Fibrinogen-to-prealbumin and C-reactive protein-to-prealbumin ratios as prognostic indicators in severe fever with thrombocytopenia syndrome.

Background: The primary aim of this study is to investigate the correlation between serum levels of fibrinogen-to-prealbumin ratio (FPR) and C-reactive protein-to-prealbumin ratio (CPR) and prognostic outcomes among patients with severe fever with thrombocytopenia syndrome (SFTS). SFTS, characterized by elevated mortality rates, represents a substantial public health challenge as an emerging infectious disease. Methods: The study included 159 patients with SFTS. Clinical and laboratory data were compared between the survival and death groups. Univariate and multivariate logistic regression analysis were utilized to identify independent risk factors for mortality. The predictive efficacy of FPR and CPR was evaluated using receiver operating characteristic (ROC) curve. Survival analysis was conducted using the Kaplan-Meier curve and the log-rank test was employed for comparison. Results: The death group exhibited significantly elevated levels of FPR and CPR compared to the survival group (P < 0.05). Multivariate logistic regression analysis confirmed that both FPR and CPR independently correlated with a poorer prognosis among patients with SFTS. The ROC curve analysis indicated that FPR and CPR had superior predictive capabilities compared to C-reactive protein and fibrinogen. Kaplan-Meier survival analysis demonstrated that patients with SFTS who have FPR > 0.045 (log-rank test; χ2 = 17.370, P < 0.001) or CPR > 0.05 (log-rank test; χ2 = 19.442, P < 0.001) experienced significantly lower survival rates within a 30-day follow-up period. Conclusion: Elevated levels of FPR and CPR serve as distinct risk factors for mortality among patients with SFTS, indicating their potential to predict an unfavorable prognosis in these patients.

Influenza a virus triggers acute exacerbation of chronic obstructive pulmonary disease by increasing proinflammatory cytokines secretion via NLRP3 inflammasome activation.

BACKGROUND: Influenza A virus (IAV) triggers acute exacerbation of chronic obstructive pulmonary disease (AECOPD), but the molecular mechanisms remain unclear. In this study, we investigated the role of IAV induced NLRP3 inflammasome activation to increase airway inflammation response in the progression of AECOPD. METHODS: Human bronchial epithelial cells were isolated and cultured from normal and COPD bronchial tissues and co-cultured with IAV. The NLRP3 inflammasome associated genes were identified using RNA sequencing, and the expressions of NLRP3 inflammasome components were measured using qRT-PCR and western blot after cells were transfected with siRNA and treated with MCC950. Moreover, IAV-induced COPD rat models were established to confirm the results; 37 AECOPD patients were included to measure the serum and bronchoalveolar lavage fluid (BALF) of interleukin (IL)-18 and IL-1ß. RESULTS: Increased levels of NLRP3 inflammasome components were not seen until 6 h post-inoculation in normal cells. However, both cell groups reached peak NLRP3 level at 12 h post-inoculation and maintained it for up to 24 h. ASC, Caspase-1, IL-1ß and IL-18 were also elevated in a similar time-dependent pattern in both cell groups. The mRNA and protein expression of the NLRP3 inflammasome components were decreased when COPD cells treated with siRNA and MCC950. In COPD rats, the NLRP3 inflammasome components were elevated by IAV. MCC950 alleviated lung damage, improved survival time, and reduced NLRP3 inflammasome components expression in COPD rats. Additionally, the serum and BALF levels of IL-1ß and IL-18 were increased in AECOPD patients. CONCLUSIONS: NLRP3 inflammasome is activated in COPD patients as a pre-existing condition that is further exacerbated by IAV infection.

Increased ApoE Expression in Follicular Fluid and the ApoE Genotype Are Associated With Endometriosis in Chinese Women.

More than 10% of women suffer from endometriosis (EMT) during their reproductive years. EMT can cause pain and infertility and requires further study from multiple perspectives. Previous reports have indicated that an increase inapolipoprotein E (ApoE) may be associated with a lower number of retrieved mature oocytes in older women, and an association between ApoE and spontaneous pregnancy loss may exist in patients with EMT. The purpose of this study was to investigate the existence of an increase in ApoE in follicular fluid (FF) and the possible relationship between ApoE and EMT in Chinese women. In the current study, 217 Chinese women (111 control subjects and 106 EMT patients) were included. The ApoE genotypes were identified by Sanger sequencing. We found that ApoE expression in FF was higher in patients with EMT than in the control group. In addition, a significant difference in ApoE4 carriers (ϵ3/ϵ4, ϵ4/ϵ4) was found between the control subjects and the patients with EMT. Furthermore, a nonparametric test revealed significant differences in the numbers of blastocysts and high-quality blastocysts, but not the hormone levels of FSH, LH, and E2, between the two groups. We also established a multifactor (BMI, high-quality blastocysts, and ϵ4) prediction model with good sensitivity for identifying patients who may suffer from EMT. Our results demonstrate that ApoE expression in FF is increased in EMT, the ApoE-ϵ4 allele is significantly linked to EMT, and a combined analysis of three factors (BMI, high-quality blastocysts, and ϵ4) could be used as a predictor of EMT.

