Pre-encoded responsiveness to type I interferon in the peripheral immune system defines outcome of PD1 blockade therapy.

Type I interferons (IFN-Is) are central regulators of anti-tumor immunity and responses to immunotherapy, but they also drive the feedback inhibition underlying therapeutic resistance. In the present study, we developed a mass cytometry approach to quantify IFN-I-stimulated protein expression across immune cells and used multi-omics to uncover pre-therapy cellular states encoding responsiveness to inflammation. Analyzing peripheral blood cells from multiple cancer types revealed that differential responsiveness to IFN-Is before anti-programmed cell death protein 1 (PD1) treatment was highly predictive of long-term survival after therapy. Unexpectedly, IFN-I hyporesponsiveness efficiently predicted long-term survival, whereas high responsiveness to IFN-I was strongly associated with treatment failure and diminished survival time. Peripheral IFN-I responsive states were not associated with tumor inflammation, identifying a disconnect between systemic immune potential and 'cold' or 'hot' tumor states. Mechanistically, IFN-I responsiveness was epigenetically imprinted before therapy, poising cells for differential inflammatory responses and dysfunctional T cell effector programs. Thus, we identify physiological cell states with clinical importance that can predict success and long-term survival of PD1-blocking immunotherapy.

All is not lost: learning from 9p21 loss in cancer.

The cancer research community continues to search for additional biomarkers of response and resistance to immune checkpoint treatment (ICT). The ultimate goal is to direct the use of ICT in patients whose tumors are most likely to benefit to achieve a refinement that is equivalent to that of a genotype-matched targeted treatment. Dissecting the mechanisms of ICT resistance can help us characterize ICT nonresponders more efficiently. In this opinion, we argue that there may be additional knowledge gained about immune evasion in cancer by analyzing the loss of the human 9p21.3 locus; as an example, we highlight findings of 9p21.3 loss from the investigator-initiated, pan-cancer INSPIRE study, in which patients were treated with pembrolizumab (anti-PD-1 antibody) ICT.

Identification of antigenic epitopes recognized by tumor infiltrating lymphocytes in high grade serous ovarian cancer by multi-omics profiling of the auto-antigen repertoire.

Immunotherapeutic strategies aimed at enhancing tumor cell killing by tumor-specific T cells hold great potential for reducing tumor burden and prolonging survival of cancer patients. Although many potential tumor antigens have been described, identifying relevant targets when designing anti-cancer vaccines or targeted cell therapies remains a challenge. To identify novel, potentially immunogenic candidate tumor antigens, we performed integrated tumor transcriptomic, seromic, and proteomic analyses of high grade serous ovarian cancer (HGSC) patient tumor samples. We identified tumor neo-antigens and over-expressed antigens using whole exome and RNA sequencing and examined these in relation to patient-matched auto-antibody repertoires. Focusing on MHC class I epitopes recognized by CD8+ T cells, HLA-binding epitopes were identified or predicted from the highly expressed, mutated, or auto-antibody target antigen, or MHC-associated peptides (MAPs). Recognition of candidate antigenic peptides was assessed within the tumor-infiltrating T lymphocyte (TIL) population expanded from each patient. Known tumor-associated antigens (TAA) and cancer/testis antigens (CTA) were commonly found in the auto-antibody and MAP repertoires and CD8+ TILs recognizing epitopes from these antigens were detected, although neither expression level nor the presence of auto-antibodies correlated with TIL recognition. Auto-antibodies against tumor-mutated antigens were found in most patients, however, no TIL recognition of the highest predicted affinity neo-epitopes was detected. Using high expression level, auto-antibody recognition, and epitope prediction algorithms, we identified epitopes in 5 novel antigens (MOB1A, SOCS3, TUBB, PRKAR1A, CCDC6) recognized by HGSC patient TILs. Furthermore, selection of epitopes from the MAP repertoire identified 5 additional targets commonly recognized by multiple patient TILs. We find that the repertoire of TIL specificities includes recognition of highly expressed and immunogenic self-antigens that are processed and presented by tumors. These results indicate an ongoing autoimmune response against a range of self-antigens targeted by HGSC TILs.

Exosomes Derived from Endothelial Cells Inhibit Neointimal Hyperplasia Induced by Carotid Artery Injury in Rats via ROS-NLRP3 Inflammasome Pathway.

