Caspase inhibitors induce a switch from apoptotic to proinflammatory signaling in CD95-stimulated T lymphocytes

CD95 is a major apoptosis receptor that induces caspase activation and programmed cell death in susceptible cells. CD95-induced apoptosis can be blocked by peptidic caspase inhibitors such as benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone or Ile-Glu-Thr-Asp-fluoromethyl ketone. Here we show that stimulation of CD95 in the presence of these inhibitors induces necrosis and expression of various proinflammatory cytokines in primary T lymphocytes, such as TNF-alpha, IFN-gamma and granulocyte/macrophage colony-stimulating factor. In the absence of caspase inhibition CD95 stimulation did not result in cytokine expression, indicating that this proinflammatory signaling pathway is suppressed by active caspases. Further analysis with A3.01 T cells revealed that the proinflammatory signaling activity of CD95 was mediated by MEK/ERK, p38 and NF-kappaB signaling pathways. These findings point to a pivotal role of caspases not only as mediators of apoptosis but also as enzymes that prevent proinflammatory signaling during CD95-induced apoptosis. Moreover, our findings may be useful for the development of novel pharmacological strategies.     

Follicular dendritic cells in extranodal non-Hodgkin lymphomas of MALT and non-MALT type

Extranodal lymphomas of the thyroid (n=19), kidney (n=15) and testis (n=30) were investigated histologically and immunohistochemically for follicular dendritic cell pattern using the monoclonal antibody Ki-FDC1P. This recognizes follicular dendritic cells in paraffin sections. Follicular dendritic cells were most predominant in lymphomas of the thyroid. These thyroid lymphomas showed the morphological features of mucosa-associated lymphoid tissue (MALT) type lymphomas in 18 of 19 cases and were classified as high-grade malignant lymphoma of MALT type with evidence of a low-grade malignant component (n=18). Ten of these cases contained destroyed reactive follicles of follicular dendritic cells. In 6 of these 10 cases follicular dendritic cells occurred in a pattern of tumour-associated abortive follicle type. The remaining lymphoma of the thyroid was an immunoblastic lymphoma of B-cell type showing no detectable follicular dendritic cells. In extranodal lymphomas of non-MALT type follicular dendritic cells occurred in only two cases where immunocytoma involved the kidney. Malignant lymphomas of the kidney (chronic lymphocytic leukaemia,n=2; immunocytoma,n=4; centroblastic lymphoma,n=9) and of the testis (immunocytoma,n=2; centroblastic lymphoma,n=27; immunoblastic lymphoma of B-cell type,n=1) revealed no characteristics of MALT type lymphoma, cytologically or with respect to follicular dendritic cells. Classical lymphoepithelial lesions formed by centrocyte-like cells, a hallmark of MALT, occurred exclusively in thyroid lymphomas of MALT type. Although occurrence of classical lymphoepithelial lesions formed by centrocyte-like cells was limited to thyroid lymphomas of MALT type, a growth pattern of lymphoid blasts, with formation of lesions mimicking lymphoepithelial lesions superficially, was found in 6 of 27 testicular centroblastic lymphomas. Follicular dendritic cells in non-Hodgkin's lymphomas of MALT type show distinct follicular patterns not found in other extranodal lymphomas such as those found in the kidney and testis.     

High intensity focused ultrasound--a surgical technique for the treatment of discrete liver tumours

The treatment of discrete liver tumours is often a difficult clinical problem. High intensity, focused ultrasound may provide one form of therapy for such disease. The ability to focus ultrasound precisely on a predetermined volume allows the possibility of selective tissue destruction at this position without damage to intervening tissues. We have investigated this both in vivo and in excised liver samples in vitro. Quantitative and qualitative studies have been carried out on the relationship between the ultrasonic exposure and the lesion shape, position and volume. In addition, the highly echogenic nature of the ultrasonic lesion has been studied, in an attempt to determine whether 'real time' observation of the extent of tissue damage is feasible.     

Cellular and humoral observations in a patient with allergic bronchopulmonary aspergillosis during a nonasthmatic exacerbation

A patient is described with an asymptomatic exacerbation of allergic bronchopulmonary aspergillosis (ABPA), clinically characterized by pulmonary infiltrates, with absence of obstructive reactions and a short period of hemoptysis 2 weeks before hospitalization. Cell counts and antibody concentrations were measured in serum, and bronchoalveolar fluid (BAF) samples and values were compared with data from previous periods of symptomatic exacerbations. During the asymptomatic exacerbation, concentrations of antibody to Aspergillus fumigatus, total IgE, and precipitating antibodies were elevated in peripheral blood. No quantitative differences in specific antibody concentrations (IgE, IgG, IgA, and IgM) against A. fumigatus were found between sera from symptomatic and asymptomatic periods of ABPA. In contrast to observations in the serum, protein concentrations in BAL fluid were normal during the asymptomatic period, whereas high concentrations were found during the symptomatic phases. Local antibody concentrations (in BAF) were characterized by high levels of IgA antibodies against A. fumigatus. During asymptomatic and symptomatic phases, eosinophils were elevated in peripheral blood, in sputum, in BAF, and highly elevated in tissue biopsy specimens. Activated eosinophils were found, as indicated by the presence of light-density cells in the circulation and monoclonal antieosinophil cationic protein binding to bronchoalveolar lavage eosinophils. In contrast to the symptomatic phase of ABPA in 1980, demonstrating aspecific airway reactivity to several pharmacologically active substances, no such hyperreactivity was found during the asymptomatic phase of ABPA in 1986. It is proposed that the asymptomatic infiltrative phase of ABPA is an intermediate stage that can develop into a symptomatic phase after prolonged and intensified infiltration of eosinophils. Mediators from the inflammatory cells may be involved in the induction of bronchial hyperresponsiveness. After induction of this hyperreactive stage of the airways, additional liberation of mediators from either eosinophils and/or mast cells will lead to a symptomatic (obstructive) phase of ABPA.     

