Very high high-density lipoprotein cholesterol may be associated with higher risk of cognitive impairment in older adults.

BACKGROUND: Previous studies have shown that high-density lipoprotein cholesterol (HDL-C) levels are positively associated with cognitive function across a range of concentrations. However, recent studies have suggested that very high HDL-C levels may lead to poorer outcomes. Therefore, we aimed to investigate the relationship between different concentrations of HDL-C and cognitive impairment risk. METHODS: We collected data from 3632 participants aged over 60 years from the U.S. National Health and Nutrition Examination Survey (NHANES) between 2011 and 2014 to assess the relationship between HDL-C and cognitive function. Cognitive function was evaluated with the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test, the animal fluency test (AFT), and the digit symbol substitution test (DSST). We used restricted cubic spline models and logistic regression to examine the association between HDL-C and cognitive function. RESULTS: A U-shaped was observed between HDL-C and cognitive outcomes, individuals with higher risk in those with both low and very high HDL-C levels compared with those with midrange values. Very high HDL-C levels (≥ 2.50 mmol/L) were associated with increased risk of cognitive impairment (OR = 2.19; 95% CI, 1.12-4.28) compared with those with HDL-C levels in the range of 1.50 to 1.99 mmol/L in older adults after adjustment for confounding factors. Interaction test demonstrated that relationship between very high HDL-C and the risk of cognitive impairment was not changed in different sex and race group (P for interaction > 0.05). CONCLUSIONS: Very high HDL-C levels were associated with an increased risk of cognitive impairment. HDL-C may not be a protective factor for maintaining brain health in older adults at very high levels.

Microbial reconstitution reverses prenatal stress-induced cognitive impairment and synaptic deficits in rat offspring.

Stress during pregnancy is often linked with increased incidents of neurodevelopmental disorders, including cognitive impairment. Here, we report that stress during pregnancy leads to alterations in the intestinal flora, which negatively affects the cognitive function of offspring. Cognitive impairment in stressed offspring can be reproduced by transplantation of cecal contents of stressed pregnant rats (ST) to normal pregnant rats. In addition, gut microbial dysbiosis results in an increase of ß-guanidinopropionic acid in the blood, which leads to an activation of the adenosine monophosphate-activated protein kinase (AMPK) and signal transducer and activator of transcription 3 (STAT3) in the fetal brain. Moreover, ß-guanidinopropionic acid supplementation in pregnant rats can reproduce pregnancy stress-induced enhanced glial differentiation of the fetal brain, resulting in impaired neural development. Using probiotics to reconstruct maternal microbiota can correct the cognitive impairment in the offspring of pregnant stressed rats. These findings suggest that microbial reconstitution reverses gestational stress-induced cognitive impairment and synaptic deficits in male rat offspring.

Astrocytic phagocytosis in the medial prefrontal cortex jeopardises postoperative memory consolidation in mice.

Memory impairment is one of the main characteristics of postoperative cognitive dysfunction. It remains elusive how postoperative pathological changes of the brain link to the memory impairment. The clinical setting of perioperation was mimicked via partial hepatectomy under sevoflurane anaesthesia together with preoperative restraint stress (Hep-Sev-stress) in mice. Memory changes were assessed with fear conditioning. The medial prefrontal cortex (mPFC)-dorsal hippocampus connectivity was evaluated with injecting neurotracer 28 days before surgery. Astrocytic activation was limited via injecting AAV-GFAP-hM4Di-eGFP into the mPFC. Astrocytic and microglial phagocytosis of synapses were visualised with co-labelling hippocampal neuronal axon terminals with PSD-95 and S100ß or Iba1. Neuroinflammation and oxidative stress status were also detected. Hep-Sev-stress impaired the memory consolidation (mean [standard error], 49.91 [2.55]% vs. 35.40 [3.97]% in the contextual memory, p = 0.007; 40.72 [2.78]% vs. 27.77 [2.22]% in cued memory, p = 0.002) and the cued memory retrieval (39.00 [3.08]% vs. 24.11 [2.06]%, p = 0.001) in mice when compared with these in the naïve controls. Hep-Sev-stress damaged the connectivity from the dorsal hippocampus to mPFC but not from the mPFC to the dorsal hippocampus and increased the astrocytic but not microglial phagocytosis of hippocampal neuronal axon terminals in the mPFC. The intervention also induced neuroinflammation and oxidative stress in the dorsal hippocampus and the mPFC in a regional-dependent manner. Limiting astrocyte activation in the mPFC alleviated memory consolidation impairment induced by Hep-Sev-stress. Postoperative memory consolidation was impaired due to astrocytic phagocytosis-induced connectivity injury from the dorsal hippocampus to the medial prefrontal cortex.

