Different clinical severity of first episodes and recurrences of thrombotic thrombocytopenic purpura

The clinical course of thrombotic thrombocytopenic purpura (TTP) is characterized by recurrent disease episodes in up to 50% of cases. The clinical presentation and severity of different TTP episodes have not been systematically compared. Laboratory and clinical information from 51 patients with recurrent disease, derived from 136 patients with TTP included in the Milan TTP registry (URL: http://www.ttpdatabase.org), were used to compare mortality, symptoms and disease-related laboratory measurements in different disease episodes. The prevalence of severe neurological symptoms (coma, seizures, and focal neurological defects) was significantly lower in recurrences than in the first episode. Platelet counts and haemoglobin levels at presentation were higher in recurrences than in the first disease episode, and lactate dehydrogenase levels were lower. Also, mortality tended to be lower in the second and third disease episodes than in the first. Recurrences of TTP are generally milder than first episodes. These differences in severity should be taken into account in clinical research on TTP and in patient management.     

Role of p75 neurotrophin receptor in the neurotoxicity by beta-amyloid peptides and synergistic effect of inflammatory cytokines

The neurodegenerative changes in Alzheimer's disease (AD) are elicited by the accumulation of beta-amyloid peptides (Abeta), which damage neurons either directly by interacting with components of the cell surface to trigger cell death signaling or indirectly by activating astrocytes and microglia to produce inflammatory mediators. It has been recently proposed that the p75 neurotrophin receptor (p75(NTR)) is responsible for neuronal damage by interacting with Abeta. By using neuroblastoma cell clones lacking the expression of all neurotrophin receptors or engineered to express full-length or various truncated forms of p75(NTR), we could show that p75(NTR) is involved in the direct signaling of cell death by Abeta via the function of its death domain. This signaling leads to the activation of caspases-8 and -3, the production of reactive oxygen intermediates and the induction of an oxidative stress. We also found that the direct and indirect (inflammatory) mechanisms of neuronal damage by Abeta could act synergistically. In fact, TNF-alpha and IL-1beta, cytokines produced by Abeta-activated microglia, could potentiate the neurotoxic action of Abeta mediated by p75(NTR) signaling. Together, our results indicate that neurons expressing p75(NTR), mostly if expressing also proinflammatory cytokine receptors, might be preferential targets of the cytotoxic action of Abeta in AD.     

A new method for quantitative analysis of dentinal tubules

Conventional methods to estimate the number of dentinal tubules cannot be considered reliable and repeatable, because results depends on the operator outlining of the tubules contours. In this study, we propose a totally automated computerized analysis technique to evaluate dentinal tubules and their surface area. The comparison test of these conventional with a semi-automatic methods shows that the automated analysis allowed a reliable identification and numbering of dentinal tubules, by means of high-quality images. No statistically significant difference exists in the number of tubules and the total tubule surface area between the control and test groups.     

Proteasome inhibitor-induced apoptosis in human monocyte-derived dendritic cells

Proteasome inhibitors possess potent antitumor activity against a broad spectrum of human malignancies. However, the effects of these compounds on the immune system still have to be clearly determined. In the present study, we have investigated the effects of proteasome inhibitors on dendritic cells (DC), antigen-presenting cells playing a key role in the initiation of immune responses. Exposure to the proteasome inhibitors bortezomib, MG132 or epoxomicin was found to promote apoptosis of human monocyte-derived DC and to reduce the yield of viable DC when given to monocytes early during differentiation to DC. DC apoptosis via proteasome inhibition was accompanied by mitochondria disruption and subsequent activation of the caspase cascade. Up-regulation and intracellular redistribution of Bcl-2-associated X protein (Bax), a pro-apoptotic Bcl-2 family protein, were observed in DC treated with these compounds and represent a suitable mechanism leading to activation of the intrinsic apoptotic pathway. Finally, active protein synthesis was found to represent an upstream prerequisite for DC apoptosis induced by proteasome inhibitors, since the translation inhibitor cycloheximide blocked all of the steps of the observed apoptotic response. In conclusion, induction of apoptosis in DC may represent a novel mechanism by which proteasome inhibitors affect the immune response at the antigen-presenting cell level.     

Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells

Summary: Emerging evidence indicates that the Achilles' heel of cancer immunotherapies is often the complex interplay of tumor-derived factors and deviant host properties, which involve a wide range of immune elements in the lymphoid and myeloid compartments. Regulatory lymphocytes, tumor-conditioned myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and dysfunctional and immature dendritic cells take part in a complex immunoregulatory network. Despite the fact that some mechanisms governing tumor-induced immune tolerance and suppression are starting to be better understood and their complexity dissected, little is known about the diachronic picture of immune tolerance. Based on observations of MDSCs, we present a time-structured and topologically consistent idea of tumor-dependent tolerance progression in tumor-bearing hosts.     

Quick change versus double pump while changing the infusion of inotropes: an experimental study

Background: Quick change (QC) and double pumping (DP) are common methods of substituting the infusion of inotropes given through intravenous pump. Aims: The aim of the study was to compare two methods in respect with the variation in mean arterial pressure (MAP). The hypothesis was that the DP method could be the most effective in achieving haemodynamic stability. Design: The study is a randomized research in an open randomized clinical trial. Methods: The study took place at the Paediatric Intensive Care Unit of Padua Hospital. It considered patients of 0–36 months, not premature, treated with inotropic infusion with monitoring of blood pressure. The research obtained the approval of the Hospital Research Ethics committee and parents signed informed consent. Comparison of the two groups made use of the Wilcoxon test for the continuous variables and the Fisher’s exact test for the comparison of frequencies, at significance value of 5%. The data were registered in an Excel spreadsheet and analysed with SAS. Results: The sample comprised 30 patients of age between 1 and 27 months, of whom 13 (43%) were male. They were all affected by cardiac, respiratory or infective pathology, all of them intubated and on artificial respiratory support, sedated and infused with dopamine. The characteristics of the patients of the two groups did not differ significantly. The percentage variation of the baseline value of MAP after 30 min from starting the treatment between the two methods was not statistically significant (p = 0·85). The 95% confidence interval for the difference in the percentage variation of MAP between the two groups was (?3·1, +3·7). From a clinical perspective, the methods are to be considered equivalent. Conclusions: The study was conducted on a limited sample; no statistically significant differences were detected; QC is the quickest and more cost‐effective method.     

Expression of protectin (CD59) in human melanoma and its functional role in cell- and complement-mediated cytotoxicity

Immunohistochemical and/or indirect immunofluorescence analysis with monoclonal antibody (MAb) H19 demonstrated the expression of protectin (CD59) in 54 surgically removed metastatic melanoma lesions and on 8 out of 12 melanoma cell lines. CD59 expression had a low degree of intra- and intertumor heterogeneity. SDS-PAGE analysis showed that the molecular weight of CD59 expressed on melanoma cells is about 20 kDa. Treatment of melanoma cells with 5 U/ml of phosphatidylinositol-specific phospholipase C completely abolished cell-surface expression of CD59. Interferon-γ and/or tumor necrosis factor-α or phorbol 12-myristate 13-acetate neither modulated the expression of CD59 by melanoma cells nor influenced the amounts of CD59-specific mRNA. F(ab')₂ fragments of anti-CD59 MAb YTH53.1 did not inhibit the lysis of melanoma cells by allogeneic natural killer (NK) cells or lymphokine-activated killer (LAK) cells. In contrast, the whole lg molecule of MAb H19 or YTH53. I significantly (p < 0.05) enhanced NK-cell-mediated lysis of melanoma cells, suggesting the induction of antibody-dependent cell-mediated cytotoxicity. Lastly, masking of CD59 by MAb YTH53. I or its F(ab')₂ fragments significantly (p < 0.05) enhanced, in a dose-dependent fashion, the lysis of anti-GD3-sensitized melanoma cells by homologous complement. These data demonstrate that CD59 expressed by human melanoma cells might regulate host-tumor interaction by protecting neoplastic cells from complement-mediated lysis. © 1995 Wiley-Liss, Inc.