Cognitive Training for Reduction of Delirium in Patients Undergoing Cardiac Surgery: A Randomized Clinical Trial.

IMPORTANCE: Postoperative delirium is a common and impactful neuropsychiatric complication in patients undergoing coronary artery bypass grafting surgery. Cognitive training may enhance cognitive reserve, thereby reducing postoperative delirium. OBJECTIVE: To determine whether preoperative cognitive training reduces the incidence of delirium in patients undergoing coronary artery bypass grafting. DESIGN, SETTING, and PARTICIPANTS: This prospective, single-blind, randomized clinical trial was conducted at 3 university teaching hospitals in southeastern China with enrollment between April 2022 and May 2023. Eligible participants included those scheduled for elective coronary artery bypass grafting who consented and enrolled at least 10 days before surgery. INTERVENTIONS: Participating patients were randomly assigned 1:1, stratified by site, to either routine care or cognitive training, which included substantial practice with online tasks designed to enhance cognitive functions including memory, imagination, reasoning, reaction time, attention, and processing speed. MAIN OUTCOMES AND MEASURES: The primary outcome was occurrence of delirium during postoperative days 1 to 7 or until hospital discharge, diagnosed using the Confusion Assessment Method or the Confusion Assessment Method for Intensive Care Units. Secondary outcomes were postoperative cognitive dysfunction, delirium characteristics, and all-cause mortality within 30 days following the operation. RESULTS: A total of 218 patients were randomized and 208 (median [IQR] age, 66 [58-70] years; 64 female [30.8%] and 144 male [69.2%]) were included in final analysis, with 102 randomized to cognitive training and 106 randomized to routine care. Of all participants, 95 (45.7%) had only a primary school education and 54 (26.0%) had finished high school. In the cognitive training group, 28 participants (27.5%) developed delirium compared with 46 participants (43.4%) randomized to routine care. Those receiving cognitive training were 57% less likely to develop delirium compared with those receiving routine care (adjusted odds ratio [aOR] 0.43; 95% CI, 0.23-0.77; P = .007). Significant differences were observed in the incidence of severe delirium (aOR, 0.46; 95% CI, 0.25-0.82; P = .01), median (IQR) duration of delirium (0 [0-1] days for cognitive training vs 0 [0-2] days for routine care; P = .008), and median (IQR) number of delirium-positive days (0 [0-1] days for cognitive training vs 0 [0-2] days for routine care; P = .007). No other secondary outcomes differed significantly. CONCLUSIONS AND RELEVANCE: In this randomized trial of 208 patients undergoing coronary artery bypass grafting, preoperative cognitive training reduced the incidence of postoperative delirium. However, our primary analysis was based on fewer than 75 events and should therefore be considered exploratory and a basis for future larger trials. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2200058243.

Promising candidates from drug clinical trials: Implications for clinical treatment of Alzheimer's disease in China.

Alzheimer's disease is the most common neurodegenerative disease. Prior to 2017, National Medical Products Administration approved only four drugs to treat Alzheimer's disease, including three cholinesterase inhibitors and one N-methyl-D-aspartate receptor antagonist. We queried ClinicalTrials.gov to better understand Alzheimer's drug development over the past 5 years and found 16 promising candidates that have entered late-stage trials and analyzed their impact on clinical treatment of Alzheimer's disease in China. The 16 compounds selected include disease-modifying therapies and symptomatic therapies. The research and development pipeline now focuses on disease-modifying therapies such as gantenerumab, aducanumab, ALZ-801, ALZT-OP1, donanemab, lecanemab, simufilam, NE3107, semaglutide, and GV-971, which could put an end to the situation where Alzheimer's patients in China have no effective treatment alternatives. The reuse of drugs or combinations currently under investigation for the psychiatric treatment of Alzheimer's disease, including AXS-05, AVP-786, nabilone, brexpiprazole, methylphenidate, and pimavanserin, could provide physicians with additional treatment options. Although most of these drugs have not been explored in China yet, due to the current development trend in this field in China, it is expected that China will be involved in research on these drugs in the future.

