Atherosclerotic plaque rupture: local or systemic process?

It is generally established that the unstable plaque is the major cause of acute clinical sequelae of atherosclerosis. Unfortunately, terms indicating lesions prone to plaque instability, such as "vulnerable plaque," and the different phenotypes of unstable plaques, such as plaque rupture, plaque fissuring, intraplaque hemorrhage, and erosion, are often used interchangeably. Moreover, the different phenotypes of the unstable plaque are mostly referred to as plaque rupture. In the first part of this review, we will focus on the definition of true plaque rupture and the definitions of other phenotypes of plaque instability, especially on intraplaque hemorrhage, and discuss the phenotypes of available animal models of plaque instability. The second part of this review will address the pathogenesis of plaque rupture from a local and a systemic perspective. Plaque rupture is thought to occur because of changes in the plaque itself or systemic changes in the patient. Interestingly, contributing factors seem to overlap to a great extent and might even be interrelated. Finally, we will propose an integrative view on the pathogenesis of plaque rupture.     

Studies on the nonmevalonate terpene biosynthetic pathway: metabolic role of IspH (LytB) protein

Isopentenyl diphosphate and dimethylallyl diphosphate serve as the universal precursors for the biosynthesis of terpenes. Although their biosynthesis by means of mevalonate has been studied in detail, a second biosynthetic pathway for their formation by means of 1-deoxy-D-xylulose 5-phosphate has been discovered only recently in plants and certain eubacteria. Earlier in vivo experiments with recombinant Escherichia coli strains showed that exogenous 1-deoxy-D-xylulose can be converted into 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate by the consecutive action of enzymes specified by the xylB and ispCDEFG genes. This article describes the transformation of exogenous [U-(13)C(5)]1-deoxy-D-xylulose into a 5:1 mixture of [U-(13)C(5)]isopentenyl diphosphate and [U-(13)C(5)]dimethylallyl diphosphate by an E. coli strain engineered for the expression of the ispH (lytB) gene in addition to recombinant xylB and ispCDEFG genes.     

Influence of intraperitoneal therapy with mitomycin C adsorbed on activated carbon on anastomotic and wound healing in rats

In an effort to prevent intraperitoneal dissemination of gastric carcinoma, local chemotherapy with mitomycin C adsorbed to activated carbon (MMC-CH) has been implemented. Results of clinical studies showed improved survival and a reduced systemic toxicity after the use of prophylactic treatment with MMC-CH. A significantly higher rate of intraperitoneal septic complications following MMC-CH therapy was found. The aim of this study was to assess whether intraperitoneal MMC-CH affects wound healing or healing of intestinal anastomoses. Standardized laparotomy was performed in 77 rats. The examinations were performed in 27 animals in the control group, 24 animals in the charcoal group, and 26 animals in the MMC-CH group. The animals and groups were distributed randomly. After an ileal anastomosis was performed, MMC-CH, charcoal, or sodium chloride 0.9% was administered intraperitoneally. After 10 days, collagen content as well as bursting strength/pressure of the fasciotomy and the anastomotic site was examined. Body weight and blood parameters analyzed included hemoglobin level, white blood cell count, platelet count, and total protein. Concerning body weight and hematology, no significant changes were observed. Three of 26 animals in the MMC-CH group, 2/24 in the charcoal group and 1/27 in the control group developed an anastomotic leakage. The bursting pressure of the anastomoses and the bursting strength of the fasciotomy as well as the relative collagen content did not differ significantly after treatment with charcoal or mitomycin C compared to the control group. Local inflammation consisting of charcoal-laden granulomas was detected histologically in the MMC-CH group and to a lesser extent in the charcoal group. In conclusion, no significant influence of intraperitoneal mitomycin C adsorbed on activated charcoal, in terms of its effect systemically or its effect on wound healing, could be demonstrated as a result of slow release. Histological changes seen with the use of activated charcoal suggest that perhaps a more ideal absorbable carrier should be sought.     

