Diagnosing Alzheimer's disease(AD)in the early stage is challenging.Informative biomarkers can be of great value for population-based screening.Metabolomics studies have been used to find potential biomarkers,but commonly used tissue sources can be difficult to obtain.The objective of this study was to determine the potential utility of erythrocyte metabolite profiles in screening for AD.Unlike some commonly-used sources such as cerebrospinal fluid and brain tissue,erythrocytes are plentiful and easily accessed.Moreover,erythrocytes are metabolically active,a feature that distinguishes this sample source from other bodily fluids like plasma and urine.In this preliminary pilot study,the erythrocyte metab-olomes of 10 histopathologically confirmed AD patients and 10 patients without AD(control(CTRL))were compared.Whole blood was collected post-mortem and erythrocytes were analyzed using ultra-performance liquid chromatography tandem mass spectrometry.Over 750 metabolites were identified in AD and CTRL erythrocytes.Seven were increased in AD while 24 were decreased(P＜0.05).The ma-jority of the metabolites increased in AD were associated with amino acid metabolism and all of the decreased metabolites were associated with lipid metabolism.Prominent among the potential bio-markers were 10 sphingolipid or sphingolipid-related species that were consistently decreased in AD patients.Sphingolipids have been previously implicated in AD and other neurological conditions.Furthermore,previous studies have shown that erythrocyte sphingolipid concentrations vary widely in normal,healthy adults.Together,these observations suggest that certain erythrocyte lipid phenotypes could be markers of risk for development of AD.

Myelodysplastic syndromes (MDS) are a subset of myeloid malignancies defined by clonality of immature hematopoietic stem cells that leads to faulty blood cell development. These syndromes can lead to an increased risk of infection and may transform into acute myeloid leukemia, making it critical to determine effective treatments for the condition. While hypomethylating agents such as azacitidine and decitabine, as well as stem cell transplants, have been delineated as favored treatments for MDS, not all patients are physiologically receptive to these treatments. However, black raspberries (BRBs) have been shown to exert hypomethylating effects in various malignancies, with minimal adverse effects and thus a broader range of potential candidacies. This study aimed to investigate the potential of BRBs to exert such effects on MDS using Addition of Sex Combs Like/Tet Methylcytosine Dioxygenase 2 (Asxl1/Tet2) double knockout mice (Vav-cre Asxl1fl/fl Tet2fl/fl ), which typically manifest symptoms around 25 weeks of age, mirroring genetic mutations found in humans with MDS. Following a 12-week dietary supplementation of Vav-cre Asxl1fl/fl Tet2fl/fl mice with 5% BRBs, we observed both hyper- and hypomethylation at multiple transcription start sites and intragenic locations linked to critical pathways, including hematopoiesis. This methylation profile may have implications for delaying the onset of MDS, prompting a need for in-depth investigation. Our results emphasize the importance of exploring whether an extended BRB intervention can effectively alter MDS risk and elucidate the relationship between BRB-induced methylation changes, thus further unlocking the potential benefits of BRBs for MDS patients.

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon, with a steadily rising prevalence in Western and newly industrialized countries. UC patients have a cancer incidence as high as 10% after 20 years of the disease. Although the importance of fruits and vegetables in defense against UC is beginning to be appreciated, the mechanisms remain largely unclear. In the current study, we reported that dietary black raspberries (BRBs) decreased colonic inflammation in the mucosa and submucosa of interleukin (IL)-10 knockout (KO) mice. We then used colon, spleen, and plasma from those mice to investigate whether BRBs exert their anti-inflammatory effects by correcting dysregulated toll-like receptor (TLR)-4 signaling to downregulate prostaglandin E2 (PGE2). Other studies reported that spleen is the reservoir of macrophages and depletion of macrophages in IL-10 KO mice prevents the development of colitis. Our results showed that BRBs decreased the percentages of macrophages in spleens of IL-10 KO mice. Moreover, mechanistically, the BRB diet corrected dysregulated TLR-4 signaling in cells from the colon and spleen, decreased PGE2 and prostaglandin I2, and increased 15-lipoxygenase and its product, 13-S-hydroxyoctadecadienoic acid, in plasma of IL- 10 KO mice. Therefore, we have elucidated one of the anti-inflammatory mechanisms of BRBs, and have identified biomarkers that could be indicators of response in UC patients treated with them. Our findings with BRBs could well apply to many other commonly consumed fruits and vegetables.

