BACKGROUND As per the latest Surviving Sepsis Campaign guidelines,fluid resuscitation should be guided by repeated measurements of blood lactate levels until normalization.Nevertheless,raised lactate levels should be ...BACKGROUND As per the latest Surviving Sepsis Campaign guidelines,fluid resuscitation should be guided by repeated measurements of blood lactate levels until normalization.Nevertheless,raised lactate levels should be interpreted in the clinical context,as there may be other causes of elevated lactate levels.Thus,it may not be the best tool for real-time assessment of the effect of hemodynamic resuscitation,and exploring alternative resuscitation targets should be an essential research priority in sepsis.AIM To compare the 28-d mortality in two clinical patterns of septic shock:hyperlactatemic patients with hypoperfusion context and hyperlactatemic patients without hypoperfusion context.METHODS This prospective comparative observational study carried out on 135 adult patients with septic shock that met Sepsis-3 definitions compared patients with hyperlactatemia in a hypoperfusion context(Group 1,n=95)and patients with hyperlactatemia in a non-hypoperfusion context(Group 2,n=40).Hypoperfusion context was defined by a central venous saturation less than 70%,central venousarterial PCO_(2)gradient[P(cv-a)CO_(2)]≥6 mmHg,and capillary refilling time(CRT)≥4 s.The patients were observed for various macro and micro hemodynamic parameters at regular intervals of 0 h,3 h,and 6 h.All-cause 28-d mortality and all other secondary objective parameters were observed at specified intervals.Nominal categorical data were compared using theχ^(2)or Fisher’s exact test.Nonnormally distributed continuous variables were compared using the Mann-Whitney U test.Receiver operating characteristic curve analysis with the Youden index determined the cutoff values of lactate,CRT,and metabolic perfusion parameters to predict the 28-d all-cause mortality.A P value of<0.05 was considered significant.RESULTS Patient demographics,comorbidities,baseline laboratory,vital parameters,source of infection,baseline lactate levels,and lactate clearance at 3 h and 6 h,Sequential Organ Failure scores,need for invasive mechanical ventilation,days on mechanical ventilation,and renal replacement therapy-free days within 28 d,duration of intensive care unit stay,and hospital stay were comparable between the two groups.The stratification of patients into hypoperfusion and nonhypoperfusion context did not result in a significantly different 28-d mortality(24%vs 15%,respectively;P=0.234).However,the patients within the hypoperfusion context with high P(cva)CO_(2)and CRT(P=0.022)at baseline had significantly higher mortality than Group 2.The norepinephrine dose was higher in Group 1 but did not achieve statistical significance with a P>0.05 at all measured intervals.Group 1 had a higher proportion of patients requiring vasopressin and the mean vasopressor-free days out of the total 28 d were lower in patients with hypoperfusion(18.88±9.04 vs 21.08±8.76;P=0.011).The mean lactate levels and lactate clearance at 3 h and 6 h,CRT,P(cv-a)CO_(2)at 0 h,3 h,and 6 h were found to be associated with 28-d mortality in patients with septic shock,with lactate levels at 6 h having the best predictive value(area under the curve lactate at 6 h:0.845).CONCLUSION Septic shock patients fulfilling the hypoperfusion and non-hypoperfusion context exhibited similar 28-d all-cause hospital mortality,although patients with hypoperfusion displayed a more severe circulatory dysfunction.Lactate levels at 6 h had a better predictive value in predicting 28-d mortality than other parameters.Persistently high P(cv-a)CO_(2)(>6 mmHg)or increased CRT(>4 s)at 3 h and 6 h during early resuscitation can be a valuable additional aid for prognostication of septic shock patients.展开更多
Xiao-Xu-Ming decoction has been widely used to treat stroke and sequelae of stroke. We have previously shown that the active fractions of Xiao-Xu-Ming decoction attenuate cerebral ischemic injury. However, the global ...Xiao-Xu-Ming decoction has been widely used to treat stroke and sequelae of stroke. We have previously shown that the active fractions of Xiao-Xu-Ming decoction attenuate cerebral ischemic injury. However, the global protein profile and signaling conduction pathways regulated by Xiao-Xu-Ming decoction are still unclear. This study established a two-vessel occlusion rat model by bilateral common carotid artery occlusion. Rats were intragastrically administered 50 or 150 mg/kg Xiao-Xu-Ming decoction for 4 consecutive weeks. Learning and memory abilities were measured with Morris water maze. Motor ability was detected with prehensile test. Coordination ability was examined using the inclined screen test. Neuronal plasticity was observed by immunofluorescent staining. Differentially expressed proteins of rat hippocampus were analyzed by label-free quantitative proteomics. Real time-polymerase chain reaction and western blot assay were used to identify the changes in proteins. Results showed that Xiao-Xu-Ming decoction dramatically alleviated learning and memory deficits, and motor and coordination dysfunction, and increased the expression of microtubule-associated protein 2. Xiao-Xu-Ming decoction extract remarkably decreased 13 upregulated proteins and increased 39 downregulated proteins. The regulated proteins were mainly involved in oxidation reduction process, intracellular signaling cascade process, and protein catabolic process. The signaling pathways were mainly involved in ubiquitin mediated proteolysis and the phosphatidylinositol signaling system. Furthermore, there was an interaction among Rab2 a, Ptpn1, Ppm1 e, Cdk18, Gorasp2, Eps15, Capza2, Syngap1 and Mt-nd1. Protein analyses confirmed the changes in expression of MTND1. The current findings provide new insights into the molecular mechanisms of Xiao-Xu-Ming decoction extract's effects on chronic cerebral hypoperfusion.展开更多
Cerebral small vessel disease (CSVD) is a leading cause of stroke and dementia. As the most common type of inherited CSVD, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CA...Cerebral small vessel disease (CSVD) is a leading cause of stroke and dementia. As the most common type of inherited CSVD, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by the NOTCH3 gene mutation which leads to Notch3 ectodomain deposition and extracellular matrix aggregation around the small vessels. It further causes smooth muscle cell degeneration and small vessel arteriopathy in the central nervous system. Compromised cerebral blood flow occurs in the early stage of CADASIL and is associated with white matter hyperintensity, the typical neuroimaging pathology of CADASIL. This suggests that cerebral hypoperfusion may play an important role in the pathogenesis of CADASIL. However, the mechanistic linkage between NOTCH3 mutation and cerebral hypoperfusion remains unknown. Therefore, in this mini-review, it examines the cellular and molecular mechanisms contributing to cerebral hypoperfusion in CADASIL.展开更多
