Objective: Adult-onset Still's disease(AOSD)is a rare but clinically well-known polygenic systemic autoinflammatory disease.In this review,we aim to present frontiers in the pathogenesis,clinical features,diagnosis,biomarkers,disease course,prognosis,and treatment in AOSD.Data sources: We retrieved information from the PubMed database up to July 2019,using various search terms and relevant words,including AOSD and Still's disease.Study selection: We included data from peer-reviewed journals.Both basic and clinical studies were selected.Results: Pathogenesis of AOSD involves genetic background,infectious triggers,and immunopathogenesis,mainly the activation of macrophages and neutrophils followed by a cytokine storm.Diagnosis and prognosis evaluation of AOSD is still challenging;therefore,there is an urgent need to identify better biomarkers.Biologic agents,including interleukin(IL)-1β,IL-6,and tumor necrosis factor-α antagonists in the treatment of AOSD,have good prospect.Conclusion: This review highlights the advances in pathogenesis,potential biomarkers,disease course,and treatment in AOSD.

Objective To investigate the expression of the interleukin-1 receptor(IL-1R)Ⅰ,IL-1RⅡand IL-1R accessory protein(IL-1RAcP)in osteoarthritis and analyse their biological significance.Methods Immunohistochemistry and reverse transcription-polymerase chain raction(RT-PCR)were adopted to detect the expression of IL-1RⅠ,IL-1RⅡand IL-1RAcP on the synovium of 107 OA patients.Results Immunohis- tochemistry showed strong positive expression of IL-1RⅠand IL-1RAcP,and positive expression of IL-1RⅡ. The expression was distributed in lining cells,monocyts and vascular endothelial cells of the sublining area, but all of them were negative or weak positive in normal synoviums.RT-PCR showed the expression of IL-1RⅠ,IL-1RⅡand IL-1RAcP in OA synoviums was significantly enhanced than normal synoviums (P＜0.05),and the expression of IL-1RⅠwas significantly enhanced than IL-1RⅡ(P＜0.05),but no sig- nificant difference with IL-1RAcP(P＞0.05).In stageⅡandⅢOA synoviums,the expression of IL-1RⅠand IL-1 RAcP had no significant difference with normal synoviums(P＞0.05).The expression of IL-1RⅡin stageⅢOA synoviums was significantly enhanced than normal(P＜0.05).Conclusion IL-1RⅠ,IL-1RⅡand IL-1RAcP play significant roles in the pathogenesis of OA,especially IL-1RⅠand IL-1RAcP.But their increase is only observed in the early stage of OA.These suggest that they may have no association with the development of OA and have no direct association with the severity of OA.OA can be cured by interrupting the signal transduction path in which IL-1 has played biological roles.

To raise the syndrome sequence quantification, differentiation and classification algorithm based on data envelopment analysis for solving the modeling issue of syndrome differentiation and classification of traditional Chinese medicine (TCM). This algorithm has three steps: first, in order to obtain basic units for explaining pathogenesis, and establish a syndrome collection on this basis mechanisms of syndrome differentiation and classification were analyzed and classified according to TCM theory, mechanisms of syndrome differentiation and classification were analyzed and classified according to TCM theory; second, regularity and syndromes of corresponding prescriptions were sought according to the incidence and development progress of syndromes, and mathematical tools of data envelopment analysis were used to calculate state data of syndromes in each stage and obtain quantitative syndrome sequence; finally, syndrome sequence was taken as the measurement standard to quantify candidate syndromes and diagnostic information, and the similarity was calculated to obtain the matching degree between diagnostic information and candidate syndromes, so as to complete the syndrome differentiation and classification calculation. According to the results of model-based reasoning, the algorithm could indicate the regularity implied in prescription materials, and grasp the dynamic process of syndromes in an all-round way, and its results were verified through calculation and analysis on clinical cases. At least, it provides an idea for quantitative modeling of TCM.
Data Mining ; Diagnosis, Differential ; Drugs, Chinese Herbal ; therapeutic use ; Humans ; Medicine, Chinese Traditional ; Models, Theoretical ; Phytotherapy