This study attempted to investigate whether exosomes derived from rat endothelial cells (EC-Exo) attenuate intimal hyperplasia after balloon injury using hematoxylin and eosin staining, immunohistochemistry, immunofluorescence staining, Evans blue staining, and Western blotting. The results indicated that EC-Exo inhibited intimal hyperplasia in the carotid artery after balloon injury, promoted re-endothelialization, and reduced vascular inflammation and ROS-NLRP3-mediated cell pyroptosis. Thus, EC-Exo can inhibit neointimal hyperplasia after carotid artery injury in rats presumably by inhibiting the ROS-NLRP3 inflammasome and phenotypic transformation of vascular smooth muscle cells.

[COL11A1 regulates PI3K/Akt/GSK-3ß pathway and promotes human lung adenocarcinoma primary cell migration and invasion].

Objective: To investigate the role and mechanism of COL11A1 in lung adenocarcinoma migration and invasion. Methods: Surgical pathological tissues of 4 patients with lung adenocarcinoma admitted to the Affiliated Hospital of Guizhou Medical University from September to November 2020 were used. Immunohistochemical methods were used to identify lung adenocarcinoma tissues, para-cancerous tissues and parallel transcriptome sequencing. Genetic prognostic analysis was conducted by TCGA and GTEx databases.The expression level of COL11A1 gene in lung adenocarcinoma and adjacent tissues was detected by Western blotting.The primary human lung adenocarcinoma cells cultured. The COL11A1 siRNA was transfected into primary human lung adenocarcinoma cells, then the transcriptome sequencing of differential genes was performed,and KEGG enrichment analysis of differential gene enrichment pathway was conducted. Protein expression and phosphorylation were detected by Western blot method. Cell migration was detected by scratch healing test. Cell proliferation was detected by CCK8 method and invasion ability was detected by Transwell method. Results: Ten differentially expressed genes were screened by transcription sequencing in lung adenocarcinoma. Prognostic analysis of single gene showed that COL11A1 gene expression level was correlated with survival rate (P<0.001). The expression of COL11A1 in lung adenocarcinoma was higher than that in adjacent tissues by Western blot (P<0.001). Transcriptome sequencing of COL11A1 siRNA transfection into primary human lung adenocarcinoma cells showed that differential genes were concentrated in PI3K-akt pathway. The expression of tumor suppressor gene PTEN in siRNA transfection group was significantly higher than that in control group and negative transfection group by Western blot. The expression of Aktp-Akt 473 p-Akt 308 p-PTENp-PDK1p-c-Rafp-GSK-3 ß was down-regulated (all P<0.05).Compared with the negative control group, the ability of migration, proliferation and invasion of primary human lung adenocarcinoma cells in siRNA transfection group decreased (all P<0.05). COL11A1 regulates PI3K/Akt/GSK-3 ß pathway to promote migration and invasion of primary human lung adenocarcinoma cells. Conclusion: COL11A1 regulates PI3K/Akt/GSK-3 ß pathway to promote migration and invasion of primary human lung adenocarcinoma cells.

Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation.

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10-15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10-8) and mtDNA replication (p = 1.2 × 10-7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10-4).

[Role of the CCL28-CCR10 pathway in monocyte migration in rheumatoid arthritis].