Early tirofiban administration for patients with acute ischemic stroke treated with intravenous thrombolysis or bridging therapy: Systematic review and meta-analysis.

OBJECTIVE: In the present systematic review and meta-analysis, we sought to compare the efficacy and safety of tirofiban administered in patients with acute ischemic stroke (AIS) after intravenous thrombolysis (IVT) with or without mechanical thrombectomy (MT). METHODS: We searched PubMed, Web of Science, Embase and the Cochrane Library for randomized clinical trials and observational studies published between 2001 and 2021 that provided outcomes of AIS patients who underwent IVT alone or IVT bridging with or without tirofiban. The primary outcome was the proportion of patients achieving a modified Rankin Scale (mRS) score of 0-2 at 90 days. The secondary outcomes included the rates of (1) an excellent outcome defined as a mRS score of 0 or 1 at 90 days, (2) any type of intracranial hemorrhage (ICH), (3) symptomatic intracranial hemorrhage (sICH), (4) mortality, and (5) successful recanalization. RESULTS: We included 722 patients with IVT bridging therapy in 3 trials; there were 171 patients in the tirofiban group and 551 patients in the nontirofiban group. We included 846 patients with IVT alone in 7 studies; there were 471 patients in the tirofiban group and 375 patients in the nontirofiban group. The patients treated with tirofiban had a reduced risk of mortality compared to the patients treated without tirofiban during IVT bridging (OR, 0.46; 95 % CI, 0.24-0.89; p = 0.02), but no significant differences were found in safety outcomes on sICH, ICH, recanalization or efficacy outcomes on modified Rankin scale 0-2 (p > 0.05). Pooled results showed that tirofiban combined with IVT alone did not increase the risks of sICH, ICH or mortality but was significantly associated with excellent (OR, 2.68; 95 % CI, 1.58-4.55; P = 0.0003) and favorable (OR, 2.36; 95 % CI, 1.58-3.52; p < 0.0001) functional outcomes at 90 days. CONCLUSION: In AIS patients who underwent IVT or bridging therapy, early administration of tirofiban may be effective and safe, but further studies are needed to confirm the efficacy.

Effect of Propofol or Etomidate as General Anaesthesia Induction on Gastric Cancer: A Retrospective Cohort Study with 10 Years' Follow-Up.

Objective: The aim is to study the effect of intraoperative application of propofol and etomidate on the long-term prognosis of patients with gastric cancer at the same tumor stage. Methods: A total of 1018 patients who underwent radical gastric cancer surgery at the First Affiliated Hospital of Anhui Medical University from January 2010 to December 2010 were selected and divided into the propofol and etomidate groups according to the different anesthetic induction drugs. Results: Among 244 patients in TNM stage IIIA, survival times were 36.10 and 41.79 for etomidate and propofol, respectively, which were statistically different (p < 0.05). Among the 82 patients in TNM stage IIIC, survival times were 26.57 and 35.20 for etomidate and propofol, respectively, which were statistically different (p < 0.05). Conclusion: In patients undergoing radical gastric cancer surgery, the application of propofol during induction of anaesthesia is more beneficial in improving the postoperative survival time compared to the application of etomidate at a specific TNM stage.

High-dose ulinastatin reduces postoperative bleeding and provides platelet-protective effects in patients undergoing heart valve replacement surgery.

