[Interventional effect and inflammatory regulation mechanism of dihydroartemisinin combined with pregabalin on neuropathic pain mice].

This study aims to clarify the effects of dihydroartemisinin(DHA) combined with pregabalin(PGB) on neuropathic pain(NP) in mice and explore the neuroinflammatory regulatory mechanism. NP mice model was established using spinal nerve ligation, whereas the sham group exposed the spinal nerve without ligation. The mice were randomly divided into sham group, model group, PGB groups of low, medium, and high doses(PGB-L, PGB-M, and PGB-H, with 22, 45, and 91 mg·kg~(-1)), DHA group(16 mg·kg~(-1)), and DHA combined with PGB groups of low, medium, and high doses(DHA + PGB-L, DHA + PGB-M, and DHA + PGB-H). Administration by gavage 18 days after modeling. Von Frey and cold plate were used to detect mechanical pain threshold and cold pain sensitivity in mice. The tail suspension test and forced swimming test were used to investigate depressive behavior, and the open field test was used to estimate anxiety behavior. The Morris water maze was used to evaluate cognitive function. Liquid suspension chip technology was used to quantitatively analyze immune inflammation-related factors. Immunofluorescence was used to detect the expression of CC chemokine ligand 3(CCL3) and transmembrane protein 119(TMEM119). The results showed that compared with the sham group, the mechanical pain and cold pain sensitivity thresholds of the model group were significantly reduced, and the struggle time was significantly increased in the tail suspension test and forced swimming test. The activity time in the central area was significantly reduced in the open field test. The residence time in the second/fourth quadrant was significantly longer than that in other quadrants, and the latency time of platform climbing significantly increased after platform withdrawal in the Morris water maze experiment. The expression of CCL3 was significantly increased; the number of TMEM119 positive cells and the cell body area were significantly increased. Compared with the model group, the DHA + PGB-M group showed a significant increase in mechanical pain and cold pain sensitivity thresholds, as well as a significant increase in struggle time in the tail suspension test and forced swimming test. The activity time in the central area of the open field test was significantly reduced. The residence time in the second/fourth quadrant was significantly shorter than that in other quadrants, and the latency time of platform climbing after platform withdrawal was significantly reduced. Compared with the PGB-M group, the mechanical pain threshold of D14-17 in the DHA + PGB-M group was significantly increased, and the struggle time during forced swimming was significantly increased. The residence time in the second/fourth quadrant of the Morris water maze was significantly shorter than that in other quadrants. Compared with the model group, the expression of CCL3, the number of TMEM119 positive cells, and the cell body area in the DHA + PGB-M group were significantly decreased. This study indicates that DHA + PGB can enhance the analgesic effect of PGB on NP mice, break through the limitations of PGB tolerance, and make up for the shortcomings of PGB in antidepressant and cognitive improvement. Its mechanism may be related to regulating neuroinflammation by inhibiting the activation of microglial cells and expression of CCL3.

Metabolites from Two Dominant Thermophilic Fungal Species Thermomyces lanuginosus and Scytalidium thermophilum.

Thermomyces lanuginosus and Scytalidium thermophilum are among the most ubiquitous thermophilic fungi in compost and soil. Chemical study on these two prevalent strains collected from Yunnan led to isolation of 23 metabolites, including one new metabolite, therlanubutanolide, and 15 known compounds, isolated from the YGP culture broth of Thermomyces lanuginosus and 7 known compounds isolated from Scytalidium thermophilum, respectively. Therlanubutanolide shared the quite similar features of the same carbon skeleton and saturation as natural hexadecanoic acids. This was the first reported discovery of such a lactone as natural occurring metabolite. All the compounds were reported for the first time from thermophilic fungi. Among them, N-[(2S,3R,4E,8E)-1,3-dihydroxy-9-methyloctadeca-4,8-dien-2-yl]acetamide was for the first time reported to be a naturally occurring metabolite and its NMR data was first provided in this study. A type of PKS-derived metabolites, three 3,4-dihydronaphthalen-1(2H)-ones, which were widely found in plant pathogenic fungi as phytotoxins and reported to have antimicrobial activity, were obtained from both dominant thermophilic fungi. The frequent occurrence of such PKS phytotoxins in these two thermophilic fungi might suggest particular ecological interest.