To the Editor:Establishing dual arterial and portal inflow is essential for liver transplantation[1].Inadequate portal inflow compromises graft function and graft survival[2].Portal hypoperfusion is usually a conseque...To the Editor:Establishing dual arterial and portal inflow is essential for liver transplantation[1].Inadequate portal inflow compromises graft function and graft survival[2].Portal hypoperfusion is usually a consequence of spontaneous portosystemic shunt,ligation of which results in improvement of portal inflow[3].We encountered a patient with portal hypoperfusion,where no significant shunting could be identified.Portal inflow was boosted with incorporating arterial supply using right gastroepiploic artery.The early results were promising.A 39-year-old man with decompensated alcoholic cirrhosis underwent deceased-donor liver transplantation in June 2017.展开更多
Objective To evaluate the sensitivity of arterial ketone body ratio as an indicator for multiple organ failure.Materials and methods The experimental model of multiple organ failure was made in adult and old rats by h...Objective To evaluate the sensitivity of arterial ketone body ratio as an indicator for multiple organ failure.Materials and methods The experimental model of multiple organ failure was made in adult and old rats by hypoperfusion-induced hemorrhagic shock. After blood sampling, the arterial acetoacetate, β-hydroxybutyrate, total ketone body, ALT, AST, BUN, creatinine at 2, 4, 8 hr in hypoperfusion were examined to compare the differences of ketone body ratio and organ failure between adult and old rats. Hepatic and mitochondrial metabolism were assessed by comparing ketone body ratios (AcAc/β-OHB) and free NAD+/NADH ratios. Results Ketone body ratio in old rats at 2, 4, 8 hr after the induction of hemorrhagic shock decreased from 0.68 to 0.31, 0.27 and 0.22, respectively. In adult rats, it decreased from 1.12 to 0.17, 0.12 and 0.09, respectively. Changes of ketone body ratio in the adult group were larger than in the elderly group ( P ＜ 0.001). The development of multiple organ failure is associated with the time of hemorrhagic shock development. Conclusions There was a different ketone body ratio between multiple organ failure in the elderly (MOFE) and multiple organ failure (MOF) in general adults. Ketone body ratio is a better indicator than ALT and AST in reflecting hepatic function in the early status of MOF. (J Geriatr Cardiol 2004;1(2) :125-128. )展开更多
Aim To investigate whether tluoxetine, a selective serotonin reuptake inhibitor（ SSRI） , could amelio- rate cognitive impairments induced by chronic cerebral hypopeffusion in rats and to clarify the underlying mecha...Aim To investigate whether tluoxetine, a selective serotonin reuptake inhibitor（ SSRI） , could amelio- rate cognitive impairments induced by chronic cerebral hypopeffusion in rats and to clarify the underlying mecha- nisms of its efficacy. Methods Rats were subjected to permanent bilateral occlusion of the common carotid arteries （two-vessel occlusion, 2VO）. Two weeks later, rats were treated with 30 mg · kg^-1 fluoxetine （intragastric injec- tion, i. g. ） for 6 weeks. Cognitive function was evaluated by Morris water maze （MWM） and novel objects recog- nition （NOR） test. Long-term potentiation （LTP） was used to address the underlying synaptic mechanisms. West- ern blot was used to quantify the protein levels. Results Fluoxetine treatment significantly improved the cognitive 2VO impairments caused by 2VO, accompanied with a reversion of 2VO-induced inhibitory of LTP. Furthermore, caused an up-regulation of hyperpolarization-activated cyclic nueleotide-gated channel 2 （HCN2） surface expres- sions in the hippocampal CA1 area and fluoxetine also effectively recovered the up-regulation of HCN2 surface ex- pressions. Conclusion Fluoxetine can ameliorate cognitive impairments induced by chronic cerebral hypopeffusion and a possible mechanism may via down-regulating HCN2 surface expression in the Hippocampal CA1 area.展开更多
Ohjectire To examine the hypothesis of normal perjusion pressure breakthrough (NPPB). Methods A modified Spetzler carotid -jugular (CJ) fistula model was created to imitate NPPB. In 9 male adult Sprague- Dawley rats, ...Ohjectire To examine the hypothesis of normal perjusion pressure breakthrough (NPPB). Methods A modified Spetzler carotid -jugular (CJ) fistula model was created to imitate NPPB. In 9 male adult Sprague- Dawley rats, the ipsilateral vertebral artery and bilateral external carotid arteries were occluded. The period of hypoperfusion CJ fistula was extended to 14 weeks, as a modofcation of Spetzler model. The histological change were examtned under transmission electron microscope 14 weeks after creation of the listula. Results Ischemic histological changes such as increased pinocytosis, increased lucency of the basal lamina, and frank necrosis of the cerebral capillary were found in rats of CJ fistula group. Conclusion The findings in this study suggest that blood - braln barrier (BBB) was impaired by chronic hypoperfusion. The impaired BBB mny be one of the important causes of the NPPB phenomenon.展开更多
MicroRNAs (miRNAs) are small noncoding single-stranded RNA molecules that act as negative regulators of gene expression and modulate the stability and/or the translational efficiency of target messenger RNAs. Studies ...MicroRNAs (miRNAs) are small noncoding single-stranded RNA molecules that act as negative regulators of gene expression and modulate the stability and/or the translational efficiency of target messenger RNAs. Studies have shown that miRNAs control diverse aspects of brain disease. In this study, the expression of miR-124 was investigated to explore the possible impacts of them on cerebral hypoperfusion. The model of aging rats with cerebral hypoperfusion was established by permanent occlusion of bilateral common carotid arteries (2VO). The expression of miR-124 was determined by real-time PCR. Cell cycle analysis was performed by fluorescence-activated cell sorting (FACS). Results showed that compared with control group, the expression of miR-124 decreased at early stage after operation in 2VO rats, the lowest level appeared on day 7 (p < 0.05). Then the expression of miR-124 increased slightly on day 14. Overexpression of miR-124 in SH-SY5Y cell exposed to oxygen and glucose deprivation (OGD) induced cell cycle arrested in G1 phase. MiR-124 is potentially involved in cerebral hypoperfusion progression which may provide a novel therapeutic strategy for treatment of cerebral hypoperfusion.展开更多
