The Anti-Neuroinflammatory Effect of Extra-Virgin Olive Oil in the Triple Transgenic Mouse Model of Alzheimer's Disease.

Background: Chronic intake of extra virgin olive oil is beneficial for brain health and protects from age-related cognitive decline and dementia, whose most common clinical manifestation is Alzheimer's disease. Besides the classical pathologic deposits of amyloid beta peptides and phosphorylated tau proteins, another frequent feature of the Alzheimer's brain is neuroinflammation. Objective: In the current study, we assessed the effect that extra virgin olive oil has on neuroinflammation when administered to a mouse model of the disease. Methods: Triple transgenic mice were randomized to receive a diet enriched with extra virgin olive oil or regular diet for 8 weeks. At the end of this treatment period the expression level of several inflammatory biomarkers was assessed in the central nervous system. Results: Among the 79 biomarkers measured, compared with the control group, mice receiving the extra virgin olive oil had a significant reduction in MIP-2, IL-17E, IL-23, and IL-12p70, but an increase in IL-5. To validate these results, specific ELISA kits were used for each of them. Confirmatory results were obtained for MIP-2, IL-17E, IL-23, and IL-12-p70. No significant differences between the two groups were observed for IL-5. Conclusions: Our results demonstrate that chronic administration of extra virgin olive oil has a potent anti-neuroinflammatory action in a model of Alzheimer's disease. They provide additional pre-clinical support and novel mechanistic insights for the beneficial effect that this dietary intervention has on brain health and dementia.

Colonization of multidrug-resistant Gram-negative bacteria increases risk of surgical site infection after hemorrhoidectomy: a cross-sectional study of two centers in southern China.

PURPOSE: The present study aims to determine the rectoanal colonization rate and risk factors for the colonization of present multidrug-resistant bacteria (MDRBs). In addition, the relationship between MDRB colonization and surgical site infection (SSI) following hemorrhoidectomy was explored. METHODS: A cross-sectional study was conducted in the Department of Colorectal Surgery of two hospitals. Patients with hemorrhoid disease, who underwent hemorrhoidectomy, were included. The pre-surgical screening of multidrug-resistant Gram-negative bacteria (MDR-GNB) colonization was performed using rectal swabs on the day of admission. Then, the MDRB colonization rate was determined through the rectal swab. Logistic regression models were established to determine the risk factors for MDRB colonization and SSI after hemorrhoidectomy. A p-value of < 0.05 was considered statistically significant. RESULTS: A total of 432 patients met the inclusion criteria, and the MDRB colonization prevalence was 21.06% (91/432). The independent risk factors for MDRB colonization were as follows: patients who received ≥ 2 categories of antibiotic treatment within 3 months (odds ratio (OR): 3.714, 95% confidence interval (CI): 1.436-9.605, p = 0.007), patients with inflammatory bowel disease (IBD; OR: 6.746, 95% CI: 2.361-19.608, p < 0.001), and patients with high serum uric acid (OR: 1.006, 95% CI: 1.001-1.010, p = 0.017). Furthermore, 41.57% (37/89) of MDRB carriers and 1.81% (6/332) of non-carriers developed SSIs, with a total incidence of 10.21% (43/421). Based on the multivariable model, the rectoanal colonization of MDRBs (OR: 32.087, 95% CI: 12.052-85.424, p < 0.001) and hemoglobin < 100 g/L (OR: 4.130, 95% CI: 1.556-10.960, p = 0.004) were independently associated with SSI after hemorrhoidectomy. CONCLUSION: The rectoanal colonization rate of MDRBs in hemorrhoid patients is high, and this was identified as an independent risk factor for SSI after hemorrhoidectomy.

[Comparison of clinical efficacy between closed reduction combined with semi-circular external fixator and minimally invasive percutaneous plate osteosynthesis (MIPPO) in the treatment of middle and distal tibia fractures].