Influence of a glutamate carboxypeptidase II (GCPII) polymorphism (1561C-->T) on plasma homocysteine,folate and vitamin B(12) levels and its relationship to cardiovascular disease risk

Elevated levels of total homocysteine and low folate in blood are independent and graded risk factors for arterial occlusive disease. An impairment of folate distribution can be an important cause of hyperhomocysteinemia. Glutamate carboxypeptidase II (GCPII) regulates the absorption of dietary folates. In the present study, we examined the relationship of a 1561C-->T variant in the GCPII gene with fasting, post-methionine load plasma homocysteine, folate and vitamin B(12) levels and the risk of cardiovascular disease (CVD) in 190 vascular disease patients and in 601 apparently healthy controls. Fasting as well as post-load homocysteine concentrations associated with the 1561TT genotype tended to be lower, whereas the homocysteine concentrations of the 1561CT individuals were not different from their 1561CC peers. The 1561C-->T polymorphism significantly increased both red blood cell folate and plasma folate concentrations (ANOVA P=0.013; test for linear trend P=0.03, respectively), but had no effect on vitamin B(12) levels (ANOVA P=0.35). Since not only homocysteine itself is considered to be positively associated with the risk of CVD, but also a decreased folate status, the results of this study indicate that the 1561C-->T polymorphism may affect the predisposition to CVD.     

Diffusion weighted imaging in the liver

Diffusion weighted magnetic resonance imaging (DWI) is an imaging technique which provides tissue contrast by the measurement of diffusion properties of water molecules within tissues. Diffusion is expressed in an apparent diffusion coefficient (ADC), which reflects the diffusion properties unique to each type of tissue. DWI has been originally used in neuroradiology. More recently, DWI has increasingly been used in addition to conventional unenhanced and enhanced magnetic resonance imaging (MRI) in other p...     

Alcohol Expectancies and Drinking Refusal Self‐Efficacy Mediate the Association of Impulsivity With Alcohol Misuse

Background: Recent work suggests that 2 biologically based traits convey risk for alcohol misuse: reward sensitivity/drive and (rash) impulsiveness. However, the cognitive mechanisms through which these traits convey risk are unclear. This study tested a model predicting that the risk conveyed by reward sensitivity is mediated by a learning bias for the reinforcing outcomes of alcohol consumption (i.e., positive alcohol expectancy). The model also proposed that the risk conveyed by rash impulsiveness (RI) is mediated by drinkers’ perceived ability to resist alcohol (i.e., drinking refusal self‐efficacy). Methods: Study 1 tested the model in a sample of young adults (n = 342). Study 2 tested the model in a sample of treatment‐seeking substance abusers (n = 121). All participants completed a battery of personality, cognitive, and alcohol use questionnaires and models were tested using structural equation modeling. Results: In both studies, the hypothesized model was found to provide a good fit to the data, and a better fit than alternative models. In both young adults and treatment‐seeking individuals, positive alcohol expectancy fully mediated the association between reward sensitivity and hazardous alcohol use. For treatment seekers, drinking refusal self‐efficacy fully mediated the association between RI and hazardous drinking. However, there was partial mediation in the young adult sample. Furthermore, neither trait was directly associated with the other cognitive mediator. Conclusions: The hypothesized model was confirmed on a large sample of young adults and replicated on a sample of treatment‐seeking substance abusers. Taken together, these findings shed further light on the mechanisms through which an impulsive temperament may convey risk for alcohol misuse.     

Down-regulation of candidate tumor suppressor genes within chromosome band 13q14.3 is independent of the DNA methylation pattern in B-cell chronic lymphocytic leukemia

Loss of genomic material from chromosomal band 13q14.3 is the most common genetic imbalance in B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma, pointing to the involvement of this region in a tumor suppressor mechanism. From the minimally deleted region, 3 candidate genes have been isolated, RFP2, BCMS, and BCMSUN. DNA sequence analyses have failed to detect small mutations in any of these genes, suggesting a different pathomechanism, most likely haploinsufficiency. We, therefore, tested B-CLL patients for epigenetic aberrations by measuring expression of genes from 13q14.3 and methylation of their promotor region. RB1, CLLD7, KPNA3, CLLD6, and RFP2 were down-regulated in B-CLL patients as compared with B cells of healthy donors, with RFP2 showing the most pronounced loss of expression. To test whether this loss of gene expression is associated with methylation of CpG islands in the respective promotor regions, we performed methylation-sensitive quantitative polymerase chain reaction analyses and bisulfite sequencing on DNA from B-CLL patients. No difference in the methylation patterns could be detected in any CpG island of the minimally deleted region. Down-regulation of genes within chromosomal band 13q14.3 in B-CLL is in line with the concept of haploinsufficiency, but this tumor-specific phenomenon is not associated with DNA methylation.     