OBJECTIVE: To examine the expression of chemokine receptor CCR10 on monocytes/macrophages in the joints of patients with rheumatoid arthritis (RA), and to investigate the role of chemokine CCL28 and its receptor CCR10 in the migration of RA monocytes and its mechanism. METHODS: The expression of CCR10 in synovial tissues from 8 RA patients, 4 osteoarthritis (OA) patients, and 4 normal controls was analyzed by immunohistochemistry, and cell staining was scored on a 0-5 scales. Flow cytometry was used to measure the percentage of CCR10 positive cells in CD14+ monocytes from peripheral blood of 26 RA patients and 20 healthy controls, as well as from synovial fluid of 15 RA patients. The chemotactic migration of monocytes from RA patients and healthy controls in response to CCL28 was evaluated using an in vitro Transwell system. Western blotting was conducted to assess phosphorylation of the extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) pathways in RA monocytes upon CCL28 treatment. RESULTS: CCR10 was predominantly expressed in RA synovial lining cells and sublining macrophages, endothelial cells, and lymphocytes. CCR10 expression was significantly increased on lining cells and sublining macrophages in RA synovial tissue compared with OA and normal synovial tissue (both P < 0.01). The patients with RA had markedly elevated expression of CCR10 on peripheral blood CD14+ monocytes compared with the healthy controls [(15.6±3.0)% vs. (7.7±3.8)%, P < 0.01]. CCR10 expression on synovial fluid monocytes from the RA patients was (32.0±15.0)%, which was significantly higher than that on RA peripheral blood monocytes (P < 0.01). In vitro, CCL28 caused significant migration of CD14+ monocytes from peripheral blood of the RA patients and the healthy controls at concentrations ranging from 10-100 µg/L (all P < 0.01). The presence of neutralizing antibody to CCR10 greatly suppressed CCL28-driven chemotaxis of RA monocytes (P < 0.01). Stimulation of RA monocytes with CCL28 induced a remarkable increase in phosphorylation of ERK and Akt (both P < 0.05). ERK inhibitor (U0126) and phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002) strongly reduced the migration of RA monocytes in response to CCL28 (both P < 0.01). CONCLUSION: RA patients had increased CCR10 expression on peripheral blood, synovial fluid, and synovial tissue monocytes/macrophages. CCL28 ligation to CCR10 promoted RA monocyte migration through activation of the ERK and PI3K/Akt signaling pathways. The CCL28-CCR10 pathway could participate in monocyte recruitment into RA joints, thereby contributing to synovial inflammation and bone destruction.

[The surveillance analysis of the adverse events following immunization of the domestic 13-valent pneumococcal polysaccharide conjugate vaccine in Zhejiang Province].

To evaluate the safety of the domestic 13-valent pneumococcal polysaccharide conjugate vaccine-tetanus toxoid protein (PCV13-TT) after its licensure. The adverse event following immunization (AEFI) and the vaccination data of PCV13-TT in Zhejiang province from July 2020 to October 2021 were collected from national adverse event following immunization surveillance system and Zhejiang provincial immunization information system. Descriptive epidemiological method was used for this analysis. From July 2020 to October 2021, 302 317 doses of PCV13-TT were administered in children under 6 years old in Zhejiang Province and 636 AEFI case reports were received, with a reporting rate of 21.04 per 10 000 doses. Of these AEFI cases, 97.17% were mild vaccine product-related reaction (20.54 per 10 000 doses) and 95.44% occurred in the 0-1 d after vaccination (20.08 per 10 000 doses). The most common clinical diagnoses of AEFI included fever (224 cases), redness (204 cases), and induration (190 cases), while allergic rash (11 cases) was the most common diagnosis among the abnormal reactions. In conclusion,the present results bolstered that the domestic PCV13-TT was generally well tolerated in children under 6 years old in Zhejiang Province.

Lifetime risks of hip fracture in patients with type 2 diabetic: Taiwan Diabetes Study.

This study is to estimate the lifetime risks of hip fracture in Chinese patients with type 2 diabetes. INTRODUCTION: The lifetime risks of hip fracture have not been reported across the age spectrum in male adults and female adults with type 2 diabetes. METHODS: A retrospective cohort study was conducted on 25275 men and 27953 women with type 2 diabetes aged 30-100 years old and participated in the National Diabetes Case Management Program in 2002-2004 in Taiwan. Sociodemographic factors, biomarkers, and comorbidity at the baseline and hip fracture events were analyzed with Cox proportional hazards regression models with age as the time scale. RESULTS: Significant differences in the lifetime risks of hip fracture were observed between men and women with type 2 diabetes. The cumulative lifetime incidences (%) of hip fracture at 50, 60, 65, 70, 75, 80, and 85 years old for men were 0.11, 0.40, 0.84, 1.84, 3.82, 8.53, and 16.72, respectively. The corresponding lifetime incidences (%) for women at 50, 60, 65, 70, 75, 80, and 85 years old were 0.05, 0.50, 1.36, 3.89, 9.56, 21.19, and 35.45, respectively. With competing risks, the significant multivariate-adjusted hazard ratio of developing hip fracture included smoking, alcohol drinking, duration of diabetes, type of oral hypoglycemic drugs use (no medication, sulfonylurea only, thiazolidinediones (TZD) only or TZD plus others, other single or multiple oral agents, insulin use, insulin plus oral hypoglycemic drug use), loop diuretics use, use of corticosteroids, normal weight or underweight, hyperlipidemia, and chronic obstructive pulmonary disease. CONCLUSIONS: The gender differences in lifetime hip fracture risk were significant. Thiazolidinediones and insulin use are factors with the greater magnitude of strength of association among those significantly associated with hip fracture.