OBJECTIVE: To compare the clinical efficacy between closed reduction combined with semi-circular external fixator and minimally invasive percutaneous plate osteosynthesis (MIPPO) in the treatment of middle anddistal tibia fractures. METHODS: The clinical data of sixty patients with middle and distal tibia fractures admitted between January 2019 and November 2022, were retrospectively analyzed. These patients were categorized into external fixation group (n=30) and internal fixation group (n=30). There were 18 males and 12 females in the external fixation group, with an average age of (49.29±2.35) years old. Among them, 14 patients presented with fractures on the left side, and 16 patients presented with fractures on the right side. Closed reduction, arched wire, and semi-circular external fixator were used for treatment. There were 20 males and 10 females in the internal fixation group, with an average age of (48.96±1.87) years old. Among them, 15 patients presented with fractures on the left side, and 15 patients presented with fractures on the right side. MIPPO technique was used for the treatment. Perioperative parameters, including time injury to surgery, surgical duration, incision length, intraoperative bleeding, time to active activity, and incision healing level, were compared between the two groups. Clinical outcomes were also assessed, including Johner-Wruhs scores, time to minimum pain-adapted full weight-bearing, visual analog scale (VAS), SF-36 scale, and complications. RESULTS: The external fixation group exhibited a significantly shorter incision length (1.36±0.86) cm and lower intraoperative bleeding (10.83±5.73) ml compared to the internal fixation group (12.74±3.12) cm and (86.47±8.90) ml, respectively(P<0.05). The postoperative active activity time (1.50±0.54) days and minimum pain-adapted full weight-bearing activity time(108.87±3.43) days in the external fixation group were slightly delayed than the internal fixation group(1.15±0.98) days and (105.27±3.68) days, respectively(P<0.05). Over a mean postoperative follow-up duration of (6.23±1.89) months, both groups showed improved VAS and SF-36 scale scores. There were no statistically significant differences in VAS and SF-36 scale scores 1, 3, 6 months post-operatively between the two groups(P>0.05). The intraoperative surgical time in the external fixation group (35.42±9.31) minutes was shorter than that in the internal fixation group(74.22±7.81) minutes (P<0.05). There was no intraoperative vascular or nerve injury, nor postoperative skin necrosis in the external fixation group. However, skin necrosis was observed in 6 patientsin the internal fixation group, representing a statistically significant difference (P<0.05). CONCLUSION: Both external fixation and plate internal fixation are effective methods for the treatment of middle and distal tibia fractures. External fixation exhibits the advantage of less surgical trauma and a lower incidence of complications.

[Retracted] TGF­ß1 induces peritoneal fibrosis by activating the Smad2 pathway in mesothelial cells and promotes peritoneal carcinomatosis.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the fluorescence microscopy data shown in Fig. 6A and B were strikingly similar to data appearing in different form in Fig. 7 in a previously published paper [Lv Z­D, Na D, Liu F­N, Du Z­M, Sun Z, Li Z, Ma X­Y, Wang Z­N and Xu H­M: Induction of gastric cancer cell adhesion through transforming growth factor­beta1­mediated peritoneal fibrosis. J Exp Clin Cancer Res 29: 139, 2010], which featured some of the same authors, although the data were shown to portray results obtained under different experimental conditions. Furthermore, the data in Fig. 7A for the 'TGF­ß1' and the 'TGF­ß1 + siRNAcon' experiments contained an overlapping section, such that these data appeared to have been derived from the same original source, even though they were intended to show the results from differently performed experiments. Owing to the fact that the contentious data in the above article had already been published prior to its submission to International Journal of Molecular Medicine, and due to a lack of overall confidence in the presented data, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they accepted the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 29: 373­379, 2012; DOI: 10.3892/ijmm.2011.852].

A Cohort Study on Deficiency of ADA2 from China.