Objective:To evaluate the role of N-methyl-D-aspartate receptors (NMDA receptors) in sevoflurane anesthesia-caused necroptosis in hippocampal neurons of aged mice.Methods:Ninety clean-grade healthy male C57BL/6 mice, aged 18 months, weighing 27-30 g, were divided into 3 groups ( n=30 each) using a random number table method: control group (group C), sevoflurane anesthesia group (group S) and sevoflurane anesthesia plus NMDA receptor antagonist memantine hydrochloride group (group S+ M). Mice inhaled 3% sevoflurane for 2 h for 3 consecutive days in S group and S+ M group, and memantine hydrochloride 20 mg/kg was intraperitoneally injected at 1 h before each inhalation of sevoflurane in S+ M group.Mice only inhaled pure oxygen for 2 h in group C. Ten mice of each group were selected on 1 day before anesthesia and 3 and 7 days after anesthesia to perform Morris water maze test.The mice were sacrificed immediately after Morris water maze test, and hippocampus was removed for microscopic examination of pathological changes (with a light microscope) and for determination of the necroptosis rate of neurons and cytoplasmic free calcium concentration([Ca 2+ ] i)(by flow cytometry), and expression of NMDA receptor subtypes GluN2A, GluN2B and receptor-interacting protein kinase 1 (RIP1) (by Western blot). Results:Compared with group C, the escape latency was significantly prolonged, and the frequency of crossing the original platform was decreased, and the [Ca 2+ ] i and neuronal necroptosis rate in the hippocampus were increased at each time point after anesthesia, and the expression of GluN2A, GluN2B and RIP1 was up-regulated( P<0.05), and the pathologic changes were accentuated in S group and S+ M group.Compared with group S, the escape latency was significantly shortened, and the frequency of crossing the original platform was increased, and the [Ca 2+ ] i and neuronal necroptosis rate in the hippocampus were decreased at each time point after anesthesia, and the expression of GluN2A, GluN2B and RIP1 was down-regulated ( P<0.05), and the pathologic changes were attenuated in group S+ M. Conclusions:NMDA receptors are involved in the process of cognitive dysfunction induced by sevoflurane anesthesia in aged mice, and the mechanism may be related to the promotion of necrptosis in hippocampal neurons.

Free fatty acid receptor 2 (FFAR2) has been reported as a tumor suppressor in colon cancer development. The current study investigated the effects of FFAR2 signaling on energy metabolism and gut microbiota profiling in a colorectal cancer mouse model (ApcMin/+). FFAR2 deficiency promoted colonic polyp development and enhanced fatty acid oxidation and bile acid metabolism. Gut microbiome sequencing analysis showed distinct clustering among wild-type, ApcMin/+, and ApcMin/+-Ffar2-/- mice. The relative abundance of Flavobacteriaceae and Verrucomicrobiaceae was significantly increased in the ApcMin/+-Ffar2-/- mice compared to the ApcMin/+ mice. In addition, knocking-down FFAR2 in the human colon cancer cell lines (SW480 and HT29) resulted in increased expression of several key enzymes in fatty acid oxidation, such as carnitine palmitoyltransferase 2, acyl-CoA dehydrogenase, longchain acyl-CoA dehydrogenase, C-2 to C-3 short chain, and hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, alpha subunit. Collectively, these results demonstrated that FFAR2 deficiency significantly altered profiles of fatty acid metabolites and gut microbiome, which might promote colorectal cancer development.

Free fatty acid receptor 2 (FFAR2) has been reported as a tumor suppressor in colon cancer development. The current study investigated the effects of FFAR2 signaling on energy metabolism and gut microbiota profiling in a colorectal cancer mouse model (ApcMin/+). FFAR2 deficiency promoted colonic polyp development and enhanced fatty acid oxidation and bile acid metabolism. Gut microbiome sequencing analysis showed distinct clustering among wild-type, ApcMin/+, and ApcMin/+-Ffar2-/- mice. The relative abundance of Flavobacteriaceae and Verrucomicrobiaceae was significantly increased in the ApcMin/+-Ffar2-/- mice compared to the ApcMin/+ mice. In addition, knocking-down FFAR2 in the human colon cancer cell lines (SW480 and HT29) resulted in increased expression of several key enzymes in fatty acid oxidation, such as carnitine palmitoyltransferase 2, acyl-CoA dehydrogenase, longchain acyl-CoA dehydrogenase, C-2 to C-3 short chain, and hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, alpha subunit. Collectively, these results demonstrated that FFAR2 deficiency significantly altered profiles of fatty acid metabolites and gut microbiome, which might promote colorectal cancer development.

Myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are bone marrow disorders characterized by cytopenias and progression to acute myeloid leukemia. Hypomethylating agents (HMAs) are Food and Drug Administration-approved therapies for MDS and MDS/MPN patients. HMAs have improved patients’ survival and quality of life when compared with other therapies. Although HMAs are effective in MDS and MDS/MPN patients, they are associated with significant toxicities that place a large burden on patients. Our goal is to develop a safer and more effective HMA from natural products. We previously reported that black raspberries (BRBs) have hypomethylating effects in the colon, blood, spleen, and bone marrow of mice. In addition, BRBs exert hypomethylating effects in patients with colorectal cancer and familial adenomatous polyposis. In the current study, we conducted a pilot clinical trial to evaluate the hypomethylating effects of BRBs in patients with low-risk MDS or MDS/MPN. Peripheral blood mononuclear cells (PBMCs) were isolated before and after three months of BRB intervention. CD45 + cells were isolated from PBMCs for methylation analysis using a reduced-representation bisulfite sequencing assay. Each patient served as their own matched control, with their measurements assessed before intervention providing a baseline for post-intervention results. Clinically, our data showed that BRBs were well-tolerated with no side effects. When methylation data was combined, BRBs significantly affected methylation levels of 477 promoter regions. Pathway analysis suggests that BRB-induced intragenic hypomethylation drives leukocyte differentiation. A randomized, placebo-controlled clinical trial of BRB use in low-risk MDS or MDS/ MPN patients is warranted.

OBJECTIVE: This study aimed to compare the demographic characteristics and trauma service structures and processes of hospitals in 15 countries across the Asia Pacific, and to provide baseline data for the integrated trauma database: the Pan-Asian Trauma Outcomes Study (PATOS).METHODS: Medical directors and emergency physicians at PATOS-participating hospitals in countries across the Asia Pacific were surveyed through a standardized questionnaire. General information, trauma care system data, and trauma emergency department (ED) outcomes at each hospital were collected by email and analyzed using descriptive statistics.RESULTS: Survey data from 35 hospitals across 15 countries were collected from archived data between June 2014 and July 2015. Designated trauma centers were identified as the highest hospital level for trauma patients in 70% of surveyed countries. Half of the hospitals surveyed had special teams for trauma care, and almost all prepared activation protocol documents for these teams. Most hospitals offered specialized trauma education programs, and 72.7% of hospitals had a hospital-based trauma registry. The total number of trauma patients visiting the ED across 25 of the hospitals was 300,376. The overall survival-to-discharge rate was 97.2%; however, it varied greatly between 85.1% and 99.7%. The difference between survival-to-discharge rates of moderate and severe injury groups was highest in Taiwan (41.8%) and lowest in Thailand (18.6%).CONCLUSION: Trauma care systems and ED outcomes vary widely among surveyed hospitals and countries. This information is useful to build further detailed, systematic platforms for trauma surveillance and evidence-based trauma care policies.
Asia ; Asian Continental Ancestry Group ; Cross-Sectional Studies ; Education ; Electronic Mail ; Emergencies ; Emergency Service, Hospital ; Epidemiology ; Humans ; Physician Executives ; Taiwan ; Thailand ; Trauma Centers

Objective: To compare relevant dosimetric parameters of non-coplanar volumetric modulated arc therapy (VMAT) in treating brain tumors in conventional flattening filter (FF) or flattening filter-free (FFF) delivery mode, aiming to explore the appropriate evaluation method of accelerator for stereotactic radiosurgery (SRS). Methods: Clinical data of 10 patients with single cranial tumor were retrospectively analyzed. All patients received non-coplanar VMAT at a prescription dose of 25 Gy in 1 fraction. Dosimetric parameters including conformity index (CI), heterogeneity index (HI), gradient index (GI₅₀, GI₂₅), gradient, volume of the brain tissue receiving larger than 10 Gy and 12 Gy(V₁₀ and V₁₂) and beam-on time were statistically compared between two treatment plans by paired sample t-test. Results: When FFF-VMAT was compared with FF-VMAT in SRS for intracranial tumors, Paddick gradient index GI₅₀ was 2.91±0.34 vs.3.07±0.35, 6.91±0.28 vs.7.35±0.27 for GI₂₅, (0.57±0.07) cm vs.(0.61±0.08) cm for gradient, respectively (all P<0.05), whereas CI did not significantly differ (P>0.05). For the normal brain tissues, the average dose was (160.64±43.64) cGy vs.(174.27±53.98) cGy, (45.35±30.32)% vs.(48.37±30.88)% for V₁₀ and (36.69±25.15)% vs.(39.48±25.37)% for V₁₂, respectively (all P<0.05). Conclusions Non-coplanar VMAT in FFF delivery mode can improve dose distribution and normal brain tissue sparing in the treatment of intracranial single tumors. Meanwhile, supplement of GI index and gradient index can implement comprehensive evaluation of the SRS planning.