The antibiofilm and collagen-stabilizing effects of proanthocyanidin as an auxiliary endodontic irrigant.

AIM: To evaluate the antibiofilm effect of proanthocyanidin (PA) solution as an irrigant against Enterococcus faecalis (E. faecalis) and its influence on the mechanical properties and biodegradation resistance of demineralized root dentine. METHODOLOGY: Enterococcus faecalis were introduced into human root dentine tubules by a serial centrifugation method and grown for 1 week. Dentine blocks infected with 1-week-old E. faecalis biofilms were treated with the following irrigants: sterile water (control), 2% chlorhexidine (CHX), 2% PA, 5% PA and 10% PA. After treatment, the live and dead bacteria proportions within E. faecalis biofilms were analysed using confocal laser scanning microscopy. To evaluate the biostability of fully demineralized dentine treated by the aforementioned irrigants, the elastic modulus and hydroxyproline release of human dentine incubated in collagenase solution were tested at baseline, after irrigant treatment and after biodegradation, respectively. Furthermore, the surface chemical bond of demineralized dentine collagen treated by various irrigants was characterized by X-ray photoelectron spectroscopy (XPS). Statistical analysis was performed using one-way anova and Tukey's post hoc multiple comparisons with the significance level at 5%. RESULTS: The proportion of dead E. faecalis volume was significantly higher in the PA and CHX groups than that in the control group (P < 0.05). PA irrigation significantly increased the mechanical properties of demineralized dentine (P < 0.05), and the effect was enhanced with increasing PA concentration. CHX and PA groups had significantly less elasticity loss and hydroxyproline release (P < 0.05). The biomodification of dentine collagen by PA was verified by increased C-O/C-N peak percentage under C1s and C-O peak percentage under O1s narrow-scan XPS spectra. CONCLUSIONS: Proanthocyanidin killed E. faecalis within biofilms and enhanced the biostability of the collagen matrix of demineralized root dentine. It might be used as an auxiliary endodontic irrigant with antibiofilm and collagen-stabilizing effects.

[Clinical characteristics of patients with Klebsiella pneumoniae pyogenic liver abscess].

Objective: To summarize the clinical features of patients with Klebsiella pneumoniae pyogenic liver abscess(KP-PLA). Methods: Clinical data of 133 patients with pyogenic liver abscess(PLA) and positive results of blood or pus culture were retrospectively analyzed in Huashan Hospital Affiliated to Fudan University from 2009 to 2018. According to the culture results, patients were divided into KP-PLA group (n=92) and non-KP-PLA group (n=41). Results: KP-PLA and non-KP-PLA were similar in gender composition with males accounting for 67.39% and 70.73%, and had age of (56.8±13.8) years and (55.0±13.0) years (χ(2)=0.146, 0.708, P>0.05) respectively. The underlying diseases were more common in KP-PLA group, including diabetes accounting for 45.65% and 24.39%, and hypertension accounting for 32.61% and 14.63% (χ(2)=5.384, 4.642, P<0.05) respectively. Patients with KP-PLA had more invasive infections beyond liver than those with non-KP-PLA, which were 27.17% and 9.76% (χ(2)=5.046, P=0.025). The laboratory results showed that hemoglobin levels in KP-PLA and non-KP-PLA were (109.88±20.97) g/L and (97.75±20.25) g/L (t=3.086, P=0.002). Serum alkaline phosphatase levels were 146.50 (114.50, 237.50) U/L and 220.50 (120.00, 316.75) U/L in KP-PLA and non-KP-PLA (U=2 239.500, P=0.048) patients. Conclusions: KP-PLA mainly develops in middle-aged and elderly men, especially those with diabetes and hypertension. Patients with KP-PLA need to be paid more attention for invasive manifestations beyond liver.

[Screening core genes and cyclin B2 as a potential diagnosis, treatment and prognostic biomarker of hepatocellular carcinoma based on bioinformatics analysis].

