ABSTRACT␣7 Nicotinic acetylcholine receptor (␣7 nAChR) has been found in several non-neuronal cells and is described as an important regulator of cellular function. Naturally occurring CD4 ϩ CD25 ϩ regulatory T cells (Tregs) are essential for the active suppression of autoimmunity. The present study investigated whether naturally occurring Tregs expressed ␣7 nAChR and investigated the functionary role of this receptor in controlling suppressive activity of these cells. We found that CD4 ϩ CD25ϩ Tregs from naive C57BL/6J mice positively expressed ␣7 nAChR, and its activation by nicotine enhanced the suppressive capacity of Tregs. Nicotine stimulation up-regulated the expression of cytotoxic T-lymphocyte-associated antigen (CTLA)-4 and forkhead/winged helix transcription factor p3 (Foxp3) on Tregs but had no effect on the production of interleukin (IL)-10 and transforming growth factor-␤1 by Tregs. In the supernatants ofϪ T-cell cocultures, we observed a decrease in the concentration of IL-2 in nicotine-stimulated groups, but nicotine stimulation had no effect on the ratio of IL-4/interferon (IFN)-␥, which partially represented T-cell polarization. The above-mentioned effects of nicotine were reversed by a selective ␣7 nAChR antagonist, ␣-bungarotoxin. In addition, the ratio of IL-4/IFN-␥ was increased by treatment with ␣-bungarotoxin. We conclude that nicotine might increase Treg-mediated immune suppression of lymphocytes via ␣7 nAChR. The effect is related to the up-regulation of CTLA-4 as well as Foxp3 expression and decreased IL-2 secretion in CD4 ϩ CD25ϩ Tregs/ CD4 ϩ CD25Ϫ T-cell coculture supernatants. ␣7 nAChR seems to be a critical regulator for immunosuppressive function of CD4 ϩ CD25ϩ Tregs.

Gliadins, specified by six compound chromosomal loci (Gli-A1/B1/D1 and Gli-A2/B2/D2) in hexaploid bread wheat, are the dominant carriers of celiac disease (CD) epitopes. Because of their complexity, genome-wide characterization of gliadins is a strong challenge. Here, we approached this challenge by combining transcriptomic, proteomic and bioinformatic investigations. Through third-generation RNA sequencing, full-length transcripts were identified for 52 gliadin genes in the bread wheat cultivar Xiaoyan 81. Of them, 42 were active and predicted to encode 25 α-, 11 γ-, one δ- and five ω-gliadins. Comparative proteomic analysis between Xiaoyan 81 and six newly-developed mutants each lacking one Gli locus indicated the accumulation of 38 gliadins in the mature grains. A novel group of α-gliadins (the CSTT group) was recognized to contain very few or no CD epitopes. The δ-gliadins identified here or previously did not carry CD epitopes. Finally, the mutant lacking Gli-D2 showed significant reductions in the most celiac-toxic α-gliadins and derivative CD epitopes. The insights and resources generated here should aid further studies on gliadin functions in CD and the breeding of healthier wheat.

PurposeResurfacing the patella in one-stage bilateral total knee arthroplasty (TKA) remains debatable. This study aimed to assess the mid-term outcomes of patients after one-stage bilateral TKA performed with and without patellar resurfacing, respectively, with at least five years of follow-up.MethodsSixty-six patients (132 knees) scheduled for first-ever one-stage bilateral TKA due to osteoarthritis received patellar resurfacing and retention, respectively, on one knee and the other, randomly selected. All patients received Scorpio NRG knee prostheses and were evaluated by radiology (anteroposterior, lateral, and axial views) pre-operatively and yearly post-operatively, for at least five years. Knee Society Score and Feller Score values were measured. Anterior knee pain, patellar clunk, and patient satisfaction were assessed.ResultsOne patient died within five years of operation and four were lost to follow-up. One patient developed severe dementia and could not be constructively questioned. Therefore, 60 patients (120 knees) were finally analyzed. There were significantly improved Knee Society and Feller scores (P < 0.001) in the resurfacing group compared with the non-resurfacing group post-operatively. Anterior knee pain and patellar clunk rates were lower on the resurfaced side compared with the non-resurfaced side (P < 0.001). Meanwhile, 47% and only 7% patients preferred the resurfaced and non-resurfaced sides, respectively, at final follow-up. No revision was performed for patellofemoral complications, and no significant differences were found between the two groups in radiographic outcomes.ConclusionsUsing the Scorpio NRG knee prosthesis, patellar resurfacing is superior to non-resurfacing in patients with osteoarthritis observed for ≥ five years.Registration trials number NCT03600922 Key Points• Findings Patellar resurfacing is superior to non-resurfacing in osteoarthritis (OA) patients undergoing total knee arthroplasty (TKA) with the Scorpio NRG knee prosthesis.• Implications Patellar resurfacing should be performed in OA patients during TKA.• Caution Several prosthesis types should be assessed in the same study setting, and multicenter studies are required before generalizability of the present findings.Electronic supplementary materialThe online version of this article (10.1007/s00264-019-04361-7) contains supplementary material, which is available to authorized users.