Successful cure of a patient with urosepsis using a combination of extracorporeal membrane oxygenation and continuous renal replacement therapy: A case report and literature review.

Holmium laser lithotripsy (HLL) is one of the common surgical methods for urolithiasis. It causes minor surgical trauma, but complications are not rare. Extracorporeal membrane oxygenation (ECMO) treatment of sepsis is common, but venoarterial (VA)-ECMO treatment of urosepsis has not been reported yet. In this article, we reported a 67-year-old female patient with refractory septic shock caused by HLL under percutaneous nephroscope, involving breathing, heart, kidney and other organs, and organs support treatment was ineffective for the patient. Finally, we successfully treated the patient under VA-ECMO with continuous renal replacement therapy (CRRT). Combined ECMO and CRRT may provide a solution for addressing refractory sepsis. Here we present the case and review relevant literature, so as to provide a treatment strategy for patients with refractory urogenic sepsis and to reduce the mortality rate.

[Analgesic effect of Fengshi Qutong Capsules on mice with chronic inflammatory pain caused by complete Freund's adjuvant].

The aim was to observe the analgesic effect of Fengshi Qutong Capsules(FSQTC) on chronic inflammatory pain in mice, and investigate its effect on p-ERK/COX-2 signal molecular activity. A model of chronic inflammatory pain was induced in mice by complete Freund's adjuvant(CFA). The mice were divided into normal control group, model group, model+FSQTC 0.3, 0.6 and 1.2 g·kg~(-1 )groups, model+positive control drug ibuprofen(IBP, 0.34 mg·kg~(-1)·d~(-1)) group, and normal control+ FSQTC 1.2 g·kg~(-1)group. FSQTC or IBP was given once a day by oral administration. Standard Von Frey fiber was used to evaluate the mechanical pain threshold, and the acetone stimulation was used to induce inflammatory plantar and observe the cold pain reaction scores. The mechanical pain threshold and cold pain reaction scores were observed before administration and 1, 2, 3, 4, 6 h after administration on the first day, as well as 3 h after administration on the 3 rd to 7 th day. The protein levels of PGE_2, COXs-1,2 and p-ERK in the spinal cord of the inflammatory foot and lumbar 4-5 were detected by enzyme-linked immunosorbent assay, Western blot, immunohistochemistry and immunofluorescence. The results showed that the mechanical pain threshold of the model group decreased and the cold pain reaction score increased as compared with the normal group. FSQTC application could dose-dependently increase the mechanical pain threshold and decrease the cold pain reaction score. The effect lasted for 6 h, most significant at 3 h. The effect of ibuprofen was similar to that of the 0.6 g·kg~(-1) dose group. In addition, FSQTC could reduce the abnormally increased protein content of PGE_2, COX-2 and p-ERK in the inflammatory foot and/or spinal cord of the model group, and the effect was most significant in middle and high dose groups. However, it had no effect on COX-1 in the inflammatory foot and spinal cord of mice. The results suggest that FSQTC has ob-vious analgesic effect on chronic inflammatory pain in mice, which may be related to inhibition of p-ERK/COX-2 signaling pathway.

[Systematic reviews of effects of Tripterygium Glycosides Tablets on pro-inflammatory factors in rheumatoid arthritis].

