Predictive validation of existing bleeding and thromboembolic scores in elderly patients with comorbid atrial fibrillation and acute coronary syndrome

BACKGROUND The validation of various risk scores in elderly patients with comorbid atrial fibrillation(AF)and acute coron-ary syndrome(ACS)has not been reported.The present study compared the predictive performance of existing risk scores in patients.these METHODS A total of 1252 elderly patients with AF and ACS comorbidities(≥65 years old)were consecutively enrolled from January 2015 to December 2019.All patients were followed up for one year.The predictive performance of risk scores in predict-bleeding and thromboembolic events was calculated and compared.ing RESULTS During the 1-year follow-up,183(14.6%)patients had thromboembolic events,198(15.8%)patients had BARC class≥2 bleeding events,and 61(4.9%)patients had BARC class≥3 bleeding events.For the BARC class≥3 bleeding events,discrimina-tion of the existing risk scores was low to moderate,PRECISE-DAPT(C-statistic:0.638,95%CI:0.611-0.665),ATRIA(C-statistic:0.615,95%CI:0.587-0.642),PARIS-MB(C-statistic:0.612,95%CI:0.584-0.639),HAS-BLED(C-statistic:0.597,95%CI:0.569-0.624)and CRUSADE(C-statistic:0.595,95%CI:0.567-0.622).However,the calibration was good.PRECISE-DAPT showed a higher in-tegrated discrimination improvement(IDI)than PARIS-MB,HAS-BLED,ATRIA,and CRUSADE(P<0.05)and the best decision curve analysis(DCA).For thromboembolic events,the discrimination of GRACE(C-statistic:0.636,95%CI:0.608-0.662)was higher than CHA2DS2-VASc(C-statistic:0.612,95%CI:0.584-0.639),OPT-CAD(C-statistic:0.602,95%CI:0.574-0.629)and PARIS-CTE(C-statistic:0.595,95%CI:0.567-0.622).The calibration was good.Compared to OPT-CAD and PARIS-CTE,the IDI of the GRACE score slightly improved(P<0.05).However,NRI analysis showed no significant difference.DCA showed that the clinical practic-of thromboembolic risk scores was similar.ability CONCLUSIONS The discrimination and calibration of existing risk scores in predicting 1-year thromboembolic and bleeding events were unsatisfactory in elderly patients with comorbid AF and ACS.PRECISE-DAPT showed higher IDI and DCA than other risk scores in predicting BARC class≥3 bleeding events.The GRACE score showed a slight advantage in predicting throm-botic events.

TLR4 upregulates CBS expression through NF-κB activation in a rat model of irritable bowel syndrome with chronic visceral hypersensitivity

AIM:To investigate the roles of toll-like receptor 4(TLR4) and nuclear factor(NF)-κB on cystathionine βsynthetase(CBS) expression and visceral hypersensitivity in rats.METHODS:This study used 1-7-wk-old male SpragueDawley rats.Western blot analysis was employed to measure the expression of TLR4,NF-kB and the endogenous hydrogen sulfide-producing enzyme CBS in colon dorsal root ganglia(DRG) from control and "irritable bowel syndrome" rats induced by neonatal colonic inflammation(NCI).Colon-specific DRG neurons were labeled with Dil and acutely dissociated to measure excitability with patch-clamp techniques.Immunofluorescence was employed to determine the co-expression of TLR4,NF-kB and CBS in Dil-labeled DRG neurons.RESULTS:NCI significantly upregulated the expression of TLR4 in colon-related DRGs(0.34 ± 0.12 vs 0.72 ±0.02 for the control and NCI groups,respectively,P <0.05).Intrathecal administration of the TLR4-selective inhibitor CLI-095 significantly enhanced the colorectal distention threshold of NCI rats.CLI-095 treatment also markedly reversed the hyperexcitability of colonspecific DRG neurons and reduced the expression of CBS(1.7 ± 0.1 vs 1.1 ± 0.04,p < 0.05) and of the NF-kB subunit p65(0.8 ± 0.1 vs 0.5 ± 0.1,P< 0.05).Furthermore,the NF-KB-selective inhibitor pyrrolidine dithiocarbamate(PDTC) significantly reduced the upregulation of CBS(1.0 ± 0.1 vs 0.6 ± 0.1,P< 0.05)and attenuated visceral hypersensitivity in the NCI rats.In vitro,incubation of cultured DRG neurons with the TLR4 agonist lipopolysaccharide significantly enhanced the expression of p65(control vs 8 h:0.9 ± 0.1 vs1.3 ± 0.1;control vs 12 h:0.9 ± 0.1 vs 1.3 ± 0.1,P< 0.05;control vs 24 h:0.9 ± 0.1 vs 1.6 ± 0.1,P <0.01) and CBS(control vs 12 h:1.0 ± 0.1 vs 2.2 ±0.4;control vs 24 h:1.0 ± 0.1 vs 2.6 ± 0.1,P< 0.05),whereas the inhibition of p65 via pre-incubation with PDTC significantly reversed the upregulation of CBS expression(1.2 ± 0.1 vs 0.6 ± 0.0,P< 0.01).CONCLUSION:Our results suggest that the activation of TLR4 by NCI upregulates CBS expression,which is mediated by the NF-kB signaling pathway,thus contributing to visceral hypersensitivity.