Yu-ping-feng-san (YPFS) is a Chinese medical formula that is used clinically for allergic diseases and characterized by reducing allergy relapse. Our previous studies demonstrated that YPFS efficiently inhibited T helper 2 cytokines in allergic inflammation. The underlying mechanisms of action of YPFS and its effective components remain unclear. In this study, it was shown that YPFS significantly inhibited production of thymic stromal lymphopoietin (TSLP), an epithelial cell-derived initiative factor in allergic inflammation, in vitro and in vivo. A method of human bronchial epithelial cell (16HBE) binding combined with HPLC-MS (named 16HBE-HPLC-MS) was established to explore potential active components of YPFS. The following five components bound to 16HBE cells: calycosin-7-glucoside, ononin, claycosin, sec-o-glucosylhamaudol and formononetin. Serum from YPFS-treated mice was analyzed and three major components were detected claycosin, formononetin and cimifugin. Among these, claycosin and formononetin were detected by 16HBE-HPLC-MS and in the serum of YPFS-treated mice. Claycosin and formononetin decreased the level of TSLP markedly at the initial stage of allergic inflammation in vivo. Nuclear factor (NF)-κB, a key transcription factor in TSLP production, was also inhibited by claycosin and formononetin, either in terms of transcriptional activation or its nuclear translocation in vitro. Allergic inflammation was reduced by claycosin and formononetin when they are administered only at the initial stage in a murine model of atopic contact dermatitis. Thus, epithelial cell binding combined with HPLC-MS is a valid method for screening active components from complex mixtures of Chinese medicine. It was demonstrated that the compounds screened from YPFS significantly attenuated allergic inflammation probably by reducing TSLP production via regulating NF-κB activation.

Osteoarthritis is the most prevalent form of arthritis, affecting a large part of population. It has been reported that muscle weakness and inflammation contribute to osteoarthritis development and progression. Oxidative stress plays important roles in muscle dysfunction and inflammation induction. Crocin, a component of saffron, has excellent antioxidative property. However, it is unclear if crocin can be a potential medicine for osteoarthritis therapy. Osteoarthritis in rats was induced by meniscectomy (MNX) surgery. Then, rats were given with 30 mg/kg of crocin daily for 10 days after osteoarthritis induction. The parameters were determined 7 days after crocin administration. MNX surgery induced osteoarthritis in rats. Crocin treatment significantly decreased osteoarthritis-associated joint pain, decreased muscular interleukin-6 (IL-6) level, and increased citrate synthase (CS) activity, as well as myosin heavy chain (MHC) IIα expression. In addition, crocin reduced muscular lipid peroxidation (LPO) and Nrf2 expression and increased glutathione production and glutathione peroxidase activity. Finally, crocin inhibited the activity of JNK, but not ERK, to repress NF-κB activation and inflammation induction. Crocin attenuates osteoarthritis symptoms through alleviating oxidative stress and inflammation, suggesting that crocin is a potential medicine for osteoarthritis therapy.