Identification of SARS-CoV-2 Variants and Their Clinical Significance in Hefei, China.

The ongoing coronavirus disease 2019 (COVID-19) pandemic represents one of the most exigent threats of our lifetime to global public health and economy. As part of the pandemic, from January 10 to March 10, 2020, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) began to spread in Hefei (Anhui Province, China) with a total of 174 confirmed cases of COVID-19. During this period, we were able to gather critical information on the transmission and evolution of pathogens through genomic surveillance. Particularly, the objective of our study was to track putative variants of SARS-CoV-2 circulating in Hefei for the first time and contribute to the global effort toward elucidating the molecular epidemic profile of the virus. Patients who showed symptoms of COVID-19 were routinely tested for SARS-CoV-2 infections via RT-PCR at the First Affiliated Hospital of Anhui Medical University. Whole-genome sequencing was performed on 97 clinical samples collected from 29 confirmed COVID-19 patients. As a result, we identified a local novel single-nucleotide polymorphism site (10,380) harboring a G → T mutation (Gly → Val) in Hefei. Further phylogenetic network analysis with all the sequences of SARS-CoV-2 deposited in GenBank collected in East and Southeast Asia revealed a local subtype of S-type SARS-CoV-2 (a1) harboring a C → T synonymous mutation (Leu) at position 18,060 of ORF1b, likely representing a local SARS-CoV-2 mutation site that is obviously concentrated in Hefei and the Yangtze River Delta region. Moreover, clinical investigation on the inflammatory cytokine profile of the patients suggested that mutations at positions 18,060 (the shared variable site of subtype a1) and 28,253(harboring a C → T synonymous mutation, Phe) were associated with milder immune responses in the patients.

Modular synthesis of (E)-cinnamaldehydes directly from allylarenes via a metal-free DDQ-mediated oxidative process.

An efficient synthesis of (E)-cinnamaldehydes by a metal-free DDQ-mediated oxidative transformation of allylarenes was developed. The protocol provides a practical method to prepare diverse (E)-cinnamaldehydes with broad functional group tolerance in good to excellent yields, including easy access to natural products randainal and geranyloxy sinapyl aldehyde from plant extracts. Finally, the mechanism of a single-electron transfer process was proposed.

6-Methoxy-indanone derivatives as potential probes for ß-amyloid plaques in Alzheimer's disease.

A series of 6-methoxy indanone derivatives was synthesized and evaluated as potential probes for ß-amyloid plaque imaging in Alzheimer's disease (AD). Two derivatives (5d and 5k) displayed significant binding abilities in fluorescent staining experiments using the brain sections of AD patients. Two derivatives showed high binding affinities to ß-amyloid aggregates (5j, Ki = 5.82 ± 0.19 nM) and brain homogenates of AD patients (5j, Ki = 18.96 ± 0.28 nM) in in vitro binding assay. With a log P value of 3.45, [125I]5k exhibited an excellent initial brain uptake (5.29%ID g-1, 2 min after i.v.) and a fast clearance from the brain in biodistribution experiments in normal mice. In autoradiography, [125I]5k exhibited an obvious binding ability to ß-amyloid plaques and a relatively low nonspecific binding in the brain sections of AD patients (in vitro) and APP/PS1 transgenic mice (in vitro and ex vivo). Results suggest that 5k is a potential probe for detecting ß-amyloid plaques in vivo.

Respiratory infectious phenotypes in acute exacerbation of COPD: an aid to length of stay and COPD Assessment Test.

PURPOSE: To investigate the respiratory infectious phenotypes and their impact on length of stay (LOS) and the COPD Assessment Test (CAT) Scale in acute exacerbation of COPD (AECOPD). PATIENTS AND METHODS: We categorized 81 eligible patients into bacterial infection, viral infection, coinfection, and non-infectious groups. The respiratory virus examination was determined by a liquid bead array xTAG Respiratory Virus Panel in pharyngeal swabs, while bacterial infection was studied by conventional sputum culture. LOS and CAT as well as demographic information were recorded. RESULTS: Viruses were detected in 38 subjects, bacteria in 17, and of these, seven had both. Influenza virus was the most frequently isolated virus, followed by enterovirus/rhinovirus, coronavirus, bocavirus, metapneumovirus, parainfluenza virus types 1, 2, 3, and 4, and respiratory syncytial virus. Bacteriologic analyses of sputum showed that Pseudomonas aeruginosa was the most common bacteria, followed by Acinetobacter baumannii, Klebsiella, Escherichia coli, and Streptococcus pneumoniae. The longest LOS and the highest CAT score were detected in coinfection group. CAT score was positively correlated with LOS. CONCLUSION: Respiratory infection is a common causative agent of exacerbations in COPD. Respiratory coinfection is likely to be a determinant of more severe acute exacerbations with longer LOS. CAT score may be a predictor of longer LOS in AECOPD.