Objective To explore the expression of hypoxia-inducible factor-1?(HIF-1?) protein and its mRNA in cultured cortical neurons after hypoxia,ischemia or hypoxia-ischemia(HI) and explore the possibilities of HIF-1? gene therapy in HI neurons.Methods The in vitro models of HI,pure hypoxia and pure ischemia were established using embryonic day 16-18 rats cortical neurons.Immunohistochemical and in-situ hybridization were performed to examine the expression of HIF-1? protein and its mRNA at different reperfusion time points in neurons.Results The expression of HIF-1? protein was very week in normoxic cultured neurons,but was up-regulated while treated with hypoxia and(or) ischemia.HIF-1? expression reached peak at 4 to 8 h after reperfusion with HI,which were statistically significant higher than that at other time points(Pa=0),and decreased gradually at 12 h.Furthermore,HIF-1? protein expression was significantly higher in HI group compared with that in the pure hypoxia or ischemia group(Pa=0).HIF-1? mRNA reached peak immediately after HI,decreased gradually at 2 h,and returned to the baseline at 8 h after reperfusion.Conclusions HIF-1? expression on cortical neurons is regulated differently with hypoxia,ischemia or HI treatment,HIF-1? gene therapy for HI neurons maybe a useful method in the future studies.

OBJECTIVETo investigate the effects of protein tyrosine kinase (PTK), protein tyrosine phosphatase (PTP) and protein kinase C (PKC) on apoptosis and observe the changes of cytosolic calcium ([Ca(2+)]i) of arsenic trioxide (As2O3) treated human leukemia cells NB4 and cortex neurons.

METHODS[Ca(2+)]i of NB4 cells and cortex neurons was probed with Fluo-3/AM, its changes were assayed with laser confocal microscopy in real-time after As2O3 treatment at different concentrations, the effects of PTK and PTP and the activation of PKC on these changes with confocal microscopy and phosphorus radioisotope assay. DNA ladders of NB4 cells and cortex neurons after exposed to As2O3 were observed.

RESULTSAs2O3 at 1 micromol/L could remarkably increase the [Ca(2+)]i of NB4 cells but had no effects on neurons. Vanadate, a kind of PTP inhibitor, could promote the increase of [Ca(2+)]i treated by 2, 5, 10 micromol/L As2O3 in a dose-dependent manner. The mean total increase rates at 240 seconds after exposed to As2O3 at different concentrations were (6.5 +/- 2.3)%, (21.7 +/- 2.1)%, (49.2 +/- 2.5)% for NB4 cells, and (6.7 +/- 2.1)%, (19.4 +/- 2.5)%, (52.3 +/- 2.7)% for cortex neurons, respectively. Genistein, a kind of PTK inhibitor, could decrease the increase of [Ca(2+)]i treated by 2, 5, 10 micromol/L As2O3 in a dose-dependent manner. The mean total inhibited rates at 240 seconds after As2O3 treatment at different concentrations were (6.7 +/- 2.9)%, (25.6 +/- 2.5)%, (52.2 +/- 3.5)% for NB4 cells, and (7.8 +/- 3.1)%, (18.1 +/- 2.8)%, (51.3 +/- 3.3)% for cortex neurons, respectively. The activation of PKC began to increase as exposed to As2O3 at 1 micromol/L for 3 h, and kept rising continuously in NB4 cells and at 24 h DNA ladders emerged. However, none of the above results was found in human cortex neurons, but when exposed to 2 micromol/L As2O3, the activation of PKC and DNA ladders did emerge in neurons.

CONCLUSIONSThe phosphorylation and dephosphorylation of PTK and PTP participated in nonspecific apoptosis signal transduction pathway related to As2O3, and accompanied with PKC activation. The [Ca(2+)]i elevation was closely related to increased PKC activation. There existed difference in dose tolerances to As2O3 between NB4 cell and cortex neurons.