Objective: To screen out and explore the core gene (Hub gene) involvement and the potential role of cyclin B2 (CCNB2) in the development and prognosis of hepatocellular carcinoma (HCC) through bioinformatics methods. Methods: Four HCC-related datasets were screened, and downloaded from the GEO database. GEO2R tool was used to analyze data and identify the differentially expressed genes (DEGs). Gene Ontology (GO) and KEGG signal pathway enrichment analysis were completed using DAVID database and Cytoscape (ClueGO) plug-in, respectively. Protein-protein interaction network (PPI) of DEGs was established using the STRING database. Cytoscape software was used to visualize PPI network, key modules (cluster) construction and core genes identification. UCSC and UALCAN database were used to analyze the differential expression and survival of TCGA hepatocellular carcinoma core genes. Firebrowse, Oncomine and UALCAN databases were used to analyze the expression of core genes in multiple tumors including HCC. Real-time quantitative reverse transcription PCR (RT-qPCR) was used to detect the expression levels of candidate genes in HCC tissues and liver cancer cell lines. Results: A total of 73 DEGs were identified from the four datasets, including 15 up-regulated genes and 58 down-regulated genes. KEGG pathway enrichment analysis signal showed that DEGs were mainly enriched in tumor-related pathways. PPI network based on DEGs had screened the key modules and 10 core genes. CCNB2 and NCAPG were highly expressed in liver cancer tissues in multiple databases. CCNB2 was positively correlated with NCAPG and was considered as a key gene related to prognosis (P < 0.01). RT-qPCR results showed that CCNB2 was highly expressed in human HCC tissues and cell lines (P < 0.01). Conclusion: Successfully screened DEGs and core genes related to HCC. Among them, CCNB2 is highly expressed in HCC and is related to the survival and prognosis of patients, so it is expected to become a biomarker for the diagnosis and prognosis of HCC.

Visit-to-visit blood pressure variability and hip fracture risk in older persons.

We investigated the association between blood pressure variability measured by the coefficient of variation (CV) of blood pressure and hip fracture in older persons with diabetes. After excluding patients with acute complications and comorbidities, a positive association with similar magnitude of strength was found between BP variability and hip fracture, compared with that in the original analysis. INTRODUCTION: Hypertension is a risk factor of osteoporosis and hip fracture, but studies have yet to investigate whether blood pressure variability measured by the CV of blood pressure can predict hip fracture in older persons with diabetes. METHODS: We conducted a retrospective cohort study on 21,160 patients who suffered from type 2 diabetes (age ≥ 50 years) and participated in the National Diabetes Care Management Program in Taiwan. The patients' 1-year variability in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at the baseline and subsequent hip fracture incidence for 8.2 years were analyzed. RESULTS: There were 937 recorded incident hip fractures. SBP-CV and DBP-CV were classified based on their tertiles. After multivariate adjustment was conducted, SBP-CV found to be a predictor of hip fracture, and its hazard ratio was 1.18 (95% CI 1.00-1.40) for the third tertile compared with the first tertile. CONCLUSIONS: Our study suggests SBP stability is a predictor for hip fracture incidence in older persons with type 2 diabetes.

Risk score prediction model for dementia in patients with type 2 diabetes.

BACKGROUND AND PURPOSE: No study has established a prediction dementia model in the Asian populations. This study aimed to develop a prediction model for dementia in Chinese type 2 diabetes patients. METHODS: The retrospective cohort study included 27 540 Chinese type 2 diabetes patients (aged 50-94 years) enrolled in the Taiwan National Diabetes Care Management Program. Participants were randomly allocated into derivation and validation sets at a 2:1 ratio. Cox proportional hazards regression models were used to identify risk factors for dementia in the derivation set. Steps proposed by the Framingham Heart Study were used to establish a prediction model with a scoring system. RESULTS: The average follow-up was 8.09 years, with a total of 853 incident dementia cases in the derivation set. The dementia risk score summed up the individual scores (from 0 to 20). The areas under the curve of 3-, 5- and 10-year dementia risks were 0.82, 0.79 and 0.76 in the derivation set and 0.84, 0.80 and 0.75 in the validation set, respectively. CONCLUSIONS: The proposed score system is the first dementia risk prediction model for Chinese type 2 diabetes patients in Taiwan.

Sol-Gel Derived Antibacterial Ag-Containing ZnO Films on Biomedical Titanium.