Angiotensin II stimulation of NAD(P)H oxidase activity: upstream mediators

Angiotensin II (Ang II)-stimulated hypertrophy of vascular smooth muscle cells is mediated by reactive oxygen species (ROS) derived from NAD(P)H oxidases. The upstream signaling mechanisms by which Ang II activates these oxidases are unclear but may include protein kinase C, tyrosine kinases, phosphatidylinositol-3-kinase, and Rac, a small molecular weight G protein. We found that Ang II-stimulated ROS production is biphasic. The first phase occurs rapidly (peak at 30 seconds) and is dependent on protein kinase C activation. The larger second phase of ROS generation (peak at 30 minutes) requires Rac activation, because inhibition of Rac by either Clostridium difficile toxin A or dominant-negative Rac significantly inhibits Ang II-induced ROS production. Phosphatidylinositol-3-kinase inhibitors (wortmannin or LY294002) and the epidermal growth factor (EGF) receptor kinase blocker AG1478 attenuate both Rac activation and ROS generation. The upstream activator of EGF receptor transactivation, c-Src, is also required for ROS generation, because PP1, an Src kinase inhibitor, abrogates the Ang II stimulation of both responses. These results suggest that c-Src, EGF receptor transactivation, phosphatidylinositol-3-kinase, and Rac play important roles in the sustained Ang II-mediated activation of vascular smooth muscle cell NAD(P)H oxidases and provide insight into the integrated signaling mechanisms whereby Ang II stimulation leads to activation of the growth-related NAD(P)H oxidases.     

Functionally distinct dendritic cell (DC) populations induced by physiologic stimuli: prostaglandin E(2) regulates the migratory capacity of specific DC subsets

Migration of antigen (Ag)-loaded dendritic cells (DCs) from sites of infection into draining lymphoid tissues is fundamental to the priming of T-cell immune responses. We evaluated monocyte-derived DCs (MoDCs) and peripheral blood DCs (PBDCs) to respond to proinflammatory mediators, CD40L, and intact bacteria. All classes of stimuli induced DC phenotypic maturation. However, for MoDCs, only prostaglandin E(2) (PGE(2))-containing stimuli induced migratory-type DCs. Thus, immature MoDCs that encountered proinflammatory cytokines or CD40L or intact bacteria in the presence of PGE(2) acquired migratory capacity but secreted low levels of cytokines. Conversely, MoDCs that encountered pathogens or CD40L alone become nonmigratory cytokine-secreting cells (proinflammatory type). Interestingly, both migratory- and proinflammatory-type DCs expressed equivalent levels of chemokine receptors, suggesting that the role of PGE(2) was to switch on migratory function. We demonstrate that PGE(2) induces migration via the E-prostanoid 2/E-prostanoid 4 (EP(2)/EP(4)) receptors and the cAMP pathway. Finally, migratory-type MoDCs stimulated T-cell proliferation and predominantly IL-2 secretion, whereas proinflammatory-type MoDCs induced IFN-gamma production. In contrast, CD1b/c(+) PBDC rapidly acquired migratory capacity irrespective of the class of stimulus encountered and secreted low levels of cytokines. This suggests that not all mature stages of DCs are destined to migrate to lymphoid organs and that the sequence in which stimuli are encountered significantly affects which functions are expressed. Thus, certain immature DC subsets recruited from the resting precursor pool may have multiple functional fates that play distinct roles during the induction and effector phases of the immune response. These findings have important implications for the clinical utility of DCs in immunotherapy.