Introduction: Routinely monitored parameters such as blood pressure (BP) and heart rate may not reliably detect per- fusion abnormalities. However, central venous oxygen saturation (ScvO2) and lactate levels can detec...Introduction: Routinely monitored parameters such as blood pressure (BP) and heart rate may not reliably detect per- fusion abnormalities. However, central venous oxygen saturation (ScvO2) and lactate levels can detect occult hypoper- fusion (OH) and identify patients at risk for complications. The study objective was to assess the impact of an OH treatment pathway on morbidity and length of stay (LOS) post coronary bypass and valve surgery. Methods: This is a prospective cohort observational study following the implementation of a treatment pathway for OH, defined by ScvO2 2 mMol/L with systolic BP ≥ 90 mmHg. Initial treatment included volume resuscitation and/or blood transfusion, followed by additional interventions when ScvO2 remained hours postoperatively. Primary outcomes were intensive care unit (ICU)/hospital LOS and complications. Results: Comparing 53 patients managed by the OH pathway against 21 historical controls, median ICU LOS was 40.4 vs. 49.2 hours (p = 0.122), median hospital LOS 9.2 vs. 11.0 days (p = 0.0093), ICU readmission rate 7.5% vs. 28.6% (p = 0.026), and complication rate 26.4% vs. 47.6% (p = 0.101). Repeat lactate was checked 18 hours postoperatively in 47 of the 53 patients. Comparing 33 patients with repeat lactate at goal ( 2 mMoL/L) with 14 patients not at goal, median ICU LOS was 35.3 vs. 68.4 hours (p = 0.061), median hospital LOS 8.9 vs. 11.2 days (p = 0.058), median length of mechanical ventilation (LOMV) 13.3 vs. 28.4 hours (p = 0.0038), and complication rate 15.2% vs. 50.0% (p = 0.025). Conclusions: An OH screening and treatment pathway following cardiovascular surgery was associated with signifi- cantly shorter hospital LOS and lower ICU readmission rate. Among the OH pathway patients, achieving lactate goal 18 hours postoperatively was associated with significantly shorter LOMV and lower complication rate.展开更多
Cognitive impairment caused by chronic cerebral hypoperfusion(CCH)is associated with white matter injury(WMI),possibly through the alteration of autophagy.Here,the autophagy—lysosomal pathway(ALP)dysfunction in white...Cognitive impairment caused by chronic cerebral hypoperfusion(CCH)is associated with white matter injury(WMI),possibly through the alteration of autophagy.Here,the autophagy—lysosomal pathway(ALP)dysfunction in white matter(WM)and its relationship with cognitive impairment were investigated in rats subjected to two vessel occlusion(2VO).The results showed that cognitive impairment occurred by the 28th day after 2VO.Injury and autophagy activation of mature oligodendrocytes and neuronal axons sequentially occurred in WM by the 3rd day.By the 14th day,abnormal accumulation of autophagy substrate,lysosomal dysfunction,and the activation of mechanistic target of rapamycin(MTOR)pathway were observed in WM,paralleled with mature oligodendrocyte death.This indicates autophagy activation was followed by ALP dysfunction caused by autophagy inhibition or lysosomal dysfunction.To target the ALP dysfunction,enhanced autophagy by systemic rapamycin treatment or overexpression of Beclin1(BECN1)in oligodendrocytes reduced mature oligodendrocyte death,and subsequently alleviated the WMI and cognitive impairment after CCH.These results reveal that early autophagy activation was followed by ALP dysfunction in WM after 2VO,which was associated with the aggravation of WMI and cognitive impairment.This study highlights that alleviating ALP dysfunction by enhancing oligodendrocyte autophagy has benefits for cognitive recovery after CCH.展开更多
The glymphatic system plays a pivotal role in maintaining cerebral homeostasis.Chronic cerebral hypoperfusion,arising from small vessel disease or carotid stenosis,results in cerebrometabolic disturbances ultimately m...The glymphatic system plays a pivotal role in maintaining cerebral homeostasis.Chronic cerebral hypoperfusion,arising from small vessel disease or carotid stenosis,results in cerebrometabolic disturbances ultimately manifesting in white matter injury and cognitive dysfunction.However,whether the glymphatic system serves as a potential therapeutic target for white matter injury and cognitive decline during hypoperfusion remains unknown.Here,we established a mouse model of chronic cerebral hypoperfusion via bilateral common carotid artery stenosis.We found that the hypoperfusion model was associated with significant white matter injury and initial cognitive impairment in conjunction with impaired glym・phatic system function.The glymphatic dysfunction was associated with altered cerebral perfusion and loss of aquaporin 4 polarization.Treatment of digoxin rescued changes in glymphatic transport,white matter structure,and cognitive function.Suppression of glymphatic functions by treatment with the AQP4 inhibitor TGN-020 abolished this protective effect of digoxin from hypoperfusion injury.Our research yields new insight into the relationship between hemodynamics,glymphatic transport,white matter injury,and cognitive changes after chronic cerebral hypoperfusion.展开更多
Background:It remains unknow whether retinal tissue perfusion occurs in patients with Alzheimer’s disease.The goal was to determine retinal tissue perfusion in patients with clinical Alzheimer’s disease(CAD).Methods...Background:It remains unknow whether retinal tissue perfusion occurs in patients with Alzheimer’s disease.The goal was to determine retinal tissue perfusion in patients with clinical Alzheimer’s disease(CAD).Methods:Twenty-four CAD patients and 19 cognitively normal(CN)age-matched controls were recruited.A retinal function imager(RFI,Optical Imaging Ltd.,Rehovot,Israel)was used to measure the retinal blood flow supplying the macular area of a diameter of 2.5 mm centered on the fovea.Blood flow volumes of arterioles(entering the macular region)and venules(exiting the macular region)of the supplied area were calculated.Macular blood flow was calculated as the average of arteriolar and venular flow volumes.Custom ultra-high-resolution optical coherence tomography(UHR–OCT)was used to calculate macular tissue volume.Automated segmentation software(Orion,Voxeleron LLC,Pleasanton,CA)was used to segment six intra-retinal layers in the 2.5 mm(diameter)area centered on the fovea.The inner retina(containing vessel network),including retinal nerve fiber layer(RNFL),ganglion cell-inner plexiform layer(GCIPL),inner nuclear layer(INL)and outer plexiform layer(OPL),was segmented and tissue volume was calculated.Perfusion was calculated as the flow divided by the tissue volume.Results:The tissue perfusion in CAD patients was 2.58±0.79 nl/s/mm^(3)(mean±standard deviation)and was significantly lower than in CN subjects(3.62±0.44 nl/s/mm^(3),P<0.01),reflecting a decrease of 29%.The flow volume was 2.82±0.92 nl/s in CAD patients,which was 31%lower than in CN subjects(4.09±0.46 nl/s,P<0.01).GCIPL tissue volume was 0.47±0.04 mm^(3) in CAD patients and 6%lower than CN subjects(0.50±0.05 mm^(3),P<0.05).No other significant alterations were found in the intra-retinal layers between CAD and CN participants.Conclusions:This study is the first to show decreased retinal tissue perfusion that may be indicative of diminished tissue metabolic activity in patients with clinical Alzheimer’s disease.展开更多