To systematically evaluate the effects of Tripterygium Glycosides Tablets alone or in combination with methotrexate(MTX) and leflunomide(LEF) on the levels of pro-inflammatory cytokines in patients or animal models with rheumatoid arthritis(RA), and to provide reference for clinical application and related basic research, this study systematically searched databases of CNKI, VIP, WanFang, PubMed, Embase and Cochrane Library, collected relevant clinical or animal experimental studies, used risk assessment tools to evaluate the quality of research, and used Revman 5.3 software to conduct Meta-analysis or descriptive analysis of the outcome indicators included in the literatures. Of the 1 709 papers retrieved, 3 clinical studies and 12 animal experiments were included. The results showed that compared with MTX alone, Tripterygium Glycosides Tablets combined with MTX could further reduce the expression levels of peripheral blood TNF-α(SMD=-8.88,95%CI[-10.77,-6.99],P<0.000 01),IL-1ß(P<0.000 01) and IL-6(SMD=-8.63, 95%CI[-10.57,-6.69], P<0.000 01) in RA patients. Compared with LEF alone, the combination of Tripterygium Glycosides Tablets and LEF could not further reduce the expression levels of TNF-α(P=0.20), IL-1ß(P=0.17), IL-6(P=0.31). In RA animal model, compared with model group, Tripterygium Glycosides Tablets could reduce the expression levels of peripheral blood IL-1ß(SMD=-6.29,95%CI[-9.64,-2.93],P<0.000 2)in peripheral blood(SMD=-1.39,95%CI[-1.77,-1.02],P<0.000 01), joint fluid(P<0.000 01) and paw plasma(P=0.02), and also reduce the expression levels of TNF-α in RA animal model group. Compared with MTX alone, Tripterygium Glycosides Tablets alone reduced the same levels of TNF-α(P=0.42) and IL-6(P=0.08) in joint fluid, while Tripterygium Glycosides Tablets combined with MTX could further reduce the levels of IL-6(P=0.000 1) in joint fluid; compared with LEF alone, Tripterygium Glycosides Tablets have the similar effects on reducing the expression levels of peripheral blood TNF-α(P=0.16), IL-1ß(P=0.32), IL-6(P=0.12), while Tripterygium Glycosides Tablets combined with LEF could further reduce the expression levels of TNF-α(P=0.008), IL-1ß(P=0.02), IL-6(P<0.000 1) in peripheral blood. Therefore, Tripterygium Glycosides Tablets combined with MTX could further reduce the expression levels of pro-inflammatory cytokines in peripheral blood of RA patients. Tripterygium Glycosides Tablets alone could reduce the expression levels of pro-inflammatory cytokines in peripheral blood and local joint of RA animal models. Tripterygium Glycosides Tablets combined with MTX or LEF could further reduce the express levels of pro-inflammatory cytokines in peripheral blood of RA animal models. Due to the limitation of literature, this conclusion needs to be further validated.

Molecular mechanisms of the analgesic action of Wu-tou Decoction on neuropathic pain in mice revealed using microarray and network analysis.

Wu-tou Decoction (WTD) is a classic herbal formula in traditional Chinese medicine for the treatment of joint diseases, neuropathic pain (NP) and inflammatory pain. In this study we investigated whether WTD produced analgesic action in a mouse spinal nerve ligation (SNL) model and elucidated the underlying molecular mechanisms. Mice were subjected to SNL and orally treated with WTD (3.15, 6.30 or 12.60 g·kg-1·d-1) for 21 d. SNL induced mechanical hyperalgesia and heat hyperalgesia characterized by rapid and persistent pain hypersensitivity. In addition, the expression levels of IL-1ß, TNF-α, CCL2 and CXCL1 in the spinal cord dorsal horn were dramatically increased on the 10th d post-surgery. Oral administration of WTD dose-dependently suppressed both mechanical and heat hyperalgesia as well as the expression levels of inflammatory cytokines in the spinal cord dorsal horn on the 21st d post-surgery. Then whole-genome microarray analyses were conducted to detect the gene expression profiles of spinal cord dorsal horn in SNL mice with or without WTD treatment. After construction of the WTD-SNL-network and topological analysis, a list of candidate target genes of WTD acting on SNL-induced NP was identified and found to be functionally enriched in several glial cell activation-related pathways and neuroinflammatory pathways. Our data have clarified the gene expression patterns in the mouse spinal cord under the NP condition. We also demonstrate the analgesic action of WTD through suppression of glial cell activation and neuroinflammation, which suggest the potential of WTD as a promising candidate for the treatment of NP.

[Application of three artemisinin derivatives in neuropathic pain: evaluating co-curation of nociceptive and emotional syndromes in spinal cord ligation mice].

