Variability in Plasma Lipids Between Intensive Statin Therapy and Conventional-Dose Statins Combined with Ezetimibe Therapy in Patients with Coronary Atherosclerosis Disease.

Dyslipidemia has been widely recognized as a significant risk factor for coronary atherosclerosis disease (CAD). In fact, lipid variability has emerged as a more reliable predictor of cardiovascular events. In this study, we aimed to examine the variability in plasma lipids under two different lipid-lowering regimens (intensive statin therapy versus the combination of conventional-dose statins with ezetimibe). In total, we have retrospectively examined 1275 patients with CAD from January 2009 to April 2019 and divided them into two groups: intensive statin group and conventional-dose statins combined with ezetimibe group. All patients were followed up for at least 1 year. Lipid variability was verified by standard deviation (SD), coefficient of variation (CV), and variability independent of mean (VIM) triple methods. Multiple linear regression and subgroup analyses were performed. In the overall participants, the mean age was 62.3 ± 10.4 years old, and 72.8% were male. Multivariate linear regression analysis indicated that the intensive statin group had lower variability in terms of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and non-high-density lipoprotein cholesterol (non-HDL-C) in all SD, CV, and VIM triple methods than statins combined with ezetimibe group (P for all <0.05). Similar results were established in the subgroup analyses based on atorvastatin or rosuvastatin, diabetes mellitus or not, and hypertension or not (P for all < 0.05). Thus, we can conclude that intensive statin therapy could contribute in lowering lipid variability than conventional-dose statins combined with ezetimibe therapy among patients with CAD.

Estrogen alleviates acute and chronic itch in mice.

Itching is associated with various skin diseases, including atopic dermatitis and allergic dermatitis, and leads to repeated scratching behavior and unpleasant sensation. Although clinical and laboratory research data have shown that estrogen is involved in regulating itch, the molecular and cellular basis of estrogen in itch sensation remains elusive. In the present study, it was found that estrogen-treated mice exhibited reduced scratching bouts when challenged with histamine, chloroquine, the proteinase-activated receptor-2 activating peptide SLIGRL-NH2 (SLIGRL), compound 48/80, and 5-hydroxytryptamine when compared with mice in the placebo group. Moreover, estrogen also suppressed scratching bouts in the mouse model of chronic itch induced by acetone-ether-water treatment. Notably, consistent with the behavioral tests, the present RNA-seq analysis showed that estrogen treatment caused significantly reduced expression levels of itch-related molecules such as Mas-related G-protein coupled receptor member A3, neuromedin B and natriuretic polypeptide b. In addition, estradiol attenuated histamine-induced and chloroquine-induced calcium influx in dorsal root ganglion neurons. Collectively, the data of the present study suggested that estrogen modulates the expression of itch-related molecules and suppresses both acute and chronic itch in mice.

Association of Pre-procedural Nutritional Indicators with Periprocedural Myocardial Infarction in Patients Undergoing Elective Percutaneous Coronary Intervention.

Nutritional risk is closely related to the poor prognosis of hospitalized patients. However, the association of pre-procedural nutritional risk with periprocedural myocardial infarction (PMI) after percutaneous coronary intervention (PCI) remains unclear.A total of 22,267 patients who underwent elective PCI were enrolled in this retrospective cross-sectional study. Nutritional risk was evaluated by three nutritional risk assessment tools, namely, controlling nutritional status (CONUT), prognostic nutritional index (PNI), and geriatric nutritional risk index (GNRI). PMI after PCI was defined as elevation of cardiac troponin I (cTnI) values > 5 × 99th percentile upper reference limit. Linear regression analysis was performed to explore the association of nutritional risk assessment tools with cTnI fold elevation. Log-binomial regression analysis was conducted to determine the association of nutritional risk assessment tools with PMI.The average age of the enrolled patients was 66.4 years old, and 2,647 of them (11.9%) suffered PMI after PCI. Multivariable linear regression analysis determined a linear association between nutritional risk assessment tools and cTnI fold elevation (CONUT: ß = 0.220, 95% CI [0.088-0.352], P = 0.001; PNI: ß = -0.105, 95% CI [-0.146 to -0.065], P < 0.001; GNRI: ß = -0.090, 95% CI [-0.122 to -0.057], P < 0.001). Log-binomial regression analysis showed that nutritional risk assessment tools were strongly associated with PMI after PCI (CONUT [4-12 versus 0-1]: RR = 1.168, 95% CI [1.054-1.295], P = 0.003; PNI [< 44 versus ≥ 52]: RR = 1.168, 95% CI [1.038-1.315], P = 0.010; GNRI [< 98 versus ≥ 108]: RR = 1.128, 95% CI [1.006-1.264], P = 0.039).Pre-procedural nutritional status, assessed by CONUT, PNI, and GNRI, was significantly and strongly associated with PMI in patients undergoing elective PCI.

