Recent advances indicate that, in various chronic inflammatory disorders, the activation of the immune system is triggered locally rather than in lymphoid organs. In this study, we have evaluated whether the humoral alloimmune response involved in chronic rejection is elicited within the graft. We used the rat aortic interposition model and microdissected the adventitia of the graft. Over time, the T cell infiltrate shifted toward a B helper phenotype. B lymphocyte clusters were detected and were the site of intense proliferation and apoptosis. Simultaneously, adventitial vascular endothelium acquired a high endothelial venule phenotype. Similar features were evidenced in the interstitium of chronically allografts (hearts and kidneys). Strikingly, ganocultured graft interstitial tissue was found to be the site of production of antibodies directed against donor MHC-I molecules. These findings, therefore, document the appearance of germinal centers in chronically rejected tissues. This lymphoid neogenesis implies that the graft is not only the target of the alloimmune response but also a site where this response actually develops, so as to optimize the communication between the targeted tissue and the immune effectors.chronic rejection ͉ transplantation ͉ B cells ͉ germinal centers ͉ adventitia D espite recent advances in transplantation, the long-term outcome of transplanted organs remains impeded by chronic rejection (1). Accumulating evidence suggests that humoral immunity (2-4) and, particularly, alloantibodies directed against donor MHC I molecules (5-8) are critical in the pathogenesis of chronic vascular rejection.Clinically, chronic rejection is responsible for a slow deterioration of graft function, which correlates with typical histological changes. Excluding organ-specific manifestations, the most common histopathological feature is chronic vascular rejection, also known as allograft arteriosclerosis, characterized by widespread and diffuse narrowing of the vascular lumen as a result of intimal proliferation of smooth muscle cells and fibroblasts and destruction of smooth muscle cells from the media (9-12). Chronic vascular rejection is also typified by an abundant adventitial inflammatory infiltrate (9). We therefore evaluated whether the humoral alloimmune response was elicited within the adventitia of the graft. In such case, chronic vascular rejection would be similar to other chronic inflammatory disorders in which tissue destruction results from a vicious circle maintained by an uncontrolled local immune response.We demonstrate the involvement of intragraft lymphoid neogenesis in the development of chronic rejection in an animal model, based on aortic transplantation between histoincompatible strains of rats (13-16). We show that the adventitial inflammatory infiltrate harbors a secondary lymphoid organ structure and that anti-donor MHC I antibodies are produced within these structures. Additionally, we provide insights into the clinical relevance of these observations because similar lymphoid str...

Human abdominal aortic aneurysm (AAA) expansion has been linked to the presence of a mural thrombus. Here we explored the mechanism of the continual luminal renewal of this thrombus and its ability to release biological markers potentially detectable in plasma. We also explored the ability of platelet inhibition to pacify the thrombus and to limit aneurysm progression in an experimental model. Blood samples and mural thrombi were collected in 20 AAA patients. In parallel, segments of sodium dodecyl sulfate-decellularized guinea pig aorta were xenografted onto the abdominal aorta of 30 rats to induce aneurysms. Fifteen rats received abciximab treatment and fifteen received irrelevant immunoglobulins. Procoagulant activity and platelet activation markers (microparticles, sP-selectin, sGPV, sCD40L) were increased threefold to fivefold in eluates from the luminal thrombus layer compared to other layers. All these markers were increased twofold to fivefold in patients' plasma compared to matched controls (P < 0.005). In the rat model, abciximab reduced both thrombus area and aneurysmal enlargement (P < 0.05). Platelet aggregation is probably responsible for the renewal of the thrombus in AAA. The luminal thrombus released markers of platelet activation that could easily be detected in plasma. Platelet inhibition limited aortic aneurysm expansion in a rat model, providing new therapeutic perspectives in the prevention of AAA enlargement.

When studying the neural responses to acupuncture with a block-designed paradigm, its temporal dynamics predicted by the general linear model (GLM) conforms to typical "on-off" variations during a limited period of the experiment manipulation. Despite a lack of direct evidence associating its psychophysiological response, numerous clinical reports suggest that acupuncture can provide pain relief beyond a needling session. Therefore, a typical GLM analysis may be insensitive or inappropriate for identifying altered neural responses resulting from acupuncture. We developed a new approach to investigate the dynamics underlying sustained effects of acupuncture. Specifically, we designed two separate models to evaluate the baseline activities (prior to stimulation) and neural activities in sequential epochs, using three block-designed functional runs: acupuncture at acupoint ST36, nonmeridian point (NMP) stimulation, and a visual task. We found that the activity patterns during rest were associated with the stimulus types and that the resting activities might be even higher than that of stimulation phases. Such effects of the elevated activity during rest may reduce or eliminate the activity during stimulus conditions or even reverse the sign of brain activation using conventional GLM analysis. Moreover, such sustained responses, followed by acupuncture at ST36 and NMP, exhibited distinct patterns in wide brain structures, particularly in the limbic system and brainstem. These findings may pose great implications for the design and interpretation of a range of acupuncture neuroimaging studies.

BackgroundRecently, increasing evidence has indicated that the primary acupuncture effects are mediated by the central nervous system. However, specific brain networks underpinning these effects remain unclear.ResultsIn the present study using fMRI, we employed a within-condition interregional covariance analysis method to investigate functional connectivity of brain networks involved in acupuncture. The fMRI experiment was performed before, during and after acupuncture manipulations on healthy volunteers at an acupuncture point, which was previously implicated in a neural pathway for pain modulation. We first identified significant fMRI signal changes during acupuncture stimulation in the left amygdala, which was subsequently selected as a functional reference for connectivity analyses. Our results have demonstrated that there is a brain network associated with the amygdala during a resting condition. This network encompasses the brain structures that are implicated in both pain sensation and pain modulation. We also found that such a pain-related network could be modulated by both verum acupuncture and sham acupuncture. Furthermore, compared with a sham acupuncture, the verum acupuncture induced a higher level of correlations among the amygdala-associated network.ConclusionOur findings indicate that acupuncture may change this amygdala-specific brain network into a functional state that underlies pain perception and pain modulation.

