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Objective To look for evidence of a relation between antibiotic resistance and prescribing by general practitioners by analysis of prescribing at both practice and individual patient level. Design Repeated cross-sectional study in 1995 and 1996. Setting 28 general practices in the Ninewells Hospital laboratory catchment area, Tayside, Scotland. Subjects reviewed 8833 patients registered with the 28 practices who submitted urine samples for analysis. Main outcome measures Resistance to trimethoprim in bacteria isolated from urine samples at practice and individual level simultaneously in a multilevel model. Results Practices showed considerable variation in both the prevalence of trimethoprim resistance (26-50% of bacteria isolated) and trimethoprim prescribing (67-357 prescriptions per 100 practice patients). Although variation in prescribing showed no association with resistance at the practice level after adjustment for other factors (P = 0.101), in the multilevel model resistance to trimethoprim was significantly associated with age, sex, and individual-level exposure to trimethoprim (P < 0.001) or to other antibiotics (P = 0.002). The association with trimethoprim resistance was strongest for people recently exposed to trimethoprim, and there was no association for people with trimethoprim exposure more than six months before the date of the urine sample. Discussion Analysis of practice level data obscured important associations between antibiotic prescribing and resistance. The results support efforts to reduce unnecessary prescribing of antibiotics in the community and show the added value of individual patient data for research on the outcomes of prescribing.

To investigate the apoptosis effect of SARS coronavirus nucleocapsid protein on cultured cell lines and to explore the possible pathway of apoptosis. pCDNA3.1(-)/his-myc vector containing the SARS coronavirus nucleocapsid gene (N), matric gene (M), spike gene (S) were transfected into COS-1, Huh-7 and HepG2 cells. Apoptosis induced by SARS coronavirus N protein under starvation of serum of COS-1 cells was monitored by Annexin V and electron microscopy assays. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (DeltaPsim) were determined by flow cytometric assay. Cytochrome C, cleaved caspase (cysteine aspartic acid protease)-3, 9, and poly (ADP-ribose) polymerase (PARP) were detected by Western blot. After removal of serum in COS-1 cells, we observed the loss of DeltaPsim, the increase of ROS and cytochrome C release into cytosol and subsequent activation of caspase-3 and PARP cleavage. The pan-caspase inhibitor z-VAD-fmk can block the activation of caspase 3, 9 and PARP cleavage. In conclusion, SARS coronavirus N protein can induce apoptosis of COS-1 cells by activating mitochondrial pathway. SARS coronavirus M, S protein can not induce apoptosis in COS-1, HepG2 and Huh-7 and SARS coronavirus N protein can not induce apoptosis in HepG2 and Huh-7 by methods used in this study.

Background: Dyslipidemia is one of the modifiable risk factors for cardiovascular diseases (CVD). Identifying subjects with lipid abnormality facilitates preventative interventions.Objectives: To evaluate the effects of lipid indices on the risks of ischemic stroke (IS), coronary heart disease (CHD), CVD, all-cause death, and CVD death.Methods: The cohort study of 4,128 subjects started in May 2009 and followed up to July 2020. Restricted cubic spline (RCS) regression analysis was used to explore the dose-response relationship between lipid indices with outcomes. Cox proportional hazard regression analysis was used to estimate the association with a hazard ratio (HR) and 95% CI.Results: RCS analysis showed that there were significant linear associations of TG with IS, non-high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (ApoB), and total cholesterol (TC)/HDL-C ratio with all-cause death, non-HDL-C and RC with CVD death, and significant non-linear associations of ApoB with IS and CVD, TC, LDL-C, ApoAI, and TC/HDL-C ratio with CHD, and TC with all-cause death (all P &lt;0.1). Cox regression analysis revealed that subjects with TC &lt;155 mg/dl (vs. 155–184 mg/dl), &gt; 185 mg/dl (vs. 155–184 mg/dl), and ApoB &lt;0.7 g/l (vs. ≥0.7 g/l) had higher risks of CHD (P &lt; 0.05), the adjusted HRs (95% CIs) were 1.933 (1.248–2.993), 1.561 (1.077–2.261), and 1.502 (1.01–2.234), respectively. Subjects with ApoAI &gt; 2.1 g/l (vs. 1.6–2.1 g/l) and TG &lt;80 mg/dl (vs. 80–177 mg/dl) had higher risks of CVD and all-cause death (P &lt; 0.05), the adjusted HRs (95% CIs) were 1.476 (1.031–2.115) and 1.234 (1.002–1.519), respectively.Conclusions: Lower or higher levels of TC, higher level of ApoAI, and lower level of ApoB were associated with increased risks of CVD, and lower level of TG was associated with increased all-cause death. Maintaining optimal lipid levels would help to prevent CVD and reduce mortality.