Background:Insufficient cerebral perfusion is suggested to play a role in the development of Alzheimer disease(AD).However,there is a lack of direct evidence indicating whether hypoperfusion causes or aggravates AD pa...Background:Insufficient cerebral perfusion is suggested to play a role in the development of Alzheimer disease(AD).However,there is a lack of direct evidence indicating whether hypoperfusion causes or aggravates AD pathology.We investigated the effect of chronic cerebral hypoperfusion on AD-related pathology in humans.Methods:We enrolled a group of cognitively normal patients(median age:64 years)with unilateral chronic cerebral hypoperfusion.Regions of interest with the most pronounced hypoperfusion changes were chosen in the hypoperfused region and were then mirrored in the contralateral hemisphere to create a control region with normal perfusion.11C-Pittsburgh compound-positron emission tomography standard uptake ratios and brain atrophy indices were calculated from the computed tomography images of each patient.Results:The median age of the 10 participants,consisting of 4 males and 6 females,was 64 years(47-76 years).We found that there were no differences in standard uptake ratios of the cortex(volume of interest[VOI]:P=0.721,region of interest[ROI]:P=0.241)and grey/white ratio(VOI:P=0.333,ROI:P=0.445)and brain atrophy indices(Bicaudate,Bifrontal,Evans,Cella,Cella media,and Ventricular index,P>0.05)between the hypoperfused regions and contralateral normally perfused regions in patients with unilateral chronic cerebral hypoperfusion.Conclusion:Our findings suggest that chronic hypoperfusion due to large vessel stenosis may not directly induce cerebralβ-amyloid deposition and neurodegeneration in humans.展开更多
Many studies have demonstrated that leukoaraiosis is associated with impaired cerebrovascular reserve function. However, the definitive hemodynamic changes that occur in leukoaraiosis are not clear, and there are many...Many studies have demonstrated that leukoaraiosis is associated with impaired cerebrovascular reserve function. However, the definitive hemodynamic changes that occur in leukoaraiosis are not clear, and there are many controversies. This study aimed to investigate hemodynamic changes in symptomatic leukoaraiosis using transcranial Doppler ultrasonography and the breath-holding test in a Chinese Han population, from northern China. A total of 203 patients who were diagnosed with ischemic stroke or clinical chronic progressive ischemic symptoms were enrolled in this study, including 97 males and 106 females, with an age range of 43-93 years. The severity of leukoaraiosis was evaluated according to the Fazekas grading scale, and patients were divided into four groups accordingly. Grade 0 was no leukoaraiosis, and grades I, II, and III were mild, moderate, and severe leukoaraiosis, respectively, with 44, 79, 44, and 36 cases in each group. Transcranial Doppler ultrasonography and the breath-holding test were performed. The mean blood flow velocity of the bilateral middle cerebral artery was measured and the breath-holding index was calculated. The breath holding index was correlated with leukoaraiosis severity and cognitive impairment. Patients with a low breath holding index presented poor performance in the Montreal Cognitive Assessment (MoCA) and executive function tests. That is, the lower the breath holding index, the lower the scores for the MoCA and the higher for the trail-making test Parts A and B. These results indicate that the breath-holding index is a useful parameter for the evaluation of cerebrovascular reserve impairment in patients with leukoaraiosis. In addition, the breath-holding index can reflect cognitive dysfunction, providing a new insight into the pathophysiology of leukoaraiosis. This study was approved by the Ethics Committee of the Fifth Peoples Hospital of Shenyang, China (approval No. 20160301) and registered in the Chinese Clinical Trial Registry (registration number: ChiCTR1800014421).展开更多
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL)is an early-onset inherited small vessel disease.Decreased cerebral blood flow(CBF)may contribute to white matter hype...Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL)is an early-onset inherited small vessel disease.Decreased cerebral blood flow(CBF)may contribute to white matter hyperintensity(WMH)severity in CADASIL,but more evidence is needed to support this hypothesis.This study comprised six patients with CADASIL who harbored mutations in the coding sequence of NOTCH3 and twelve age-matched neurologically healthy controls.We collected clinical and imaging data from patients with CADASIL and divided the brain into four regions:WMH,normal-appearing white matter(NAWM),gray matter(GM),and global brain.We analyzed the relationship between CBF of each region and the WMH volume.Compared with the control group,CBF was significantly decreased in all four regions in the CADASIL group.Lower CBF in these regions was correlated with higher WMH volume in CADASIL.CBF in the NAWM,GM and global regions was positively correlated with that in WMH region.However,after correction tests,only CBF in the WMH region but not in NAWM,GM and global regions was associated with WMH volume.Our findings suggest that CBF in the WMH region is an influencing factor of the WMH severity in CADASIL.展开更多