PURPOSE: Deficiency of adenosine deaminase 2 (DADA2), an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function variants in adenosine deaminase 2 (ADA2), has not been systemically investigated in Chinese population yet. We aim to further characterize DADA2 cases in China. METHODS: A retrospective analysis of patients with DADA2 identified through whole exome sequencing (WES) at seventeen rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype, and treatment response were analyzed. RESULTS: Thirty patients with DADA2 were enrolled between January 2015 and December 2021. Adenosine deaminase 2 enzymatic activity was low in all tested cases to confirm pathogenicity. Median age of disease presentation was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects died from complications of their disease. The patients most commonly presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient presented with bone marrow failure (BMF) with variable cytopenia. Twenty-three (76.7%) patients were treated with TNF inhibitors (TNFi), while two (6.7%) underwent hematopoietic stem cell transplantation (HSCT). They all achieved clinical remission. A total of thirty-nine ADA2 causative variants were identified, six of which were novel. CONCLUSION: To establish early diagnosis and improve clinical outcomes, genetic screening and/or testing of ADA2 enzymatic activity should be performed in patients with suspected clinical features. TNFi is considered as first line treatment for those with vascular phenotypes. HSCT may be beneficial for those with hematological disease or in those who are refractory to TNFi.

Effect of a disposable endoscope precleaning kit in the cleaning procedure of gastrointestinal endoscope: A multi-center observational study.

BACKGROUND: Precleaning is a key step in endoscopic reprocessing. AIM: To develop an effective and economic endoscope cleaning method by using a disposable endoscope bedside precleaning kit. METHODS: Altogether, 228 used gastrointestinal endoscopes were selected from five high-volume endoscopy units and precleaned by a traditional precleaning bucket (group T) or a disposable endoscope bedside precleaning kit (group D). Each group was further subdivided based on the replacement frequency of the cleaning solution, which was replaced every time in subgroups T1 and D1 and every several times in subgroups Ts and Ds. The adenosine triphosphate (ATP) level and residual proteins were measured three times: Before and after precleaning and after manual cleaning. RESULTS: After precleaning, the precleaning kit significantly reduced the ATP levels (P = 0.034) and has a more stable ATP clearance rate than the traditional precleaning bucket. The precleaning kit also saved a quarter of the cost of enzymatic detergent used during the precleaning process. After manual cleaning, the ATP levels were also significantly lower in the precleaning kit group than in the traditional precleaning bucket group (P < 0.05). Meanwhile, the number of uses of the cleaning solution (up to four times) has no significant impact on the cleaning effect (P > 0.05). CONCLUSION: Considering its economic cost and cleaning effect, the use of a disposable endoscope bedside precleaning kit can be an optimal option in the precleaning stage with the cleaning solution being replaced several times in the manual cleaning stage.

The value of NSE to predict ICU mortality in patients with septic shock: A prospective observational study.

To investigate the predictive value of neuron-specific enolase (NSE) on intensive care unit (ICU) mortality in patients with septic shock. Seventy-five patients with septic shock hospitalized in the emergency intensive care unit (EICU) of Hebei General Hospital from March 2020 to September 2021 were included, and the patients' baseline characteristics and laboratory findings were collected. NSE levels on the first and fourth days after admission were retrieved. NSE% [(NSEday1 - NSEday4)/NSEday1 × 100%] and δNSE (NSEday1 - NSEday4) were calculated. The outcome indicator was ICU mortality. The patients were divided into the survivors group (n = 57) and the nonsurvivors group (n = 18). Multivariate analysis was performed to assess the relationship between NSE and ICU mortality. The predictive value of NSE was evaluated using receiver operating characteristic (ROC) curve. There were no significant differences in age, gender, systolic blood pressure (SBP), heart rate (HR), acute physiology and chronic health evaluation II score (APACHE II score), source of infection, and comorbidities between the 2 groups (all P > .05). Interleukin-6 (IL-6), NSE (day1), and NSE (day4) were significantly higher in patients in the nonsurvivors group (all P < .05), and there were no statistical differences in other laboratory tests between the 2 groups (all P > .05). APACHE II score, IL-6, lactate (Lac), total bilirubin (TBil), NSE (day1), and NSE (day4) showed a weak positive correlation with ICU mortality in patients with septic shock (all P < .05). Multivariate logistic regression analysis demonstrated that APACHE II score (odds ratio [OR] = 1.166, 95% confidence interval [95% confidence interval [CI]] 1.005-1.352, P = .042), IL-6 (OR = 1.001, 95% CI 1.000-1.001, P = .003) and NSE (day4) (OR = 1.099, 95% CI 1.027-1.176, P = .006) were independently associated with the ICU mortality of sepsis shock patients. The area under the curve (AUCs) of APACHE II score, IL-6, NSE (day1), and NSE (day4) for predicting prognosis were 0.650, 0.694, 0.758 and 0.770, respectively (all P < .05). NSE(day4) displayed good sensitivity and specificity (Sn = 61.11%, Sp = 91.23%) for predicting ICU mortality with a cutoff value of 25.94 ug/L. High-level NSE (day4) is an independent predictor of ICU mortality in sepsis shock patients, which may become a good alternate option for evaluating sepsis severity. More extensive studies are needed in the future to demonstrate the prognosis value of NSE.