ZnO and Ag-containing ZnO (ZnO/Ag) films with the Ag/Zn molar ratio of 3.3 and 9.1%, respectively were sol-gel coated on biomedical titanium for antibacterial and bioactive surface modification. X-ray diffraction analysis indicates that ZnO peaks increase with the calcination temperature of the samples. Scanning electron microscopy and energy dispersive of X-ray analyses reveal Ag-rich white particles (300~750 nm) on ZnO/Ag samples that were calcined at 400 °C. X-ray photoelectron spectroscopy analysis of ZnO/Ag samples shows that Zn and O exist as ZnO and Ag presents in metallic state. The coating samples exhibit similar UV light-induced hydrophilic conversion behavior. Potentiodynamic polarization test in a Ca-free Hank's balanced solution demonstrates better corrosion resistance of the coating samples compared with the polished sample. In the in vitro bioactivity test using the simulated body fluid, a layer of apatite is gradually deposited on the surface of sample ZnO/9Ag after 12 days of soaking. The MTT assay test shows that ZnO and ZnO/Ag films have weak compatibility with the L929 cells. The antibacterial test against E. Coli by the disk diffusion assay reveals that antibacterial activity of the coating samples increases with silver content of the films.

Repeated Measurement of Fractional Exhaled Nitric Oxide Is Not Essential for Asthma Screening.

BACKGROUND AND OBJETIVE: Older guidelines recommend that fractional exhaled nitric oxide (FeNO) should be checked more than twice during the same session to confirm an asthma diagnosis. Recent studies show the excellent reproducibility of FeNO measurements. Objetive: We aimed to determine whether repeated FeNO measurements during the same session are necessary for asthma screening. MATERIAL AND METHODS: We retrospectively reviewed the electronic medical records of adult outpatients who visited the respiratory medicine department for diagnosis of asthma and assessed FeNO measurements obtained from June 2016 to July 2017. RESULTS: Of the 132 patients enrolled, 79 (59.8%) were diagnosed with asthma. Repeated FeNO measurements taken during the same session showed high reproducibility (intraclass correlation coefficient >0.9; P<.001) and a strong correlation (Pearson coefficient >0.9; P<.001), although reproducibility and correlation were slightly weaker in patients with low FeNO values. The value of repeated measurement was not significant; however, the second FeNO measurement was significantly higher than the first measurement in patients with the worst and best lung function. The predictive power of the first measurement of FeNO (sensitivity, 80.5%; specificity, 85.1%) was not inferior to the second (sensitivity, 76.6%; specificity 85.1%). The same was true of the geometric mean of the two. CONCLUSIONS: Repeated FeNO measurement during the same session is not essential for asthma screening in cases where the first acceptable FeNO measurement is performed using the proper method.

Influence of supplementing a methionine derivative, N-acetyl-l-methionine, in dairy diets on production and ruminal fermentation by lactating cows during early to mid lactation.

The present study investigated production responses and ruminal fermentation characteristics of lactating dairy cows when supplemented with N-acetyl-l-Met (NALM) as a source of rumen-protected Met in metabolizable protein (MP)-deficient (MPD) or MP-adequate diet (MPA). Eight lactating dairy cows (53 ± 10.4 d in milk, average ± standard deviation) were blocked by parity and days in milk, and the experiment was performed in a replicated 4 × 4 Latin square design. Within each square, cows were randomly assigned to a sequence of 4 diets during each of the four 21-d periods (14 d of treatment adaptation and 7 d of data collection and sampling). A 2 × 2 factorial arrangement was used; MPD or MPA was combined without or with NALM: MPD without NALM, MPD with NALM (MPD+NALM), MPA without NALM, and MPA with NALM (MPA+NALM). A NALM product was supplemented in the MPD+NALM and the MPA+NALM at 30 g/cow per d. Supplementation of NALM did not affect dry matter intake (DMI) and milk yield regardless of MP concentration. In addition, supplementing NALM resulted in a similar milk true protein concentration and yield. In contrast, NALM supplementation increased milk fat concentration and yield and 3.5% fat-corrected milk yield and tended to increase energy-corrected milk yield regardless of MP difference. Additionally, trends were observed for increased 3.5% fat-corrected milk yield/DMI and energy-corrected milk yield/DMI, and the positive effects were greater under the MPA than the MPD diet, resulting in trends toward interactions between MP and NALM. Dietary treatments had similar effects on ruminal fermentation characteristics and microbial protein yield. Plasma concentration of Met increased under the MPD but not the MPA diet, leading to an MP × NALM interaction. Overall results in the current study suggest that NALM exerted a minor influence on ruminal metabolism, but increased milk fat concentration, resulting in increases in milk fat yield and feed efficiency. Yet, potential effects of NALM on intermediary metabolism between the gastrointestinal tract, the liver, and the mammary gland need to be explored to understand utilization efficiency for production of dairy cows.