Cancer stemness represents a major source of development and progression of colorectal cancer (CRC). c-Met critically contributes to CRC stemness, but how c-Met is activated in CRC remains elusive. We previously identified the lipolytic factor ABHD5 as an important tumour suppressor gene in CRC. Here, we show that loss of ABHD5 promotes c-Met activation to sustain CRC stemness in a non-canonical manner. Mechanistically, we demonstrate that ABHD5 interacts in the cytoplasm with the core subunit of the SET1A methyltransferase complex, DPY30, thereby inhibiting the nuclear translocation of DPY30 and activity of SET1A. In the absence of ABHD5, DPY30 translocates to the nucleus and supports SET1A-mediated methylation of YAP and histone H3, which sequesters YAP in the nucleus and increases chromatin accessibility to synergistically promote YAP-induced transcription of c-Met, thus promoting the stemness of CRC cells. This study reveals a novel role of ABHD5 in regulating histone/non-histone methylation and CRC stemness.

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The intranasal (i.n.) route is an ideal vaccination approach for infectious respiratory diseases like influenza. Polycationic polyethylenimine (PEI) could form nanoscale complexes with negatively charged viral glycoproteins. Here we fabricated PEI-hemagglutinin (HA) and PEI-HA/CpG nanoparticles and investigated their immune responses and protective efficacies with an i.n. vaccination regimen in mice. Our results revealed that the nanoparticles significantly enhanced HA immunogenicity, providing heterologous cross-protection. The conserved HA stalk region induced substantial antibodies in the nanoparticle immunization groups. In contrast to the Th2-biased, IgG1-dominant antibody response generated by PEI-HA nanoparticles, PEI-HA/CpG nanoparticles generated more robust and balanced IgG1/IgG2a antibody responses with augmented neutralization activity and Fc-mediated antibody-dependent cellular cytotoxicity (ADCC). PEI-HA/CpG nanoparticles also induced enhanced local and systemic cellular immune responses. These immune responses did not decay over six months of observation postimmunization. PEI and CpG synergized these comprehensive immune responses. Thus, the PEI-HA/CpG nanoparticle is a potential cross-protective influenza vaccine candidate. Polycationic PEI nanoplatforms merit future development into mucosal vaccine systems.

Influenza is one of the major threats to public health. Current influenza vaccines cannot provide effective protection against drifted or shifted influenza strains. Researchers have considered two important strategies to develop novel influenza vaccines with improved immunogenicity and broader protective efficacy. One is applying fewer variable viral antigens, such as the haemagglutinin stalk domain. The other is including adjuvants in vaccine formulations. Adjuvants are promising and helpful boosters to promote more rapid and stronger immune responses with a dose-sparing effect. However, few adjuvants are currently licensed for human influenza vaccines, although many potential candidates are in different trials. While many advantages have been observed using adjuvants in influenza vaccine formulations, an improved understanding of the mechanisms underlying viral infection and vaccination-induced immune responses will help to develop new adjuvant candidates. In this review, we summarize the works related to adjuvants in influenza vaccine research that have been used in our studies and other laboratories. The review will provide perspectives for the utilization of adjuvants in developing next-generation and universal influenza vaccines.