ObjectivesExamine whether osteoarthritis (OA) progression can be delayed by halofuginone in anterior cruciate ligament transection (ACLT) rodent models.Methods3-month-old male C57BL/6J (wild type; WT) mice and Lewis rats were randomised to sham-operated, ACLT-operated, treated with vehicle, or ACLT-operated, treated with halofuginone. Articular cartilage degeneration was graded using the Osteoarthritis Research Society International (OARSI)-modified Mankin criteria. Immunostaining, flow cytometry, RT-PCR and western blot analyses were conducted to detect relative protein and RNA expression. Bone micro CT (μCT) and CT-based microangiography were quantitated to detect alterations of microarchitecture and vasculature in tibial subchondral bone.ResultsHalofuginone attenuated articular cartilage degeneration and subchondral bone deterioration, resulting in substantially lower OARSI scores. Specifically, we found that proteoglycan loss and calcification of articular cartilage were significantly decreased in halofuginone-treated ACLT rodents compared with vehicle-treated ACLT controls. Halofuginone reduced collagen X (Col X), matrix metalloproteinase-13 and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS 5) and increased lubricin, collagen II and aggrecan. In parallel, halofuginone-attenuated uncoupled subchondral bone remodelling as defined by reduced subchondral bone tissue volume, lower trabecular pattern factor (Tb.pf) and increased thickness of subchondral bone plate compared with vehicle-treated ACLT controls. We found that halofuginone exerted protective effects in part by suppressing Th17-induced osteoclastic bone resorption, inhibiting Smad2/3-dependent TGF-β signalling to restore coupled bone remodelling and attenuating excessive angiogenesis in subchondral bone.ConclusionsHalofuginone attenuates OA progression by inhibition of subchondral bone TGF-β activity and aberrant angiogenesis as a potential preventive therapy for OA.

ObjectivesTo investigate the use of oral anticoagulants (AC) and antiplatelet agents (AP) in the management of atrial fibrillation (AF) among patients in primary care in England.DesignEpidemiological study.Setting1857 general practices in England representing a practice population of 13.1 million registered patients.Patients231 833 patients with a history of AF.Main outcome measuresThe primary outcome was AC and AP use by CHADS2 score and age groups <30 years, 30–49 years, 50–64 years, 65–79 years and >79 years.Results231 833 patients with a history of AF were identified, giving a prevalence among uploading practices of 1.76%. Prevalence of AF varied markedly between practices, related to differing practice age profiles. The total number of patients with AF in a practice was strongly predicted by the number of patients aged 65 years and over in the practice. 57.0% of the AF population had a CHADS2 score ≥2 and 83.7%≥1. 114 212 (49.3%) patients received AC therapy. AC uptake increased with increasing CHADS2 score up to a score of 3, but thereafter reached a plateau. Among 132 099 patients with a CHADS2 score ≥2, 72 211 (54.7%) received an AC, 14 987(11.3%) were recorded as having a contraindication or having declined AC therapy, leaving 44 901 (34.0%) not on AC therapy and without a recorded contraindication or recorded refusal. Among patients not prescribed an AC, 79.9% were prescribed an AP. The use of AC declined in the elderly (for CHADS2≥2, 47.4% of patients ≥80 years, compared with 64.5% for patients aged <80 years, p<0.001). By contrast, AP uptake was more prevalent among elderly patients.ConclusionsOver one-third of patients with AF and known risk factors who are eligible for AC do not receive them. There is a high use of AP among patients not receiving AC. Uptake of AC is particularly poor among patients aged 80 years and over.

Backgrounds/Aims: Long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) is involved in the progression of several tumors. The interaction between lncRNA and miRNA or miRNA’s target genes is reported to play crucial roles in malignancy. In addition, Androgen receptor (AR) is considered to be involved in bladder cancer progression. In this study, we investigated the role of XIST in human bladder cancer and its interaction with miR-124 and AR. Methods: XIST and AR expression was detected in bladder tumor samples and cell lines. Effects of XIST and AR on bladder cancer cells growth, invasion and migration were analyzed. Bioinformatic analysis and luciferase assays were used to identify the interaction among XIST, AR and miR-124. The correlations of miR-124 with XIST and AR in bladder cancer samples were statistically analyzed. Results: XIST and AR were upregulated in bladder cancer tissues and positively correlated. Higher XIST and AR expression were related to poorer TNM stage of bladder cancer. XIST knockdown reduced bladder cancer cells’ proliferation, invasion and migration. While this inhibitory effect could be partially restored by AR overexpression. XIST inhibited miR-124 expression by directly targeting. Moreover, miR-124 could bind to the 3’UTR of AR to regulate its expression. MiR-124 inhibition partially restored the XIST knockdown-induced reduction of AR, c-myc, p27, MMP13 and MMP9 expression. In bladder cancer tissues, miR-124 level was inversely correlated with the expression of XIST and AR, respectively. Conclusion: These findings indicated that XIST might be an oncogenic lncRNA that promoted the bladder cancer growth, invasion and migration via miR-124 dependent AR regulation.