In this study, on aspects of the nociceptive, anxiety and depressive syndromes in neuropathic pain (NP), the effects of dihydroartemisinine (DHA), artesunate (ART) and artemether (ARTN) (40 mg·kg⁻¹) were analyzed in the spinal cord ligation (SNL) mice. Clinical equivalent dose of the first-line drug for NP, pregabalin (PGB, 25 mg·kg⁻¹) and amitriptyline (ARP, 20 mg·kg⁻¹), were used as positive controls. General, from day 7 to 14, significant remissions of the nociceptive, anxiety and depressive behaviors were achieved by DHA, ART and ARTN separately. Moreover, on day 14, on aspects of the nociceptive behaviors, analyzed 1.5 h after the gavage administration, no significant difference between the shamed mice and mice administrated with DHA, ART and ARTN was detected; analyzed 3 h after the gavage, significant decreases of pain thresholds in ARTN, but not in DHA nor ART group, were detected as compared with thresholds measured 1.5 h; analyzed 24 h after gavage, pain thresholds in DHA, ART and ARTN were still higher than PGB, in spite of the significant decreases as compared to Sham group. On aspects of the anxiety and depressive behaviors, no significant difference was detected between the shamed mice and mice administrated with DHA nor ART. However, differences still remained between the shamed ones and ones administrated with ARTN. Preliminarily, the effects of DHA, ART and ARTN were consolidated in SNL mice. On aspects of the duration of analgesic effects and the control of negative emotion, ART and ARTN were proven more favorable than ARTN.

[Preparation and evaluation of gastric adhesive-floating pellets for Bolo leaf phenols].

Gastric adhesive-floating pellets for Bolo leaf phenols (BLP) were prepared by extrusion-spheronization method, with chitosan as skeleton bioadhesive material, and stearyl alcohol as help-bleaching agent to evaluate its in vitro adhesivity, floatability and in vivo retention situation, and investigate its in vitro release characteristics. The in vitro adhesivity and floatability were evaluated respectively by in vitro tissue retention method and visual observation method. The retention of pellets in rats was investigated by in vivo tissue retention method and in vivo imaging of small animals. In addition, the in vitro release of p-coumaric acid and caffeic acid as the index components in pellets were evaluated. Results showed that the in vitro adhesivity of the prepared gastric adhesive-floating pellets reached (73.2±3.4)%, and the pellets could float immediately in simulated gastric fluid for more than 12 h; the retention rate of adhesive-floating pellets in rats reached more than 40% after 6 h, while the retention rate of common reference pellets was decreased by 15% as compared with the gastric adhesive-floating pellets, with significant difference (P<0.01); the drug in vitro release time can reach more than 6 h, and the drug release behaviors were lined with Higuchi equation. In vivo and in vitro studies showed that, the gastrointestinal bioadhesive and floating pellets prepared in this study have good bioadhesivity, floatability and good sustained release characteristics.

[Bioavailability in vivo and in vitro transepithelial transport across Caco-2 cell monolayer of pueraria flavonoids bio-adhesive and floating pellets].

To study the bioavailability of pueraria flavonoids bio-adhesive and floating pellets, the absorption of puerarin was studied using Caco-2 cell monolayer by liquid chromatography (HPLC) method, comparing the P(app) of pueraria flavonoids bio-adhesive and floating pellets with different bio-adhesive materials. Drugs were administered at a dose of 100 mg·kg(-1) via ig. The plasma concentration of puerarin was determined by HPLC, the pharmacokinetics were calculated with the WinNonlin 6.0 software. The results showed that the P(app) of bio-adhesive and floating pellets with hydroxypropyl methylcellulose (HPMC)-cabomer was largest, which had a significant difference (P < 0.05). The AUC(0-t) of pueraria flavonoids bio-adhesive and floating pellets was 1.79 times of pueraria flavonoids, the C(max) of pueraria flavonoids bio-adhesive and floating pellets and pueraria flavonoids had a significant difference (P < 0.05). What's more the MRT had prolonged. In conclusion, pueraria flavonoids bio-adhesive and floating pellets with HPMC-cabomer could significantly facilitate the transport of puerarin on Caco-2 cellular monolayers. The bioavailability of pueraria flavonoids bio-adhesive and floating pellets with HPMC-cabomer was increased more than pueraria flavonoids with a sustained release effect.

Efficacy and safety of phosphodiesterase type-5 inhibitors for pulmonary arterial hypertension: A meta-analysis focusing on 6MWD.

