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Defects in Phosphate Acquisition and Storage Influence Virulence of <i>Cryptococcus neoformans</i>
Kretschmer, Matthias,Reiner, Ethan,Hu, Guanggan,Tam, Nicola,Oliveira, Debora L.,Caza, Melissa,Yeon, Ju Hun,Kim, Jeongmi,Kastrup, Christian J.,Jung, Won Hee,Kronstad, James W. American Society for Microbiology 2014 Infection and immunity Vol.82 No.7
<P>Nutrient acquisition and sensing are critical aspects of microbial pathogenesis. Previous transcriptional profiling indicated that the fungal pathogen <I>Cryptococcus neoformans</I>, which causes meningoencephalitis in immunocompromised individuals, encounters phosphate limitation during proliferation in phagocytic cells. We therefore tested the hypothesis that phosphate acquisition and polyphosphate metabolism are important for cryptococcal virulence. Deletion of the high-affinity uptake system interfered with growth on low-phosphate medium, perturbed the formation of virulence factors (capsule and melanin), reduced survival in macrophages, and attenuated virulence in a mouse model of cryptococcosis. Additionally, analysis of nutrient sensing functions for <I>C. neoformans</I> revealed regulatory connections between phosphate acquisition and storage and the iron regulator Cir1, cyclic AMP (cAMP)-dependent protein kinase A (PKA), and the calcium-calmodulin-activated protein phosphatase calcineurin. Deletion of the <I>VTC4</I> gene encoding a polyphosphate polymerase blocked the ability of <I>C. neoformans</I> to produce polyphosphate. The <I>vtc4</I> mutant behaved like the wild-type strain in interactions with macrophages and in the mouse infection model. However, the fungal load in the lungs was significantly increased in mice infected with <I>vtc4</I> deletion mutants. In addition, the mutant was impaired in the ability to trigger blood coagulation <I>in vitro</I>, a trait associated with polyphosphate. Overall, this study reveals that phosphate uptake in <I>C. neoformans</I> is critical for virulence and that its regulation is integrated with key signaling pathways for nutrient sensing.</P>
Singer, Oliver C.,Humpich, Marek C.,Fiehler, Jens,Albers, Gregory W.,Lansberg, Maarten G.,Kastrup, Andiras,Rovira, Alex,Liebeskind, David S.,Gass, Achim,Rosso, Charlotte,Derex, Laurent,Kim, Jong S.,Ne Wiley Subscription Services, Inc., A Wiley Company 2008 Annals of neurology Vol.63 No.1
<B>Objective</B><P>The risk for symptomatic intracerebral hemorrhage (sICH) associated with thrombolytic treatment has not been evaluated in large studies using diffusion-weighted imaging (DWI). Here, we investigated the relation between pretreatment DWI lesion size and the risk for sICH after thrombolysis.</P><B>Methods</B><P>In this retrospective multicenter study, prospectively collected data from 645 patients with anterior circulation stroke treated with intravenous or intraarterial thrombolysis within 6 hours (<3 hours: n = 320) after symptom onset were pooled. Patients were categorized according to the pretreatment DWI lesion size into three prespecified groups: small (≤10ml; n = 218), moderate (10–100ml; n = 371), and large (>100ml; n = 56) DWI lesions.</P><B>Results</B><P>In total, 44 (6.8%) patients experienced development of sICH. The sICH rate was significantly different between subgroups: 2.8, 7.8, and 16.1% in patients with small, moderate, and large DWI lesions, respectively (p < 0.05). This translates to a 5.8 (2.8)-fold greater sICH risk for patients with large DWI lesions as compared with patients with small (or moderate) DWI lesions. The results were similar in the large subgroup (n = 536) of patients treated with intravenous tissue plasminogen activator. DWI lesion size remained an independent risk factor when including National Institutes of Health Stroke Scale, age, time to thrombolysis, and leukoariosis in a logistic regression analysis.</P><B>Interpretation</B><P>This multicenter study provides estimates of sICH risk in potential candidates for thrombolysis. The sICH risk increases gradually with increasing DWI lesion size, indicating that the potential benefit of therapy needs to be balanced carefully against the risk for sICH, especially in patients with large DWI lesions. Ann Neurol 2007</P>
Postthrombolysis hemorrhage risk is affected by stroke assessment bias between hemispheres
Audebert, H. J.,Singer, O. C.,Gotzler, B.,Vatankhah, B.,Boy, S.,Fiehler, J.,Lansberg, M. G.,Albers, G. W.,Kastrup, A.,Rovira, A.,Gass, A.,Rosso, C.,Derex, L.,Kim, J. S.,Heuschmann, P. Ovid Technologies (Wolters Kluwer) - American Acad 2011 Clinical Neurophysiology Vol.76 No.7
Isabel Siow,Benjamin Y.Q. Tan,Keng Siang Lee,Natalie Ong,Emma Toh,Anil Gopinathan,Cunli Yang,Pervinder Bhogal,Erika Lam,Oliver Spooner,Lukas Meyer,Jens Fiehler,Panagiotis Papanagiotou,Andreas Kastrup 대한뇌졸중학회 2022 Journal of stroke Vol.24 No.1
Background and Purpose Mechanical thrombectomy (MT) is an effective treatment for patients with basilar artery occlusion (BAO) acute ischemic stroke. It remains unclear whether bridging intravenous thrombolysis (IVT) prior to MT confers any benefit. This study compared the outcomes of acute BAO patients who were treated with direct MT versus combined IVT plus MT. Methods This multicenter retrospective cohort study included patients who were treated for acute BAO from eight comprehensive stroke centers between January 2015 and December 2019. Patients received direct MT or combined bridging IVT plus MT. Primary outcome was favorable functional outcome defined as modified Rankin Scale 0–3 measured at 90 days. Secondary outcome measures included mortality and symptomatic intracranial hemorrhage (sICH). Results Among 322 patients, 127 (39.4%) patients underwent bridging IVT followed by MT and 195 (60.6%) underwent direct MT. The mean±standard deviation age was 67.5±14.1 years, 64.0% were male and median National Institutes of Health Stroke Scale was 16 (interquartile range, 8 to 25). At 90-day, the rate of favorable functional outcome was similar between the bridging IVT and direct MT groups (39.4% vs. 34.4%, P=0.361). On multivariable analyses, bridging IVT was not associated with favorable functional outcome, mortality or sICH. In subgroup analyses, patients with underlying atherosclerosis treated with bridging IVT compared to direct MT had a higher rate of favorable functional outcome at 90 days (37.2% vs. 15.5%, P=0.013). Conclusions Functional outcomes were similar in BAO patients treated with bridging IVT versus direct MT. In the subgroup of patients with underlying large-artery atherosclerosis stroke mechanism, bridging IVT may potentially confer benefit and this warrants further investigation.