Differential temporal expression of matrix metalloproteinases following sciatic nerve crush

We previously performed transcriptome sequencing and found that genes for matrix metalloproteinases（MMPs）,such as MMP7 and 12,seem to be highly upregulated following peripheral nerve injury,and may be involved in nerve repair.In the present study,we systematically determined the expression levels of MMPs and their regulators at 1,4,7 and 14 days after sciatic nerve crush injury.The number of differentially expressed genes was elevated at 4 and 7 days after injury,but decreased at 14 days after injury.Among the differentially expressed genes,those most up-regulated showed fold changes of more than 214,while those most down-regulated exhibited fold changes of more than 2-10.Gene sequencing showed that,at all time points after injury,a variety of MMP genes in the “Inhibition of MMPs” pathway were up-regulated,and their inhibitor genes were down-regulated.Expression of key up-and down-regulated genes was verified by quantitative real-time polymerase chain reaction analysis and found to be consistent with transcriptome sequencing.These results suggest that MMP-related genes are strongly involved in the process of peripheral nerve regeneration.

Senktide blocks aberrant RTN3 interactome to retard memory decline and tau pathology in social isolated Alzheimer’s disease mice

Sporadic or late-onset Alzheimer’s disease(LOAD)accounts for more than 95%of Alzheimer’s disease(AD)cases without any family history.Although genome-wide association studies have identified associated risk genes and loci for LOAD,numerous studies suggest that many adverse environmental factors,such as social isolation,are associated with an increased risk of dementia.However,the underlying mechanisms of social isolation in AD progression remain elusive.In the current study,we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD mice.We also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 dentate gyrus(DG)-enriched miRNAs,which simultaneously target reticulon 3(RTN3),an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fibre boutons(MFBs)by recruiting multiple mitochondrial and vesicle-related proteins.Interestingly,the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation,which,in turn,further elevates RTN3 and forms a vicious cycle.Finally,using an artificial intelligence-assisted molecular docking approach,we determined that senktide,a selective agonist of neurokinin3 receptors(NK3R),could reduce the binding of RTN3 with its partners.Moreover,application of senktide in vivo effectively restored DG circuit disorders in socially isolated AD mice.Taken together,our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD.

Overexpression of Purinergic P2X4 Receptors in Hippocampus Rescues Memory Impairment in Rats with Type 2 Diabetes

Purinergic receptors have been reported to be involved in brain disorders.In this study,we explored their roles and mechanisms underlying the memory impairment in rats with type 2 diabetes mellitus(T2 DM).T2 DM rats exhibited a worse performance in the T-maze and Morris water maze(MWM) than controls.Microglia positive for P2 X purinoceptor 4(P2 X4 R) in the hippocampus were reduced and activated microglia were increased in T2 DM rats.Long Amplicon PCR(LA-PCR) showed that DNA amplification of the p2 x4 r gene in the hippocampus was lower in T2 DM rats.Minocycline significantly reduced the number of activated microglia and the mean distance traveled by T2 DM rats in the MWM.Most importantly,P2 X4 R overexpression suppressed the activated microglia and rescued the memory impairment of T2 DM rats.Overall,T2 DM led to excessive activation of microglia in the hippocampus,partly through the DNA damagemediated downregulation of P2 X4 Rs,thus contributing to memory impairment.