Current nanodrug-based cancer therapy is susceptible to the problems of rapid clearance from circulation and limited therapeutic efficacy. Herein, we report a magnetically targeted and photothermal-triggered drug release nanotheranostics system based on superparamagnetic iron oxide (Fe3O4), IR780, doxorubicin (DOX), and perfluoropentane (PFP) entrapped poly-lactide-co-glycolide (PLGA) nanoparticles (IR780/Fe3O4@PLGA/PFP/DOX NPs) for triple-modal imaging-guided synergistic therapy of breast cancer. In this work, IR780 and Fe3O4 convert light into heat, which triggers DOX release from IR780/Fe3O4@PLGA/PFP/DOX NPs and a phase-shift thermoelastic expansion of PFP; this procedure further accelerates the DOX release and tissue extrusion deformation. Fe3O4 NPs also serve as the target moiety by an external magnet directed to the tumor. Specifically, the IR780/Fe3O4@PLGA/PFP/DOX NPs can be used for triple-modal imaging, including near infrared fluorescence, magnetic resonance, and ultrasound. Furthermore, the antitumor therapy studies reveal the extraordinary performance of IR780/Fe3O4@PLGA/PFP/DOX NPs in magnetically targeted synergistic chemo-photothermal therapy of cancer. Therefore, the multifunctional IR780/Fe3O4@PLGA/PFP/DOX NPs guided by the magnetic field show a great potential for cancer theranostics.

In patients with conventional wider LBBB morphology, the presence of mid-QRS notching or slurring is a strong predictor of better response to CRT.

BackgroundThe Internet hospital, an innovative approach to providing health care, is rapidly developing in China because it has the potential to provide widely accessible outpatient service delivery via Internet technologies. To date, China’s Internet hospitals have not been systematically investigated.ObjectiveThe aim of this study was to describe the characteristics of China’s Internet hospitals, and to assess their health service capacity.MethodsWe searched Baidu, the popular Chinese search engine, to identify Internet hospitals, using search terms such as “Internet hospital,” “web hospital,” or “cloud hospital.” All Internet hospitals in mainland China were eligible for inclusion if they were officially registered. Our search was carried out until March 31, 2017.ResultsWe identified 68 Internet hospitals, of which 43 have been put into use and 25 were under construction. Of the 43 established Internet hospitals, 13 (30%) were in the hospital informatization stage, 24 (56%) were in the Web ward stage, and 6 (14%) were in full Internet hospital stage. Patients accessed outpatient service delivery via website (74%, 32/43), app (42%, 18/43), or offline medical consultation facility (37%, 16/43) from the Internet hospital. Furthermore, 25 (58%) of the Internet hospitals asked doctors to deliver health services at a specific Web clinic, whereas 18 (42%) did not. The consulting methods included video chat (60%, 26/43), telephone (19%, 8/43), and graphic message (28%, 12/43); 13 (30%) Internet hospitals cannot be consulted online any more. Only 6 Internet hospitals were included in the coverage of health insurance. The median number of doctors available online was zero (interquartile range [IQR] 0 to 5; max 16,492). The median consultation fee per time was ¥20 (approximately US $2.90, IQR ¥0 to ¥200).ConclusionsInternet hospitals provide convenient outpatient service delivery. However, many of the Internet hospitals are not yet mature and are faced with various issues such as online doctor scarcity and the unavailability of health insurance coverage. China’s Internet hospitals are heading in the right direction to improve provision of health services, but much more remains to be done.

Near-infrared (NIR) laser-induced photothermal therapy (PTT) uses a photothermal agent to convert optical energy into thermal energy and has great potential as an effective local, minimally invasive treatment modality for killing cancer cells. To improve the efficacy of PTT, we developed poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) encapsulating superparamagnetic iron oxide (Fe3O4), indocyanine green (ICG), and perfluoropentane (PFP) as synergistic agents for NIR laser-induced PTT. We fabricated a novel type of phase-shifting fluorescent magnetic NPs, Fe3O4/ICG@PLGA/PFP NPs, that effectively produce heat in response to NIR laser irradiation for an enhanced thermal ablation effect and a phase-shift thermoelastic expansion effect, and thus, can be used as a photothermal agent. After in vitro treatment of MCF-7 breast cancer cells with Fe3O4/ICG@PLGA/PFP NPs and NIR laser irradiation, histology and electron microscopy confirmed severe damage to the cells and the formation of many microbubbles with iron particles at the edge or outside of the microbubbles. In vivo experiments in mice with MCF-7 tumors demonstrated that Fe3O4/ICG@PLGA/PFP NPs could achieve tumor ablation upon NIR laser irradiation with minimal toxicity to non-irradiated tissues. Together, our results indicate that Fe3O4/ICG@PLGA/PFP NPs can be used as effective nanotheranostic agents for tumor ablation.

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