TRPV4 is not the molecular sensor for bacterial lipopolysaccharides-induced calcium signaling.

Lipopolysaccharides (LPS) is one of the most potent pathogen-associated signals for the immune system of vertebrates. In addition to the canonical pathway of LPS detection mediated by toll-like receptor 4 (TLR4) signaling pathway, TRP channel-mediated pathways endow sensory neurons and epithelial cells with the ability to detect and react to bacterial endotoxins. Previous work revealed that LPS triggers TRPV4-dependent calcium influx in urothelial cells (UCs) and mouse tracheobronchial epithelial cells (mTEC). In marked contrast, here we show that most subtypes of LPS could not directly activate TRPV4 channel. Although LPS from Salmonella enterica serotype Minnesota evoked a [Ca2+]i response in freshly isolated human bronchial epithelial cells (ECs), freshly isolated mouse ear skin single-cell suspensions, or HEK293T cells transiently transfected with mTRPV4, this activation occurred in a TRPV4-independent manner. Additionally, LPS from either E. coli strains or Salmonella enterica serotype Minnesota did not evoke significant difference in inflammation and pain hyperalgesia between wild type and TRPV4 deficient mice. In summary, our results demonstrate that in vitro and in vivo effects induced by LPS are independent of TRPV4, thus providing a clarity to the questioned role of LPS in TRPV4 activation.

Notch1 signaling contributes to TLR4-triggered NF-κB activation in macrophages.

Macrophages substantially influence the development, progression, and complications of inflammation-driven diseases. Although numerous studies support the critical role of Notch signaling in most inflammatory diseases, there is limited data on the role of Notch signaling in TLR4-induced macrophage activation and interaction of Notch signaling with other signaling pathways in macrophages during inflammation, such as the NF-κB pathway. This study confirmed that stimulation with lipopolysaccharide (LPS), a TLR4 ligand, upregulated Notch1 expression in monocyte/macrophage-like RAW264.7 cells and bone marrow-derived macrophages (BMDMs). LPS also induced increased mRNA expression of Notch target genes Notch1 and Hes1 in macrophages, suggesting that TLR4 signaling enhances activation of the Notch pathway. The upregulation of Notch1, Notch1 intracellular domain (NICD), and Hes1 proteins by LPS treatment was inhibited by DAPT, a Notch1 inhibitor. Additionally, the increased TNF-α, IL-6, and IL-1ß expression induced by LPS was inhibited by DAPT and rescued by jagged1, a Notch1 ligand. Furthermore, suppression of Notch signaling by DAPT upregulated Cylindromatosis (CYLD) expression but downregulated TRAF6 expression, IκB kinase (IKK) α/ß phosphorylation, and subsequently, phosphorylation and degradation of IκB-α, indicating that DAPT inhibited NF-κB activation triggered by TLR-4. Interestingly, DAPT did not inhibit the increased MyD88 expression induced by LPS. Our study findings demonstrate that macrophage stimulation via the TLR4 signaling cascade triggers activation of Notch1 signaling, which regulates the expression patterns of genes involved in pro-inflammatory responses by activating NF-κB. This effect may be dependent on the CYLD-TRAF6-IKK pathway. Thus, Notch1 signaling may provide a therapeutic target against infectious and inflammation-driven diseases.

Hypercholesterolemia attenuates cardioprotection of ischemic preconditioning and postconditioning with α7 nicotinic acetylcholine receptor agonist by enhancing inflammation and inhibiting the PI3K/Akt/eNOS pathway.