Chronic cerebral hypoperfusion can cause progressive demyelination as well as ischemic vascular dementia,however no effective treatments are available.Here,based on magnetic resonance imaging studies of patients with ...Chronic cerebral hypoperfusion can cause progressive demyelination as well as ischemic vascular dementia,however no effective treatments are available.Here,based on magnetic resonance imaging studies of patients with white matter damage,we found that this damage is associated with disorganized cortical structure.In a mouse model,optogenetic activation of glutamatergic neurons in the somatosensory cortex significantly promoted oligodendrocyte progenitor cell(OPC)proliferation,remyelination in the corpus callosum,and recovery of cognitive ability after cerebral hypoperfusion.The therapeutic effect of such stimulation was restricted to the upper layers of the cortex,but also spanned a wide time window after ischemia.Mechanistically,enhancement of glutamatergic neuron-OPC functional synaptic connections is required to achieve the protection effect of activating cortical glutamatergic neurons.Additionally,skin stroking,an easier method to translate into clinical practice,activated the somatosensory cortex,thereby promoting OPC proliferation,remyelination and cognitive recovery following cerebral hypoperfusion.In summary,we demonstrated that activating glutamatergic neurons in the somatosensory cortex promotes the proliferation of OPCs and remyelination to recover cognitive function after chronic cerebral hypoperfusion.It should be noted that this activation may provide new approaches for treating ischemic vascular dementia via the precise regulation of glutamatergic neuron-OPC circuits.展开更多
文摘BACKGROUND As per the latest Surviving Sepsis Campaign guidelines,fluid resuscitation should be guided by repeated measurements of blood lactate levels until normalization.Nevertheless,raised lactate levels should be interpreted in the clinical context,as there may be other causes of elevated lactate levels.Thus,it may not be the best tool for real-time assessment of the effect of hemodynamic resuscitation,and exploring alternative resuscitation targets should be an essential research priority in sepsis.AIM To compare the 28-d mortality in two clinical patterns of septic shock:hyperlactatemic patients with hypoperfusion context and hyperlactatemic patients without hypoperfusion context.METHODS This prospective comparative observational study carried out on 135 adult patients with septic shock that met Sepsis-3 definitions compared patients with hyperlactatemia in a hypoperfusion context(Group 1,n=95)and patients with hyperlactatemia in a non-hypoperfusion context(Group 2,n=40).Hypoperfusion context was defined by a central venous saturation less than 70%,central venousarterial PCO_(2)gradient[P(cv-a)CO_(2)]≥6 mmHg,and capillary refilling time(CRT)≥4 s.The patients were observed for various macro and micro hemodynamic parameters at regular intervals of 0 h,3 h,and 6 h.All-cause 28-d mortality and all other secondary objective parameters were observed at specified intervals.Nominal categorical data were compared using theχ^(2)or Fisher’s exact test.Nonnormally distributed continuous variables were compared using the Mann-Whitney U test.Receiver operating characteristic curve analysis with the Youden index determined the cutoff values of lactate,CRT,and metabolic perfusion parameters to predict the 28-d all-cause mortality.A P value of<0.05 was considered significant.RESULTS Patient demographics,comorbidities,baseline laboratory,vital parameters,source of infection,baseline lactate levels,and lactate clearance at 3 h and 6 h,Sequential Organ Failure scores,need for invasive mechanical ventilation,days on mechanical ventilation,and renal replacement therapy-free days within 28 d,duration of intensive care unit stay,and hospital stay were comparable between the two groups.The stratification of patients into hypoperfusion and nonhypoperfusion context did not result in a significantly different 28-d mortality(24%vs 15%,respectively;P=0.234).However,the patients within the hypoperfusion context with high P(cva)CO_(2)and CRT(P=0.022)at baseline had significantly higher mortality than Group 2.The norepinephrine dose was higher in Group 1 but did not achieve statistical significance with a P>0.05 at all measured intervals.Group 1 had a higher proportion of patients requiring vasopressin and the mean vasopressor-free days out of the total 28 d were lower in patients with hypoperfusion(18.88±9.04 vs 21.08±8.76;P=0.011).The mean lactate levels and lactate clearance at 3 h and 6 h,CRT,P(cv-a)CO_(2)at 0 h,3 h,and 6 h were found to be associated with 28-d mortality in patients with septic shock,with lactate levels at 6 h having the best predictive value(area under the curve lactate at 6 h:0.845).CONCLUSION Septic shock patients fulfilling the hypoperfusion and non-hypoperfusion context exhibited similar 28-d all-cause hospital mortality,although patients with hypoperfusion displayed a more severe circulatory dysfunction.Lactate levels at 6 h had a better predictive value in predicting 28-d mortality than other parameters.Persistently high P(cv-a)CO_(2)(>6 mmHg)or increased CRT(>4 s)at 3 h and 6 h during early resuscitation can be a valuable additional aid for prognostication of septic shock patients.
基金supported in part by the National Natural Science Foundation of China,No.81473383(to YHW)the Significant New-Drugs Creation of Science and Technology Major Projects in China,No.2018ZX09711001-003-019(to YHW)the Innovation Fund for Graduate of Beijing Union Medical College of China,No.2017-1007-02(to XC)
文摘Xiao-Xu-Ming decoction has been widely used to treat stroke and sequelae of stroke. We have previously shown that the active fractions of Xiao-Xu-Ming decoction attenuate cerebral ischemic injury. However, the global protein profile and signaling conduction pathways regulated by Xiao-Xu-Ming decoction are still unclear. This study established a two-vessel occlusion rat model by bilateral common carotid artery occlusion. Rats were intragastrically administered 50 or 150 mg/kg Xiao-Xu-Ming decoction for 4 consecutive weeks. Learning and memory abilities were measured with Morris water maze. Motor ability was detected with prehensile test. Coordination ability was examined using the inclined screen test. Neuronal plasticity was observed by immunofluorescent staining. Differentially expressed proteins of rat hippocampus were analyzed by label-free quantitative proteomics. Real time-polymerase chain reaction and western blot assay were used to identify the changes in proteins. Results showed that Xiao-Xu-Ming decoction dramatically alleviated learning and memory deficits, and motor and coordination dysfunction, and increased the expression of microtubule-associated protein 2. Xiao-Xu-Ming decoction extract remarkably decreased 13 upregulated proteins and increased 39 downregulated proteins. The regulated proteins were mainly involved in oxidation reduction process, intracellular signaling cascade process, and protein catabolic process. The signaling pathways were mainly involved in ubiquitin mediated proteolysis and the phosphatidylinositol signaling system. Furthermore, there was an interaction among Rab2 a, Ptpn1, Ppm1 e, Cdk18, Gorasp2, Eps15, Capza2, Syngap1 and Mt-nd1. Protein analyses confirmed the changes in expression of MTND1. The current findings provide new insights into the molecular mechanisms of Xiao-Xu-Ming decoction extract's effects on chronic cerebral hypoperfusion.
