Immunological changes after highly active antiretroviral therapy with lopinavir-ritonavir in heavily pretreated HIV-infected children

We evaluated the effect of salvage antiretroviral therapy with lopinavir/ritonavir (LPV/r) on the immune system of heavily antiretroviral pretreated HIV-infected children. We carried out a longitudinal study in 20 antiretroviral experienced HIV-infected children to determine the changes in several immunological parameters (T cell subsets, thymic function) every 3 months during 18 months of follow-up on salvage therapy with LPV/r. Statistical analyses were performed with the Wilcoxon test, taking as a reference the basal value at the entry in the study. HIV-infected children showed an increase of CD4+ T cells, a decrease in CD8+ T cells, and an increase in T cell rearrangement excision circle (TRECs) levels. The percentage of HIV children with undetectable viral load (VL < or = 400 copies/ml) increased significantly (p = 0.007) and the percentage with SI viral phenotype decreased significantly (p = 0.002) at the end of the study. Thus, the viral phenotype changed to NSI/R5 after salvage therapy with LPV/r. Interestingly, we observed a significant decrease of memory (CD4+ CD45RO+) and a moderate decrease of activated (CD4+ HLA-DR+, CD4+ HLA-DR+CD38, CD4+, CD45RO+HLA-DR+) CD4+ T cells during the follow-up. On the other hand, memory (CD8+ CD45RO+ and CD8+ CD45RO+CD38+), activated (CD8+ HLA-DR+CD38+, CD8+ HLA-DR+, CD8+ CD38+), and effector (CD8+ CD57+, CD8+ CD28(-)CD57+) CD8+ T cells had a very significant decrease during follow-up. Our data indicate an immune system reconstitution in heavily pretreated HIV-infected children in response to salvage therapy with LPV/r as a consequence of a decrease in immune system activation and an increase in thymic function.     

MT1-MMP collagenolytic activity is regulated through association with tetraspanin CD151 in primary endothelial cells

MT1-MMP plays a key role in endothelial function, as underscored by the angiogenic defects found in MT1-MMP deficient mice. We have studied the molecular interactions that underlie the functional regulation of MT1-MMP. At lateral endothelial cell junctions, MT1-MMP colocalizes with tetraspanin CD151 (Tspan 24) and its associated partner alpha3beta1 integrin. Biochemical and FRET analyses show that MT1-MMP, through its hemopexin domain, associates tightly with CD151, thus forming alpha3beta1 integrin/CD151/MT1-MMP ternary complexes. siRNA knockdown of HUVEC CD151 expression enhanced MT1-MMP-mediated activation of MMP2, and the same activation was seen in ex vivo lung endothelial cells isolated from CD151-deficient mice. However, analysis of collagen degradation in these experimental models revealed a diminished MT1-MMP enzymatic activity in confined areas around the cell periphery. CD151 knockdown affected both MT1-MMP subcellular localization and its inclusion into detergent-resistant membrane domains, and prevented biochemical association of the metalloproteinase with the integrin alpha3beta1. These data provide evidence for a novel regulatory role of tetraspanin microdomains on the collagenolytic activity of MT1-MMP and indicate that CD151 is a key regulator of MT1-MMP in endothelial homeostasis.     

P300, Disinhibited Personality, and Early-Onset Alcohol Problems

BACKGROUND: Recent research suggests that a reduced P300 amplitude of the event-related potential is associated with a vulnerability to alcoholism. This study tested the hypothesis that reductions in the P300 amplitude would be associated with specific dimensions of disinhibited personality (social deviance proneness and impulsivity) and that these personality traits would mediate the association between P300 and alcohol problems in a young adult sample that varied widely in disinhibitory traits. METHODS: Alcohol problems, personality (impulsivity, social deviance, harm avoidance, and excitement seeking), and event-related potentials were measured in a sample of 190 subjects (87 men, 103 women) with a mean age of 20.7 +/- 1.9 years. RESULTS: Social deviance, impulsivity, and alcohol problems were associated with reductions in the P300, but only in male subjects. A structural model suggested that social deviance, impulsivity, and alcohol problems were all strongly related to P300 amplitude at Fz. Further analyses indicated that for male subjects, social deviance mediated the association between P300 at Fz and alcohol problems as well as the association between impulsivity and alcohol problems. CONCLUSIONS: This study suggests that reduced P300s are strongly associated with a general tendency toward antisocial, defiant, and impulsive traits, which might, in turn, increase the risk for alcohol abuse. The lack of an association between reduced P300s and personality or alcohol problems in women was unexpected and deserves further study.     