BACKGROUND AND OBJECTIVE: Phosphodiesterase type-5 inhibitors (PDE-5 inhibitors) have been suggested as a first-line drug for treating pulmonary arterial hypertension (PAH). The aim of present meta-analysis was to fully evaluate the efficacy and safety of treating PAH with PDE-5 inhibitors, focusing on the improvement of 6-min walk distance (6MWD). METHODS: Studies were identified from The Cochrane Library, EMBASE, and PUBMED databases. We calculated odds ratios (OR) for dichotomous data and weighted mean differences with 95% confidence intervals (CI) for continuous data. RESULTS: Six studies with a total of 1056 patients (729 patients in PDE-5 inhibitors treatment group and 327 patients in placebo group) were included. All-cause mortality rate in the control group and PDE-5 inhibitors group was 2.6% and 0.7%, respectively. In an average of 12.3-week follow-up, PDE-5 inhibitors treatment was associated with a 71% reduction in mortality (OR 0.29; 95 %CI 0.07-1.15; P = 0.08), and increased 6MWD by 40.17 m, improved NYHA functional class and hemodynamic parameters. As for monotherapy and combination therapy patients, 6MWD has improved by 48.94 m and 21.75 m, respectively. CONCLUSIONS: The results of present meta-analysis suggest that treatment with PDE-5 inhibitors improves the 6MWD, clinical symptoms, hemodynamic parameters, and a tendency of survival benefits. In patients treated with PDE-5 inhibitor monotherapy, the 6MWD significantly increased when compared to combination therapies.

Relationships of multimorbidity and income with hospital admissions in 3 health care systems.

Associations of multimorbidity and income with hospital admission were investigated in population samples from 3 widely differing health care systems: Scotland (n = 36,921), China (n = 162,464), and Hong Kong (n = 29,187). Multimorbidity increased odds of admissions in all 3 settings. In Scotland, poorer people were more likely to be admitted (adjusted odds ratio [aOR] = 1.62; 95% CI, 1.41-1.86 for the lowest income group vs the highest), whereas China showed the opposite (aOR = 0.58; 95% CI, 0.56-0.60). In Hong Kong, poorer people were more likely to be admitted to public hospitals (aOR = 1.68; 95% CI, 1.36-2.07), but less likely to be admitted to private ones (aOR = 0.18; 95% CI, 0.13-0.25). Strategies to improve equitable health care should consider the impact of socioeconomic deprivation on the use of health care resources, particularly among populations with prevalent multimorbidity.

Epidemiology of multimorbidity in China and implications for the healthcare system: cross-sectional survey among 162,464 community household residents in southern China.

BACKGROUND: China, like other countries, is facing a growing burden of chronic disease but the prevalence of multimorbidity and implications for the healthcare system have been little researched. We examined the epidemiology of multimorbidity in southern China in a large representative sample. The effects of multimorbidity and other factors on usual source of healthcare were also examined. METHODS: We conducted a large cross-sectional survey among approximately 5% (N = 162,464) of the resident population in three prefectures in Guangdong province, southern China in 2011. A multistage, stratified random sampling was adopted. The study population had many similar characteristics to the national census population. Interviewer-administered questionnaires were used to collect self-report data on demographics, socio-economics, lifestyles, healthcare use, and health characteristics from paper-based medical reports. RESULTS: More than one in ten of the total study population (11.1%, 95% confidence interval (CI) 10.6 to 11.6) had two or more chronic conditions from a selection of 40 morbidities. The prevalence of multimorbidity increased with age (adjusted odds ratio (aOR) = 1.36, 95% CI 1.35 to 1.38 per five years). Female gender (aOR = 1.70, 95% CI 1.64 to 1.76), low education (aOR = 1.26, 95% CI 1.23 to 1.29), lack of medical insurance (aOR = 1.79, 95% CI 1.71 to 1.89), and unhealthy lifestyle behaviours were independent predictors of multimorbidity. Multimorbidity was associated with the regular use of secondary outpatient care in preference to primary care. CONCLUSIONS: Multimorbidity is now common in China. The reported preferential use of secondary care over primary care by patients with multimorbidity has many major implications. There is an urgent need to further develop a strong and equitable primary care system.

Preventive effect of phosphodiesterase 5 inhibitor tadalafil on experimental post-pyelonephritic renal injury in rats.