基金This work was supported by National Natural Science Foundation of China(Grants No.81873727 and 82171196).
文摘Cerebral small vessel disease (CSVD) is a leading cause of stroke and dementia. As the most common type of inherited CSVD, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by the NOTCH3 gene mutation which leads to Notch3 ectodomain deposition and extracellular matrix aggregation around the small vessels. It further causes smooth muscle cell degeneration and small vessel arteriopathy in the central nervous system. Compromised cerebral blood flow occurs in the early stage of CADASIL and is associated with white matter hyperintensity, the typical neuroimaging pathology of CADASIL. This suggests that cerebral hypoperfusion may play an important role in the pathogenesis of CADASIL. However, the mechanistic linkage between NOTCH3 mutation and cerebral hypoperfusion remains unknown. Therefore, in this mini-review, it examines the cellular and molecular mechanisms contributing to cerebral hypoperfusion in CADASIL.
文摘To the Editor:Establishing dual arterial and portal inflow is essential for liver transplantation[1].Inadequate portal inflow compromises graft function and graft survival[2].Portal hypoperfusion is usually a consequence of spontaneous portosystemic shunt,ligation of which results in improvement of portal inflow[3].We encountered a patient with portal hypoperfusion,where no significant shunting could be identified.Portal inflow was boosted with incorporating arterial supply using right gastroepiploic artery.The early results were promising.A 39-year-old man with decompensated alcoholic cirrhosis underwent deceased-donor liver transplantation in June 2017.
文摘Objective To evaluate the sensitivity of arterial ketone body ratio as an indicator for multiple organ failure.Materials and methods The experimental model of multiple organ failure was made in adult and old rats by hypoperfusion-induced hemorrhagic shock. After blood sampling, the arterial acetoacetate, β-hydroxybutyrate, total ketone body, ALT, AST, BUN, creatinine at 2, 4, 8 hr in hypoperfusion were examined to compare the differences of ketone body ratio and organ failure between adult and old rats. Hepatic and mitochondrial metabolism were assessed by comparing ketone body ratios (AcAc/β-OHB) and free NAD+/NADH ratios. Results Ketone body ratio in old rats at 2, 4, 8 hr after the induction of hemorrhagic shock decreased from 0.68 to 0.31, 0.27 and 0.22, respectively. In adult rats, it decreased from 1.12 to 0.17, 0.12 and 0.09, respectively. Changes of ketone body ratio in the adult group were larger than in the elderly group ( P ＜ 0.001). The development of multiple organ failure is associated with the time of hemorrhagic shock development. Conclusions There was a different ketone body ratio between multiple organ failure in the elderly (MOFE) and multiple organ failure (MOF) in general adults. Ketone body ratio is a better indicator than ALT and AST in reflecting hepatic function in the early status of MOF. (J Geriatr Cardiol 2004;1(2) :125-128. )
文摘Aim To investigate whether tluoxetine, a selective serotonin reuptake inhibitor（ SSRI） , could amelio- rate cognitive impairments induced by chronic cerebral hypopeffusion in rats and to clarify the underlying mecha- nisms of its efficacy. Methods Rats were subjected to permanent bilateral occlusion of the common carotid arteries （two-vessel occlusion, 2VO）. Two weeks later, rats were treated with 30 mg · kg^-1 fluoxetine （intragastric injec- tion, i. g. ） for 6 weeks. Cognitive function was evaluated by Morris water maze （MWM） and novel objects recog- nition （NOR） test. Long-term potentiation （LTP） was used to address the underlying synaptic mechanisms. West- ern blot was used to quantify the protein levels. Results Fluoxetine treatment significantly improved the cognitive 2VO impairments caused by 2VO, accompanied with a reversion of 2VO-induced inhibitory of LTP. Furthermore, caused an up-regulation of hyperpolarization-activated cyclic nueleotide-gated channel 2 （HCN2） surface expres- sions in the hippocampal CA1 area and fluoxetine also effectively recovered the up-regulation of HCN2 surface ex- pressions. Conclusion Fluoxetine can ameliorate cognitive impairments induced by chronic cerebral hypopeffusion and a possible mechanism may via down-regulating HCN2 surface expression in the Hippocampal CA1 area.
文摘Ohjectire To examine the hypothesis of normal perjusion pressure breakthrough (NPPB). Methods A modified Spetzler carotid -jugular (CJ) fistula model was created to imitate NPPB. In 9 male adult Sprague- Dawley rats, the ipsilateral vertebral artery and bilateral external carotid arteries were occluded. The period of hypoperfusion CJ fistula was extended to 14 weeks, as a modofcation of Spetzler model. The histological change were examtned under transmission electron microscope 14 weeks after creation of the listula. Results Ischemic histological changes such as increased pinocytosis, increased lucency of the basal lamina, and frank necrosis of the cerebral capillary were found in rats of CJ fistula group. Conclusion The findings in this study suggest that blood - braln barrier (BBB) was impaired by chronic hypoperfusion. The impaired BBB mny be one of the important causes of the NPPB phenomenon.
文摘MicroRNAs (miRNAs) are small noncoding single-stranded RNA molecules that act as negative regulators of gene expression and modulate the stability and/or the translational efficiency of target messenger RNAs. Studies have shown that miRNAs control diverse aspects of brain disease. In this study, the expression of miR-124 was investigated to explore the possible impacts of them on cerebral hypoperfusion. The model of aging rats with cerebral hypoperfusion was established by permanent occlusion of bilateral common carotid arteries (2VO). The expression of miR-124 was determined by real-time PCR. Cell cycle analysis was performed by fluorescence-activated cell sorting (FACS). Results showed that compared with control group, the expression of miR-124 decreased at early stage after operation in 2VO rats, the lowest level appeared on day 7 (p < 0.05). Then the expression of miR-124 increased slightly on day 14. Overexpression of miR-124 in SH-SY5Y cell exposed to oxygen and glucose deprivation (OGD) induced cell cycle arrested in G1 phase. MiR-124 is potentially involved in cerebral hypoperfusion progression which may provide a novel therapeutic strategy for treatment of cerebral hypoperfusion.