Detection of leptospiral DNA by nucleic acid hybridisation with 32P- and biotin-labelled probes

Dot hybridisation with 32P- and biotin-labelled probes prepared from leptospiral DNA was performed to develop a sensitive and specific diagnostic method for early infection with leptospires. The smallest amounts of leptospiral DNA that could be detected with 32P- and biotin-labelled probes was 1.5 pg and 5 pg, respectively, corresponding to about 750 and 2500 leptospires. Dot hybridisation with a 32P-labelled probe detected leptospiral DNA in sera from all of 14 experimentally infected golden hamsters. The smallest amount of leptospiral DNA detected in these experiments corresponded to about 2500 leptospires. In the test conditions described in this study, the sensitivity of dot hybridisation with a biotin-labelled probe was lower. Little cross-hybridisation was observed with unrelated DNAs which indicates that dot hybridisation could be a useful diagnostic method.     

Effects of diadenosine polyphosphates,ATP and angiotensin II on membrane voltage and membrane conductances of rat mesangial cells

Diadenosine polyphosphates have been shown to influence renal perfusion pressure. As mesangial cells may contribute to these effects we investigated the effects of diadenosine triphosphate (Ap₃A), diadenosine tetraphosphate (Ap₄A), diadenosine pentaphosphate (Ap₅A) and diadenosine hexaphosphate (Ap₆A) on membrane voltage (V _m) and membrane conductance (g _m) in mesangial cells (MC) of normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats in primary and long-term culture. We applied the patch-clamp technique in the fast-whole-cell configuration to measure V _m and g _m. To compare the effects of diadenosine polyphosphates with hitherto known agonists we also tested adenosine 5-triphosphate (ATP) and angiotensin II (Ang II). As there was no significant difference in the V _m values in MC of WKY (–42±1 mV, n=70) and SHR rats (–45±2 mV, n=99) as well as in the agonist-induced changes of V _m, all data were pooled. The V _m of all the cells was –44±1 mV (n=169) and g _m was 15.9±1.8 nS (n=141). Ion-exchange experiments showed the presence of a K⁺ and a non-selective cation conductance in resting MC whereas a Cl^– conductance or a Na⁺selective conductance could not be observed. Ap₃A, Ap₄A, Ap₅A, AP₆A and ATP each at a concentration of 5 mol/l, led to a significant depolarization of V _m by 5±2 mV (n=14), 7±1 mV (n=25), 3±1 mV (n=23), 2±1 mV (n=16), and 14±2 mV (n=23), respectively. For Ap₄A, the most potent diadenosine polyphosphate, we determined the half-maximally effective concentration (EC ₅₀) as 6 mol/l (n=5–25), for ATP as 2 mol/l (n=9–37), and for Ang II as 8 nmol/l (n=6–18). Ap₄A 100 mol/l increased g _m significantly by 55±20% (n=16), 100 mol/l ATP by 135±60% (n=18). The diadenosine polyphosphates examined were able to depolarize V _m (Ang II >ATP> Ap₄A>Ap₃A>Ap₅A>Ap₆A) by activation of a Cl^– conductance and a non-selective cation conductance, as do ATP or Ang II.     

Investigation of the polymerization of octanelactam initiated with hydrochloric acid

The polymerization of octanelactame ( 1 ) initiated by HCl takes place according to the characteristic kinetic curves. Both characteristics, i.e., the fast initial and the extremely slow further stages, and the kinetic anomaly (in certain cases under otherwise identical conditions less polymer is formed at higher than at lower temperatures) can be interpreted easily on the basis of a mechanism already suggested by the authors. The two relevant chain growth reactions, i.e., lactam addition on \documentclass{article}\pagestyle{empty}\begin{document}$ {\rm R}\mathop {\rm N}\limits^ \oplus {\rm H}_{\rm 3} $\end{document}-groups and the reaction between \documentclass{article}\pagestyle{empty}\begin{document}$ {\rm R}\mathop {\rm N}\limits^ \oplus {\rm H}_{\rm 3} $\end{document} and N-acylamide groups, proceed through a tetrahedral intermediate in two directions, one of them being the known chain growth, the other one an amidine (or acylamidine) formation, in which the active groups, ensuring chain growth, desactivate. Both kinetic characteristics could be interpreted on the basis of the suggested mechanism, by measuring the amounts of amino and amidine groups with the progress of polymerization.     

Validation of the PAM-13 instrument in the Hungarian general population 40 years old and above

The European Journal of Health Economics - Patient activation comprises the skills, knowledge and motivation necessary for patients’ effective contribution to their care. We adapted and...