BACKGROUND: To evaluate the effects of Tadalafil, a phosphodiesterase 5 enzyme inhibitor, on Escherichia coli-induced renal damage in an acute pyelonephritis (PN) rat model. METHODS: Experimental PN was induced in 32 Wistar rats, and four groups were formed: group 1 (no treatment), group 2 (antibiotic), group 3 (Tadalafil), and group 4 (antibiotic + Tadalafil). Antibiotic was given on days 3 to 8, and Tadalafil was administered between days 0 and 28 of bacterial inoculation. Half of the rats were killed on the ninth day (early period) and histopathological parameters, immunohistochemical renal fibrosis markers, and oxidant/antioxidant system activities were evaluated. The rest of the rats were killed at the sixth week of the study and evaluated for histopathological parameters and renal fibrosis markers. RESULTS: Inflammatory activity was significantly milder in rats treated with antibiotic + Tadalafil versus no treatment group both in the early and late periods. In the late period, interstitial fibrosis or tubular atrophy was lower in the antibiotic + Tadalafil group versus the no treatment and antibiotic groups, and in Tadalafil versus antibiotic group. Tadalafil administration significantly reduced renal malondialdehyde and nitric oxide levels and enhanced superoxide dismutase and catalase activities. In addition, circulating tumor necrosis factor α, interleukin 1ß was greatly reduced in Tadalafil group versus the no treatment group. CONCLUSIONS: We have provided the first evidence that phosphodiesterase 5 enzyme inhibitor Tadalafil ameliorates circulating inflammatory cytokines, reverses oxidant/antioxidant dysfunction and eventually possesses an overall protective effect on renal tissue from Escherichia coli-induced PN-related kidney injury. Phophodieterase 5 inhibitor might be a novel therapeutic target for PN.

Effect of rapid plasma volume expansion during anesthesia induction on haemodynamics and oxygen balance in patients undergoing gastrointestinal surgery.

AIMS: To investigate the reasonable dose of Voluven for rapid plasma volume expansion during the anaesthesia induction patients receiving gastrointestinal surgery. METHODS: Sixty patients were randomly divided into three groups (n=20): Group A (5 ml/kg), Group B (7 ml/kg) and Group C (9 ml/kg). HES 130/0.4 was intravenously transfused at a rate of 0.3 ml/kg/min) at 30 min before anaesthesia induction. Besides standard haemodynamic monitoring, cardiac index (CI), systemic vascular resistance index (SVRI) and stroke volume variation (SVV) was continuously detected with the FloTrac/Vigileo system. Haemodynamic variables were recorded immediately before fluid transfusion (T0), immediately before induction (T1), immediately before intubation (T2), immediately after intubation (T3) and 5 min, 10 min, 20 min and 60 min after intubation (T4-T7). Arterial and venous blood was collected for blood gas analysis, Hb and Hct before volume expansion (t0), immediately after volume expansion (t1) and at 1 h after volume expansion (t2). Oxygen delivery (DO2), oxygen extraction ratio (ERO2) and volume expansion rate were calculated. RESULTS: 1) MAP and CI decreased in Group A in T2~T7 and remained changed in Group B and C. 2) CVP increased in three groups after fluid infusion without significant difference. 3) The decrease in SVRI was more obvious in Group B and C than that in Group A after induction and more obvious in Group C than in Group B in T2-T4 and T6~T7. 4) SVV was lower in Group B and C than that in Group A after intubation, and lower in Group C than that in Group B in T3-T6. 5) Hb and Hct decreased after fluid infusion, and the decrease in Hb and Hct was in the order of C>B>A. 6) Volume expansion rate was in the order of C>B>A. 7) ScvO2, PaO2 and DO2 increased in three groups after fluid infusion and the increase in DO2 was in the order of C>B>A. CONCLUSIONS: Rapid plasma volume expansion with Voluven at 7-9 ml/kg can prevent haemodynamic fluctuation during anaesthesia induction, maintain the balance between oxygen supply and oxygen consumption during gastrointestinal surgery, and Voluven at 9 ml/kg can improve the oxygen delivery.

Stroke volume variation for prediction of fluid responsiveness in patients undergoing gastrointestinal surgery.

