. Immunostaining on serial frozen sections revealed their close topographical association with cytotoxic/suppressor T-cells, suggesting that Mac387+ HLA-DR+ dendritic cells play an immunomodulatory role in the effector arm of the cellular immune response that takes place in the periphery of portal tracts and the lobular parenchyma, and that involves activation and proliferation of cytotoxic T cells. Finally, large Mac387- HLA-DR+ dendritic cells expressing the LN2 marker were situated amidst helper/inducer T-cells in the centre of severely inflamed portal tracts.(ABSTRACT TRUNCATED AT 250 WORDS)     

Handcycling: different modes and gear ratios

For patients with coronary artery disease and left ventricular dysfunction who undergo revascularization, it is important to estimate the left ventricular ejection fraction (LVEF) improvement after revascularization, as this is a strong indicator of the long-term outcome. Identification of viable segments from echocardiography has been considered a predictive sign of LVEF improvement. However, a quantitative relation between segmental function recovery and global ejection fraction improvement has not been established. There is a clinical need to determine parameters that are predictive to LVEF improvement. A cylindrical left ventricular model is proposed to establish the relation between segmental myocardial function and LVEF based on a 12-segment echocardiograph model. Model results show that LVEF improvement is directly related to the contraction ratio in normal segments and a weighted sum of the number of viable segments that recover to normal or hypokinetic, which is equal to a weighted sum of the change in wall motion scores. This new combined parameter is a better predictor of the amount of LVEF improvement than the total number of viable segments or preoperative ejection fraction. The predictive value of the model was illustrated in a group of four patients with coronary artery disease who underwent revascularization.     

Contribution of inflammatory mast cell mediators to alterations in macrophage function after malathion administration

Recent studies using mast cell-deficient mice showed that the presence of mast cells was necessary for the increase in macrophage function observed after oral administration of malathion and reconstitution with bone marrow-derived mast cells restored the ability of malathion to increase macrophage function. In addition, the release of mast cell mediators (blocked by cromolyn) and histamine (action blocked by pyrilamine) was shown to be involved in the action of malathion on macrophage function. In the present study, the contribution of inflammatory mediators (i.e. arachidonic acid metabolites and tumor necrosis factor [TNF]) which may be generated by mast cells after oral administration of malathion, was examined. Controls in this study included the effect of the agent to be examined on: (1) resident peritoneal macrophages; and (2) macrophages elicited with pristane, an agent shown previously to stimulate macrophage function in the absence of mast cells. Intraperitoneal administration of indomethacin, an inhibitor of cycloxygenase, or neutralizing antibody to TNF 30 h before and 4 h after oral malathion blocked the ability of malathion to increase macrophage function, as measured by the generation of respiratory burst activity and the production of cathepsin D. On the other hand, administration of these agents to mice injected intraperitoneally with pristane did not affect the observed increase in cathepsin D production. Respiratory burst function after elicitation with pristane was slightly decreased (indomethacin) or not affected (antibody to TNF). The effect of intraperitoneal administration of nordihydroguaiaretic acid (NDGA), an inhibitor of both cycloxygenase and lipoxygenase, was also examined. Intraperitoneal administration of NDGA partially blocked the effects of oral administration of malathion on peritoneal macrophage function, but did not affect the function of resident or pristane-elicited peritoneal macrophages. These data suggest that inflammatory mediators (potentially released from mast cells upon stimulation) contribute to the elevation in macrophage function observed after oral malathion administration.     

Hybrid approach of ventricular assist device and autologous bone marrow stem cells implantation in end-stage ischemic heart failure enhances myocardial reperfusion

We challenge the hypothesis of enhanced myocardial reperfusion after implanting a left ventricular assist device together with bone marrow mononuclear stem cells in patients with end-stage ischemic cardiomyopathy. Irreversible myocardial loss observed in ischemic cardiomyopathy leads to progressive cardiac remodelling and dysfunction through a complex neurohormonal cascade. New generation assist devices promote myocardial recovery only in patients with dilated or peripartum cardiomyopathy. In the setting of diffuse myocardial ischemia not amenable to revascularization, native myocardial recovery has not been observed after implantation of an assist device as destination therapy. The hybrid approach of implanting autologous bone marrow stem cells during assist device implantation may eventually improve native cardiac function, which may be associated with a better prognosis eventually ameliorating the need for subsequent heart transplantation. The aforementioned hypothesis has to be tested with well-designed prospective multicentre studies.     

Connexin37: a potential modifier gene of inflammatory disease

There is an increasing appreciation of the importance of gap junction proteins (connexins) in modulating the severity of inflammatory diseases. Multiple epidemiological gene association studies have detected a link between a single nucleotide polymorphism in the human connexin37 (Cx37) gene and coronary artery disease or myocardial infarction in various populations. This C1019T polymorphism causes a proline-to-serine substitution (P319S) in the regulatory C terminal tail of Cx37, a protein that is expressed in the vascular endothelium as well as in monocytes and macrophages. Indeed, these three cell types are key players in atherogenesis. In the early phases of atherosclerosis, blood monocytes are recruited to the sites of injury in response to chemotactic factors. Monocytes adhere to the dysfunctional endothelium and transmigrate across endothelial cells to penetrate the arterial intima. In the intima, monocytes proliferate, mature, and accumulate lipids to progress into macrophage foam cells. This review focuses on Cx37 and its impact on the cellular and molecular events underlying tissue function, with particular emphasis of the contribution of the C1019T polymorphism in atherosclerosis. We will also discuss evidence for a potential mechanism by which allelic variants of Cx37 are differentially predictive of increased risk for inflammatory diseases.