Single exposure to anesthesia/surgery in neonatal mice induces cognitive impairment in young adult mice.

BACKGROUND: The effects of a solitary neonatal exposure to anesthesia plus surgery (anesthesia/surgery) on cognitive function and the underlying mechanism in developing brains remains largely undetermined. We, therefore, set out to investigate the impact of single exposure to anesthesia/surgery in neonatal mice. METHODS: Six-day-old male and female mice received abdominal surgery under 3% sevoflurane plus 50% oxygen for 2 h. The new object recognition (NOR) and Morris water maze (MWM) were used to evaluate cognitive function in young adult mice. Western blot, ELISA and RT-PCR were used to measure levels of NR2B and IL-6 in medial prefrontal cortex and IL-6 in blood of the mice. We employed NR2B siRNA and IL-6 antibody in the interaction studies. RESULTS: The anesthesia/surgery decreased the ratio of novel time to novel plus familiar time in NOR and the number of platform crossings, but not escape latency, in MWM compared to sham condition. The mice in anesthesia/surgery group had increased NR2B expression in medial prefrontal cortex, and IL-6 amounts in blood and medial prefrontal cortex. Local injection of NR2B siRNA in medial prefrontal cortex alleviated the anesthesia/surgery-induced cognitive impairment. IL-6 antibody mitigated the anesthesia/surgery-induced upregulation of NR2B and cognitive impairment in young adult mice. CONCLUSIONS: These results suggest that a single neonatal exposure to anesthesia/surgery causes impairment of memory, but not learning, in young adult mice through IL-6-regulated increases in NR2B concentrations in medial prefrontal cortex, highlighting the need for further research on the underlying mechanisms of anesthesia/surgery's impact on cognitive function in developing brains.

Corrigendum: Probiotics for the treatment of docetaxel-related weight gain of breast cancer patients-A single-center, randomized, double-blind, and placebo-controlled trial.

[This corrects the article DOI: 10.3389/fnut.2021.762929.].

Optimal dose of neostigmine antagonizing cisatracurium-induced shallow neuromuscular block in elderly patients: a randomized control study.

BACKGROUND: Residual neuromuscular block after using neuromuscular blocking agents is a common and potentially harmful complication of general anesthesia. Neostigmine is a widely used antagonist, but its optimal dose for elderly patients is unclear. OBJECTIVES: To compare the optimal dosage and safety of neostigmine for reversing shallow residual block in elderly patients after cisatracurium-induced neuromuscular block. METHODS: A randomized controlled trial was conducted in 196 elderly patients undergoing non-cardiac surgery under general anesthesia with cisatracurium. Patients were assigned to receive either no neostigmine (control group) or neostigmine at 20 µg/kg, 40 µg/kg or 50 µg/kg when train-of-four (TOF) ratio reached 0.2 at the end of surgery. The primary outcome was the time to reach TOF ratio of 0.9 after administration. Secondary outcomes included TOF ratio at 10 min after administration, postoperative nausea and vomiting, postoperative cognitive impairment and post-anesthesia care unit (PACU) stay time. RESULTS: The time to reach TOF ratio of 0.9 in the 20 µg/kg, 40 µg/kg and 50 µg/kg groups was significantly shorter than the control group (H = 104.257, P < 0.01), and the time of 40 µg/kg group and 50 µg/kg group was significantly shorter than the 20 µg/kg group (P < 0.001). There was no significant difference between 40 µg/kg and 50 µg/kg groups (P = 0.249). The TOF ratio at 10 min after administration showed similar results. There were no significant differences among groups in postoperative nausea and vomiting, postoperative cognitive impairment or post-operation hospital stay. CONCLUSIONS: Timely use of neostigmine after general anesthesia in elderly patients can significantly shorten time of TOF value reaching 0.9, among which 40 µg/kg dosage may be a more optimized choice. TRIAL REGISTRATION: this study was registered on chictr.org.cn (ChiCTR2100054685, 24/12/2021).