Adult ; Apoptosis ; drug effects ; Arsenicals ; pharmacology ; Calcium ; metabolism ; Cell Line, Tumor ; Cells, Cultured ; Cerebral Cortex ; cytology ; Cytoplasm ; metabolism ; Dose-Response Relationship, Drug ; Humans ; Leukemia, Promyelocytic, Acute ; enzymology ; metabolism ; pathology ; Male ; Neurons ; cytology ; drug effects ; metabolism ; Oxides ; pharmacology ; Protein Kinase C ; metabolism ; Protein Tyrosine Phosphatases ; metabolism ; Protein-Tyrosine Kinases ; metabolism

Objective To investigate the effect of stromal interaction molecule 1 (STIM1) silencing on EPCs cell cycle. Methods Rat bone marrow derived endothelial progenitor cells (EPCs) were isolated and cultured in L-DMEM with 20% FBS. Ad-si/rSTIM1 and Ad-hSTIM1 were then transfected into EPCs and the expression of STIM1 mRNA was detected by RT-PCR. The cell cycle was determined using flow cytometry analysis and intracellular free Ca2+ was measured using LSCM. Co-immunoprecipitation was performed to examine the interaction between STIM1 and TRPC1. Protein levels of inositol 1, 4, 5-trisphosphate were analyzed with ELISA assay. Results Forty-eight hours after transfection, the expression of STIM1 mRNA was significantly downregulated (0.37±0.02 vs.1.00±0.02, P<0.05) and intracellular free Ca2+ level was significantly reduced (34.07±4.10 vs. 86.51±14.12,P<0.05) in Ad-si/rSTIM1 group compared with control group. The cell cycle was arrested at G1 phase[(90.91±1.10)% vs. (77.10±0.56)%, P<0.05]and the store-operated channel entry was strikingly inhibited in EPCs after treatment with Ad-si/rSTIM1. However, cotransfection of Ad-hSTIM1 with Ad-si/rSTIM1 significantly reversed these responses. Interestingly, co-immunoprecipitation study showed that STIM1 co-precipitated with TRPC1, and IP3 levels measured by ELISA were similar among three groups (P>0.05). Conclusion siRNA-mediated knockdown of STIM1 inhibited EPCs proliferation by reducing intracellular free Ca2+ through TRPC1-SOC signaling pathway.

Diabetes mellitus is a chronic syndrome of abnormal metabolism, determined by interaction of multifactorial genetic and environmental factors. Some specific types of diabetes, such as MODY, Leprechaunism, lipoatrophic diabetes, and Rabson-Mendenhall syndrome, are monogenic forms of diabetes and are inherited as a Mendelian pattern. The article reviews the research development of these Mendelian inherited diabetes will be reviewed.
Diabetes Mellitus, Type 2 ; etiology ; genetics ; Genetic Predisposition to Disease ; Glucokinase ; genetics ; Humans ; Mutation ; genetics

OBJECTIVETo explore the functions of phospholipase C (PLC)-independent protein kinase C signaling pathway (PTH/nonPLC/PKC) of parathyroid hormone (PTH) and its role in bone metabolism.

METHODSOsteoblasts isolated from the calvaria of 2- or 3-day-old C57BL mice, identified by alkaline phosphatase staining and Alizarin red staining, were treated for 4 h with 100 nmol/L [Gly(1), Arg(19)]hPTH(1-28) plus 10 nmol/L RP-cAMP, 10 nmol/L [Gly(1), Arg(19)]hPTH(1-34) plus 10 nmol/L RP-cAMP , 10 nmol/L PTH(1-34), or and 0.1% trifluoroacetic acid (TFA). The total RNA was then isolated for screening differentially expressed genes related to PTH/nonPLC/PKC pathway using Affymetrix mouse 12x135K gene expression profile microarray, and the identified genes were confirmed by real-time quantitative PCR. MC3T3-E1 cells treated with [Gly(1), Arg(19)]hPTH(1-28)+RP-cAMP, [Gly(1), Arg(19)]hPTH(1-34)+RP-cAMP, [Gly(1), Arg(19)]hPTH(1-34)+ RP-cAMP +100 nmol/L Go6983, or 0.1% TFA were also examined for GR(1-28)- or GR(1-34)-mediated gene expression changes using real-time quantitative PCR.