Objective-To assess the safety and clinical efficacy of stenting for patients with symptomatic M1 stenosis of middle cerebral artery (MCA), and to assess the significance of classification based on location, morphology, and access of intracranial stenosis (LMA classification) in MCA stenting. Methods-Forty patients with 42 symptomatic M1 stenoses refractory to medical therapy were enrolled in this study. The lesions were situated at M1 trunk (nϭ13), M1 origin (nϭ12), and M1 bifurcation (nϭ17), respectively, which were classified into type N (nonbifurcation lesions, nϭ13) and type A (prebifurcation, nϭ11), B (postbifurcation, nϭ14), C (lesion across the nonstenotic ostium of its branch, nϭ1), D (across the stenotic ostium of its branch, nϭ2), F (combinative lesions of prebifurcation and its small branch ostium, nϭ1) locations, morphologically into type A (nϭ15), B (nϭ23) and C (nϭ4) lesions, and into type I (mild-to-moderate tortuosity and smooth access, nϭ17), II (severe tortuosity and/or irregular arterial wall, nϭ18), and III (excessively severe tortuosity, nϭ7) accesses. Results-The technical successful rate was 97.6% for total lesions and 100%, 100%, and 85.7% for types I, II, and III accesses, respectively. The total complication rate was 10%. The mortality was 2.5% (1/40 patients), and 0%, 0%, and 25% for types A, B, and C lesions, respectively. During the median 10 months follow-up, there was no recurrence of transient ischemic attack or stroke in 38 available patients. Among 8 stenting vessels of seven patients with six-month follow-up angiography, 7 showed good patency and one showed restenosis. Conclusion-Stenting appears to be an effective and feasible therapy for symptomatic M1 stenoses, but also appears to have the higher periprocedural complications, which need strict procedural and periprocedural management to reduce the mortality and morbidity. The LMA classification seems to be helpful to work out the individual therapy and predict the results of stenting. A further study is needed to confirm the benefits of stenting of MCA stenosis.

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BackgroundAccumulating neuroimaging studies in humans have shown that acupuncture can modulate a widely distributed brain network, large portions of which are overlapped with the pain-related areas. Recently, a striking feature of acupuncture-induced analgesia is found to be associated with its long-last effect, which has a delayed onset and gradually reaches a peak even after acupuncture needling being terminated. Identifying temporal neural responses in these areas that occur at particular time -- both acute and sustained effects during acupuncture processes -- may therefore shed lights on how such peripheral inputs are conducted and mediated through the CNS. In the present study, we adopted a non-repeated event-related (NRER) fMRI paradigm and control theory based approach namely change-point analysis in order to capture the detailed temporal profile of neural responses induced by acupuncture.ResultsOur findings demonstrated that neural activities at the different stages of acupuncture presented distinct temporal patterns, in which consistently positive neural responses were found during the period of acupuncture needling while much more complex and dynamic activities found during a post-acupuncture period. These brain responses had a significant time-dependent effect which showed different onset time and duration of neural activities. The amygdala and perigenual anterior cingulate cortex (pACC), exhibited increased activities during the needling phase while decreased gradually to reach a peak below the baseline. The periaqueductal gray (PAG) and hypothalamus presented saliently intermittent activations across the whole fMRI session. Apart from the time-dependent responses, relatively persistent activities were also identified in the anterior insula and prefrontal cortices. The overall findings indicate that acupuncture may engage differential temporal neural responses as a function of time in a wide range of brain networks.ConclusionsOur study has provided evidence supporting a view that acupuncture intervention involves complex modulations of temporal neural response, and its effect can gradually resolve as a function of time. The functional specificity of acupuncture at ST36 may involve multiple levels of differential activities of a wide range of brain networks, which are gradually enhanced even after acupuncture needle being terminated.

Background-The cell response to transforming growth factor-␤1 (TGF-␤1), a multipotent cytokine with healing potential, varies according to tissue context. We have evaluated the ability of TGF-␤1 overexpression by endovascular gene therapy to stabilize abdominal aortic aneurysms (AAAs) already injured by inflammation and proteolysis. Methods and Results-Active TGF-␤1 overexpression was obtained in already-developed experimental AAAs in rats after endovascular delivery of an adenoviral construct encoding for a mutated form of active simian TGF-␤1 and in an explant model using human atherosclerotic AAA fragments incubated with recombinant active TGF-␤1. Transient exogenous TGF-␤1 overexpression by endovascular gene delivery was followed by induction of endogenous rat TGF-␤1. Overexpression of active TGF-␤1 in experimental AAAs was associated with diameter stabilization, preservation of medial elastin, decreased infiltration of monocyte-macrophages and T lymphocytes, and a decrease in matrix metalloproteinase-2 and -9, which was also observed in the explant model, in both thrombus and wall. In parallel with downregulation of the destructive process, active TGF-␤1 overexpression triggered endoluminal reconstruction, replacing the thrombus by a vascular smooth muscle cell-, collagen-, and elastin-rich intima. Conclusions-Local TGF-␤1 self-induction after transient exogenous overexpression reprograms dilated aortas altered by inflammation and proteolysis and restores their ability to withstand arterial pressure without further dilation. This first demonstration of stabilization of expanding AAAs by delivery of a single multipotent self-promoting gene supports the view that endovascular gene therapy should be considered for treatment of aneurysms.