A tetrazole-based fluorescence "turn-on" sensor for Al(III) and Zn(II) ions and its application in bioimaging.

A tetrazole derivative 1-[(1H-tetrazol-5-ylimino)methyl]naphthalen-2-ol (H2L) as a fluorescent chemosensor for Al(3+) in DMSO and Zn(2+) in DMF was designed and synthesized. From (1)H NMR data, the Job plot and the ESI-MS spectrum, 1 : 1 stoichiometric complexation between H2L and Al(3+)/Zn(2+) was found in DMSO and DMF, respectively. The theoretical calculations at the level of B3LYP/6-311G** for the ground state and TD-B3LYP/6-311G** for the excited state revealed the sensing mechanism is the inhibition of excited state intramolecular proton transfer (ESIPT). And the possible fluorescent species formed in the DMSO and DMF solutions were deduced to be [Al(HL)(OH)(NO3)(H2O)(DMSO)] and [Zn(HL)(OH)(H2O)(DMF)]. What's more, it is confirmed that H2L could be used to detect Al(3+) and Zn(2+) in cells by bioimaging.

Serum ß-amyloid peptide levels spike in the early stage of Alzheimer-like plaque pathology in an APP/PS1 double transgenic mouse model.

Serum levels of ß-amyloid (Aß) peptides may represent an early biomarker in the diagnosis of Alzheimer's disease (AD). In the present study, we investigated the temporal kinetic changes in the levels of serum Aß 1-42 and 40 in an amyloid precursor protein (APP)/presenilin (PS)1 double transgenic mouse model of AD. Serum Aß peptide levels in 2-, 3-, 6-, 9- and 18-month old, and liver Aß 1-40 level in 6-month old mice were measured using enzyme-linked immunosorbent assay (ELISA) kits. Results revealed that serum Aß levels peaked in 3-month old transgenic mice, and the Aß level in non-transgenic and transgenic mice is comparable in liver. Compared to the 6-month old transgenic mice, Congo red staining showed that the 3-month old transgenic mice had minimum brain Aß plaques, corresponding to the early stage of Alzheimer-like plaque pathology, and confocal microscope images showed that the deposition of Aß in their cerebral vessels was minimal. Furthermore, results of the water maze test, showed that memory was normal for the 3- month old transgenic mice when compared to age-matched non-transgenic mice. These results suggest that serum Aß peptide levels may be peaked during the early stage of AD. Monitoring serum Aß peptide levels in the potential AD population may provide an early diagnosis of AD prior to the appearance of clinical symptoms.

The binding of resveratrol to monomer and fibril amyloid beta.

As currently understood, Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is driven by the aggregation of amyloid beta (Aß) protein. It has been shown that resveratrol (RES) may attenuate amyloid ß peptide-induced toxicity, promote Aß clearance and reduce senile plaques. However, it remains to be determined whether RES could interact directly with Aß. The aim of the present study was to examine the direct binding of RES to monomer and fibril Aß. Using surface plasmon resonance (SPR) and proton nuclear magnetic resonance ((1)H NMR), our results identified the direct binding of RES to Aß. The ability of RES to bind to both fibril and monomer Aß(1-40 and 1-42) was further analyzed by SPR. The binding response of RES to fAß(1-42) was higher than that to monomer Aß(1-42), whereas the binding response of RES to fAß(1-40) was lower than that to monomer Aß(1-40). The K(D) of RES for fibril Aß(1-40 or 1-42) was higher than that for the corresponding monomer Aß. Compared to the control compound Congo red (CR), the binding responses of RES to monomer Aß(1-42) and Aß(1-40) were stronger, but binding to fibril Aß(1-42) was weaker, and the K(D)s of RES with both monomer and fibril Aß(1-40) and Aß(1-42) were higher than that of CR. When Aß(1-40 or 1-42) was co-incubated with RES (50µM), the thioflavin T fluorescence of the mixture was weakened, and the number and length of amyloid fibrils were decreased. Furthermore, the results of staining in consecutive brain slices from AD patients showed that RES (10(-4)M) could stain senile plaques. These results indicated that RES could bind directly to Aß in different states, which may provide new insight into the protective properties of RES against AD.

Novel indanone derivatives as potential imaging probes for ß-amyloid plaques in the brain.