Developmental dysplasia of the hip (DDH) is common, and features a widened Sharp's angle as observed on pelvic x-ray images. Determination of Sharp's angle, essential for clinical decisions, can overwhelm the workload of orthopedic surgeons. To aid diagnosis of DDH and reduce false negative diagnoses, a simple and cost-effective tool is proposed. The model was designed using artificial intelligence (AI), and evaluated for its ability to screen anteroposterior pelvic radiographs automatically, accurately, and efficiently.Orthotopic anterior pelvic x-ray images were retrospectively collected (n = 11574) from the PACS (Picture Archiving and Communication System) database at Second Hospital of Jilin University. The Mask regional convolutional neural network (R-CNN) model was utilized and finely modified to detect 4 key points that delineate Sharp's angle. Of these images, 11,473 were randomly selected, labeled, and used to train and validate the modified Mask R-CNN model. A test dataset comprised the remaining 101 images. Python-based utility software was applied to draw and calculate Sharp's angle automatically. The diagnoses of DDH obtained via the model or the traditional manual drawings of 3 orthopedic surgeons were compared, each based on the degree of Sharp's angle, and these were then evaluated relative to the final clinical diagnoses (based on medical history, symptoms, signs, x-ray films, and computed tomography images).Sharp's angles on the left and right measured via the AI model (40.07°± 4.09°and 40.65°± 4.21°), were statistically similar to that of the surgeons' (39.35°± 6.74°and 39.82°± 6.99°). The measurement time required by the AI model (1.11 ± 0.00 s) was significantly less than that of the doctors (86.72 ± 1.10, 93.26 ± 1.12, and 87.34 ± 0.80 s). The diagnostic sensitivity, specificity, and accuracy of the AI method for diagnosis of DDH were similar to that of the orthopedic surgeons; the diagnoses of both were moderately consistent with the final clinical diagnosis.The proposed AI model can automatically measure Sharp's angle with a performance similar to that of orthopedic surgeons, but requires far less time. The AI model may be a viable auxiliary to clinical diagnosis of DDH.

Thyroid hormone, as a modifiable risk factor for dementia, promotes neurocognitive function and regulates metabolic processes. Various studies have defined different thyroid-stimulating hormone cutoffs, but the safest thyroid-stimulating hormone concentration was absent. A dose–response meta-analysis describing the overall functional relation and identifying exposure intervals associated with a higher or lower disease risk is thus desirable. Therefore, our current analysis was conducted to understand the influence of thyroid dysfunction on dementia risk. We searched PubMed, Embase, and Web of Science before May 1, 2020 for human studies published in English. Studies were considered for inclusion if they used a cohort study design to measure the risk of dementia in different thyroid function status groups, diagnosed thyroid functional status and all-cause dementia, included participants aged > 18 years, and provided quantitative measures of data. The analysis contained 17 articles with 344,248 individuals with a 7.8-year mean follow-up. Ten studies with 329,287 participants indicated that only subclinical hyperthyroidism was associated with an increased risk of dementia. In contrast, subclinical hypothyroidism, clinical hyperthyroidism, and clinical hypothyroidism did not affect dementia. In the dose–response meta-analysis with 46,417 samples from 11 studies, the association of thyroid-stimulating hormone with the risk of dementia exhibited a U-shaped curve. Our study indicated that subclinical hyperthyroidism was associated with the risk of dementia and the thyroid-stimulating hormone concentration at around 1.55–1.60 mU/L as the optimum range for the risk of dementia.

Rationale:Fenofibrate is a fibric acid derivative indicated for use in hypertriglyceridemia and mixed dyslipidemia treatment among adults. Rhabdomyolysis is a syndrome characterized by muscle necrosis and the release of intracellular muscle contents into the systemic circulation, which is the most serious and fatal side effect of fenofibrate. The objective of this paper is to discuss fatal side effect of fenofibrate and keep safe medication.Patient concerns:A patient with hypothyroidism who presented with rhabdomyolysis during fenofibrate monotherapy for hypertriglyceridemia was reported.Diagnoses:Fenofibrate Monotherapy Induced Rhabdomyolysis.Interventions:Fenofibrate was stopped. Adequate fluid resuscitation, mannitol diuresis, myocardium protection, hepatoprotection and urine alkalinization with sodium bicarbonate were performed.Outcomes:Blood tests were normal and the patient was good and discharged 2 weeks later.Lessons:13 cases associated with fenofibrate monotherapy-induced rhabdomyolysis were reviewed, which had been published in the English literature. The severity of fenofibrate muscle toxicity may be the result of the combination of two rhabdomyolysis enhancers, such as hypothyroidism and female gender. To avoid it, strict clinical and laboratory monitoring should be maintained, particularly hypothyroidism. Patients should be informed of possible potentially irreversible effects after taking fibrates.