BACKGROUND: The aim of this prospective study was to investigate the effect of a high dose of ulinastatin on platelets and coagulation in patients undergoing mitral valve and/or aortic valve replacement with cardiopulmonary bypass (CPB). MATERIALS AND METHODS: 273 patients were enrolled in this open-label study. According to patients' willingness, 243 patients were assigned to the ulinastatin group and 30 to the control group. In the ulinastatin group, ulinastatin (300,000 U) was given after the induction of anesthesia, ulinastatin (400,000 U) was added to the CPB pump prime, and then ulinastatin (300,000 U) was administered after weaning from CPB. Complete blood count and coagulation function test were conducted 1 day before surgery and on the first postoperative day. Bleeding and other safety events were recorded during hospitalization. RESULTS: Less postoperative major bleeding occurred in the ulinastatin group (0.4 vs. 6.7%, p = 0.03). Moreover, 1 day after CPB, platelet count in the ulinastatin group increased significantly compared to that in the control group (157.7 ± 71.0 vs. 132.1 ± 59.6, p = 0.03). Interestingly and contrary to what was expected, activated partial thromboplastin time (APTT) and prothrombin time (PT) did not differ significantly between the two groups. Ulinastatin application did not cause significant increase in total costs (p = 0.89). CONCLUSION: In heart valve replacement surgery with CPB, high-dose ulinastatin could reduce postoperative bleeding and promote platelet recovery with no significant additional medical cost.

Cancer Related Subarachnoid Hemorrhage: A Multicenter Retrospective Study Using Propensity Score Matching Analysis.

OBJECTIVE: To investigate the clinical features, risk factors and underlying pathogenesis of cancer related subarachnoid hemorrhage (SAH). METHODS: Clinical data of SAH in patients with active cancer from January 2010 to December 2020 at four centers were retrospectively reviewed. Patients with active cancer without SAH were matched to SAH patients with active cancer group. Logistic regression was applied to investigate the independent risk factors of SAH in patients with active cancer, after a 1:1 propensity score matching (PSM). A receiver operator characteristic curve was configured to calculate the optimal cut-off value of the joint predictive factor for cancer related SAH. RESULTS: A total of 82 SAH patients with active cancer and 309 patients with active cancer alone were included. Most SAH patients with cancer had poor outcomes, with 30-day mortality of 41.5%, and with 90-day mortality of 52.0%. The PSM yielded 75 pairs of study participants. Logistic regression revealed that a decrease in platelet and prolonged prothrombin time were the independent risk factors of cancer related SAH. In addition, receiver operator characteristic curve of the joint predictive factor showed the largest AUC of 0.8131, with cut-off value equaling to 11.719, with a sensitivity of 65.3% and specificity of 89.3%. CONCLUSION: Patients with cancer related SAH often have poor outcomes. The decrease in platelet and prolonged prothrombin time are the independent risk factors of cancer related SAH, and the joint predictive factor with cutoff value equal to 11.719 should hence serve as a novel biomarker of cancer related SAH.

The Impact of a Simplified Scoring System on Long-Term Survival Outcomes in Patients with Gastric Cancer Undergoing Gastrectomy.

Gastric cancer (GC) is a worldwide public health concern. We aimed to investigate the association between preoperative prognostic scoring system based on the combination of age, American Society of Anesthesiologists physical status (ASA-PS), and prognostic nutritional index (PNI) and long-term survival outcomes in patients with (GC). Data from 513 patients were analyzed using Cox proportional hazards regression models to evaluate the association between this prognostic score system and risks of all-cause mortality. This simple prognostic score system (0-3 points) was an independent predictor of long-term survival outcomes in patients with GC after radical gastrectomy based on multivariate analyses. Prognostic 1-point score, 2-point score, and 3-point score significantly increased 50% (95% CI, 14%-98%; P = 0.004), 75% (95% CI, 22%-151%; P = 0.003), and 116% (95% CI, 26%-271%; P = 0.005) hazards of 5-year all-cause mortality, respectively, compared to prognostic 0-point score. Five-year overall survival rates were significantly decreased as prognostic scores increased, (0 point, 57.3%; 1-point, 41.3%; 2-ponint, 36.6%; 3-point, 25.9%; P < 0.01; area under the curve [AUC] = 0.62). A prognostic scoring method based on combination of age, ASA-PS, and PNI may serve as an independent risk stratification metric for long-term survival in patients with GC.

Gasdermin D in peripheral nerves: the pyroptotic microenvironment inhibits nerve regeneration.

