Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Diss. (sammanfattning) Umeå : Umeå universitet, 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 6 uppsatser.

Thesis (Ph. D.)--Cornell University, May, 1998. / Vita. Includes bibliographical references (leaves 154-181).

Thesis (Ph.D.) - University of Queensland, 2006. / Includes bibliography.

<p>Evidence from experimental models of epilepsy support that prolonged seizures (status epilepticus, SE) promote pathological hippocampal synaptodendritic remodeling which contributes to the development of seizures and cognitive decline. One potential mechanism underlying the SE-induced sequelae is microgliosis. </p> <p>Evidence from models of experimental epilepsy supports a significant spatiotemporal correlation between SE-induced decreases in the microtubule associated protein 2 (Map2) loss and microgliosis in the hippocampus. In addition, pharmacological suppression of microgliosis after SE with the drug rapamycin attenuated the losses of Map2 and the dendritic ion channels Kv.4.2 and HCN1 in the hippocampus. This microglia suppression paralleled a recovery of the SE-induced recognition and spatial memory deficits. Based on these studies, we hypothesized that the inhibition of microgliosis during epileptogenesis will attenuate the SE-induced hippocampal dendritic and cognitive pathology. To further investigate the role of microgliosis in the SE-induced dendritic pathology, we tested the efficacy of a more selective inhibitor <a>of the survival and proliferation of </a>microglia, PLX3397, using the pilocarpine model of SE and acquired epilepsy. PLX3397 binds to colony stimulating factor 1 receptor (CSF1R) on microglia and inhibits the downstream signaling responsible for survival and proliferation of these cells. </p> <p>To test this hypothesis, we induced SE in male rats with pilocarpine (280-300mg/kg) <a>while and controls (Ctrl) received saline. </a>Rats were randomly assigned to a diet of either chow alone (vehicle; Veh) or chow with PLX3397 (50mg/kg) for 20 days post-SE. At two weeks post-SE, rats were subjected to novel object recognition (NOR) and Barnes maze (BM) to evaluate hippocampal-dependent recognition memory, and spatial learning and memory, respectively. Following the behavioral assessments, rats were sacrificed for brain analysis at 20 days post-SE. We used histological analysis to determine the amount of microgliosis with IBA1 and dendritic stability with Map2. We used western blotting to measure the protein levels of molecules involved in the crosstalk between microglia and astrocytes: GFAP, IL-6, C3, and iC3b. We also measured the protein levels of the dendritic ion channels Kv4.2 and HCN1, and the synaptic marker PSD95.</p> <p>NOR showed that the Ctrl+Veh and Ctrl+PLX3397 groups spent significantly more time exploring the novel object (<i>p</i> < .05), while the SE+Veh and SE+PLX3397 did not. Similar results were observed in the BM test, Ctrl+Veh and Ctrl+PLX3397 groups had a faster latency to find the target compared to the SE+Veh and SE+PLX3397 groups (<i>p</i> < .05). These data suggest that recognition and spatial memory deficits induced by SE were not attenuated by treatment with PLX3397. We found that the PLX3397 treatment significantly decreased microgliosis in Ctrl+PLX3397 rats compared to Ctrl+Veh rats (<i>p</i> < .05). As expected, we found a significant increase in the number of microglial cells in hippocampi of SE+Veh rats compared to Ctrl+Veh rats (<i>p</i> < .05). Interestingly, in the PLX3397-treated SE group, we observed two distinctive groups which we categorized as responders and non-responders when compared to the SE+Veh group. The SE+PLX responders had significantly decreased microgliosis compared to the SE+Veh group (<i>p</i> < .05). The SE+PLX non-responders had higher levels of microgliosis compared to the SE+Veh group (<i>p</i> < .05). We found levels of GFAP were increased in the SE+Veh group compared to the Ctrl+Veh group (<i>p</i> < .05). Treatment with PLX3397 in the SE group reduced these levels compared to the vehicle treated SE group (<i>p</i> < .05). We also found increases in C3 and iC3b following the induction of SE compared to Ctrl+Veh group (<i>p</i> < .05), and these levels remained similar in the SE+PLX3397 group compare to the SE+Veh group (<i>p</i> > .05). There was a reduction in Map2 immunoreactivity as well as the protein levels of Kv4.2 and PSD95 in the SE+Veh group compared to the Ctrl+Veh group (<i>p</i> < .05). We found that treatment with PLX3397 recovered the SE-induced loss of Map2 labeled dendrites compared to SE+Veh group (<i>p</i> < .05). However, treatment with PLX3397 did not recover the SE-induced reduction Kv4.2 and PSD95 (<i>p</i> > .05). <a>In parallel, we found that a group of SE+PLX3397 animals did not have reduced microgliosis compared to the SE+Veh group (<i>p </i>< .05), and therefore was categorized as a non-responder group. </a></p> Our findings are the first to show that blocking CSF1R signaling with PLX3397 suppressed microgliosis in the hippocampus, partially recovered the SE-induced decline of Map2 immunoreactivity in the hippocampal CA1 region but had no effect in the recognition or spatial memory deficits. These data suggest that while hippocampal microgliosis may play a role in the disruption of dendritic structural stability in the hippocampus it does not seem to critically contribute to the memory decline that occurs during epileptogenesis.