BACKGROUND: Stroke volume variation (SVV) has been shown to be a reliable predictor of fluid responsiveness. However, the predictive role of SVV measured by FloTrac/Vigileo system in prediction of fluid responsiveness was unproven in patients undergoing ventilation with low tidal volume. METHODS: Fifty patients undergoing elective gastrointestinal surgery were randomly divided into two groups: Group C [n(1)=20, tidal volume (V(t)) = 8 ml/kg, frequency (F) = 12/min] and Group L [n(2)=30, V(t)= 6 ml/kg, F=16/min]. After anesthesia induction, 6% hydroxyethyl starch130/0.4 solution (7 ml/kg) was intravenously transfused. Besides standard haemodynamic monitoring, SVV, cardiac output, cardiac index (CI), stroke volume (SV), stroke volume index (SVI), systemic vascular resistance (SVR) and systemic vascular resistance index (SVRI) were determined with the FloTrac/Vigileo system before and after fluid loading. RESULTS: After fluid loading, the MAP, CVP, SVI and CI increased significantly, whereas the SVV and SVR decreased markedly in both groups. SVI was significantly correlated to the SVV, CVP but not the HR, MAP and SVR. SVI was significantly correlated to the SVV before fluid loading (Group C: r = 0.909; Group L: r = 0.758) but not the HR, MAP, CVP and SVR before fluid loading. The largest area under the ROC curve (AUC) was found for SVV (Group C, 0.852; Group L, 0.814), and the AUC for other preloading indices in two groups ranged from 0.324 to 0.460. CONCLUSION: SVV measured by FloTrac/Vigileo system can predict fluid responsiveness in patients undergoing ventilation with low tidal volumes during gastrointestinal surgery.

Identification of feature genes and key biological pathways in immune-mediated necrotizing myopathy: High-throughput sequencing and bioinformatics analysis.

Background: Immune-mediated necrotizing myopathy (IMNM), a subgroup of idiopathic inflammatory myopathies (IIMs), is characterized by severe proximal muscle weakness and prominent necrotic fibers but no infiltration of inflammatory cells. IMNM pathogenesis is unclear. This study investigated key biomarkers and potential pathways for IMNM using high-throughput sequencing and bioinformatics technology. Methods: RNA sequencing was conducted in 18 IMNM patients and 10 controls. A combination of weighted gene coexpression network analysis (WGCNA) and differentially expressed gene (DEG) analysis was conducted to identify IMNM-related DEGs. Feature genes were screened out by employing the protein-protein interaction (PPI) network, support vector machine-recursive feature elimination (SVM-RFE), and least absolute shrinkage selection operator (LASSO). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to verify their differential expression, and the receiver operating characteristic curve (ROC) was used to evaluate their diagnostic efficiency. Functional enrichment analysis was applied to reveal the hidden functions of feature genes. Furthermore, 28 immune cell abundance patterns in IMNM samples were measured. Results: We identified 193 IMNM-related DEGs that were aberrantly upregulated in the IMNM population and were closely associated with immune-inflammatory responses, regulation of skeletal and cardiac muscle contraction, and lipoprotein metabolism. With the help of the PPI network and the LASSO and SVM-RFE algorithms, three feature genes, LTK, MYBPH, and MYL4, were identified and further confirmed by qRT-PCR. ROC curves among IMNM, dermatomyositis (DM), inclusion body myositis (IBM), and polymyositis (PM) samples validated the LTK and MYL4 genes as IMNM-specific feature markers. In addition, all three genes had a notable association with the autophagy-lysosome pathway and immune-inflammatory responses. Ultimately, IMNM displayed a marked immune-cell infiltrative microenvironment. The most significant correlation was found between CD4 T cells, CD8 T cells, macrophages, natural killer (NK) cells, and dendritic cells (DCs). Conclusions: LTK, MYBPH, and MYL4 were identified as potential key molecules for IMNM and are believed to play a role in the autophagy-lysosome pathway and muscle inflammation.

Potential common molecular mechanisms between Sjögren syndrome and inclusion body myositis: a bioinformatic analysis and in vivo validation.

