Current status of small peripheral adenocarcinomas of the lung and their importance to pathologists

There has been a large amount of work done recently on small peripheral stage I adenocarcinomas that come to resection. Radiological (including proportion of ground glass opacity) and pathological features of these lesions (predominant bronchioloalveolar component, central scar with or without invasion <0.5 cm) have been shown to be prognostically favorable with cure rate approaching 100% in some series. Most of these studies emanate from Japan. The relevance of these studies to other parts of the world, particularly North America, is discussed in light of the fact that some recent chemotherapeutic studies with gefitinib have shown increased response in individuals of Asian origin, suggesting that some genetic differences may be significant. The relevance of these findings to pathologists and the pathological study of small peripheral adenocarcinomas from elsewhere in the world are discussed.     

Increased expression and release of functional tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by T cells from lupus patients with active disease

Increased expression of TRAIL in membrane-bound and soluble form in patients with systemic lupus erythematosus (SLE) has been previously reported. In this study, we characterized the upregulation of T-cell-associated and soluble TRAIL (sTRAIL) in vivo and the modulation of TRAIL expression and soluble protein release in vitro following T cell activation and IFNalpha exposure. The expression of membrane-bound TRAIL as determined by flow cytometry was higher on CD4(+) and CD8(+) T cells from lupus patients compared to controls, particularly on activated CD69(+)CD8(+) T cells. Similarly, sTRAIL levels determined by ELISA were significantly elevated in serum from patients with active SLE and correlated with levels of IFNalpha. In vitro, both T-cell-associated and sTRAIL were maximally induced by T cell activation plus IFNalpha in patients and controls. By Western blot analysis, sTRAIL was detected in sera in both the monomeric and multimeric, functional form. Both forms of TRAIL were functional in vitro as determined by Annexin V staining and (51)Cr release assay but the apoptotic activity of membrane TRAIL was 2.5-fold higher compared to that of sTRAIL. These results indicate that IFNalpha-induced enhancement of TRAIL expression and of TRAIL-mediated apoptosis may amplify the abnormal apoptotic process in SLE.     

Central nervous system inflammatory response after cerebral infarction as detected by magnetic resonance imaging

Brain inflammation contributes to the tissue injury caused by ischemic stroke. Macrophages as the most abundant inflammatory cell population in stroke lesions can be visualized using ultrasmall superparamagnetic iron oxide (USPIO) as a cell-specific contrast agent for magnetic resonance imaging (MRI). The aim of our present study was to delineate the inflammatory response during experimental cerebral infarction by means of USPIO-enhanced MRI and to correlate the spatial distribution of USPIO-induced MR signal alterations with cellular infiltration and iron deposition. To this end USPIOs were administered to Wistar rats 5 days after photothrombotic cerebral infarction. MR imaging at 7 T performed 24 h later displayed a rim-like signal loss around the infarction in the USPIO treated animals. On histological brain sections obtained from the same animals after MRI the distribution of iron and ED1+ phagocytes was in full spatial agreement with the signal loss seen on T2*-weighted images. Our study validates USPIO-enhanced MRI as an important tool for the noninvasive visualization of brain inflammation in stroke and other CNS pathologies.     

Differences Between Treatment Seekers in an Obese Population: Medical Intervention vs. Dietary Restriction

This study examined two groups of people who were pursuing treatment for obesity: either medical intervention (a hospital group; N = 20) or support for dietary restriction (a community group; N = 18). This study addressed four questions: (1) Were there differences between the two groups in terms of their psychological distress (as measured by the Symptom Checklist)? (2) Does binge eating moderate psychological distress? (3) Do feelings of ineffectiveness moderate psychological distress? and (4) Which variables best accounted for group membership (i.e., type of treatment sought)? Results suggested that the hospital group was significantly more distressed than the community group. However, there were no differences between the two groups with respect to binge eating or feelings of ineffectiveness. These findings suggest that it is the effects of morbid obesity that are most likely to moderate psychological distress.     

Angiogenic and lymphangiogenic microvessel density in breast carcinoma: correlation with clinicopathologic parameters and VEGF-family gene expression.

Angiogenesis and lymphangiogenesis are essential for breast cancer progression and are regulated by vascular endothelial growth factors (VEGF). To determine clinical and molecular correlates of these processes, we measured blood and lymphatic vascular microvessel density in 29 invasive carcinomas (22 ductal, six lobular, one papillary), using the vascular marker CD31 and the novel lymphatic marker D2-40. Microvessel density was assessed microscopically and by image cytometry, and was compared with tumor histology, grade, stage, lymph node metastasis, hormone receptors, HER2/neu status, and expression of VEGF, VEGF-C and VEGF-D by immunohistochemistry or quantitative RT-PCR. Strong correlation was observed between visual and image cytometric microvessel density using D2-40 but not CD31 (P=0.016 and 0.1521, respectively). Image cytometric CD31 microvessel density correlated with tumor size, grade, stage and lymph node metastasis (P=0.0001, 0.0107, 0.0035 and 0.0395, respectively). D2-40 microvessel density correlated with tumor stage (P=0.0123 by image cytometry) and lymph node metastasis (P=0.0558 by microscopy). Immunohistochemical VEGF signal in peritumoral blood vessels correlated with image cytometric CD31 and D2-40 microvessel density (P=0.022 and 0.0012, respectively), consistent with the role of VEGF in blood and lymphatic vascular growth. Intratumoral VEGF-C and VEGF-D expression by quantitative RT-PCR correlated with D2-40 (P=0.0291 by image cytometry) but not with CD31 microvessel density, which could suggest a selective role of VEGF-C and VEGF-D in lymphangiogenesis. CD31 and D2-40 microvessel density correlated significantly with several prognostic factors, including lymph node metastasis. Thus, measurements of angiogenesis and lymphangiogenesis may have utility for breast cancer pathology, particularly for estimation of metastatic risk.     