文摘Introduction: Routinely monitored parameters such as blood pressure (BP) and heart rate may not reliably detect per- fusion abnormalities. However, central venous oxygen saturation (ScvO2) and lactate levels can detect occult hypoper- fusion (OH) and identify patients at risk for complications. The study objective was to assess the impact of an OH treatment pathway on morbidity and length of stay (LOS) post coronary bypass and valve surgery. Methods: This is a prospective cohort observational study following the implementation of a treatment pathway for OH, defined by ScvO2 2 mMol/L with systolic BP ≥ 90 mmHg. Initial treatment included volume resuscitation and/or blood transfusion, followed by additional interventions when ScvO2 remained hours postoperatively. Primary outcomes were intensive care unit (ICU)/hospital LOS and complications. Results: Comparing 53 patients managed by the OH pathway against 21 historical controls, median ICU LOS was 40.4 vs. 49.2 hours (p = 0.122), median hospital LOS 9.2 vs. 11.0 days (p = 0.0093), ICU readmission rate 7.5% vs. 28.6% (p = 0.026), and complication rate 26.4% vs. 47.6% (p = 0.101). Repeat lactate was checked 18 hours postoperatively in 47 of the 53 patients. Comparing 33 patients with repeat lactate at goal ( 2 mMoL/L) with 14 patients not at goal, median ICU LOS was 35.3 vs. 68.4 hours (p = 0.061), median hospital LOS 8.9 vs. 11.2 days (p = 0.058), median length of mechanical ventilation (LOMV) 13.3 vs. 28.4 hours (p = 0.0038), and complication rate 15.2% vs. 50.0% (p = 0.025). Conclusions: An OH screening and treatment pathway following cardiovascular surgery was associated with signifi- cantly shorter hospital LOS and lower ICU readmission rate. Among the OH pathway patients, achieving lactate goal 18 hours postoperatively was associated with significantly shorter LOMV and lower complication rate.
基金the Natural Science Foundation of Liaoning Province(LJKQZ2021031,2022-MS-246,China)to Yueyang Liu。
文摘Cognitive impairment caused by chronic cerebral hypoperfusion(CCH)is associated with white matter injury(WMI),possibly through the alteration of autophagy.Here,the autophagy—lysosomal pathway(ALP)dysfunction in white matter(WM)and its relationship with cognitive impairment were investigated in rats subjected to two vessel occlusion(2VO).The results showed that cognitive impairment occurred by the 28th day after 2VO.Injury and autophagy activation of mature oligodendrocytes and neuronal axons sequentially occurred in WM by the 3rd day.By the 14th day,abnormal accumulation of autophagy substrate,lysosomal dysfunction,and the activation of mechanistic target of rapamycin(MTOR)pathway were observed in WM,paralleled with mature oligodendrocyte death.This indicates autophagy activation was followed by ALP dysfunction caused by autophagy inhibition or lysosomal dysfunction.To target the ALP dysfunction,enhanced autophagy by systemic rapamycin treatment or overexpression of Beclin1(BECN1)in oligodendrocytes reduced mature oligodendrocyte death,and subsequently alleviated the WMI and cognitive impairment after CCH.These results reveal that early autophagy activation was followed by ALP dysfunction in WM after 2VO,which was associated with the aggravation of WMI and cognitive impairment.This study highlights that alleviating ALP dysfunction by enhancing oligodendrocyte autophagy has benefits for cognitive recovery after CCH.
基金supported by Grants from the National Natural Science Foundation of China(81873749 and 81801072)。
文摘The glymphatic system plays a pivotal role in maintaining cerebral homeostasis.Chronic cerebral hypoperfusion,arising from small vessel disease or carotid stenosis,results in cerebrometabolic disturbances ultimately manifesting in white matter injury and cognitive dysfunction.However,whether the glymphatic system serves as a potential therapeutic target for white matter injury and cognitive decline during hypoperfusion remains unknown.Here,we established a mouse model of chronic cerebral hypoperfusion via bilateral common carotid artery stenosis.We found that the hypoperfusion model was associated with significant white matter injury and initial cognitive impairment in conjunction with impaired glym・phatic system function.The glymphatic dysfunction was associated with altered cerebral perfusion and loss of aquaporin 4 polarization.Treatment of digoxin rescued changes in glymphatic transport,white matter structure,and cognitive function.Suppression of glymphatic functions by treatment with the AQP4 inhibitor TGN-020 abolished this protective effect of digoxin from hypoperfusion injury.Our research yields new insight into the relationship between hemodynamics,glymphatic transport,white matter injury,and cognitive changes after chronic cerebral hypoperfusion.
基金supported by the McKnight Brain Institute,NIH Center Grant P30 EY014801,UM Dean's NIH Bridge Award(UM DBA 2019-3)a grant from Research to Prevent Blindness(RPB)and the North American Neuroophthalmology Society.
文摘Background:It remains unknow whether retinal tissue perfusion occurs in patients with Alzheimer’s disease.The goal was to determine retinal tissue perfusion in patients with clinical Alzheimer’s disease(CAD).Methods:Twenty-four CAD patients and 19 cognitively normal(CN)age-matched controls were recruited.A retinal function imager(RFI,Optical Imaging Ltd.,Rehovot,Israel)was used to measure the retinal blood flow supplying the macular area of a diameter of 2.5 mm centered on the fovea.Blood flow volumes of arterioles(entering the macular region)and venules(exiting the macular region)of the supplied area were calculated.Macular blood flow was calculated as the average of arteriolar and venular flow volumes.Custom ultra-high-resolution optical coherence tomography(UHR–OCT)was used to calculate macular tissue volume.Automated segmentation software(Orion,Voxeleron LLC,Pleasanton,CA)was used to segment six intra-retinal layers in the 2.5 mm(diameter)area centered on the fovea.The inner retina(containing vessel network),including retinal nerve fiber layer(RNFL),ganglion cell-inner plexiform layer(GCIPL),inner nuclear layer(INL)and outer plexiform layer(OPL),was segmented and tissue volume was calculated.Perfusion was calculated as the flow divided by the tissue volume.Results:The tissue perfusion in CAD patients was 2.58±0.79 nl/s/mm^(3)(mean±standard deviation)and was significantly lower than in CN subjects(3.62±0.44 nl/s/mm^(3),P<0.01),reflecting a decrease of 29%.The flow volume was 2.82±0.92 nl/s in CAD patients,which was 31%lower than in CN subjects(4.09±0.46 nl/s,P<0.01).GCIPL tissue volume was 0.47±0.04 mm^(3) in CAD patients and 6%lower than CN subjects(0.50±0.05 mm^(3),P<0.05).No other significant alterations were found in the intra-retinal layers between CAD and CN participants.Conclusions:This study is the first to show decreased retinal tissue perfusion that may be indicative of diminished tissue metabolic activity in patients with clinical Alzheimer’s disease.
