Background and Purpose
Thrombolysis with tPA is the only FDA-approved therapy for acute ischemic stroke. But its widespread application remains limited by narrow treatment time windows and the related risks of cerebral hemorrhage. In this study, we ask whether minocycline can prevent tPA-associated cerebral hemorrhage and extend the reperfusion window in an experimental stroke model in rats.
Spontaneously hypertensive rats were subjected to embolic focal ischemia using homologous clots and treated with: saline at 1 hour; early tPA at 1 hour, delayed tPA at 6 hours; minocycline at 4 hours; combined minocycline at 4 hours plus tPA at 6 hours. Infarct volumes and hemorrhagic transformation were quantified at 24 hours. Gelatin zymography was used to measure blood levels of circulating matrix metalloproteinase-9 (MMP-9).
Early 1-hour thrombolysis restored perfusion and reduced infarction. Late 6-hour tPA did not decrease infarction but instead worsened hemorrhagic conversion. Combining minocycline with delayed 6-hour tPA decreased plasma MMP-9 levels, reduced infarction, and ameliorated brain hemorrhage. Blood levels of MMP-9 were also significantly correlated with volumes of infarction and hemorrhage.
Combination therapy with minocycline may extend tPA treatment time windows in ischemic stroke.
Background and Purpose-Emerging data suggest that neuroglobin (Ngb) may protect against hypoxic/ischemic neuronal insults. However, the underlying mechanisms in vivo and implications for long-term outcomes are still not well understood. Methods-Using our newly created Ngb overexpressing transgenic (Ngb-Tg) mice, we measured brain infarction on day 1 and day 14 after transient focal cerebral ischemia and performed neurobehavioral assessments in sensorimotor deficits on days 1, 3, 7, and 14. To test the hypothesis that Ngb may play a role in reducing oxidative stress after stroke, intracellular malondialdehyde levels were measured and compared in Ngb-Tg and wild-type mice.
Amide proton transfer (APT) imaging is a variant form of chemical exchange saturation transfer (CEST) imaging that is based on the magnetization exchange between bulk water and labile endogenous amide protons. Given that chemical exchange is pH-dependent, APT imaging has been shown capable of imaging ischemic tissue acidosis, and as such, may serve as a surrogate metabolic imaging marker complementary to perfusion and diffusion MRI. In order for APT imaging to properly diagnose heterogeneous pathologies such as stroke and cancer, fast volumetric APT imaging has to be developed. In this study the evolution of CEST contrast after RF irradiation was solved showing that although the CEST steady state is reached by the apparent longitudinal relaxation rate, the decreases of CEST contrast after irradiation is governed by the intrinsic relaxation constant. A volumetric APT imaging sequence is proposed that acquires multislice images immediately after a single long continuous wave (CW) RF irradiation, wherein the relaxation-induced loss of CEST contrast is compensated for during postprocessing. The proposed technique was verified by numerical simulation, a tissue-like dual-pH phantom, and demonstrated on an embolic stroke animal model. In summary, our study has established a fast volumetric pH-weighted APT imaging technique, allowing further investigation to fully evaluate its diagnostic power. Chemical exchange saturation transfer (CEST) imaging provides enormous sensitivity enhancement over typical imaging methods, permitting quantification of the properties of certain dilute exchangeable groups (1). CEST imaging renders MRI, which usually detects only bulk water signal, sensitive to informative metabolites and their byproducts such as glucose and lactate (2,3). In particular, the chemical exchange between bulk water and amide protons from endogenous proteins and peptides has been shown sensitive to ischemic tissue acidosis, and has hence given rise to a novel imaging technique dubbed amide proton transfer (APT) imaging (4,5). Since tissue pH decreases in response to abnormal glucose/oxygen metabolism during acute ischemia, pH-sensitive APT imaging may serve as a new surrogate metabolic imaging marker for stroke (6,7). In fact, we recently showed that ischemic tissue with APT deficit correlates with the final lesion measured from follow-up T 2 hyperintensity; the perfusion lesion tends to overestimate stroke infarction, while the diffusion lesion underestimates it (8). In that it complements perfusion and diffusion MRI, APT imaging may allow us to better characterize penumbra for predicting ischemic tissue outcome and eventually help guide thromobolytic and/or neuroprotective therapies for acute stroke.One limitation of our previous APT imaging technique is that it permitted only single-slice acquisition (5,8 -10). This limitation is largely a factor of the very long continuous wave (CW) RF irradiation-typically a few secondsrequired to reach the steady state for quantitative APT imaging. Repeating RF irradiation for ...
Yeasts used in bread making are exposed to high concentrations of sucrose during sweet dough fermentation. Despite its importance, tolerance to high-sucrose stress is poorly understood at the gene level. To clarify the genes required for tolerance to high-sucrose stress, genome-wide screening was undertaken using the complete deletion strain collection of diploid Saccharomyces cerevisiae. The screening identified 273 deletions that yielded high sucrose sensitivity, approximately 20 of which were previously uncharacterized. These 273 deleted genes were classified based on their cellular function and localization of their gene products. Cross-sensitivity of the high-sucrose-sensitive mutants to high concentrations of NaCl and sorbitol was studied. Among the 273 sucrose-sensitive deletion mutants, 269 showed cross-sensitivities to sorbitol or NaCl, and four (i.e. ade5,7, ade6, ade8, and pde2) were specifically sensitive to high sucrose. The general stress response pathways via high-osmolarity glycerol and stress response element pathways and the function of the invertase in the ade mutants were similar to those in the wild-type strain. In the presence of high-sucrose stress, intracellular contents of ATP in ade mutants were at least twofold lower than that of the wild-type cells, suggesting that depletion of ATP is a factor in sensitivity to high-sucrose stress. The genes identified in this study might be important for tolerance to high-sucrose stress, and therefore should be target genes in future research into molecular modification for breeding of yeast tolerant to high-sucrose stress.
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