A bibliometric analysis of studies on gut microbiota in attention-deficit and hyperactivity disorder from 2012 to 2021.

Background: An increasing number of studies have focused on the role of gut microbiota in the treatment of ADHD, but its related molecular mechanisms are not yet clear, and there is still room for development of studies targeting this area. This study analyzes publications from 2012 to 2021 in a comprehensive and multi-faceted visualization, with the aim of grasping the existing research profile and guiding scholars to make more in-depth studies. Methods: The 1,677 articles and 298 review articles on gut microbiota in ADHD were retrieved from the Web of Science Core Collection. CiteSpace, VOSviewer, Microsoft Excel 2019, Scimago Graphica, Bibliometrix and Pajek metrics software were used for visualization and analysis of the included literature. Results: On August 3, 2022, a total of 1975 English-language articles on gut microbiota in ADHD were retrieved from Web of Science Core Collection (WoSCC) from January 2012 to December 2021, with a steady upward trend in the number of articles published in this field over the decade. The top three countries in terms of the number of articles published are the United States, China, and Spain. Meanwhile, CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS CSIC, UNIV OF CALIFORNIA SYSTEM, and UDICE FRENCH RESEARCH UNIV have made significant contributions in this field. In the analysis of the published journals, PLoS One was not only the first in terms of number of articles published but also the most cited. Wang J was the most prolific author and CAPORASO JG ranked first in terms of co-cited authors. In addition, "Diet rapidly and reproducibly alters the human gut microbiome," published by David LA et al., has the highest citation frequency in this field. The most frequently occurring keyword was "gut microbiota." Conclusion: The results of this paper clarify the current status of research on gut microbiota in ADHD. Based on the research on the mechanism of gut microbiota in other diseases, there is reason to believe that the exploration of gut microbiota in ADHD must be increasingly mature. And the study speculates that future research may focus on "nutrition supplements," "lipid metabolism," and "gut brain axis." It is imperative to promote a closer international cooperation among scholars in this field.

Adipose mesenchymal stem cell-derived extracellular vesicles reduce glutamate-induced excitotoxicity in the retina.

Adipose mesenchymal stem cells (ADSCs) have protective effects against glutamate-induced excitotoxicity, but ADSCs are limited in use for treatment of optic nerve injury. Studies have shown that the extracellular vesicles (EVs) secreted by ADSCs (ADSC-EVs) not only have the function of ADSCs, but also have unique advantages including non-immunogenicity, low probability of abnormal growth, and easy access to target cells. In the present study, we showed that intravitreal injection of ADSC-EVs substantially reduced glutamate-induced damage to retinal morphology and electroretinography. In addition, R28 cell pretreatment with ADSC-EVs before injury inhibited glutamate-induced overload of intracellular calcium, downregulation of α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor (AMPAR) subunit GluA2, and phosphorylation of GluA2 and protein kinase C alpha in vitro. A protein kinase C alpha agonist, 12-O-tetradecanoylphorbol 13-acetate, inhibited the neuroprotective effects of ADSC-EVs on glutamate-induced R28 cells. These findings suggest that ADSC-EVs ameliorate glutamate-induced excitotoxicity in the retina through inhibiting protein kinase C alpha activation.

The association between hemoglobin A1c and all-cause mortality in the ICU: A cross-section study based on MIMIC-IV 2.0.