文摘Background:Insufficient cerebral perfusion is suggested to play a role in the development of Alzheimer disease(AD).However,there is a lack of direct evidence indicating whether hypoperfusion causes or aggravates AD pathology.We investigated the effect of chronic cerebral hypoperfusion on AD-related pathology in humans.Methods:We enrolled a group of cognitively normal patients(median age:64 years)with unilateral chronic cerebral hypoperfusion.Regions of interest with the most pronounced hypoperfusion changes were chosen in the hypoperfused region and were then mirrored in the contralateral hemisphere to create a control region with normal perfusion.11C-Pittsburgh compound-positron emission tomography standard uptake ratios and brain atrophy indices were calculated from the computed tomography images of each patient.Results:The median age of the 10 participants,consisting of 4 males and 6 females,was 64 years(47-76 years).We found that there were no differences in standard uptake ratios of the cortex(volume of interest[VOI]:P=0.721,region of interest[ROI]:P=0.241)and grey/white ratio(VOI:P=0.333,ROI:P=0.445)and brain atrophy indices(Bicaudate,Bifrontal,Evans,Cella,Cella media,and Ventricular index,P>0.05)between the hypoperfused regions and contralateral normally perfused regions in patients with unilateral chronic cerebral hypoperfusion.Conclusion:Our findings suggest that chronic hypoperfusion due to large vessel stenosis may not directly induce cerebralβ-amyloid deposition and neurodegeneration in humans.
文摘Many studies have demonstrated that leukoaraiosis is associated with impaired cerebrovascular reserve function. However, the definitive hemodynamic changes that occur in leukoaraiosis are not clear, and there are many controversies. This study aimed to investigate hemodynamic changes in symptomatic leukoaraiosis using transcranial Doppler ultrasonography and the breath-holding test in a Chinese Han population, from northern China. A total of 203 patients who were diagnosed with ischemic stroke or clinical chronic progressive ischemic symptoms were enrolled in this study, including 97 males and 106 females, with an age range of 43-93 years. The severity of leukoaraiosis was evaluated according to the Fazekas grading scale, and patients were divided into four groups accordingly. Grade 0 was no leukoaraiosis, and grades I, II, and III were mild, moderate, and severe leukoaraiosis, respectively, with 44, 79, 44, and 36 cases in each group. Transcranial Doppler ultrasonography and the breath-holding test were performed. The mean blood flow velocity of the bilateral middle cerebral artery was measured and the breath-holding index was calculated. The breath holding index was correlated with leukoaraiosis severity and cognitive impairment. Patients with a low breath holding index presented poor performance in the Montreal Cognitive Assessment (MoCA) and executive function tests. That is, the lower the breath holding index, the lower the scores for the MoCA and the higher for the trail-making test Parts A and B. These results indicate that the breath-holding index is a useful parameter for the evaluation of cerebrovascular reserve impairment in patients with leukoaraiosis. In addition, the breath-holding index can reflect cognitive dysfunction, providing a new insight into the pathophysiology of leukoaraiosis. This study was approved by the Ethics Committee of the Fifth Peoples Hospital of Shenyang, China (approval No. 20160301) and registered in the Chinese Clinical Trial Registry (registration number: ChiCTR1800014421).
基金This work was supported by National Natural Science Foundation of China(Grants No.81873727 and 82171196).
文摘Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL)is an early-onset inherited small vessel disease.Decreased cerebral blood flow(CBF)may contribute to white matter hyperintensity(WMH)severity in CADASIL,but more evidence is needed to support this hypothesis.This study comprised six patients with CADASIL who harbored mutations in the coding sequence of NOTCH3 and twelve age-matched neurologically healthy controls.We collected clinical and imaging data from patients with CADASIL and divided the brain into four regions:WMH,normal-appearing white matter(NAWM),gray matter(GM),and global brain.We analyzed the relationship between CBF of each region and the WMH volume.Compared with the control group,CBF was significantly decreased in all four regions in the CADASIL group.Lower CBF in these regions was correlated with higher WMH volume in CADASIL.CBF in the NAWM,GM and global regions was positively correlated with that in WMH region.However,after correction tests,only CBF in the WMH region but not in NAWM,GM and global regions was associated with WMH volume.Our findings suggest that CBF in the WMH region is an influencing factor of the WMH severity in CADASIL.
基金We would like to thank the Core Facilities,Zhejiang University School of Medicine for technical support.This work was supported by the National Natural Science Foundation of China(81973302,81903580)the National Key R&D Program of China(2020YFA0803900)the Zhejiang Provincial Natural Science Foundation of China(LR17H310001,LYY22H310003).
文摘Chronic cerebral hypoperfusion can cause progressive demyelination as well as ischemic vascular dementia,however no effective treatments are available.Here,based on magnetic resonance imaging studies of patients with white matter damage,we found that this damage is associated with disorganized cortical structure.In a mouse model,optogenetic activation of glutamatergic neurons in the somatosensory cortex significantly promoted oligodendrocyte progenitor cell(OPC)proliferation,remyelination in the corpus callosum,and recovery of cognitive ability after cerebral hypoperfusion.The therapeutic effect of such stimulation was restricted to the upper layers of the cortex,but also spanned a wide time window after ischemia.Mechanistically,enhancement of glutamatergic neuron-OPC functional synaptic connections is required to achieve the protection effect of activating cortical glutamatergic neurons.Additionally,skin stroking,an easier method to translate into clinical practice,activated the somatosensory cortex,thereby promoting OPC proliferation,remyelination and cognitive recovery following cerebral hypoperfusion.In summary,we demonstrated that activating glutamatergic neurons in the somatosensory cortex promotes the proliferation of OPCs and remyelination to recover cognitive function after chronic cerebral hypoperfusion.It should be noted that this activation may provide new approaches for treating ischemic vascular dementia via the precise regulation of glutamatergic neuron-OPC circuits.