The present study aimed to evaluate the effects of hypercholesterolemia on cardioprotection of ischemic preconditioning and α7 nicotinic acetylcholine receptor (α7nAChR) agonist postconditioning and explore the potential mechanisms that hypercholesterolemia affected their cardioprotection. Hypercholesterolemic and normal rats were divided into the four groups that received the following treatments: i) Hypercholesterolemic control and normal control groups; ii) hypercholesterolemic ischemia/reperfusion (HI) and normal ischemia/reperfusion (NI) groups; iii) hypercholesterolemic ischemic preconditioning (HIPC) and normal ischemic preconditioning (NIPC) groups; and iv) hypercholesterolemic PNU282987 postconditioning (HPNU) and normal PNU282987 postconditioning (NPNU) groups. Serum lactate dehydrogenase (LDH), creatine kinase isoenzyme MB (CK-MB), cardiac troponin I (cTnI), tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) levels after ischemia/reperfusion were assayed. Furthermore, infarct size and expression levels of Akt, phosphorylated (p)-Akt and endothelial nitric oxide synthase (eNOS) in ischemic myocardium were assessed. Compared with the NI group, serum LDH, CK-MB, cTnI, TNF-α and IL-6 levels and infarct size were significantly decreased, and myocardial p-Akt/Akt and eNOS/GAPDH ratios were significantly increased in the NIPC and NPNU groups. Compared with the HI group, serum CK-MB, cTnI, TNF-α and IL-6 levels and infarct size were significantly decreased in the HIPC group; however, myocardial p-Akt/Akt and eNOS/GAPDH ratios did not significantly change in the HIPC group. Furthermore, there were no significant difference between the HI and HPNU groups in serum LDH, CK-MB, cTnI, TNF-α and IL-6 levels, infarct size, myocardial p-Akt/Akt and eNOS/GAPDH ratios. In conclusion, hypercholesterolemia could aggravate myocardial ischemia/reperfusion injury, attenuate cardioprotection of ischemic preconditioning and eliminate cardioprotection from α7nAChR agonist postconditioning by enhancing inflammation and inhibiting PI3K/Akt/eNOS pathway.

BNP facilitates NMB-encoded histaminergic itch via NPRC-NMBR crosstalk.

Histamine-dependent and -independent itch is conveyed by parallel peripheral neural pathways that express gastrin-releasing peptide (GRP) and neuromedin B (NMB), respectively, to the spinal cord of mice. B-type natriuretic peptide (BNP) has been proposed to transmit both types of itch via its receptor NPRA encoded by Npr1. However, BNP also binds to its cognate receptor, NPRC encoded by Npr3 with equal potency. Moreover, natriuretic peptides (NP) signal through the Gi-couped inhibitory cGMP pathway that is supposed to inhibit neuronal activity, raising the question of how BNP may transmit itch information. Here, we report that Npr3 expression in laminae I-II of the dorsal horn partially overlaps with NMB receptor (NMBR) that transmits histaminergic itch via Gq-couped PLCß-Ca2+ signaling pathway. Functional studies indicate that NPRC is required for itch evoked by histamine but not chloroquine (CQ), a nonhistaminergic pruritogen. Importantly, BNP significantly facilitates scratching behaviors mediated by NMB, but not GRP. Consistently, BNP evoked Ca2+ responses in NMBR/NPRC HEK 293 cells and NMBR/NPRC dorsal horn neurons. These results reveal a previously unknown mechanism by which BNP facilitates NMB-encoded itch through a novel NPRC-NMBR cross-signaling in mice. Our studies uncover distinct modes of action for neuropeptides in transmission and modulation of itch in mice.