Background: Hyperglycemia has been reported to be associated with the outcomes of patients in the intensive care unit (ICU). However, the relationship between hemoglobin A1c (HbA1c) and long-term or short-term mortality in the ICU is still unknown. This study used the Medical Information Mart for Intensive Care (MIMIC)-IV database to investigate the relationship between HbA1c and long-term or short-term mortality among ICU patients without a diabetes diagnosis. Methods: A total of 3,154 critically ill patients without a diabetes diagnosis who had HbA1c measurements were extracted and analyzed from the MIMIC-IV. The primary outcome was 1-year mortality, while the secondary outcomes were 30-day mortality and 90-day mortality after ICU discharge. HbA1c levels were classified into four levels according to three HbA1c values (5.0%, 5.7%, and 6.5%). The Cox regression model was used to investigate the relationship between the highest HbA1c measurement and mortality. Finally, this correlation was validated using the XGBoost machine learning model and Cox regression after propensity score matching (PSM). Results: The study eventually included 3,154 critically ill patients without diabetes who had HbA1c measurements in the database. HbA1c levels of below 5.0% or above 6.5% were significantly associated with 1-year mortality after adjusting for covariates in Cox regression (HR: 1.37; 95% CI: 1.02-1.84 or HR: 1.62; 95% CI: 1.20-2.18). In addition, HbA1c 6.5% was linked to 30-day mortality (HR: 1.81; 95% CI: 1.21-2.71) and 90-day mortality (HR: 1.62; 95% CI: 1.14-2.29). The restricted cubic spline demonstrated a U-shaped relationship between HbA1c levels and 1-year mortality. The AUCs of the training and testing datasets in the XGBoost model were 0.928 and 0.826, respectively, while the SHAP plot revealed that HbA1c was somewhat important for the 1-year mortality. Higher HbA1c levels in Cox regression were still significantly associated with 1-year mortality after PSM for other factors. Conclusions: The 1-year mortality, 30-day mortality, and 90-day mortality rates for critically ill patients after discharge from ICU are significantly associated with HbA1c. HbA1c < 5.0% and ≥6.5% would increase 30-day, 90-day, and 1-year mortality, while levels between 5.0% and 6.5% of HbA1c did not significantly affect these outcomes.

The efficacy and safety of using pyrotinib combined with capecitabine as neoadjuvant therapy in elderly patients with HER2-positive breast cancer: a single-arm prospective clinical trial.

Background: Pyrotinib combined with capecitabine has been approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer in China. To date, the management of early-stage or locally advanced HER2-positive breast cancer in the clinic remains challenging. We conducted this trial to investigate the efficacy and safety of pyrotinib combined with capecitabine as neoadjuvant therapy (NAT) in elderly patients with HER2-positive breast cancer. Due to the stimulation of blood vessels by chemotherapy drugs, the elasticity of blood vessels in the elderly decreases, and then chemotherapy infusion is more likely to lead to phlebitis. Both pyrotinib and capecitabine can be taken to facilitate home treatment for elderly patients with HER2-positive breast cancer (BC). Methods: From January 2020 to March 2021, patients aged between 70 and 81 years old with stage IIA-IIIB HER2-positive breast cancer were screened, enrolled, and assigned to receive six cycles of pyrotinib (320-400 mg, orally, once daily) plus capecitabine (1,250 mg/m2, orally, twice daily) on days 1-14 in every 21-day cycle. The primary endpoint was the objective response rate (ORR). Adverse events (AEs) were assessed in every neoadjuvant cycle. Surgery was performed after the last cycle, and the total pathological complete response (tpCR) was evaluated postoperatively. Results: Of the 23 patients enrolled, the ORR was 100% (23/23; 95% confidence intervals: 85 to 100). All patients underwent surgery with a tpCR rate of 43.5% (10/23; 95% confidence intervals: 23 to 66). The most common AE was diarrhea, occurring in 19 of 23 patients (82.6%); most of these patients sustained mild diarrhea (Grade 1 or Grade 2) and only three had moderate diarrhea (Grade 3). The incidences of other AEs, including weakness, loss of appetite, leukopenia, nausea, vomiting, hand-foot syndrome, etc., were low and the symptoms were mild. No severe AEs (Grade 4 or 5) were observed throughout the treatment. Conclusion: In our study, pyrotinib combined with capecitabine as neoadjuvant therapy in elderly women with HER2-positive breast cancer is safe and showed efficacy in this population, which may be widely used as a protocol for clinical neoadjuvant therapy.

