Gut microbiota and functional outcome after ischemic stroke: a Mendelian randomization study.

Background: Previous studies have shown that gut microbiota dysbiosis could affect clinical prognosis through an unknown mechanism. However, the causal relationship between the gut microbiota and the functional outcome after ischemic stroke remains unclear. We aimed to investigate the causal association between the gut microbiota and the functional outcome after ischemic stroke using Mendelian randomization (MR). Methods: Genetic instrumental variables associated with 211 bacterial traits were obtained from the MiBioGen consortium (N = 18,340). Data from genome-wide association studies (GWAS) for functional outcome after ischemic stroke were obtained from two phenotypes (i.e., overall stroke outcome and motor recovery). The inverse variance weighted method was used to estimate the causal association. Enrichment analysis was conducted based on the results of the MR analyses. Results: The genetically predicted family Peptostreptococcaceae (OR = 0.63, 95% CI = 0.41-0.98, p = 0.038) and the genera LachnospiraceaeNK4A136 group (OR = 0.65, 95% CI = 0.43-1.00, p = 0.048), LachnospiraceaeUCG004 (OR = 0.54, 95% CI = 0.33-0.90, p = 0.017), and Odoribacter (OR = 0.40, 95% CI = 0.21-0.77, p = 0.006) presented a suggestive association with favorable functional outcome, while the genera Eubacterium oxidoreducens group (OR = 1.77, 95% CI = 1.11-2.84, p = 0.018) and RuminococcaceaeUCG005 (OR = 1.85, 95% CI = 1.15-2.96, p = 0.010) were associated with unfavorable functional outcome. The genetically predicted family Oxalobacteraceae (OR = 2.12, 95% CI = 1.10-4.11, p = 0.025) and the genus RuminococcaceaeUCG014 (OR = 4.17, 95% CI = 1.29-13.52, p = 0.017) showed a suggestive association with motor recovery, while the order Enterobacteriales (OR = 0.14, 95% CI = 0.02-0.87, p = 0.035) and the family Enterobacteriaceae (OR = 0.14, 95% CI = 0.02-0.87, p = 0.035) were associated with motor weakness. Enrichment analysis revealed that regulation of the synapse structure or activity may be involved in the effect of the gut microbiota on the functional outcome after ischemic stroke. Conclusions: This study provides genetic support that the gut microbiota, especially those associated with short-chain fatty acids, could affect stroke prognosis by mediating synapse function. Our findings suggest that modifying the composition of the gut microbiota could improve the prognosis of ischemic stroke.

Effect of acute levodopa challenge test on cerebral blood flow in Parkinson's disease with the supine-to-standing transcranial Doppler test.

BACKGROUND: Levodopa, a common drug that improves symptoms of Parkinson's disease (PD), can induce a reduction in blood pressure (BP); however, the effect of levodopa on cerebral blood flow (CBF) remains unclear. OBJECTIVES: To observe the changes in BP and CBF during active standing before and after the acute levodopa challenge test (ALCT) and analyse the influencing factors of CBF in patients with PD. METHODS: BP and CBF velocity were simultaneously recorded by continuous beat-to-beat non-invasive BP monitoring and transcranial Doppler at supine and orthostatic positions twice, before and after ALCT. The patients were divided into two groups according to those with increased and decreased CBF at baseline after ALCT to analyse the influencing factors. RESULTS: We examined 64 patients with PD (59.2 ± 11.6 years, 33 males). BP decreased at all timepoints after ALCT, while there was no significant change in the magnitude of the drop in BP induced by standing. CBF was reduced after ALCT, especially within 15 s to 1 min of standing (15 s: 48.95 ± 13.50 vs. 44.93 ± 13.26, p < 0.001; 30 s: 52.46 ± 12.06 vs. 50.11 ± 12.56, p = 0.033; 1 min: 52.19 ± 11.83 vs. 50.17 ± 13.21, p = 0.044). Lower body mass index (ß = -0.280, p = 0.027) was an independent factor associated with CBF reduction after ALCT. CONCLUSIONS: Additional attention should be paid to changes in CBF and BP within 1 min after standing in patients with PD taking levodopa, especially in those with low bodyweight.

Numerical chromosomal instability mediates susceptibility to radiation treatment.

The exquisite sensitivity of mitotic cancer cells to ionizing radiation (IR) underlies an important rationale for the widely used fractionated radiation therapy. However, the mechanism for this cell cycle-dependent vulnerability is unknown. Here we show that treatment with IR leads to mitotic chromosome segregation errors in vivo and long-lasting aneuploidy in tumour-derived cell lines. These mitotic errors generate an abundance of micronuclei that predispose chromosomes to subsequent catastrophic pulverization thereby independently amplifying radiation-induced genome damage. Experimentally suppressing whole-chromosome missegregation reduces downstream chromosomal defects and significantly increases the viability of irradiated mitotic cells. Further, orthotopically transplanted human glioblastoma tumours in which chromosome missegregation rates have been reduced are rendered markedly more resistant to IR, exhibiting diminished markers of cell death in response to treatment. This work identifies a novel mitotic pathway for radiation-induced genome damage, which occurs outside of the primary nucleus and augments chromosomal breaks. This relationship between radiation treatment and whole-chromosome missegregation can be exploited to modulate therapeutic response in a clinically relevant manner.