Wallerian degeneration (WD) involves the recruitment of macrophages for debris clearance and nerve regeneration, and the cause of the foamy macrophages that are frequently observed in peripheral transection injuries is unknown. Recent studies indicated that these foamy cells are generated by gasdermin D (GSDMD) via membrane perforation. However, whether these foamy cells are pyroptotic macrophages and whether their cell death elicits immunogenicity in peripheral nerve regeneration (PNR) remain unknown. Therefore, we used GSDMD-deficient mice and mice with deficiencies in other canonical inflammasomes to establish a C57BL/6 J mouse model of sciatic nerve transection and microanastomosis (SNTM) and evaluate the role of GSDMD-executed pyroptosis in PNR. In our study, the GSDMD-/- mice with SNTM showed a significantly diminished number of foamy cells, better axon regeneration, and a favorable functional recovery, whereas irregular axons or gaps in the fibers were found in the wild-type (WT) mice with SNTM. Furthermore, GSDMD activation in the SNTM model was dependent on the NLRP3 inflammasome and caspase-1 activation, and GSDMD-executed pyroptosis resulted in a proinflammatory environment that polarized monocytes/macrophages toward the M1 (detrimental) but not the M2 (beneficial) phenotype. In contrast, depletion of GSDMD reversed the proinflammatory microenvironment and facilitated M2 polarization. Our results suggested that inhibition of GSDMD may be a potential treatment option to promote PNR.

Total chemical synthesis of the phosphorylated p62 UBA domain reveals that Ser407Pi but not Ser403Pi enhances ubiquitin binding.

As an autophagic adaptor, p62 specifically targets ubiquitinated proteins to an autophagosome for lysosomal degradation through a critical ubiquitin-associated (UBA) domain. Recent research studies reported that the Ser403 and Ser407 sites on the UBA domain were modified by phosphorylation, increasing the binding affinity between p62 and ubiquitin (Ub). However, the exact role of each phosphorylation site in the regulation of the UBA domain and Ub binding remains unclear. In this text, we applied total chemical synthesis to prepare four types of phosphorylated UBAs, among which the bisphosphorylated UBA was successfully synthesized via the pseudo-dipeptide unit and auxiliary-mediated hydrazide-based native chemical ligation (NCL). Isothermal titration calorimetry (ITC) assays showed that the phosphorylation at S407 enhanced the binding affinity between UBA and Ub, while that at S403 did not. It was suggested that phosphorylation at S407 might be important for promoting the interplay between the UBA domain and Ub, whereas phosphorylation at S403 was not directly involved in this interaction.

The Changes of Intrinsic Excitability of Pyramidal Neurons in Anterior Cingulate Cortex in Neuropathic Pain.

To find satisfactory treatment strategies for neuropathic pain syndromes, the cellular mechanisms should be illuminated. Central sensitization is a generator of pain hypersensitivity, and is mainly reflected in neuronal hyperexcitability in pain pathway. Neuronal excitability depends on two components, the synaptic inputs and the intrinsic excitability. Previous studies have focused on the synaptic plasticity in different forms of pain. But little is known about the changes of neuronal intrinsic excitability in neuropathic pain. To address this question, whole-cell patch clamp recordings were performed to study the synaptic transmission and neuronal intrinsic excitability 1 week after spared nerve injury (SNI) or sham operation in male C57BL/6J mice. We found increased spontaneous excitatory postsynaptic currents (sEPSC) frequency in layer II/III pyramidal neurons of anterior cingulate cortex (ACC) from mice with neuropathic pain. Elevated intrinsic excitability of these neurons after nerve injury was also picked up, which was reflected in gain of input-output curve, inter-spike interval (ISI), spike threshold and Refractory period (RP). Besides firing rate related to neuronal intrinsic excitability, spike timing also plays an important role in neural information processing. The precision of spike timing measured by standard deviation of spike timing (SDST) was decreased in neuropathic pain state. The electrophysiological studies revealed the elevated intrinsic excitation in layer II/III pyramidal neurons of ACC in mice with neuropathic pain, which might contribute to central excitation.

