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TLR4 is a key innate immune signal that mediates glucolipid toxicity through yet unclear mechanisms. Here, TLR4 truncation ameliorated bone metabolism disorders in diabetic rats, and the underlying mechanisms were explored by proteomics. Our study showed that TLR4 truncation inhibited bone loss induced by diabetes in rats. In addition, a proteomic analysis screen exposed the differential proteins associated with immune reactivity and T cell activation (RIAM and Class II histocompatibility antigen, M β1 chain). Further cellular experiments showed that TLR4 mediated the inhibition of osteoblast differentiation induced by glucolipotoxicity and promoted an increase in the nuclear level of RIAM-NF-κB. Mechanistic studies showed that TLR4 mediated glucolipotoxicity induced damage in bone metabolism primarily by regulating RIAM-NF-κB interactions, which promoted RIAM-NF-κB nuclear translocation. In conclusion, we confirmed that TLR4 inhibition could delay bone metabolism disorders induced by glycolipid toxicity via RIAM regulation of NF-κB nuclear translocation.

Objective To elucidate the potential of monoclonal antibodies (mAbs) of culture filtrate protein 10 (CFP-10) and early secretory antigenic target 6 (ESAT-6) in tuberculosis (TB) diagnosis. Design We generated and characterised monoclonal and polyclonal antibodies against Mycobacterium tuberculosis-specific antigens ESAT-6 and CFP-10 by immunising BALB/c mice with an ESAT-6/CFP-10 fusion protein. Stable hybridoma cell lines were established and mAbs were specifically identified by immunoblotting and immunoprecipitation. The mouse mAbs were used to coat plates, and biotin-labelled polyclonal antibodies were used to detect the antigens. One hundred and seventy-three samples of sputum culture supernatants and pleural effusion aspirates have been tested. Results The ESAT-6 enzyme-linked immunosorbent assay (ELISA) detected the culture supernatants and pleural effusion specimens that were positive for M. tuberculosis, but failed to identify M. tuberculosis-positive specimens in the non-M. tuberculosis culture supernatants or control specimens. This yielded a sensitivity of 95.4% and a specificity of 100% for the ESAT-6-specific ELISA. The CFP-10 ELISA presented less satisfactory sensitivity and specificity, of respectively 81.6% and 92.2%. Results showed positive detection rates of ESAT-6 and CFP-10 of 86.8% (33/38) and 76.3% (29/38) for the diagnosis of tuberculous pleural effusion in patients bacteriologically negative for M. tuberculosis culture. Conclusion The ESAT-6 and CFP-10 ELISAs incorporating mAbs generated in this study serve as potential tools in the laboratory diagnosis of TB.

We report here the clinical, genetic, and molecular characteristics of a large Chinese family exhibiting non-syndromic, late-onset autosomal dominant sensorineural hearing loss. Clinical evaluation revealed variable phenotypes of hearing loss in terms of severity and age-at-onset of disease in these subjects. Genome-wide linkage analysis mapped the disease gene to the DFNA5 locus with a maximum two-point log odds score of 5.39 at [theta] = 0 for marker D7S2457. DNA sequencing of DFNA5 revealed a novel heterozygous IVS8+4 A>G substitution in the splice donor site of intron 8. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed skipping of exon 8 in the mutant transcript. This mutation faithfully cosegregated with hearing loss in the family. In addition, the mutation was absent in 100 unrelated control DNA samples of Chinese origin. The IVS8+4 A>G mutation is predicted to create a shift in the reading frame and introduce a stop codon at position 372, thereby resulting in a prematurely truncated DFNA5 protein. Up to date, a total of four mutations in DFNA5 have been reported to lead to hearing impairment, all of them result in skipping of exon 8 at the mRNA level. Our findings provide further support for the hypothesis that DFNA5-associated hearing loss is caused by a very specific gain-of-function mutation.

Serum sialic acid levels were measured in 80 healthy subjects, in 60 patiens with benign tumors and in 110 patients with oral cancer. It was shown that these levels were significantly elevated in oral cancer patients compared to healthy controls and patients with benign tumors (p < 0.01); they were higher in patients with stage III and stage IV disease than in those with stage I and II disease (p < 0.01). However, no difference was observed between healthy controls and stage I and II cancer patients. The results of this study suggest that the determination of sialic acid levels may be of value in the diagnosis of oral cancer, but its usefulness as an adjunct in clinical staging is limited.

BACKGROUND: A new lower-cost rapid-throughput human papillomavirus (HPV) test (careHPV, Qiagen, Gaithersburg, USA) has been shown to have high sensitivity for the detection of high grade cervical intraepithelial neoplasia. METHODS: We assessed the outcomes and cost-effectiveness of careHPV screening in rural China, compared to visual inspection with acetic acid, when used alone (VIA) or in combination with Lugol's iodine (VIA/VILI). Using data on sexual behaviour, test accuracy, diagnostic practices and costs from studies performed in rural China, we estimated the cost-effectiveness ratio (CER) and associated lifetime outcomes for once-lifetime and twice-lifetime screening strategies, and for routine screening at 5-yearly, 10-yearly and IARC-recommended intervals. The optimal age range for once-lifetime screening was also assessed. RESULTS: For all strategies, the relative ordering of test technologies in reducing cervical cancer incidence and mortality was VIA (least effective); VIA/VILI; careHPV@1.0pg/ml and careHPV@0.5pg/ml (most effective). For once-lifetime strategies, maximum effectiveness was achieved if screening occurred between 35-50 years. Assuming a participation rate of ~70%, once-lifetime screening at age 35 years would reduce cancer mortality by 8% (for VIA) to 12% (for careHPV@0.5) over the long term, with a CER of US$557 (for VIA) to $959 (for careHPV@1.0) per life year saved (LYS) compared to no intervention; referenced to a 2008 GDP per capita in Shanxi Province of $2,975. Correspondingly, regular screening with an age-standardised participation rate of 62% (which has been shown to be achievable in this setting) would reduce cervical cancer mortality by 19-28% (for 10-yearly screening) to 43-54% (using IARC-recommended intervals), with corresponding CERs ranging from $665 (for 10-yearly VIA) to $2,269 (for IARC-recommended intervals using careHPV@1.0) per LYS. CONCLUSIONS: This modelled analysis suggests that primary careHPV screening compares favourably to visual inspection screening methodologies in rural China, particularly if used as part of a regular screening program