Background: Inclusion body myositis (IBM) is a slowly progressive inflammatory myopathy that typically affects the quadriceps and finger flexors. Sjögren's syndrome (SS), an autoimmune disorder characterized by lymphocytic infiltration of exocrine glands has been reported to share common genetic and autoimmune pathways with IBM. However, the exact mechanism underlying their commonality remains unclear. In this study, we investigated the common pathological mechanisms involved in both SS and IBM using a bioinformatic approach. Methods: IBM and SS gene expression profiles were obtained from the Gene Expression Omnibus (GEO). SS and IBM coexpression modules were identified using weighted gene coexpression network analysis (WGCNA), and differentially expressed gene (DEG) analysis was applied to identify their shared DEGs. The hidden biological pathways were revealed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Furthermore, protein-protein interaction (PPI) networks, cluster analyses, and hub shared gene identification were conducted. The expression of hub genes was validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR). We then analyzed immune cell abundance patterns in SS and IBM using single-sample gene set enrichment analysis (ssGSEA) and investigated their association with hub genes. Finally, NetworkAnalyst was used to construct a common transcription factor (TF)-gene network. Results: Using WGCNA, we found that 172 intersecting genes were closely related to viral infection and antigen processing/presentation. Based on DEG analysis, 29 shared genes were found to be upregulated and enriched in similar biological pathways. By intersecting the top 20 potential hub genes from the WGCNA and DEG sets, three shared hub genes (PSMB9, CD74, and HLA-F) were derived and validated to be active transcripts, which all exhibited diagnostic values for SS and IBM. Furthermore, ssGSEA showed similar infiltration profiles in IBM and SS, and the hub genes were positively correlated with the abundance of immune cells. Ultimately, two TFs (HDGF and WRNIP1) were identified as possible key TFs. Conclusion: Our study identified that IBM shares common immunologic and transcriptional pathways with SS, such as viral infection and antigen processing/presentation. Furthermore, both IBM and SS have almost identical immune infiltration microenvironments, indicating similar immune responses may contribute to their association.

Low T3 syndrome predicts more adverse events in patients with hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common cardiac genetic disorder that clinically manifests with sudden death and progressive heart failure. Moreover, thyroid dysfunction is associated with increased cardiovascular morbidity and mortality risks. Therefore, this study aimed to clarify whether thyroid hormones could serve as an independent predictor of adverse events in patients with HCM. METHODS: The cohort consisted of 782 patients with HCM who had thyroid hormones baseline data and were admitted to the Affiliated Hospital of Jiaxing University. Patients were divided into two groups according to serum levels of free triiodothyronine (fT3): the normal fT3 and low triiodothyronine (T3) syndrome groups. Low T3 syndrome was defined as fT3 < 2.43 pmol/L with a normal thyroid-stimulating hormone (TSH) level. Patients whose TSH levels were abnormally high or abnormally low were excluded from this study. The primary endpoint was the occurrence of sudden cardiac death (SCD) events, and the secondary endpoint was a composite of worsening heart failure (WHF) events, including heart failure death, cardiac decompensation, hospitalization for heart failure, and HCM-related stroke. The Kaplan-Meier and Cox regression were performed for the survival analysis. RESULTS: After a median follow-up of 52 months, 75 SCD events and 134 WHF events were recorded. The Kaplan-Meier survival curves showed that the cumulative incidence of SCD events and WHF events were significantly higher in patients with low T3 syndrome (log-rank p = .02 and log-rank p = .001, respectively). Furthermore, multivariate Cox regression analysis demonstrated that low T3 syndrome is a strong predictor of SCD events and WHF events (adjusted hazard ratio [HR: 1.53, 95% confidence interval [CI]: 1.13-2.24, p < .01; HR: 3.87, 95% CI: 2.91-4.98, p < .001, respectively). CONCLUSIONS: Low T3 syndrome is highly prevalent among patients with HCM and was independently associated with an increased risk of SCD events and WHF events. The routine assessment of serum fT3 levels may provide risk stratification in this population.

Thermolides, potent nematocidal PKS-NRPS hybrid metabolites from thermophilic fungus Talaromyces thermophilus.

Macrocyclic PKS-NRPS hybrid metabolites represent a unique family of natural products mainly from bacteria with broad and outstanding biological activities. However, their distribution in fungi has rarely been reported, and little has been reported regarding their nematocidal activity. Here we describe an unprecedented class of PKS-NRPS hybrid metabolites possessing a 13-membered lactam-bearing macrolactone, thermolides A-F (1-6) from a thermophilic fungus Talaromyces thermophilus. We showed that 1 and 2 displayed potent inhibitory activity against three notorious nematodes with LC(50) values of 0.5-1 µg/mL, as active as commercial avermectins. This work provided a new class of promising lead compounds for nematocide discovery.