[Characteristics and Sources of Atmospheric Inorganic Nitrogen Wet Deposition in Xueyu Cave Watershed, Outer Suburbs of Chongqing City].

Xueyu Cave watershed is located in Fengdu County in the outskirts of Chongqing, where rainfall events were monitored continuously from July 2015 to December 2017. We explored the variation of mass concentration of atmospheric dissolved inorganic nitrogen (NH4+-N and NO3--N), and quantitatively calculated its wet deposition fluxes, then the sources of NH4+-N and NO3--N were tracked using the Xueyu cave air mass backward trajectory model. The results showed that:①During the monitoring period, the average annual dissolved inorganic nitrogen (DIN) deposition in the watershed was 14.25 kg·(hm2·a)-1, of which NH4+-N and NO3--N were 7.72 kg·(hm2·a)-1 and 6.53 kg·(hm2·a)-1, accounting for 54% and 46% of DIN wet precipitation, respectively, and indicating that NH4+-N is the dominant species, followed by NO3--N; ②DIN wet deposition flux and concentration showed marked seasonal changes. The DIN wet deposition flux in spring and summer was 50% higher than that in autumn and winter, while the DIN concentration of wet deposition in autumn and winter was 30% higher than those in spring and summer. ③NH4+-N/NO3--N was between 0.29 and 2.27, and NH4+-N/NO3--N > 1 during the rainy season (April to October) and NH4+-N/NO3--N < 1 during the dry season (November to March), indicating that the main sources of DIN wet deposition results from agricultural activities in the rainy season, and urban contributions in the dry season. ④In the study area, the southeastern winds are dominant in the rainy season but southwestern winds are dominant in the dry season. These determine the sources of DIN wet deposition (agricultural or urban).

[Impact of Tourism on Bacterial Communities of Karst Underground River: A Case Study from Two Caves in Fengdu, Chongqing].

In this research, the bacterial community compositions of underground water in a tourist and pristine cave were studied. Xueyu Cave and Shuiming Cave are tourist and pristine caves, respectively, in the same karst cave system located in Chongqing, southwest China. To understand the impact of tourism on bacterial community compositions in underground water that flows through the caves, filtered materials from water were collected, and 16S rDNA gene sequences were obtained by high-throughput sequencing. The Shuiming Cave (the pristine cave) had less diversity than Xueyu Cave (the tourist cave) based on the Shannon's diversity index according to Illumina operational taxonomic units (OTUs). Proteobacteria, represented mostly by γ-Proteobacterium and Bacteroidetes, dominated both systems. OTUs from Shuiming Cave were dominated by 38% Proteobacteria, 24% Chlorobi, and 19% Bacteroidetes. In the Xueyu Cave, OTUs from upstream samples were comprised of 62% Proteobacteria but comprised 64% in the downstream samples. In the Xueyu Cave, Bacteroidetes accounted for 11% of the total OTUs in the upstream sample and 16% in the downstream. Among the γ-Proteobacterium and Bacteroidetes, Acinetobacter, Pseudomonas spp., and Flavobacteriaceae, which are related to potentially pathogenic species, were prevalent in the Xueyu Cave, while Methylococcaceae-uncultured, Methylomonas spp., and Methylobacter, all methane-oxidizing bacteria, had high relative abundances in the Shuiming Cave. These results revealed that potentially more pathogenic bacteria are present in the stream waters from the tourist cave, which has important implications for the protection of tourist caves. The RDA analysis of the environmental factor and bacteria community in groundwater showed that the distribution of pathogenic bacteria was positively correlated with the cave air CO2, and the Spearman correlation analysis of the two environmental factors indicated that the influence of the number of tourists on the structure of the bacterial community in the groundwater was more obvious and led to the disappearance of a large number of native bacteria. We proposed that tourist caves control the number of daily tourists and that they enter in batches and increase the import and export of closed devices to avoid the cave air exchange inside and outside. In addition, it was recommended that they increase the import and export of sterilization devices to reduce tourists with bacteria and organic matter, and avoid leaving garbage in the hole to avoid cave microbial exchange inside and outside. A reduction in the fixed lighting inside caves should be required to reduce long exposure, since the tourists can bring individual source lighting.

