New concepts in sickle cell anemia

Current knowledge on the pathophysiology of sickle cell anemia is reviewed and potential therapeutic options are reviewed and discussed. It is hoped that better understanding of the pathophysiology will improve the care given to these patients as well as their quality of life. Keywords : sickle cell anemia, pathophysiology, treatment Clinics in Mother and Child Health Vol. 1(1) 2004: 30-3

Integrins and adhesion molecules: Gelatinase and oncofetal fibronectin secretion is dependent on integrin expression on human cytotrophoblasts

Collagenolytic activity of cytotrophoblasts is stimulated by glycoproteins of the extracellular matrix and since this stimulation can possibly occur through integrins, we measured the gelatinolytic activity of villous and extravillous cytotrophoblasts according to the type of integrins expressed on these cells. Cytotrophoblasts were isolated from legal abortions, immunopurified with anti-CD45, separated according to their expression of histocompatibility-linked antigen (HLA)-G, α6 or α5 integrin subunits and cultured for 5 days on plastic or agarose. Fetal fibronectin, human chorionic gonadotrophin (HCG) and the gelatinolytic activity were measured in the culture supernatants. Following immunopurification with anti-CD45, the gelatinolytic activity of cytotrophoblasts was significantly higher than before, indicating that contaminating lymphomyeloid cells secreted gelatinolytic inhibitors. HLA-G positive cells secreted significantly more gelatinases than HLA-G negative cells but their HCG secretion was similar. Compared to α5 positive cells, α6 positive cytotrophoblasts secreted significantly more gelatinases, significantly less fibronectin but similar amounts of HCG. We conclude that during trophoblast invasion, extravillous cytotrophoblasts (HLA-G positive) expressing the α6 integrin subunit represent the invasive population of cells (high gelatinase and low fibronectin secretion). When expression of the α5 integrin subunit is turned on, their invasive behaviour ceases and they secrete low amounts of gelatinases and high concentrations of fibronecti

Éditorial. Une circulation des idées pédagogiques sur papier. Presse d’éducation, transferts et trajectoires transnationales des savoirs (1850-2000)

"Die vorliegende Ausgabe der Zeitschrift vereinigt [...] Beiträge, die pädagogische Zeitschriften als Teil eines kulturellen Austauschs analysieren. In dieser Ausgabe werden unterschiedliche methodische Ansätze verfolgt, die jedoch alle versuchen, die Modalitäten solcher Transfers auf dem Papier zu erfassen und die Bedeutung der pädagogischen Presse bei der disziplinären Entwicklung zu studieren. Es gilt zu überprüfen, ob Zeitschriften tatsächlich privilegierte Orte des Austauschs sind, ob Periodika die Zirkulation pädagogischen Wissens befördern - lokal, regional, national, transnational. So soll durch die Analyse von Zeitschriften erforscht werden, welche Inhalte übernommen, über welche Kanäle sie verbreitet und wie sie rezipiert werden. Indem ein besonderes Augenmerk auf die redaktionellen Eigenheiten der Zeitschriften (Redaktionsausschuss, Erscheinungshäufigkeit, Art der Verbreitung, Leserschaft, Wettbewerb zwischen den Zeitschriften etc.) sowie auf die Präsentation des Inhalts (Titel der Artikel, Chroniken, wiederkehrende Rubriken usw.) gerichtet wird, kann untersucht werden, wie pädagogisches Wissen verändert und verbreitet wird. Die pädagogische Presse ist ein wichtiges Hilfsmittel, um den transnationalen Aufbau der Pädagogik zu verstehen und um zu sehen, wie dabei "fremdes" Wissen einbezogen wird." Der einführende Beitrag bietet einen Überblick über die Artikel dieser Ausgabe. (DIPF/Orig.

Gelatinase and oncofetal fibronectin secretion is dependent on integrin expression on human cytotrophoblasts

Collagenolytic activity of cytotrophoblasts is stimulated by glycoproteins of the extracellular matrix and since this stimulation can possibly occur through integrins, we measured the gelatinolytic activity of villous and extravillous cytotrophoblasts according to the type of integrins expressed on these cells. Cytotrophoblasts were isolated from legal abortions, immunopurified with anti-CD45, separated according to their expression of histocompatibiltty-linked antigen (HLA)-G, α6 or α5 integrin subunits and cultured for 5 days on plastic or agarose. Fetal fibronectin, human chorionic gonadotrophin (HCG) and the gelatinolytic activity were measured in the culture supernatants. Following immunopurrfication with anti-CD45, the gelatinolytic activity of cytotrophoblasts was significantly higher than before, indicating that contaminating lymphomyeloid cells secreted gelatinolytic inhibitors. HLA-G positive cells secreted significantly more gelatinases than HLA-G negative cells but their HCG secretion was similar. Compared to α5 positive cells, α6 positive cytotrophoblasts secreted significantly more gelatinases, significantly less fibronectin but similar amounts of HCG. We conclude that during trophoblast invasion, extravillous cytotrophoblasts (HLA-G positive) expressing the α6 integrin subunit represent the invasive population of cells (high gelatinase and low fibronectin secretion). When expression of the α5 integrin subunit is turned on, their invasive behaviour ceases and they secrete low amounts of gelatinases and high concentrations of fibronecti