[Clipping for large paraclinoid internal carotid artery aneurysms by non-fluoroscopic occlusion via a micro-bone window frontolateral approach].

Objective: To evaluate the clinical value and outcomes of technical improvement of hybrid operatical clipping for large paraclinoid internal carotid artery aneurysms. Methods: A review was conducted on 18 cases of large paraclinoid internal carotid artery aneurysm which were clipped by balloon non-fluoroscopic occlusion of the parent artery via a micro-bone window frontolateral approach in hybrid operating room at Neurosurgery Department of Tianjin Medical University General Hospital from June 2014 to December 2017. There were 8 males and 10 females with age of (63±4) years. There were 6 cases of unruptured aneurysm and 12 cases of ruptured aneurysm of subarachnoid hemorrhage (6 cases of grade Ⅱ, 4 cases of grade Ⅲ and 2 cases of grade Ⅳ in Hunt-Hess classification). Frontolateral approach incision (average length of about 5 cm) and bone window about 3 cm×3 cm were performed. No incision of the neck was needed to expose the internal carotid artery for temporary occlusion. In the operation, the balloon was slowly pushed to the preset position of the internal carotid artery under non-fluoroscopy. The balloon was expanded to block the blood flow of internal carotid artery. Then aneurysm was clipped. The balloon was loosened and retraced to the guiding catheter after clipping. The clipping condition was examined by cerebral angiography. If there was residual aneurysm neck or stenosis of the parent artery, the balloon was pushed under non-fluoroscopy again to temporary occlusion and the clip was adjusted until the aneurysm neck was clamped satisfactorily. Results: Eighteen aneurysms were successfully clipped in hybrid operating room. Fourteen aneurysms showed complete occlusion of the aneurysm neck and no stenosis of the parent artery. Four cases showed residual aneurysm neck after clipping by intraoperative angiography, then aneurysms were clipped satisfy by adjusting the aneurysm clip. The patients were followed up for 3 months to 1 year. Ten patients recovered well (modifed Rankin score (mRS): 0), and 3 patients had no obvious disability (mRS: 1). Two patients with Hunt-Hess grade Ⅲ were slightly disabled (mRS: 2). 1 patients with Hunt-Hess grade Ⅲ were moderately disabled (mRS: 3). 1 patients with Hunt-Hess grade Ⅳ were severely disabled (mRS: 4). One elderly patients with Hunt-Hess grade Ⅳ were seriously disabled (mRS: 5). Conclusions: Application of balloon non-fluoroscopic occlusion clipping for large paraclinoid internal carotid artery aneurysm via a micro-bone window frontolateral approach is safe, effective and minimally invasive.

Acute hypoxic stress: Effect on blood parameters, antioxidant enzymes, and expression of HIF-1alpha and GLUT-1 genes in largemouth bass (Micropterus salmoides).

Dissolved oxygen (DO) plays a crucial role in survival, growth, and normal physiological functions of aquatic organisms. Nevertheless, the mechanisms involved in hypoxic stress and adaptation have not been fully elucidated in Largemouth bass (Micropterus salmoides). To reveal the effect of acute hypoxia on Largemouth bass, we simulated acute hypoxia (DO: 1.2 ± 0.2 mg/L) in the laboratory and analyzed physiological parameters (RBCs, Hb, SOD, CAT, NA+/K+-ATPase, GPx, and MDA) and gene expression (HIF-1alpha and GLUT-1) in Largemouth bass exposed to various durations of acute hypoxia (0, 1, 2, 4, 8, 12, and 24 h). Our results indicated that acute hypoxic exposure significantly increased RBCs but decreased Hb. In addition, antioxidant enzyme activity was enhanced significantly in the liver and muscles at the initial stage of acute hypoxic exposure, but decreased significantly in gills during the entire process of hypoxic exposure. Furthermore, the expression levels of HIF-1alpha and GLUT-1 mRNA were significantly up-regulated in Largemouth bass under acute hypoxic exposure. In conclusion, our study provides a valuable basis for further elucidation of hypoxic adaptation and facilitates husbandry for an economically valuable species.