[Spatial and Temporal Variation Characteristics of Drip Water Hydrogeochemistry in the Xueyu Cave of Chongqing and Its Implications for Environmental Research].

Geochemical indexes of drip water were monitored to unveil their seasonal variability and response mechanism to the external climate from March 2015 to March 2017 at four sites in Xueyu Cave, Chongqing municipality. The results showed that four drips show a significant difference in ion concentration and discharge despite all sites having simple HCO3--Ca2+ waters and being super-saturated with respect to calcite. Being subject to geochemical processes, such as bedrock dissolution, dilution, and prior calcite precipitation (PCP), the geochemistry indexes, such as Ca2+, Mg2+, HCO3-, EC, pH, pCO2, and SIc, at the four sites showed extraordinary seasonal variations and could perfectly respond to external climate events. Due to the difference of migration pathways and PCP intension, different types of drip water had diverse seasonal variations in Mg/Ca. Affected by soil CO2 content and hydrodynamic conditions, the δ13CDIC of all sites had correlations with external temperature or precipitation. On a short time scale, the δ13CDIC values reflected the precipitation amount in the site with its flow path controlled by conduit flow.

Emulsified isoflurane induces release of cytochrome C in human neuroblastoma SHSY-5Y cells via JNK (c-Jun N-terminal kinases) signaling pathway.

A large number of studies have demonstrated that inhalation anesthetic isoflurane induced neural cell death by apoptosis in various cell and animal models. Emulsified isoflurane (EIso) is a new type of intravenous preparation of isoflurane that attracts increasing research attention as a promising clinical agent due to its both advantages as an intravenous and inhalation anesthetics medication. However, its safety and underlying molecular mechanism of neurotoxicity largely remain unknown. Therefore, it is meaningful to investigate the safety of EIso and to further elucidate its mechanism of anesthetic neurotoxicity. Human neuroblastoma SHSY-5Y cells were cultured, followed by a random exposure to one of three doses of EIso (0.56mmol/l, 1.12mmol/l, and 2.24mmol/l) or the corresponding intralipid as vehicle (0.3956µl/ml, 0.7912µl/ml and 1.5824µl/ml) for 6h, 12h or 24h. Cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide (MTT) assay and the morphological changes were determined by a light microscope. We detect JNK, p-JNK and cytochrome C (cyto C) protein levels by western blotting. SP600125, a specific inhibitor of JNK, was used to detect the role of JNK pathway in the neurotoxicity of EIso. Our study showed that EIso reduced the viability of SHSY-5Y cells in a dose- and time-dependent manner. 0.56mmol/l EIso has no significant effects on cell viability, while 1.12mmol/l of EIso with 24-h and 2.24mmol/l of EIso with over 12-h exposure notably reduced cell viability. EIso dramatically increased the levels of p-JNK and cyto C. The JNK pathway inhibitor SP600125 significantly increased the cell viability of SHSY-5Y cells induced by EIso. These findings suggest that EIso induces damage in human neuroblastoma SHSY-5Y cells by JNK signaling pathway activation and cyto C release. SP600125 protects neural cells against EIso-induced injury. Our findings provide a new insight in the exploration of potential novel therapeutic strategies for the treatment of EIso-induced neurotoxicity and other neurodegenerative diseases.

JNK inhibitor alleviates apoptosis of fetal neural stem cells induced by emulsified isoflurane.