An Optimal Ablative Margin of Small Single Hepatocellular Carcinoma Treated with Image-Guided Percutaneous Thermal Ablation and Local Recurrence Prediction Base on the Ablative Margin: A Multicenter Study.

OBJECTIVE: To explore the best ablative margin (AM) for single hepatocellular carcinoma (HCC) patients with image-guided percutaneous thermal ablation (IPTA) based on MRI-MRI fusion imaging, and to develop and validate a local tumor progression (LTP) predictive model based on the recommended AM. METHODS: Between March 2014 and August 2019, 444 treatment-naïve patients with single HCC (diameter ≤3 cm) who underwent IPTA as first-line treatment from three hospitals were included, which were randomly divided into training (n= 296) and validation (n = 148) cohorts. We measured the ablative margin (AM) by MRI-MRI fusion imaging based on pre-ablation and post-ablation images. Then, we followed up their LPT and verified the optimal AM. Risk factors related to LTP were explored through Cox regression models, the nomogram was developed to predict the LTP risk base on the risk factors, and subsequently validated. The predictive performance and discrimination were assessed and compared with conventional indices. RESULTS: The median follow-up was 19.9 months (95% CI 18.0-21.8) for the entire cohort. The results revealed that the tumor size (HR: 2.16; 95% CI 1.25-3.72; P = 0.003) and AM (HR: 0.72; 95% CI, 0.61-0.85; P < 0.001) were independent prognostic factors for LTP. The AM had a pronounced nonlinear impact on LTP, and a cut-off value of 5-mm was optimal. We developed and validated an LTP predictive model based on the linear tumor size and nonlinear AM. The model showed good predictive accuracy and discrimination (training set, concordance index [C-index] of 0.751; validation set, C-index of 0.756) and outperformed other conventional indices. CONCLUSION: The 5-mm AM is recommended for the best IPTA candidates with single HCC (diameter ≤3 cm). We provided an LTP predictive model that exhibited adequate performance for individualized prediction and risk stratification.

Ruxolitinib treatment permits lower cumulative glucocorticoid dosing in children with secondary hemophagocytic lymphohistiocytosis.

BACKGROUND: This study aimed to analyze the effects of ruxolitinib on children with secondary hemophagocytic lymphohistiocytosis (HLH). METHODS: Eleven pediatric patients diagnosed with HLH and treated with ruxolitinib (ruxolitinib group: group R) between November 2017 and August 2018 were retrospectively analyzed. Eleven age-matched pediatric patients with HLH undergoing conventional treatment (control group: group C) during the same period were also analyzed. RESULTS: In group R, three patients who did not respond to methylprednisolone (MP) pulse and intravenous immunoglobulin (IVIG) therapies were treated with Ruxolitinib and their temperature decreased to normal levels. Four patients had normal temperature after conventional treatment (dexamethasone and etoposide, with or without cyclosporine A), but they had severe organ involvement, including obvious yellowing of the skin, increased liver enzyme levels and neuropsychiatric symptoms, and they were all ameliorated with ruxolitinib treatment. Four patients were relieved with ruxolitinib therapy alone. In group C, the body temperatures of eleven patients decreased to normal levels after conventional treatment. The body temperature of group R patients decreased to normal levels more rapidly than that of group C patients. The glucocorticoid dosage in group R was significantly lower than that in group C. Both groups were followed-up for 2-2.5 years. No obvious adverse drug reactions to ruxolitinib were observed during treatment and follow-up. CONCLUSION: Ruxolitinib might be an effective drug in controlling body temperature and reducing inflammation indicators. It might be a potential replacement for glucocorticoid therapy for HLH treatment in children, thereby reducing or avoiding glucocorticoid-related adverse reactions.