Autoimmune neutropenia (AIN) is characterized by antibody mediated peripheral destruction of neutrophils. Since there is no effective treatment, antibiotics have to be used frequently for recurrent infections. Five selected patients with serologically proven AIN were treated with r-metHuG- CSF at 5-8 μg/kg body weight (300-480 μg) daily: the dose and frequency of r-metHuG-CSF was reduced after neutrophil counts above 1.0 x 109/l were obtained. R-metHuG-CSF is effective in AIN and causes a sustained rise in ANC which can he maintained on a low dose administered twice or thrice weekly.

Candida albicans is an increasingly important pulmonary fungal pathogen. Resident alveolar macrophages are important in host defense against opportunistic fungal infections. Activation of Group IVA cytosolic phospholipase A2α (cPLA2α) in macrophages initiates arachidonic acid (AA) release for production of eicosanoids, which regulate inflammation and immune responses. We investigated the ability of C. albicans to activate cPLA2α in unprimed alveolar macrophages and after priming with granulocyte macrophage colony-stimulating factor (GM-CSF), which regulates alveolar macrophage maturation. AA was released within minutes by GM-CSF-primed but not unprimed alveolar macrophages in response to C. albicans, and was blocked by soluble glucan phosphate (S-GP). The expression of the β-glucan receptor dectin-1 was increased in GM-CSF-primed macrophages, and AA release from GM-CSF-primed dectin-1-/- alveolar macrophages was reduced to basal levels. The enhanced activation of extracellular signal-regulated kinases and phosphorylation of cPLA2α on Ser-505 that occurred in GM-CSF-primed macrophages were reduced by MEK1 and Syk inhibitors, which also suppressed AA release. At later times after C. albicans infection (6 h), unprimed and GM-CSF-primed macrophages released similar levels of AA. The expression of cyclooxygenase 2 and prostanoid production at 6 hours was higher in GM-CSF-primed macrophages, but the responses were not dependent on dectin-1. However, dectin-1 contributed to the C. albicans-stimulated increase in TNF-α production that occurred in GM-CSF-primed macrophages. The results demonstrate that dectin-1 mediates the acute activation of cPLA 2α in GM-CSF-primed alveolar macrophages, but not in the more delayed phase of AA release and GM-CSF-dependent prostanoid production.

Granulocyte colony-stimulating factor (GCSF) is currently the most widely used cytokine for stem cell mobilization. There are few studies suggesting GCSF administration may induce activation of both coagulation and endothelial cells that could favor the developing of thrombotic events. We report a 58-year-old female with vasculitis and renal impairment. She was found to have an underlying monoclonal gammopathy of unknown significance (MGUS). The monoclonal protein was felt to play a role in her underlying renal disease and peripheral neuropathy. She was considered a candidate for peripheral blood stem cell transplantation to manage the monoclonal protein. During stem cell mobilization with GCSF, she developed worsening of anemia; thrombocytopenia and worsening of renal function. She was diagnosed with thrombotic microangiopathy (TMA) which was successfully treated with therapeutic plasma exchange and rituximab. It is possible that GCSF may have directly (activating endothelial cells) or indirectly (activation of underlying autoimmune disorder) contributed to TMA in this patient.

No description available.