Purpose: Current chemotherapy can achieve high response rates in aggressive non-Hodgkin's lymphoma (NHL), but the factors that influence regression and survival remain unknown. The present exploratory study tested the hypothesis whether interleukin-10 (IL-10) polymorphisms predict clinical outcome, leukocytopenia, or infectivity during therapy. IL-10 was chosen because immune alterations are a major risk factor for NHL, and IL-10 is a cytokine involved in inflammatory processes associated with clinical outcome. Experimental Design: Five hundred patients with aggressive NHL treated with CHOP/CHOEP were analyzed for IL-10 gene polymorphisms, including distal loci -7400InDel, -6752AT (rs6676671), and -6208CG (rs10494879) in comparison with proximal loci -3538AT (rs1800890), -1087AG (rs1800896), and -597AC (rs1800872) according to the incidence and outcome of the lymphoma. Results: No differences in allele frequencies or haplotypes were found comparing a cohort of patients with aggressive NHL/diffuse large B-cell lymphoma with a healthy control group. Patients with aggressive NHL characterized by IL-10 -7400DelDel had shorter overall survival periods compared with the other genotypes (P = 0.004). The 3-year rate is 43.4% for IL-10 -7400DelDel and 73.4% for IL-10 -7400InIn and IL-10 -7400InDel together. A significant increased risk for event-free survival is found for carriers of the genotype IL-10 -6752TT-6208CC-3538AA (P = 0.047). Multivariate analysis of IL-10 -7400 gene variation in relation to overall survival adjusted to international prognostic index revealed a relative risk of 1.9 for carriers of IL-10 -7400Del-Del (P = 0.037). No associations were found analyzing diffuse large B-cell lymphoma patients separately. Conclusion: Our results indicate that IL-10 gene variations could be associated to the clinical course of aggressive NHL, which points out the importance of host factors and respective genetic elements for treatment response.
The species- and situation-specific sound production of grasshoppers can be stimulated by focal application of both nicotinic and muscarinic receptor agonists into the central body complex of the protocerebrum. Pressure injection of the intrinsic transmitter acetylcholine only elicits fast and short-lived responses related to nicotinic receptor-mediated excitation. Prolonged sound production that includes complex song patterns requires muscarinic receptor-mediated excitation. In addition, basal muscarinic excitation in the central body neuropil seems to determine the general motivation of a grasshopper to stridulate. To demonstrate that endogenous acetylcholinesterase limits the activation of muscarinic receptors by synaptically released acetylcholine in the central body of Chorthippus biguttulus, we investigated both its presence in the brain and effects on sound production resulting from inhibition of esterase activity. Acetylcholinesterase activity was detected in the upper and lower division of the central body. Both these neuropils known to be involved in the cephalic control of stridulation were also shown to contain muscarinic acetylcholine receptors expressed by columnar neurons suggested to serve as output neurons of the central complex. Pressure injection of the acetylcholinesterase inhibitor eserine into protocerebral control circuits of restrained male grasshoppers stimulated long-lasting stridulation that depended on scopolamine-sensitive muscarinic receptors. In restrained males, eserine released the typical response song by potentiating the stimulatory effect of the conspecific female song. Eserine-mediated inhibition of acetylcholinesterase in the central body prolongs the presence of synaptically released acetylcholine at its postsynaptic receptors and increases its potency to activate muscarinic receptor-initiated signaling pathways acting to promote grasshopper sound production.
Insect glial cells serve functions for the formation, maintenance, and performance of the central nervous system in ways similar to their vertebrate counterparts. Characterization of physiological mechanisms that underlie the roles of glia in invertebrates is largely incomplete, partly due to the lack of markers that universally label all types of glia throughout all developmental stages in various species. Studies on primary cell cultures from brains of Locusta migratoria demonstrated that the absence of anti-HRP immunoreactivity, which has previously been used to identify glial cells in undissociated brains, can also serve as a reliable glial marker in vitro, but only in combination with a viability test. As cytoplasmic membranes of cultured cells are prone to degradation when they lose viability, only cells that are both anti-HRP immunonegative and viable should be regarded as glial cells, whereas the lack of anti-HRP immunoreactivity alone is not sufficient. Cell viability can be assessed by the pattern of nuclear staining with DAPI (4',6-diamidino-2-phenylindole), a convenient, sensitive labeling method that can be used in combination with other immunocytochemical cellular markers. We determined the glia-to-neuron ratio in central brains of fourth nymphal stage of Locusta migratoria to be 1:2 both in situ and in dissociated primary cell cultures. Analysis of primary cell cultures revealed a progressive reduction of glial cells and indicated that dead cells detach from the substrate and vanish from the analysis. Such changes in the composition of cell cultures should be considered in future physiological studies on cell cultures from insect nervous systems.
Spontaneously active neurosecretory neurons in vertebrate and invertebrate nervous systems share similarities in firing frequencies, spike shapes, inhibition by the transmitters they themselves release and postactivation inhibition, an intensity-dependent period of suppressed spontaneous generation of action potentials following phases of high-frequency activity. High-frequency activation of spontaneously active serotonin-containing Retzius cells in isolated ganglia of the leech Hirudo medicinalis induced prolonged membrane hyperpolarisations causing periods of postactivation inhibition of up to 33 s. The duration of the inhibitory periods was directly related to both the number and rate of spikes during activation and was inversely proportional to a cell's spontaneous firing frequency. The periods of postactivation inhibition remained unaffected by both serotonin depletion through repeated injections of 5,7-dihydroxytryptamine and suppressing the afterhyperpolarisation following each action potential with tetraethylammonium (TEA), iberiotoxin or charybdotoxin, suggesting that neither autoinhibition by synaptic release of serotonin nor calcium-activated potassium channels contribute to the underlying mechanism. In contrast, the postactivation inhibitory period was significantly affected both by differential electrical stimulation of the same Retzius cells via microelectrodes filled with molar concentrations of either Na(+)-acetate or K(+)-acetate, and by partial inhibition of Na(+)/K(+)-ATPase with ouabain. Thus, postactivation inhibition in Retzius cells results from prolonged hyperpolarising activity of Na(+)/K(+)-ATPase stimulated by the accumulation of cytosolic Na(+ )during phases of high-frequency spike activity.
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