Lymphatic Vessel Memory Stimulated by Recurrent Inflammation

Inflammation stimulates new lymphatic vessel growth (inflammatory lymphangiogenesis). One key question is how recurrent inflammation, a common clinical condition, regulates lymphatic vessel remodeling. We show here that recurrent inflammation accelerated the development a functional lymphatic vessel network. This observation suggests a novel program of lymphangiogenesis and identifies a property of lymphatic vessel memory in response to recurrent inflammation. A brief episode of initial inflammation regressed lymphatic vessels, and a significant increase in CD11b⁺ macrophages were associated with the development of lymphatic vessel memory. These vessels had major differences in the structure and the spatial distribution of specialized lymphatic vessel features. Surprisingly, we found that the lymphatic vessel memory response did not depend on the vascular endothelial growth factor C or A pathway, indicating that different molecular pathways regulate inflammatory lymphangiogenesis and lymphatic vessel memory. These findings uncover a priming mechanism to facilitate a rapid lymphatic vessel memory response: a potential important component of peripheral host defense.The lymphatic vasculature is one component of the inflammatory response that is remarkably understudied. The lymphatic system can be broadly classified into the lymphoid tissue (tonsils, lymph nodes, and spleen) and the conduit system or lymphatic vasculature. The focus of these studies is the lymphatic capillaries which literally are the most peripheral extension of the immune system and reside intimately in the diseased tissue. Aside from the classic functions of the lymphatic vasculature described many years ago (transport of extracellular fluid, cells, antigens, and lipid), surprisingly little is known about the normal physiology of this system and how it regulates inflammation and wound recovery. Multiple lines of evidence have shown that the lymphatic vasculature proliferates in response to inflammatory conditions, suggesting an active, perhaps essential, role during the inflammatory response.^1–6 Inflammatory lymphangiogenesis is thought to be a physiological mechanism that develops to meet the increased demands of fluid, antigen, and cellular transport during an inflammatory response. New lymphatic vessel growth has been associated with beneficial effects in several different preclinical models of acute or chronic inflammatory disease.^3,7–9 It is well recognized that vascular endothelial growth factor (VEGF)-C-VEGF receptor (VEGFR)-3 and VEGF-A-VEGFR-2 pathways are important in inflammatory lymphangiogenesis.¹⁰ The most accepted model of inflammatory lymphangiogenesis is that vessels sprout and elongate from pre-existing lymphatic vessels. In contrast, is some evidence is available that circulating endothelial progenitors or macrophages differentiate into lymphatic endothelial cells to comprise newly synthesized lymphatic vessels.^11,12Clinically, two general outcomes occur after an initial episode of inflammatory disease: wound recovery or recurrent inflammation. We developed a mouse model of wound recovery and recurrent inflammation to simulate these clinical outcomes and to study the lymphatic vasculature during these conditions. We recently demonstrated that lymphatic vessel regression developed during wound recovery in the cornea.¹³ Fragmented lymphatic vessels that persisted over time were visualized in wound recovery conditions.In contrast to wound recovery, recurrent inflammation is a common clinical outcome after an initial episode of inflammation. We studied the effects of recurrent inflammation in corneal tissue recovered from an initial inflammatory response. This approach is different from earlier studies in that it features wound recovery followed by recurrent inflammation rather than an acute or chronic unrelenting pathogen or tumor-based inflammatory stimuli.^3,4,7,14 We induced recurrent inflammation in recovered corneal tissue by placing a subsequent suture in the cornea (re-suturing). Here, we show that one feature of recurrent inflammation was the accelerated localized development of a functional lymphatic vessel network. The rapid kinetics and memory response were reminiscent of an immunological memory response; for this reason we describe this process as lymphatic vessel memory. This response appeared to stimulate the anastomosis of fragmented lymphatic vessels. Unlike inflammatory lymphangiogenesis induced by initial inflammation, we showed that lymphatic vessel memory was independent of the VEGF-C and VEGF-A pathways. Thus, these studies reveal a novel program of lymphatic vessel memory.     

Three molecular classifications surrogate to four immunohistochemical markers in 374 invasive breast carcinomas with long follow-up: Which is better?

In the early 21st century, a new way to classify breast cancer appeared, based on their gene expression profiles. Various classifications have been proposed in an attempt to subrogate these molecular groups to an immunohistochemical expression of estrogen and progesterone receptors, HER2 and Ki67. We compared the three major molecular classifications (MCs) of 374 infiltrating breast carcinomas with the assumption that one is better than the others to discriminate the prognosis of patients that are classified by it. We found that [1] there was a significant statistical association with tumor grade and presence of associated HG-DCIS, but with differences in kappa indices [2]; MC3 showed a significant relationship with pathological tumor stage (p = 0.012, CI95% of 0.012–0.017); [3] only MC3 showed convincingly that the observed differences in OS were not due to chance in the univariate analysis (p = 0.04); [4] only MC3 is an independent prognostic factor of OS. In conclusion, these three classifications are not interchangeable; MC3, the only one that includes Ki67 expression in their defining criteria, is better in predicting prognosis than the others.     

Prognostic value and clinical predictors of intramyocardial hemorrhage measured by CMR T2* sequences in STEMI

The International Journal of Cardiovascular Imaging - Recent studies show that microvascular injury consists of microvascular obstruction (MVO) and intramyocardial hemorrhage (IMH). In patients...