RESULTSAlizarin red staining visualized red mineralized nodules in the osteoblasts at 28 days of culture. According to the genechip results, we selected 56 target genes related to PTH/nonPLC/PKC pathway, among which CITED1 showed higher expressions in [Gly(1), Arg(19)]hPTH(1-34)+ RP-cAMP group than in both the control group and [Gly(1), Arg(19)]hPTH(1-28)+RP-cAMP group (P<0.05), and its expression was the highest in PTH(1-34) group (P<0.05). RT-PCR of MC3T3-E1 cells yielded consist results with those in the primary osteoblasts, and the cells treated with Go6983 (a PKC inhibitor) did not show GR(1-28)- or GR(1-34)-mediated differential expression of CITED1.

CONCLUSIONThe activation of PLC-independent protein kinase C signaling pathway of PTH enhances the expression of CITED1 in mouse osteoblasts to mediate the effect of PTH on bone metabolism, and this pathway is not dependent on the activation of PLC or PKA signaling.

Animals ; Cells, Cultured ; Indoles ; Maleimides ; Mice ; Mice, Inbred C57BL ; Nuclear Proteins ; physiology ; Osteoblasts ; physiology ; Parathyroid Hormone ; physiology ; Protein Kinase C ; physiology ; Signal Transduction ; Skull ; Trans-Activators ; physiology ; Type C Phospholipases

OBJECTIVETo evaluate the efficacy of conservative treatment with teriparatide for promoting bone fracture healing in patients with osteoporotic vertebral fracture.

METHODSTwelve postmenopausal patients (aged 73±4.8 years) with osteoporotic spinal fracture confirmed by MRI or CT scanning received conservative treatment with teriparatidesc injection supplemented with calcium and analgesics for 6 months. At the beginning and at the end of the therapy, VAS score, Oswestry Disability Index (ODI), bone mass densitometry, and X-ray of the thoracic and lumbar spine, and serum P1NP and beta-CTX levels were measured. Six of the patients received a second MRI scan after the therapy to evaluate the bone healing.

RESULTSAll the 12 patients completed the treatment, during which no new fractures or adverse events occurred. At the end of the first month of treatment, analgesic was withdrawn for all the patients. The average VAS score decreased from 8±2 to 1±2 at 1 month during the therapy, and ODI was reduced from (76±12)% to (20±5)% at 1 month and further to (5±4)% at 6 month. After the 6-month therapy, the height of the fractured vertebrae (presented as the anterior to posterior wall height ratio) was insignificantly decreased from (75±20)% to (61±20)%, the BMD was increased by (20±5)%, P1NP increased significantly from 20.9±11.4 ng/mL to 80.0±41.2 ng/mL, and beta-CTX increased from 0.30±0.17 ng/mL to 0.51±0.3 ng/mL. The 6 patients re-examined with MRI demonstrated complete bone healing after the therapy.

CONCLUSIONTeriparatide is effective for conservative treatment of osteoporotic spinal fracture and can promote bone fracture healing, improve the quality of life, and prevents vertebral collapse, and can be therefore an alternative treatment to PVP or BV.

Aged ; Analgesics ; therapeutic use ; Bone Density ; Calcium ; therapeutic use ; Fractures, Compression ; drug therapy ; Humans ; Lumbar Vertebrae ; pathology ; Magnetic Resonance Imaging ; Osteoporotic Fractures ; drug therapy ; Pain Measurement ; Quality of Life ; Spinal Fractures ; drug therapy ; Teriparatide ; therapeutic use ; Treatment Outcome

This article presented a case of discovering and diagnosing three roots with four canals of the maxillary first premolar. We found and located the extra root canal by clinical diagnosis, careful observation during the operation, and multiangle X-ray. We further confirmed the existence of the three roots with four canals with the help of cone-beam computed tomography. Finally, we verified the success of the high-quality root-canal therapy through root optical microscopy.