An itch is a common sensation that makes us want to scratch. Most short-term itches are caused by histamine, a chemical that is released by immune cells following an infection or in response to an allergic reaction. Chronic itching, on the other hand, is not usually triggered by histamine, and is typically the result of neurological or skin disorders, such as atopic dermatitis. The sensation of itching is generated by signals that travel from the skin to nerve cells in the spinal cord. Studies in mice have shown that the neuropeptides responsible for delivering these signals differ depending on whether or not the itch involves histamine: GRPs (short for gastrin-releasing proteins) convey histamine-independent itches, while NMBs (short for neuromedin B) convey histamine-dependent itches. It has been proposed that another neuropeptide called BNP (short for B-type natriuretic peptide) is able to transmit both types of itch signals to the spinal cord. But it remains unclear how this signaling molecule is able to do this. To investigate, Meng, Liu, Liu, Liu et al. carried out a combination of behavioral, molecular and pharmacological experiments in mice and nerve cells cultured in a laboratory. The experiments showed that BNP alone cannot transmit the sensation of itching, but it can boost itching signals that are triggered by histamine. It is widely believed that BNP activates a receptor protein called NPRA. However, Meng et al. found that the BNP actually binds to another protein which alters the function of the receptor activated by NMBs. These findings suggest that BNP modulates rather than initiates histamine-dependent itching by enhancing the interaction between NMBs and their receptor. Understanding how itch signals travel from the skin to neurons in the spinal cord is crucial for designing new treatments for chronic itching. The work by Meng et al. suggests that treatments targeting NPRA, which was thought to be a key itch receptor, may not be effective against chronic itching, and that other drug targets need to be explored.

Distinct roles of NMB and GRP in itch transmission.

A key question in our understanding of itch coding mechanisms is whether itch is relayed by dedicated molecular and neuronal pathways. Previous studies suggested that gastrin-releasing peptide (GRP) is an itch-specific neurotransmitter. Neuromedin B (NMB) is a mammalian member of the bombesin family of peptides closely related to GRP, but its role in itch is unclear. Here, we show that itch deficits in mice lacking NMB or GRP are non-redundant and Nmb/Grp double KO (DKO) mice displayed additive deficits. Furthermore, both Nmb/Grp and Nmbr/Grpr DKO mice responded normally to a wide array of noxious stimuli. Ablation of NMBR neurons partially attenuated peripherally induced itch without compromising nociceptive processing. Importantly, electrophysiological studies suggested that GRPR neurons receive glutamatergic input from NMBR neurons. Thus, we propose that NMB and GRP may transmit discrete itch information and NMBR neurons are an integral part of neural circuits for itch in the spinal cord.

PAX5 promotes pre-B cell proliferation by regulating the expression of pre-B cell receptor and its downstream signaling.

PAX5 is indispensable for the commitment of early lymphoid progenitors to the B cell lineage as well as for the development of B cells. Although previous studies have indicated that the Pax5-conditional-knockout mouse exhibited dedifferentiation of mature B cell and the development of aggressive lymphomas, the changes of Pax5 gene expressions in pre-B cells have not been analyzed. To understand the functional importance of Pax5 gene in the proliferation and survival of pre-B cells, we established a Pax5-knockdown model using 70Z/3 pre-B cell line. Pax5 knockdown 70Z/3 cells (70Z/3-KD cells) showed down-regulations of pre-BCR compounds such as CD19, BLNK, Id2 and λ5. The signaling via pre-BCRs was significantly diminished in the 70Z/3-KD cells, and this alteration was normalized by restored Pax5 gene expression. Loss of PAX5 reduced the growth rates in the 70Z/3-KD cells, compared to the mock cells. Meanwhile, the proliferation of pre-B cells was reduced by the knockdown of Pax5 gene. Moreover, further examinations showed that PAX5 was also activated in B cell acute lymphoblastic leukemia (B-ALL) as a cell proliferation enhancer. These findings suggested that pax5 is critically important for the proliferation and survival of pre-B cells.

[Application of conscious sedation with dexmedetomidine and sufentanil in patient for plastic surgery].