Caspase-11 contributes to pain hypersensitivity in the later phase of CFA-induced pain of mice.

Chronic pain is a common disease that severely disrupts the quality of life. Persistent neuroinflammation and central sensitization play important roles in its pathogenesis. Caspase-11 is a critical modulator of inflammation of central nervous system. However, its role in chronic pain remains elusive. In this study, chronic pain and acute pain were induced via injecting complete Freund's adjuvant (CFA) and 5 % formalin into the plantar of the right hind paw of wild-type (WT) and Caspase-11 deficient (Caspase-11-/-) mice, respectively. In WT mice, CFA injection significantly decreased the hind paw mechanical pain threshold in Von Frey test on 1-7 days after injection and increased the caspase-11 level of ipsilateral dorsal horn of spinal cord on day 2 and day 5 after injection. Compared to the WT mice, Caspase-11-/- mice showed significantly higher mechanical pain threshold in the later phase of CFA-induced pain, but not in the early phase, and had no significant difference in 5 % formalin induced licking and flinching behavior. In addition, the microglial activation, and the mRNA levels of caspase-1 and IL-18 in the spinal cord of Caspase-11-/- mice restored to baseline on the day 5 after CFA injection, but not in WT mice. Our data indicated that Caspase-11 contributed to persistent inflammation in ipsilateral dorsal horn of spinal cord, and consequently pain hypersensitivity in the later phase of CFA-induced pain.

Remimazolam Tosylate Combined with Low-Dose Propofol Improves Sedation and Safety in Hysteroscopy.

Background: Propofol is widely used for sedation of hysteroscopy. It can cause injection pain, respiratory depression, and hypotension. Remimazolam is a novel ultra-short-acting benzodiazepine. Clinical practice has found that the use of remimazolam alone often leads to body movement during hysteroscopy, which decreases the safety and comfort. Here this study is to investigate whether remimazolam combined with low-dose propofol can improve the sedation effect and safety of hysteroscopy. Patients and Methods: In this prospective, randomized, parallel-controlled trial, women (18 to 60 years) undergoing hysteroscopy were randomly assigned to receive propofol (Group P), remimazolam tosylate (Group R), or remimazolam tosylate plus propofol (Group RP). Intraoperative sedation depth was kept at the bispectral index (BIS) value of 40-60. 6 µg/kg alfentanil was used for analgesic before sedation. Intraoperative low pulse oxygen saturation (SpO2), body movement, injection pain, mean arterial pressure (MAP), heart rate (HR), and postoperative recovery time, dizziness, nausea and vomiting were recorded and compared. Results: From February to July 2022, 193 patients were recruited and randomly assigned to group P (n=64), group R (n=64), or group RP (n=65). There was no significant inter-group difference of the intraoperative BIS values. The incidence of low SpO2, injection pain, hypotension, and postoperative dizziness in group RP were less than that in group P, and had no significant difference from group R. The incidence of body movement in group RP was less than that in group R, and had no significant difference from group P. Postoperative recovery time of group RP was shorter than that of the other two groups. No significant inter-group difference in bradycardia, nausea and vomiting was observed. Conclusion: Remimazolam tosylate combined with low dose of propofol improved sedation and safety in hysteroscopy, and may be a more ideal sedative method for hysteroscopy.

Age-related Loss of miR-124 Causes Cognitive Deficits via Derepressing RyR3 Expression.

Epigenetic alterations of brain contribute to age-related cognitive decline. The challenge now is to identify these tractable epigenetic molecules working as the downstream cell-signaling nodes mediating age-related cognitive decline. Here we reported age-related loss of miR-124 in human and rat brains. To further validate these findings, knockout mice in which one of the three miR-124 genes (miR-124-3) was deleted using CRISPR/Cas9-mediated gene engineering were generated. MiR-124-3 knockout mice developed cognitive deficit phenotype. MiR-124 deficiency in the mouse brain resulted in upregulation of the Ryanodine receptor 3 (RyR3) gene, and the cognitive deficits in miR-124-3 knockout mice were ameliorated by knocking down RyR3 expression using RNAi. In addition, miR-124 deficiency facilitated Aß42-induced neuron apoptosis. Our work suggested that age-related cognitive decline, at least in part, was associated with miR-124 deficiency and subsequently upregulated RyR3 expression in inducing neuronal death.