Isoflurane can provide both neuroprotection and neurotoxicity in various culture models and in rodent developing brains. Emulsified Isoflurane (EI) is an emulsion formulation of isoflurane, while its underlying molecular mechanism of developemental nerve toxicity largely remains unclear. We hypothesized that EI induced fetal neural stem cells (FNSCs) apoptosis, endoplasmic reticulum (ER) stress and c-Jun N-terminal kinase (JNK) activation. FNSCs were isolated from the cortex of SD rats during 14 days of gestation. The cell viability, cell apoptotic rates and the expression of apoptosis-related protein Caspase3, inositol requiring enzyme 1 (IRE1), poly (adenosine diphosphate-ribose) polymerase (PARP), Bax, Bcl-2, JNK, p-JNK and XBP1 were determined. Specific inhibition was performed by siRNA-targeting of JNK in FNSCs. EI could increase the p-JNK, JNK and caspase3 protein expression, the JNK pathway was activated by EI, and EI-induced apoptosis was blocked by inhibiting JNK pathway with SP600125 or JNK-small interfering RNA (siRNA), EI enhanced the level of IRE1, PARP, Bax/Bcl-2 and XBP1, which led FNSCs to apoptosis and ER stress. Meanwhile, dilatation of the ER lumens in FNSCs treated by EI for 24 h was significant. Green fluorescent protein (GFP) positive cell ratios were significantly decreased by FNSCs transfecting with JNK gene silencing. JNK was efficiently silenced in siRNA-JNK1 group. The results provided in-vitro evidence which supports that the underlying mechanisms of EI-induced apoptosis are the induction of ER stress and sequent JNK activation. Together, these data suggest that JNK inhibiting might be applied for improving therapeutic outcomes in anesthestics-induced neurotoxicity. HIGHLIGHTS: 1. Prolonged treatment with high-dose EI decreased the survival level of FNSCs by inducing apoptosis and inhibiting proliferation via the JNK signaling pathway. 2. EI induced ER stress and sequent JNK activation. 3. JNK inhibiting might be applied for improving therapeutic outcomes in anesthestics-induced neurotoxicity.

Inhibition of Kupffer Cell Autophagy Abrogates Nanoparticle-Induced Liver Injury.

The possible adverse effects of engineered nanomaterials on human health raise increasing concern as our research on nanosafety intensifies. Upon entry into a human body, whether intended for a theranostic purpose or through unintended exposure, nanomaterials tend to accumulate in the liver, leading to hepatic damage. A variety of nanoparticles, including rare earth upconversion nanoparticles (UCNs), have been reported to elicit hepatotoxicity, in most cases through inducing immune response or activating reactive oxygen species. Many of these nanoparticles also induce autophagy, and autophagy inhibition has been shown to decrease UCN-induced liver damage. Herein, using UCNs as a model engineered nanomaterial, this study uncovers a critical role for Kupffer cells in nanomaterial-induced liver toxicity, as depletion of Kupffer cells significantly exacerbates UCN-induced liver injury. Furthermore, UCN-induced prodeath autophagy in Kupffer cells, and inhibition of autophagy with 3-MA, a well-established chemical inhibitor of autophagy, enhances Kupffer cell survival and further abrogates UCN-induced liver toxicity. The results reveal the critical importance of Kupffer cell autophagy for nanoparticle-induced liver damage, and inhibition of autophagy may constitute a novel strategy for abrogating nanomaterial-elicited liver toxicity.

Perioperative risk factors and cumulative duration of "triple-low" state associated with worse 30-day mortality of cardiac valvular surgery.

ABSRACT: Hospital stay and mortality in high-risk patients after noncardiac surgery has been associated with a triple low anesthesia. However, the association between anesthesia-related factors and perioperative outcome after cardiac surgery remains unclear.We tested the effect of a novel triple low state: low mean arterial pressure (MAP) <65 mmHg and low bispectral index (BIS) <45 during a low target effect-site concentration (Ce) <1.5 µg ml-1 of propofol anesthesia on postoperative duration of hospitalization and 30-day mortality in cardiac valvular patients. In this prospective observational study, univariable and multivariable logistic regression analyses were used to determine whether perioperative factors, in particular, cumulative duration of triple low state were independently associated with duration of hospitalization and 30-day mortality among patients who underwent elective valvular replacement. 489 patients were included in the final analysis. After adjusting for related covariates, cumulative duration of the triple-low state was not associated with prolonged hospitalization (multivariable odds ratio: 1.007; 95 % confidence interval 0.997-1.017; P = 0.564), but was a significant predictor of 30-day mortality (multivariable odds ratio: 1.016; 95 % confidence interval 1.002-1.031; P = 0.030). Compared to a triple-low duration of <15 min, a duration >60 min increased the 30-day mortality rate by 8 times. After adjusting for patient- and procedure-related characteristics, the cumulative duration of a triple-low state (intraoperative low MAP, low BIS, and low Ce) was associated with poorer 30-day mortality, but not with prolonged duration of hospital stay.The mortality risk was even greater when a cumulative time >60 min.