OBJECTIVE: To observe the effectiveness of conscious sedation with dexmedetomidine and sufentanil in patients for plastic surgery. METHODS: Forty patients scheduled for elective plastic surgery under conscious sedation were infused 1 µg/kg intravenously within 15 minutes as loading dose followed by a continuous infusion of dexmedetomidine (0.5 µg·kg⁻¹·h⁻¹) and sufentanil (0.07 µg·kg⁻¹·h⁻¹) respectively. Sufentanil 0.05 µg/kg and midazolam 0.025 mg/kg were administrated intravenously 5 minutes before local infiltration, and then a bolus of sufentanil or midazolam was given as needed to maintain OAA/S score of 11 during the procedure. The drug infusion was discontinued at 5 to 10 min before the end of the surgical procedure. The complications (i.e. anoxemia, apnea, bradycardia, restlessness, nausea, vomiting, crying and excitation), if any, anesthesia duration and drug consumption were recorded. On the first postoperative day, patients were asked to rate their satisfaction with the anesthetic management and whether they would choose to receive the same sedative analgesic medications and should they require a similar surgical procedure in the future. RESULTS: The OAA/S score decreased from 20.0 ± 0 to 11.5 ± 2.5 after patients being infused the loading dose of dexmedetomidine, and was maintained 10.5-11.1 during the procedure. At the end of the procedure, the OAA/S score return to 16.1 ± 2.8. The induction of sedation produced a significant decrease in HR (P < 0.05) and no significant changes in SBP, DBP and RR values (P > 0.05). There were 38 patients completed their procedures under conscious sedation, and there were incident of crying and bradycardia in 5 and 2 patients respectively. The anesthesia duration and consumption of dexmedetomidine, sufentanil and midazolam were (128 ± 47) min, (116 ± 43) µg, (10 ± 5) µg and (2 ± 1) mg respectively. In an interview on the first postoperative day, there were 13 patients complaining no memory, 17 patients complaining fuzzy memory and 8 patients complaining awake during the procedure, respectively. There were 92% of the patients willing to receive the same anesthetic technique again in the future. CONCLUSION: Conscious sedation with dexmedetomidine and sufentanil is an effective anesthetic technique in patients for plastic surgery.

[Effects of root exudates of clover (Trifolium repens) on PAH microbial degradation and dioxygenase].

To demonstrate rhizospheric effect on the mechanism of (polycyclic aromatic hydrocarbon) PAH degradation, and to establish a proper joint phyto-microbial remediation mode, microcosms containing microorganisms and PAHs (pyrene and benzo[a]Pyrene) were added with clover (Trifolium repens) root exudates to study their effects on PAH degradation. Dioxygenase gene and 16S rDNA gene copy number changes during the biodegradation process were analyzed, and the microorganism with a good ability for degrading PAHs was identified. The results showed that Mycobacterium M1 had the capability to degrade PAHs. When total organic carbon (TOC) concentration of clover root exudates was 35.5 mg · L(-1), pyrene and benzo[a]pyrene degradation rates increased significantly, and the proportion of dioxygenase gene to 16S rDNA of Mycobacterium M1 increased. In the biodegradation process, dioxygenase gene copy number increased significantly, whereas 16S rDNA copy number increase was not so obvious, showing that the former was related to degradation process, but the latter was related to microbial numbers. It was concluded that the clover root exudates promoted the dioxygenase gene copy number of Mycobacterium M1, which contributed to the degradation of PAHs.

Reduction of Salmonella enteritidis number after infections by immunization of liposome-associated recombinant SefA.

In order to generate Salmonella enterica serovar Enteritidis (Salmonella Enteritidis) fimbriae, SEF14, the sefA gene, which encodes the main subunit of the SEF14 fimbrial protein, was amplified from Salmonella Enteritidis by polymerase chain reaction (PCR) and subcloned into a prokaryotic expression vector pET-28a(+) to yield pET-28a(+)-sefA. The recombinant SefA (rSefA) protein was highly expressed and purified by nickel-affinity chromatography. Liposome-associated rSefA was prepared for oral immunization to seek protective efficacy for intestinal infection with Salmonella Enteritidis. The titers of the IgG and IgA in the intestinal mucus were 1:256 and 1:512, respectively. Moreover, the titers of IgG and IgA in the sera were 1:256 and 1:128, respectively. Two weeks after the booster immunization, the chickens were challenged orally with 2 x 10(6) colony-forming units (CFUs) of live Salmonella Enteritidis, and fecal samples were examined for bacterial excretion from the intestinal tract. Significantly less fecal excretion of bacteria was observed in immunized chickens for 4 wk after challenge. The numbers of bacteria in the intestinal contents (cecum and rectum) were also significantly reduced in immunized chickens, in contrast with the unimmunized controls. Oral immunization with liposome-associated rSefA therefore elicits both systemic and mucosal antibody responses and results in reduced bacterial colonization in the intestinal tract and reduced excretion of Salmonella Enteritidis in the feces.