Higher Total Cholesterol Concentration May Be Associated with Better Cognitive Performance among Elderly Females.

BACKGROUND: The brain contains the highest level of cholesterol in the body, and the total amount of serum cholesterol in the blood has a huge impact on brain aging and cognitive performance. However, the association of total serum cholesterol with cognitive function remains uncertain. This study determines whether there is an association between the total amount of cholesterol in the blood and cognitive performance in elderly females without a history of stroke. METHODS: This population-based cross-sectional study was conducted on elderly (over 60 years old) females and males without a history of stroke from 2011 to 2014 in the US National Health and Nutrition Examination Survey (NHANES). The primary exposure was total blood cholesterol, and the main outcome was cognitive performance; this association was assessed with logistic regression analysis and restricted cubic splines. RESULTS: 1309 female and 1272 male participants were included. In females, higher total cholesterol was significantly associated with higher cognitive scores, particularly in the digit symbol substitution test (OR 0.51, 95% CI (0.36-0.72)) and the animal fluency test (OR 0.64, 95% CI (0.45-0.91)). This association remained significant in models adjusted for age, race, smoking status, education level, and chronic conditions (OR 0.40, 95% CI (0.25-0.63)). This association was not significant in males, however. CONCLUSIONS: A higher concentration of total cholesterol measured in later life may be a protective factor for cognitive performance among females over 60 years old without a history of stroke. Further, this association was more pronounced among women with higher levels of education than women with lower or no education.

Peripheral Transplantation of Mesenchymal Stem Cells at Sepsis Convalescence Improves Cognitive Function of Sepsis Surviving Mice.

Objective: To investigate the effects of peripheral transplantation of mesenchymal stem cells (MSCs) at sepsis convalescence on post-sepsis cognitive function and underlying mechanisms in mice. Methods: Sepsis was induced by cecal ligation and puncture (CLP) in mice. Bone marrow-derived MSCs from mice were cultured and injected via tail vein on the 8th day after CLP. Cognitive function was detected in open field, novel object recognition task, and delayed matching-to-place water maze task during 10-26 days after CLP. Neuroinflammation, neurogenesis, and peripheral inflammation were detected on the 12th and 31th days after CLP. MSCs tracing was detected during 8-10 days after CLP. Results: Transplanted MSCs were located at peripheral organs (lung, spleen, liver) and had no obvious effects on survival and weight of sepsis mice. Transplanted MSCs mitigated cognitive impairments and hippocampal microglial activation, improved hippocampal neurogenesis of sepsis surviving mice, and had no obvious effect on the leukocyte amount, the neutrophil percentage, and the inflammatory factors of peripheral blood, and the hippocampal inflammatory factors. Conclusions: Our data indicated that MSCs transplantation via peripheral vein at later phase of sepsis can improve post-sepsis cognitive impairment and hippocampal neurogenesis of sepsis surviving mice.

HDAC6 Inhibition Alleviates Anesthesia and Surgery-Induced Less Medial Prefrontal-Dorsal Hippocampus Connectivity and Cognitive Impairment in Aged Rats.