Involvement of MAPK pathway in TNF-α-induced MMP-9 expression in human trophoblastic cells

The aim of this article was to investigate the signalling pathways involved in metalloproteinase-9 (MMP-9) expression induced by tumour necrosis factor-α (TNF-α) in first-trimester trophoblastic cells. TNF-α-induced MMP-9 expression, secretion and activity were completely blocked by stress-activated protein kinase/jun kinase (SAPK/JNK) and Erk inhibitors (SP600 125 and U0126 respectively) but not by p38 mitogen-activated protein kinase (MAPK) inhibitors (SB203 580 and SB202 190). Stimulation of HIPEC 65 cells with TNF-α caused phosphorylation of JNK and extracellular signal-regulated kinase 1/2 (Erk1/2), with a peak after 20 min of treatment. Transcription factors nuclear factor-κB (NF-κB) and activator protein 1 (AP-1)-binding site were identified as the cis-elements involved in TNF-α activation as determined by electromobility shift assays. TNF-α-induced transactivation of NF-κB was inhibited by U0126, whereas TNF-α-induced transactivation of AP-1 was inhibited by SP600 125. Taken together, these results indicate that in trophoblastic cells, TNF-α probably activates two different pathways leading to MMP-9 expression: (a) Erk1/2 pathway which in turn initiates NF-κB activation and (b) SAPK/JNK pathway that activates AP-

Status of p53 in first-trimester cytotrophoblastic cells

p53 has been called the cellular gatekeeper of the genome because it can induce cell-cycle arrest in G1, apoptosis or affect DNA replication in response to DNA damage. As p53 has been observed in first-trimester cytotrophoblastic cells (CTB), but its expression in normal cells is generally not detectable because of its short half-life, p53 could play an important role in cellular differentiation and/or in the control of the invasion of trophoblastic cells; therefore, p53 status was investigated in these cells. Using different antibodies recognizing different epitopes of p53 protein, abundant p53 expression was observed both in nuclear and in cytoplasmic compartments of first-trimester CTB. Whereas p53 was detected in the nuclei of few trophoblastic cells with an antibody recognizing the N-terminal epitope of the protein, high expression level of p53 in the cytoplasm of CTB was detected with an antibody recognizing the middle part of p53. The lack of immunoreactivity of p53 with antibodies recognizing the epitopes located at the N-terminus of p53 and the high level of p53 protein observed in the cytoplasm of CTB suggest that the N-terminus of p53 is involved in the formation of complexes. These cytoplasmic complexes were detected under non-reducing conditions in western blot analysis and had apparent molecular weights (MW) of 195, 167 or 125 kDa. These complexes could prolong the half-life of p53 in the cytoplasm of CTBs. By contrast, in the nuclei of CTBs, p53 seems to be present as a tetrame

Endochin-like quinolones (ELQs) and bumped kinase inhibitors (BKIs): Synergistic and additive effects of combined treatments against Neospora caninum infection in vitro and in vivo.

The apicomplexan parasite Neospora caninum is an important causative agent of congenital neosporosis, resulting in abortion, birth of weak offspring and neuromuscular disorders in cattle, sheep, and many other species. Among several compound classes that are currently being developed, two have been reported to limit the effects of congenital neosporosis: (i) bumped kinase inhibitors (BKIs) target calcium dependent protein kinase 1 (CDPK1), an enzyme that is encoded by an apicoplast-derived gene and found only in apicomplexans and plants. CDPK1 is essential for host cell invasion and egress; (ii) endochin-like quinolones (ELQs) are inhibitors of the cytochrome bc1 complex of the mitochondrial electron transport chain and thus inhibit oxidative phosphorylation. We here report on the in vitro and in vivo activities of BKI-1748, and of ELQ-316 and its respective prodrugs ELQ-334 and ELQ-422, applied either as single-compounds or ELQ-BKI-combinations. In vitro, BKI-1748 and ELQ-316, as well as BKI-1748 and ELQ-334, acted synergistically, while this was not observed for the BKI-1748/ELQ-422 combination treatment. In a N. caninum-infected pregnant BALB/c mouse model, the synergistic effects observed in vitro were not entirely reproduced, but 100% postnatal survival and 100% inhibition of vertical transmission was noted in the group treated with the BKI-1748/ELQ-334 combination. In addition, the combined drug applications resulted in lower neonatal mortality compared to treatments with single drugs