41 research outputs found
Ex vivo characterization of neuroinflammatory and neuroreceptor changes during epileptogenesis using candidate positron emission tomography biomarkers
Objective:
Identification of patients at risk of developing epilepsy before the first spontaneous seizure may promote the development of preventive treatment providing opportunity to stop or slow down the disease. //
Methods:
As development of novel radiotracers and onâsite setup of existing radiotracers is highly timeâconsuming and expensive, we used dualâcentre in vitro autoradiography as an approach to characterize the potential of innovative radiotracers in the context of epilepsy development. Using brain slices from the same group of rats, we aimed to characterise the evolution of neuroinflammation and expression of inhibitory and excitatory neuroreceptors during epileptogenesis using translational positron emission tomography (PET) tracers; 18Fâflumazenil (18FâFMZ; GABAA receptor), 18FâFPEB (metabotropic glutamate receptor 5; mGluR5), 18Fâflutriciclamide (translocator protein; TSPO, microglia activation) and 18Fâdeprenyl (monoamine oxidase B, astroglia activation). Autoradiography images from selected time points after pilocarpineâinduced status epilepticus (SE; baseline, 24 and 48 hours, 5, 10 and 15 days and 6 and 12â14 weeks after SE) were normalized to a calibration curve, coâregistered to an MRIâbased 2D regionâofâinterest atlas, and activity concentration (Bq/mm2) was calculated. //
Results:
In epileptogenesisâassociated brain regions, 18FâFMZ and 18FâFPEB showed an early decrease after SE. 18FâFMZ decrease was maintained in the latent phase and further reduced in the chronic epileptic animals, while 18FâFPEB signal recovered from day 10, reaching baseline levels in chronic epilepsy. 18Fâflutriciclamide showed an increase of activated microglia at 24 hours after SE, peaking at 5â15 days and decreasing during the chronic phase. On the other hand, 18Fâdeprenyl autoradiography showed late astrogliosis, peaking in the chronic phase. //
Significance:
Autoradiography revealed different evolution of the selected targets during epileptogenesis. Our results suggest an advantage of combined imaging of interârelated targets like glutamate and GABAA receptors, or microglia and astrocyte activation, in order to identify important interactions, especially when using PET imaging for the evaluation of novel treatments
The host metabolite D-serine contributes to bacterial niche specificity through gene selection
Escherichia coli comprise a diverse array of both commensals and niche-specific pathotypes. The ability to cause disease results from both carriage of specific virulence factors and regulatory control of these via environmental stimuli. Moreover, host metabolites further refine the response of bacteria to their environment and can dramatically affect the outcome of the hostâpathogen interaction. Here, we demonstrate that the host metabolite, D-serine, selectively affects gene expression in E. coli O157:H7. Transcriptomic profiling showed exposure to D-serine results in activation of the SOS response and suppresses expression of the Type 3 Secretion System (T3SS) used to attach to host cells. We also show that concurrent carriage of both the D-serine tolerance locus (dsdCXA) and the locus of enterocyte effacement pathogenicity island encoding a T3SS is extremely rare, a genotype that we attribute to an âevolutionary incompatibilityâ between the two loci. This study demonstrates the importance of co-operation between both core and pathogenic genetic elements in defining niche specificity
Ex vivo characterization of neuroinflammatory and neuroreceptor changes during epileptogenesis using candidate positron emission tomography biomarkers
Objective:
Identification of patients at risk of developing epilepsy before the first spontaneous seizure may promote the development of preventive treatment providing opportunity to stop or slow down the disease. //
Methods:
As development of novel radiotracers and onâsite setup of existing radiotracers is highly timeâconsuming and expensive, we used dualâcentre in vitro autoradiography as an approach to characterize the potential of innovative radiotracers in the context of epilepsy development. Using brain slices from the same group of rats, we aimed to characterise the evolution of neuroinflammation and expression of inhibitory and excitatory neuroreceptors during epileptogenesis using translational positron emission tomography (PET) tracers; 18Fâflumazenil (18FâFMZ; GABAA receptor), 18FâFPEB (metabotropic glutamate receptor 5; mGluR5), 18Fâflutriciclamide (translocator protein; TSPO, microglia activation) and 18Fâdeprenyl (monoamine oxidase B, astroglia activation). Autoradiography images from selected time points after pilocarpineâinduced status epilepticus (SE; baseline, 24 and 48 hours, 5, 10 and 15 days and 6 and 12â14 weeks after SE) were normalized to a calibration curve, coâregistered to an MRIâbased 2D regionâofâinterest atlas, and activity concentration (Bq/mm2) was calculated. //
Results:
In epileptogenesisâassociated brain regions, 18FâFMZ and 18FâFPEB showed an early decrease after SE. 18FâFMZ decrease was maintained in the latent phase and further reduced in the chronic epileptic animals, while 18FâFPEB signal recovered from day 10, reaching baseline levels in chronic epilepsy. 18Fâflutriciclamide showed an increase of activated microglia at 24 hours after SE, peaking at 5â15 days and decreasing during the chronic phase. On the other hand, 18Fâdeprenyl autoradiography showed late astrogliosis, peaking in the chronic phase. //
Significance:
Autoradiography revealed different evolution of the selected targets during epileptogenesis. Our results suggest an advantage of combined imaging of interârelated targets like glutamate and GABAA receptors, or microglia and astrocyte activation, in order to identify important interactions, especially when using PET imaging for the evaluation of novel treatments