To investigate the underlying mechanisms of postoperative cognitive dysfunction and the impairment of medial prefrontal cortex-hippocampus connectivity. Postoperative cognitive dysfunction frequently affects elderly following surgery. The role of inter-brain-region connectivity abnormality after anesthesia and surgery on postoperative cognitive dysfunction development remains unclear. Medial prefrontal cortex-hippocampus connectivity of aged and adult rats was evaluated by injecting neurotracer biotinylated dextranamine (BDA) into bilateral hippocampus 3 days before partial hepatectomy, and biotinylated dextranamine positive cells of medial prefrontal cortex 2 days after hepatectomy were counted. HDAC6 shRNA was injected into medial prefrontal cortex and hippocampus bilaterally before hepatectomy or an HDAC6 activity inhibitor Tubastatin A was administered systemically after hepatectomy. Neuroinflammation and HDAC6 down-target ac-tubulin in medial prefrontal cortex and hippocampus were detected. Learning and memory of rats were evaluated by Barnes Maze task during 2-5 days after surgery and delayed matching-to-place water maze task during 10-23 days after surgery. Compared to the age-matched normal controls, anesthesia and surgery significantly decreased BDA-positive neurons in medial prefrontal cortex of aged rats, but not young adult rats. Local HDAC6 knockdown and systemic HDAC6 inhibition both increased BDA-positive neurons number of medial prefrontal cortex, alleviated learning and memory impairment in the Barnes Maze task and water maze task, decreased HDAC6 expression, inflammatory cytokines, astrocyte and microglial activation, and increased ac-tubulin expression in aged rats which received surgery. Our data indicated that anesthesia and surgery impaired medial prefrontal cortex-hippocampus connectivity and cognition which was associated with HDAC6 overexpression.

Short-term perioperative cognitive therapy combined with rehabilitation exercise reduces the incidence of neurocognitive disorder in elderly patients: a randomized controlled trial.

BACKGROUND: To investigate whether short-term perioperative cognitive therapy combined with rehabilitation exercise decreases the incidence of neurocognitive disorder (NCD) in elderly patients who have undergone hip joint replacement surgery. This was a randomized, parallel controlled trial on elderly patients who underwent unilateral total hip joint replacement surgery at the Third Xiangya Hospital of Central South University. METHODS: Patients in the perioperative cognitive therapy combined with rehabilitation exercise group underwent preoperative cognitive training and postoperative cognitive training, rehabilitation exercise, and standardized health care services; the control group received only postoperative standardized health care service. Patients with NCD were defined as those with two or more abnormalities on 11 neuropsychological tests. Of the 607 individuals that we screened, 86 (exercise, 50; control, 36) who completed the study were included. RESULTS: The baseline characteristics were similar for the two groups. The incidence of NCD in the exercise group (10%, 5/50) was significantly lower than that in the control group (27.8%, 10/36) (P=0.032). The HVLT-R, HVLT-R delayed recall test, and HVLT-R recognition discriminating index were significantly improved in the exercise group compared with the control group (all P<0.05). Our findings highlight the clinical significance of perioperative cognitive exercise combined with rehabilitation exercise in preventing NCD among patients after surgery and anesthesia. CONCLUSIONS: Our study indicates that perioperative cognitive therapy combined with rehabilitation exercise can effectively reduce the incidence of NCD in elderly patients after total hip joint replacement surgery.

Brain-Penetration and Neuron-Targeting DNA Nanoflowers Co-Delivering miR-124 and Rutin for Synergistic Therapy of Alzheimer's Disease.

Alzheimer disease (AD) is the leading cause of dementia that affects millions of old people. Despite significant advances in the understanding of AD pathobiology, no disease modifying treatment is available. MicroRNA-124 (miR-124) is the most abundant miRNA in the normal brain with great potency to ameliorate AD-like pathology, while it is deficient in AD brain. Herein, the authors develop a DNA nanoflowers (DFs)-based delivery system to realize exogenous supplementation of miR-124 for AD therapy. The DFs with well-controlled size and morphology are prepared, and a miR-124 chimera is attached via hybridization. The DFs are further modified with RVG29 peptide to simultaneously realize brain-blood barrier (BBB) penetration and neuron targeting. Meanwhile, Rutin, a small molecular ancillary drug, is co-loaded into the DFs structure via its intercalation into the double stranded DNA region. Interestingly, Rutin could synergize miR-124 to suppress the expression of both BACE1 and APP, thus achieving a robust inhibition of amyloid ß generation. The nanosystem could pro-long miR-124 circulation in vivo, promote its BBB penetration and neuron targeting, resulting in a significant increase of miR-124 in the hippocampus of APP/PS1 mice and robust therapeutic efficacy in vivo. Such a bio-derived therapeutic system shows promise as a biocompatible nanomedicine for AD therapy.

