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Only a few studies have investigated the use of PCT in the diagnosis of bone and joint infection, and these studies have had relatively small sample sizes. We performed a systematic review and meta-analysis of the diagnostic performance of serum procalcitonin (PCT) in the identification of osteomyelitis and septic arthritis in patients who present with fever and orthopedic symptoms. EMBASE, MEDLINE, and Cochrane databases and the reference lists of relevant articles were searched, with no language restrictions, through February 2012. All original studies that reported the use of serum PCT alone or in comparison with other biomarkers for diagnosis of osteomyelitis and septic arthritis were included. Seven studies qualified for inclusion. These studies enrolled a total of 583 patients with suspected bone or joint infection, 131 of whom had confirmed osteomyelitis or septic arthritis. Analysis of the PCT data indicated a bivariate pooled sensitivity of 0.67 (95 % CI: 0.37-0.88), specificity of 0.90 (95 % CI: 0.78-0.96), a positive likelihood ratio (LR+) of 6.48 (95 % CI: 2.28-14.6), and a negative likelihood ratio (LR-) of 0.37 (95 % CI: 0.16-0.84). Use of a lower PCT cut-off value (0.2-0.3 ng/mL) improved the LR + to 6.66 and the LR- to 0.15. Analysis of the three studies that also measured serum C-reactive protein (CRP) indicated that CRP had an LR + of 1.39 (95 % CI: 1.17-1.65) and an LR- of 0.40 (95 % CI: 0.12-1.36). Our results indicate that PCT may be more suitable as an aid for rule-in diagnosis rather than for exclusion of septic arthritis or osteomyelitis and that use of a lower cut-off value for serum PCT may improve its diagnostic performance.

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Hyperglycemia results in the formation of reactive oxygen species which in turn causes advanced glycation end products (AGEs) formation, leading to diabetic cardiomyopathy. Our previous study showed that AGE‐induced reactive oxygen species‐dependent apoptosis is mediated via protein kinase C delta (PKCδ)‐enhanced mitochondrial damage in cardiomyocytes. By using microRNA (miRNA) database, miRNA‐210 was predicted to target c‐Jun N‐terminal kinase (JNK), which were previously identified as downstream of PKCδ in regulating mitochondrial function. Therefore, we hypothesized that miR‐210 mediates PKCδ‐dependent upregulation of JNK to cause cardiac mitochondrial damage and apoptosis following AGE exposure. AGE‐exposed cells showed activated cardiac JNK, PKCδ, and apoptosis, which were reversed by treatment with a JNK inhibitor and PKCδ‐KD (deficient kinase). Cardiac miR‐210 and mitochondrial function were downregulated following AGE exposure. Furthermore, JNK was upregulated and involved in AGE‐induced mitochondrial damage. Interestingly, luciferase activity of the miR‐210 mimic plus JNK WT‐3′‐untranslated region overexpressed group was significantly lower than that of miR‐210 mimic plus JNK MT‐3′UTR group, indicating that JNK is a target of miR‐210. Moreover, JNK activation induced by AGEs was reduced by treatment with the miR‐210 mimic and reversed by treatment with the miR‐210 inhibitor, indicating the regulatory function of miR‐210 in JNK activation following AGE exposure. Additionally, JNK‐dependent mitochondrial dysfunction and apoptosis were reversed following treatment with the miR‐210 mimic, while the miR‐210 inhibitor showed no effect on JNK‐induced mitochondrial dysfunction and apoptosis in AGE‐exposed cardiac cells. Taken together, our study showed that PKCδ‐enhanced JNK‐dependent mitochondrial damage is mediated through the reduction of miR‐210 in cardiomyocytes following AGE exposure.

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Advanced glycation end products (AGEs), which are highly reactive molecules resulting from persistent high‐glucose levels, can lead to the generation of oxidative stress and cardiac complications. The carboxyl terminus of HSP70 interacting protein (CHIP) has been demonstrated to have a protective role in several diseases, including cardiac complications; however, the role in preventing AGE‐induced cardiac damages remains poorly understood. Here, we found that elevated AGE levels impaired cardiac CHIP expression in streptozotocin‐induced diabetes and high‐fat diet‐administered animals, representing AGE exposure models. We used the TUNEL assay, hematoxylin and eosin, Masson′s trichrome staining, and western blotting to prove that cardiac injuries were induced in diabetic animals and AGE‐treated cardiac cells. Interestingly, our results collectively indicated that CHIP overexpression significantly rescued the AGE‐induced cardiac injuries and promoted cell survival. Moreover, CHIP knockdown‐mediated stabilization of nuclear factor κB (NFκB) was attenuated by overexpressing CHIP in the cells. Furthermore, co‐immunoprecipitation and immunoblot assay revealed that CHIP promotes the ubiquitination and proteasomal degradation of AGE‐induced NFκB. Importantly, fluorescence microscopy, a luciferase reporter assay, electrophoretic mobility shift assay, and subcellular fractionation further demonstrated that CHIP overexpression inhibits AGE‐induced NFκB nuclear translocation, reduced its binding ability with the promoter sequences of the receptor of AGE, consequently inhibiting the translocation of the receptor AGE to the cell membrane for its proper function. Overall, our current study findings suggest that CHIP can target NFκB for ubiquitin‐mediated proteasomal degradation, and thereby potentially rescue AGE‐induced cardiac damages.