Molecular imaging probes to detect senile plaques (SPs) might help the early diagnosis of Alzheimer's disease (AD). In this study, a novel series of indanone derivatives were synthesized and characterized. In in vitro binding studies, compound 2e exhibited a K(i) value of 16 nM with a human AD brain homogenate. Although they displayed relatively low affinities for 2i and 2j--with K(i) values of 99 and 237 nM, respectively--the SPs in AD brain sections were positively stained by 2j. A method for in situ micro-autoradiography of AD brain was developed in this study and showed clear labeling of SPs by [(125)I]2i and [(125)I]2j. Both [(125)I]2i and [(125)I]2j had suitable lipophilicities and displayed high initial uptake and rapid clearance from the mouse brains. Furthermore, [(125)I]2i and [(125)I]2j were more stable in human brain homogenates than in mouse brain homogenates. These data suggest that such indanone derivatives might represent potential amyloid imaging agents for the detection of SPs in AD.

Novel anilinophthalimide derivatives as potential probes for beta-amyloid plaque in the brain.

A group of novel 4,5-dianilinophthalimide derivatives has been synthesized in this study for potential use as beta-amyloid (Abeta) plaque probes. Staining of hippocampus tissue sections from Alzheimer's disease (AD) brain with the representative compound 9 indicated selective labeling of it to Abeta plaques. The binding affinity of radioiodinated [(125)I]9 for AD brain homogenates was 0.21 nM (K(d)), and of other derivatives ranged from 0.9 to 19.7 nM, except for N-methyl-4,5-dianilinophthalimide (K(i)>1000 nM). [(125)I]9 possessed the optimal lipophilicity with LogP value of 2.16, and its in vivo biodistribution in normal mice exhibited excellent initial brain uptake (5.16% ID/g at 2 min after injection) and a fast washout rate (0.56% ID/g at 60 min). The encouraging results suggest that this novel derivative of [(123)I]9 may have potential as an in vivo SPECT probe for detecting amyloid plaques in the brain.

Study of the oxidation dynamics of ethyl cysteinate dimer in solution by ultra-performance liquid chromatography with tandem mass spectrometry.

Diaminodithiol (N2S2)-type compounds readily oxidize to produce disulfides. We found that some ligands failed to produce a prospective protonated molecular ion peak but gave a peak of [M-2+H]+, whereas others produced both [M+H]+ and [M-2+H]+ peaks in electrospray ionization mass spectra. In this study, an important N2S2 ligand, the ethyl cysteinate dimer (ECD), was investigated with high-resolution accurate mass measurements and tandem mass spectrometric analysis. The elemental compositions of ECD and its oxidized product were analyzed. The oxidation of ECD was confirmed. An ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) method in multiple reaction monitoring mode was developed, and ECD and its oxidized product were quantitated in solution. The dynamic oxidation process of ECD in solution was studied in detail. The full time course of the decrease in ECD and the increase in its oxide was observed; the oxidation procedure followed first-order kinetics, and the half-life time of ECD was 51 min.

Microdialysis combined with liquid chromatography-tandem mass spectrometry for the determination of 6-aminobutylphthalide and its main metabolite in the brains of awake freely-moving rats.

6-Aminobutylphthalide (ABP) is a new drug candidate which is currently being developed for the treatment of cerebral ischemia. The pharmacokinetics and metabolism of ABP were studied using in situ microdialysis sampling in the brains of awake freely-moving rats. Two LC-MS/MS methods were used for the quantitative and qualitative analysis of microdialysate. For comparison and confirmation, brain tissue samples were also analyzed by LC-MS/MS and GC/MS. The results described provide more authentic information in pharmacokinetics and metabolism at the site of action by using the coupling of microdialysis to LC-MS/MS technique than the traditional sampling methods.

[Determination of tanshinone IIA in rat plasma and the pharmacokinetics by RP-HPLC method].

AIM: To develop a sensitive and rapid HPLC method for the determination of tanshinone IIA (TS) in rat plasma and to study its pharmacokinetics in rats. METHODS: TS and 4-chlorodiphenyl (internal standard) were extracted from plasma with ethyl acetate. After liquid-liquid extraction, the sample was analyzed by HPLC with YMC C18 column (5 microns, 150 mm x 3.0 mm ID). The mobile phase consisted of acetontrile-water-acetic acid (74:26:1) at the flow rate of 0.3 mL.min-1, the UV detection wave length was 270 nm. RESULTS: The calibration curve was linear (r = 0.9981) in the range from 0.05 to 6.40 mg.L-1. The lowest detectable concentration was 0.05 mg.L-1. The recoveries at the concentration of 0.05, 1.60 and 6.40 mg.L-1 were 98.9%, 102.1% and 100.4%, respectively. The inter- and intra-day RSDs were all less than 5%. CONCLUSION: This method is proved to be rapid, precise and reliable enough to be applied to the pharmacokinetics studies of TS in rats after a single dose of 15 mg.kg-1 by oral administration.