Probiotic supplement attenuates chemotherapy-related cognitive impairment in patients with breast cancer: a randomised, double-blind, and placebo-controlled trial.

BACKGROUND: Chemotherapy-related cognitive impairment (CRCI) is highly prevalent in patients with cancer and is associated with poor outcomes and quality of life. To date, the management of CRCI remains a clinical challenge. Herein, we aim to determine the preventive effects of probiotics on CRCI development and underlying mechanisms. METHODS: We conducted a randomised, double-blind and placebo-controlled trial (ChiCTR-INQ-17014181) of 159 patients with breast cancer and further investigated the underlying mechanism in a pre-clinical setting. From 2018 to 2019, patients with breast cancer (Stage I-III) who needed adjuvant chemotherapy were screened, enrolled and randomly assigned to receive either probiotics or placebo (three capsules, twice/day) during chemotherapy. Their cognition, anxiety and depression were assessed with well-established assays; their plasma biomarkers, metabolites and faecal microbiota compositions were measured. In addition, the systemic effects of the metabolites found in the clinical trial on long-term potentiation, synapse injury, oxidative stress and glial activation were assessed in rats. RESULTS: Probiotics supplement significantly decreased the incidence of CRCI, improved the allover cognitive functions, changed the gut microbial composition and modulated nine plasma metabolite changes. Among these metabolites, p-Mentha-1,8-dien-7-ol, Linoelaidyl carnitine and 1-aminocyclopropane-1-carboxylic acid were negatively correlated with the occurrence of CRCI. Furthermore, probiotics supplement increased plasma p-Mentha-1,8-dien-7-ol in rats. Administration of exogenous p-Mentha-1,8-dien-7-ol significantly alleviated chemotherapy-induced long-term potentiation impairment, synapse injury, oxidative stress and glial activation in the hippocampus of rats. CONCLUSION: Our data indicated that probiotics supplement prevents the occurrence of CRCI in patients with breast cancer via modulating plasma metabolites, including p-Mentha-1,8-dien-7-ol. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR-INQ-17014181) [http://www.chictr.org.cn/showproj.aspx?proj=24294].

Perioperative probiotics attenuates postoperative cognitive dysfunction in elderly patients undergoing hip or knee arthroplasty: A randomized, double-blind, and placebo-controlled trial.

Background: Postoperative cognitive dysfunction (POCD) is a common complication in elderly patients following surgery. The preventive and/or treatment strategies for the incidence remain limited. Objective: This study aimed to investigate the preventive effect of perioperative probiotic treatment on POCD in elderly patients undergoing hip or knee arthroplasty. Methods: After obtaining ethical approval and written informed consent, 106 patients (age ≥60 years) were recruited, who scheduled elective hip or knee arthroplasty, from 16 March 2021 to 25 February 2022 for this randomized, double-blind, and placebo-controlled trial. They were randomly assigned with a 1:1 ratio to receive either probiotics or placebo treatment (four capsules, twice/day) from hospital admission until discharge. Cognitive function was assessed with a battery of 11 neuropsychological tests on the admission day and the seventh day after surgery, respectively. Results: A total of 96 of 106 patients completed the study, and their data were finally analyzed. POCD occurred in 12 (26.7%) of 45 patients in the probiotic group and 29 (56.9%) of 51 patients in the placebo group (relative risk [RR], 0.47 [95% confidence interval [CI], 0.27 to 0.81]; P = 0.003). Among them, mild POCD occurred in 11 (24.4%) in the probiotic group and 24 (47.1%) in the placebo group (RR, 0.52 [95% CI, 0.29 to 0.94]; P = 0.022). No significant difference in severe POCD incidence was found between the two groups (P = 0.209). Compared with the placebo group, the verbal memory domain cognitive function was mainly improved in the probiotic group. Conclusion: Probiotics may be used perioperatively to prevent POCD development and improve verbal memory performance in elderly patients receiving hip or knee arthroplasty. Clinical trial registration: www.chictr.org.cn, identifier: ChiCTR2100045620.