Bi-directional modulation of T cell-dependent antibody production by prostaglandin E(2).

T cell-dependent Ig production involves interaction between T cells and B cells. This study evaluated the effects of prostaglandin (PG) E(2) on Ig production in a system in which B cells were co-cultured with autologous CD4(+) T cell clones non-specifically activated by anti-CD3. The effects of PGE(2) on T cell-dependent Ig production differed substantially, depending on the T cells employed. We selected six T cell clones that were able to enhance Ig production (resistant T cell clones) and six T cell clones that inhibited Ig production in the presence of PGE(2) (sensitive T cell clones) for comparison. The resistant T cells produced high levels (>1000 pg/ml) of IL-2 and/or IL-4, and expressed high CD40L, OX40 and CD45RA, and low CD45RO. In contrast, sensitive T cells secreted low IL-2 (<500 pg/ml) and IL-4 (<200 pg/ml), and expressed low CD40, OX40 and CD45RA, and high CD45RO. Adding supernatant derived from resistant T cell clones restored Ig production inhibited by PGE(2), while removing IL-2, IL-4 or IL-10 using specific antibodies inhibited Ig production. In addition, we demonstrated a direct effect of PGE(2) on B cells to enhance Ig production. Consistently, in the presence of resistant T cells, PGE(2) increased B cell proliferation and differentiation. In conclusion, the effects of PGE(2) on Ig production consist of its indirect effects through T cells and its direct effects on B cells. The outcome of the effects can be up-regulatory or down-regulatory, depending whether resistant or sensitive T cells are involved.     

Mechanical and Cellular Changes During Compaction of a Collagen-Sponge-Based Corneal Stromal Equivalent

The need for corneas suitable for transplantation, combined with the decreasing supply, has fueled interest in the development of a corneal replacement. In this study, a collagen-sponge-based stromal equivalent, consisting of human corneal fibroblasts cultured on a type I collagen sponge, was maintained in culture for up to 21 days and characterized with respect to mechanical properties and cellular behavior. The Young's modulus of the stromal equivalent varied from 95 to 370 Pa, and its permeability varied from 5.3 x 10(-8) - 4.2 x 10(-7) m4 N(-1) s(-1). The greatest changes occurred during the first few days in culture, but the mechanical properties continued to change during the entire 21 days. Cell traction stress, determined from sponge compaction and DNA count, decreased during the compaction process with the maximum traction value the initial value of 6.6 +/- 2.9 x 10(-3) Pacm3 cell(-1). Microarray data showed that the expression level of fibronectin, decorin sulfate, collagenase, and gelatinase A was upregulated at day 14 in the sponge. This suggested that the repair fibroblast phenotype was being expressed by the fibroblasts. Additional analysis suggested that a subpopulation of cells expressed the myofibroblast phenotype.     

Modulating parameters of excitability during and after transcranial direct current stimulation of the human motor cortex

Weak transcranial direct current stimulation (tDCS) of the human motor cortex results in excitability shifts which occur during and after stimulation. These excitability shifts are polarity-specific with anodal tDCS enhancing excitability, and cathodal reducing it. To explore the origin of this excitability modulation in more detail, we measured the input–output curve and motor thresholds as global parameters of cortico-spinal excitability, and determined intracortical inhibition and facilitation, as well as facilitatory indirect wave (I-wave) interactions. Measurements were performed during short-term tDCS, which elicits no after-effects, and during other tDCS protocols which do elicit short- and long-lasting after-effects. Resting and active motor thresholds remained stable during and after tDCS. The slope of the input–output curve was increased by anodal tDCS and decreased by cathodal tDCS. Anodal tDCS of the primary motor cortex reduced intracortical inhibition and enhanced facilitation after tDCS but not during tDCS. Cathodal tDCS reduced facilitation during, and additionally increased inhibition after its administration. During tDCS, I-wave facilitation was not influenced but, for the after-effects, anodal tDCS increased I-wave facilitation, while cathodal tDCS had only minor effects. These results suggest that the effect of tDCS on cortico-spinal excitability during a short period of stimulation (which does not induce after-effects) primarily depends on subthreshold resting membrane potential changes, which are able to modulate the input-output curve, but not motor thresholds. In contrast, the after-effects of tDCS are due to shifts in intracortical inhibition and facilitation, and at least partly also to facilitatory I-wave interaction, which is controlled by synaptic activity.