Behavior-Oriented Nomogram for the Stratification of Lower-Grade Gliomas to Improve Individualized Treatment.

Secondary glioblastomas (sGBM) are derived from previously lower-grade [World Health Organization (WHO) grades II or III] gliomas. Lower-grade benign-behaving gliomas may retain their former grade following recurrence, or may become malignant higher-grade glioblastomas. Prediction of tumor behavior in lower-grade gliomas is critical for individualized glioma therapy. A total of 89 patients were included between January 2000 and January 2019 in the present study to establish a nomogram via univariate and multivariate logistic regression analyses. Nomogram predictive performance was tested in the validation group. We then analyzed 36 O-6-methylguanine-DNA methyltransferase (MGMT) unmethylated lower-grade gliomas from patients seen at West China Hospital of Sichuan University. Survival statistics were calculated with the Kaplan-Meier method. Two clinical factors (molecular diagnosis and WHO grade), five radiological factors (location, cortical involvement, multicentricity, uniformity, and margin enhancement), one biomarker (1p19q codeletion), and a combination of three biomarkers (IDH+/ATRX-/TP53-) were associated with glioma upgrading. Nomograms positive for these prognostic factors had an AUC of 0.880 in the derivation group and 0.857 in the validation group. The calibration and score-stratified survival curves for the derivation group and validation group were good. An operational nomogram was published at https://warrenwrl.shinyapps.io/DynNomapp/. The overall survival of secondary gliomas in the MGMT-unmethylated cohort were influenced independently by the use of temozolomide during the treatment of formerly low-grade gliomas (p=0.00096). Clinical and radiological factors and biomarker-based behavior-oriented nomograms may offer a feasible identification tool for the detection of sGBM precursors. This method may further assist neurosurgeons with the stratification of lower-grade glioma cases and thus the development of better, more individualized treatment plans.

Combination Treatments of Plasma Exchange and Umbilical Cord-Derived Mesenchymal Stem Cell Transplantation for Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure: A Clinical Trial in China.

BACKGROUND: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a common type of liver failure with a high mortality. This study aimed at investigating the safety and efficacy of the combination treatment of plasma exchange (PE) and umbilical cord-derived mesenchymal stem cell (UC-MSCs) transplantation for HBV-ACLF patients. METHODS: A total of 110 HBV-ACLF patients treated in our hospital from January 2012 to September 2017 were enrolled into this trial and divided into the control group (n = 30), UC-MSC group (n = 30), PE group (n = 30), and UC-MSC + PE group (n = 20) based on their treatments. The hepatic function, coagulation, and virological and immunological markers were assessed at baseline and 30, 60, 90, 180, and 360 days. The endpoint outcomes were death and unfavorable outcome (need for liver transplantation or death). RESULTS: The UC-MSC + PE group had the lowest rates of death and unfavorable outcome at 30 days, 60 days, and 90 days posttreatment among the four groups, but the difference did not reach significances. The multivariate logistic regression analysis demonstrated that hemoglobin, prothrombin activity, and MELD (model for end-stage liver disease) score were the independent factors associated with the unfavorable outcome (all P < 0.05). The levels of total bilirubin, alanine aminotransferase, aspartate transaminase, and MELD score were significantly decreased during treatments (all P < 0.05). CONCLUSION: UC-MSCs combined with PE treatment had good safety but cannot significantly improve the short-term prognosis of HBV-ACLF patients with as compared with the single treatment. The long-term efficacy should be further evaluated. This trial is registered with registration no. NCT01724398.

