Changes in D-serine levels and localization during postnatal development of the rat vestibular nuclei

The patterns of development of the vestibular nuclei (VN) and their main connections involving glutamate neurotransmission offer a good model for studying the function of the glial-derived neuromodulator D-serine in synaptic plasticity. In this study we show that D-serine is present in the VN and we analyzed its distribution and the levels of expression of serine racemase and D-amino acid oxidase (D-AAO) at different stages of postnatal (P) development. From birth to P21, high levels of D-serine were detected in glial cells and processes in all parts of the VN. This period corresponded to high expression of serine racemase and low expression of D-AAO. On the other hand, in the mature VN D-serine displayed very low levels and was mainly localized in neuronal cell bodies and dendrites. This drop of D-serine in adult stages corresponded to an increasing expression of D-AAO at mature stages. High levels of glial D-serine during the first 3 weeks of postnatal development correspond to an intense period of plasticity and synaptogenesis and maturation of VN afferents, suggesting that D-serine could be involved in these phenomena. These results demonstrate for the first time that changes in D-serine levels and distribution occur during postnatal development in the central nervous system. The strong decrease of D-serine levels and the glial-to-neuronal switch suggests that D-serine may have distinct functional roles depending on the developmental stage of the vestibular network.     

Acute monocytic leukemia chromosome studies

Cytogenetic studies have been performed on 34 acute monocytic leukemia (M5) patients, 24 of the a type and 10 of the b type. No chromosomal abnormalities were found in 12 cases, in spite of the fact that the mitoses concerned monocytes. Different chromosomal aberrations were present in the other cases. In 12 of them, an abnormality of the chromosome 11 long arm was observed (mainly in the poorly differentiated type of M5), on bands q22–q24 in nine cases and on band q14 in three cases. The chromosome 11 long arm thus appears preferentially rearranged in M5 although this is not apparent in every case. Concomitant study of the mitoses with cytological and cytogenetic techniques suggests that erythroblasts may not be involved in the M5 leukemic process.     

Aging pathways for organophosphate-inhibited human butyrylcholinesterase, including novel pathways for isomalathion, resolved by mass spectrometry.

Some organophosphorus compounds are toxic because they inhibit acetylcholinesterase (AChE) by phosphylation of the active site serine, forming a stable conjugate: Ser-O-P(O)-(Y)-(XR) (where X can be O, N, or S and Y can be methyl, OR, or SR). The inhibited enzyme can undergo an aging process, during which the X-R moiety is dealkylated by breaking either the P-X or the X-R bond depending on the specific compound, leading to a nonreactivatable enzyme. Aging mechanisms have been studied primarily using AChE. However, some recent studies have indicated that organophosphate-inhibited butyrylcholinesterase (BChE) may age through an alternative pathway. Our work utilized matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry to study the aging mechanism of human BChE inhibited by dichlorvos, echothiophate, diisopropylfluorophosphate (DFP), isomalathion, soman, sarin, cyclohexyl sarin, VX, and VR. Inhibited BChE was aged in the presence of H2O18 to allow incorporation of (18)O, if cleavage was at the P-X bond. Tryptic-peptide organophosphate conjugates were identified through peptide mass mapping. Our results showed no aging of VX- and VR-treated BChE at 25 degrees C, pH 7.0. However, BChE inhibited by dichlorvos, echothiophate, DFP, soman, sarin, and cyclohexyl sarin aged exclusively through O-C bond cleavage, i.e., the classical X-R scission pathway. In contrast, isomalathion aged through both X-R and P-X pathways; the main aged product resulted from P-S bond cleavage and a minor product resulted from O-C and/or S-C bond cleavage.     

Chronic recurrent lymphocytic Sweet syndrome as a predictive marker of myelodysplasia: a report of 9 cases

BACKGROUND: Sweet syndrome is an acute neutrophilic dermatosis that occurs with malignant diseases, mainly myeloid hemopathies, in about 20% of cases. When associated with myelodysplasia, Sweet syndrome may be clinically atypical. It can be histologically unusual. Concomitant infiltration of mature neutrophils and immature myeloid cells has been reported, and its significance is still debated. In few patients, lymphocytic infiltrates are the presenting feature of Sweet syndrome with myelodysplasia. OBSERVATIONS: We present 9 male adult patients with chronic Sweet syndrome, all with recurrent eruptions of erythematous and annular plaques that were associated with relapsing polychondritis in 4 of the 9 patients. Results from sequential biopsies showed that infiltrates were initially composed of lymphocytes and that neutrophilic dermal infiltration typical of Sweet syndrome occurred 24 to 96 months later, except in 2 cases. Moreover, atypical mononuclear cells were present on all initial biopsy specimens and strongly reacted to CD68 and myeloperoxidase, indicating a myeloid origin. Myelodysplastic syndrome occurred in all 9 patients, concomitantly with the neutrophilic infiltrate in 4 cases. CONCLUSIONS: Lymphocytic infiltrates with a clinical aspect of Sweet syndrome might represent the initial stage of a cutaneous dysgranulopoiesis syndrome and should lead to the research of atypical myeloid cells in skin infiltrate, blood, and bone marrow for the early detection of an associated myelodysplastic syndrome.     

EGFR induces expression of IRF-1 via STAT1 and STAT3 activation leading to growth arrest of human cancer cells

Recently, we reported that epidermal growth factor receptor (EGFR) induce expression of a module of genes known to be inducible by interferons and particularly interferon-gamma. Here we show that the module is tightly regulated by EGFR in the 2 human cancer cell lines that overexpress EGFR, A431 and HN5. The module of genes included the tumor suppressor IRF-1, which was used as a prototypical member to further investigate the regulation and function of the module. Ligand-activated EGFR induce expression of IRF-1 via phosphorylation of STAT1 and STAT3. In contrast, cells expressing the constitutively active cancer specific receptor EGFRvIII are unable to mediate phosphorylation of these STATs and thereby incapable of inducing IRF-1. We also demonstrate that IRF-1 is expressed in an EGF dose-dependent manner, which correlates with inhibition of cell proliferation, and that the regulation of IRF-1 is partially dependent on intracellular Src family kinase activity. Treatment with the dual specific Abl/c-Src kinase inhibitor AZD0530 significantly reduces the growth inhibitory effect of high EGF concentrations, signifying that EGFR induced IRF-1 is responsible for the observed growth inhibition. In addition, we show that media from these EGF treated cancer cells upregulate the activation marker CD69 on both B-cells and T-cells in peripheral blood. Taken together, these results suggest that cells acquiring sustained high activity of oncogenes such as EGFR are able to activate genes, whose products mediate growth arrest and activate immune effector cells, and which potentially could be involved in alerting the immune system in vivo leading to elimination of the transformed cells.