[Tracing the Fecal Contamination Sources Based on Bacteroides 16S rRNA PCR- DGGE in Karst Groundwater: Taking Laolongdong Underground River System, Nanshan, Chongqing as an Example].

Microbial contamination in karst groundwater continually increases and tracing the source researches has become a hot topic for international researchers. In this study, Laolongdong underground river at Nanshan, Chongqing was chosen as an example to adopt filter membrane methods to monitor the fecal microbial contaminations including the total bacterial concentration (TB), the total E. coli concentration (TE), the total fecal coliform (FC) and the total fecal Streptocoocci (FS). Bacteriodes was used as an indicator and PCR-DGGE analysis was used to trace fecal contamination sources in karst groundwater. The results suggested that groundwater in this area was seriously polluted by microbes from feces. The concentrations of microbial parameters exceeded limited levels greatly and the total bacterial amounts ranged 10-2.9 x 107 CFU · mL⁻¹, the concentrations of E. coli were between 4.3-4.0 x 105 CFU · mL⁻¹, the max concentration of FC was 1.1 x 106 CFU · (100 mL)⁻¹ and the max concentration of FS was 1.1 x 105 CFU · (100 mL)⁻¹. The FC/FS ratios were mostly over 2 which suggested that the main fecal source in groundwater was human feces. In addition, PCR-DGGE contrastive analysis of Bacteroides communities showed that the similarities between groundwater samples and human feces were in range of 7. 1% -69. 1% , and the similarity of the groundwater sample from Laolongdong underground river outlet was 69.1% . Bacteroides community similarities between groundwater samples and swine feces were in range of 1.1%-53.4%, and the similarity of Laolongdong underground river outlet was merely 1.5%. The similarity data implied that groundwater contamination resulted mainly from human feces, swine feces contamination composed part of animals' fecal contamination, and other animals' feces participated too. Furthermore, sequencing results of PCR-DGGE products revealed that most Bacteroides in groundwater originated from human intestinal tract and human feces.

[Modeling the Influencing Factors of Karstification and Karst Carbon Cycle in Laboratory].

To analyze the influencing factors of karstification and karst carbon cycle, a simulation experiment was carried out and 6 soil columns were designed. The results showed that the content of H2O4, hydrodynamic condition and thickness of the soil had important influence on karstification and karst carbon cycle. For the soil columns which were covered by the same thickness of soil, the concentrations of Ca2+ + Mg2+ and SO4(2-) followed the order of B20-2 > B20-1 > B20-3, B50-2 > B50-1 > B50-3. This meant that input of H2SO4 enhanced the karstification and increasing infiltration water had significant dilution effect on the chemical properties. For the soil columns with different thickness of soil but with the same slag pile and hydrodynamic conditions, the concentrations of Ca2+ + Mg2+ and SO4(2-) followed the order of B50-1 > B20-1, B50-2 > B20-2, B50-3 > B20-3. It was demonstrated that more carbonate rock was dissolved under the thick soil columns. In addition, the net consumption of CO2 mainly depended on the content of H2SO4 in this experiment due to slight contribution of H2CO3 to carbonate rock dissolution. More content of H2SO4 brought about less net consumption of C02, but B50-2 was an exception. Organic matter and other nutrients might be input into deep soil with the slag pile, and they promoted the production of soil C)2. Therefore, more CO2 was consumed due to the increased contribution of H2CO to karstification.