Sandwich-dot enzyme-linked immunosorbent assay for the detection of canine distemper virus.

A sandwich-dot enzyme-linked immunosorbent assay (dot ELISA) was developed for the detection of canine distemper virus (CDV). In 56 dogs suspected to have CD the rates of detection of CDV antigen in samples of blood lymphocytes and palpebral conjunctiva by dot ELISA and ELISA were, respectively, 91% (49/54) and 81% (44/54) for the lymphocyte samples and 88% (28/32) and 75% (24/32) for the conjunctival samples. The CDV detection limits were 10 ng/50 µL for dot ELISA and 40 ng/50 µL for ELISA. The reliability of dot ELISA relative to electron microscopy was 96% with 22 samples: all 21 samples in which CDV particles were observed by electron microscopy yielded positive results with dot ELISA; the single sample in which particles were not observed yielded false-positive results with dot ELISA. The results indicate that the dot ELISA developed can serve as a reliable rapid diagnostic test in suspected cases of CD and also be useful for epidemiologic surveillance of the disease.

Une épreuve immuno-enzymatique sandwich par point (dot ELISA) a été développée afin de détecter le virus du distemper canin (CDV). Chez 56 chiens suspectés d'avoir le CD, les taux de détection d'antigène du CDV dans des échantillons de lymphocytes sanguins et de la conjonctive palpébrale par dot ELISA et ELISA étaient, respectivement, 91 % (49/54) et 81 % (44/54) pour les échantillons de lymphocytes et 88 % (28/32) et 75 % (75/32) pour les échantillons de conjonctive. Les limites de détection de CDV étaient 10 ng/50 µL pour le dot ELISA et 40 ng/50 µL pour l'ELISA. La fiabilité du dot ELISA relativement au microscope électronique était de 96 % avec 22 échantillons : les 21 échantillons à partir desquels des particules de CDV furent observées ont donné des résultats positifs au dot ELISA; le seul échantillon à partir duquel aucune particule ne fut observée a donné un résultat faussement positif au dot ELISA. Les résultats indiquent que l'épreuve dot ELISA développée peut servir en tant que test diagnostique rapide et fiable lors de cas suspectés de CD et peut également être utile pour la surveillance épidémiologique de la maladie.(Traduit par Docteur Serge Messier).

Shikani optical stylet-guided intubation via the intubating laryngeal airway in patients with scar contracture of the face and neck.

OBJECTIVE: To evaluate the feasibility of the Shikani Optical Stylet (SOS)-guided intubation through a new Intubating Laryngeal Airway (ILA) in anticipated difficult airways caused by scar contracture of the face and neck. METHODS: Thirty-three adult patients with anticipated difficult airways undergoing selective faciocervical scar plastic surgery under general anesthesia were enrolled in this study. After anesthesia induction, a size 2.5, 3.5 or 4.5 ILA was inserted. Following good lung ventilation being verified, the SOS preloaded with an endotracheal tube was inserted via the ILA. Once the clear vocal cords came into view under the SOS, the endotracheal tube was advanced through glottis into the trachea. RESULTS: The ILA provided an effective airway in all patients. Intubation was successful at the first attempt on 22/33(66.7%) occasions and at the second attempt on 6/33 (18.2%). Intubation failed in 5 (15.1%) patients who suffered from severe limitation of head extension due to scar contracture of the neck. These patients' tracheas were finally intubated using a fibreoptic bronchoscope via the ILA. CONCLUSIONS: The SOS-guided intubating method via the ILA is a feasible technique in patients with scar contracture of the face and neck. However, in patients with severe limitation of head extension, the use of SOS cannot be recommended. The SOS can be used as an alternative apparatus when the fibreoptic bronchoscope is not available.