Elevated levels of brain homocysteine directly modulate the pathological phenotype of a mouse model of tauopathy.

A high circulating level of homocysteine (Hcy), also known as hyperhomocysteinemia, is a risk factor for Alzheimer's disease (AD). Previous studies show that elevated Hcy promotes brain amyloidosis and behavioral deficits in mouse models of AD. However, whether it directly modulates the development of tau neuropathology independently of amyloid beta in vivo is unknown. Herein, we investigate the effect of diet-induced elevated levels of brain Hcy on the phenotype of a relevant mouse model of human tauopathy. Compared with controls, tau mice fed with low folate and B vitamins diet had a significant increase in brain Hcy levels and worsening of behavioral deficits. The same mice had a significant elevation of tau phosphorylation, synaptic pathology, and astrocytes activation. In vitro studies demonstrated that Hcy effect on tau phosphorylation was mediated by an upregulation of 5-lipoxygenase via cdk5 kinase pathway activation. Our findings support the novel concept that high Hcy level in the central nervous system is a metabolic risk factor for neurodegenerative diseases, specifically characterized by the progressive accumulation of tau pathology, namely tauopathies.

Annexin A1 Mimetic Peptide AC2-26 Inhibits Sepsis-induced Cardiomyocyte Apoptosis through LXA4/PI3K/AKT Signaling Pathway.

The aim of the present study was to explore the effects of annexin A1 (ANXA1) mimetic peptide AC2-26 on sepsis-induced cardiomyocyte apoptosis in vivo and in vitro and the underlying mechanisms. In the in vivo study, a rat septic model was established by the cecal ligation and puncture (CLP). The rats were divided into control group, sepsis group and AC2-26 group. The rats in the AC2-26 group were intraperitoneally injected with AC2-26 (1 mg/kg) 2 h before CLP, and those in the control group and sepsis group were injected with the same volume of normal saline. The myocardial tissue was examined by hematoxylin and eosin (HE) staining and transmission electron microscopy (TEM). Furthermore, myocardial apoptosis was measured by terminal dUTP nick end-labeling (TUNEL) assay. In the in vitro study, H9C2 cells were cultured and divided into three groups: control group, in which cells were only given the basic culture medium; LPS group, in which cells were treated with 10 µg/mL LPS; AC2-26 group, in which cells were treated with 0.5 µmol/L AC2-26 2 h before 10 µg/mL LPS was given. The apoptosis of H9C2 cells was detected by flow cytometry. The levels of lipoxin A4 receptor (LXA4), phosphoinositide-3-kinase (PI3K) and protein kinase B (PKB or AKT) protein were measured by Western blotting, the activity of NF-κB and the level of TNF-α by ELISA and the activities of caspase-3/8 by using the caspase activity kits. The in vivo study showed that the myocardial pathological damage and myocardial ultrastructural damage were significantly alleviated and the myocardial apoptosis significantly decreased in the AC2-26 group as compared with the sepsis group (P<0.05 for all). The in vivo study revealed that the apoptosis of H9C2 cells was profoundly ameliorated in the AC2-26 group relative to the sepsis group (P<0.05). The protein expression levels of LXA4 were significantly up-regulated, and those of PI3K and AKT prominently down-regulated in the AC2-26 group when compared with those in the LPS group (P<0.05 for all). The activity of NF-κB was greatly inhibited and the level of TNF-α markedly decreased in the AC2-26 group as compared with those in the LPS group (P<0.05 for all). AC2-26 treatment also significantly suppressed the activities of caspase-3/8 in H9C2 cells. In conclusion, these findings suggest that AC2-26 may alleviate the sepsis-induced cardiomyocyte apoptosis in vivo and in vivo through the LXA4/PI3K/AKT signaling pathway.