Both cholinergic dysfunction and protein citrullination are the hallmarks of rheumatoid arthritis (RA), but the relationship between the two phenomena remains unclear. We explored whether and how cholinergic dysfunction accelerates protein citrullination and consequently drives the development of RA. Cholinergic function and protein citrullination levels in patients with RA and collagen-induced arthritis (CIA) mice were collected. In both neuron-macrophage coculture system and CIA mice, the effect of cholinergic dysfunction on protein citrullination and expression of peptidylarginine deiminases (PADs) was assessed by immunofluorescence. The key transcription factors for PAD4 expression were predicted and validated. Cholinergic dysfunction in the patients with RA and CIA mice negatively correlated with the degree of protein citrullination in synovial tissues. The cholinergic or alpha7 nicotinic acetylcholine receptor (α7nAChR) deactivation and activation resulted in the promotion and reduction of protein citrullination in vitro and in vivo, respectively. Especially, the activation deficiency of α7nAChR induced the earlier onset and aggravation of CIA. Furthermore, deactivation of α7nAChR increased the expression of PAD4 and specificity protein-3 (SP3) in vitro and in vivo. Our results suggest that cholinergic dysfunction-induced deficient α7nAChR activation, which induces the expression of SP3 and its downstream molecule PAD4, accelerating protein citrullination and the development of RA.

Objective:To analyze the clinical characteristics and diagnosis and treatment experiences of Langerhans cell histocytosis (LCH) in skull.Methods:Sixteen patients with cranial LCH admitted to our hospital from January 2015 to December 2019 were chosen in our study. Their clinical data, diagnosis and treatment procedures and prognoses were retrospectively analyzed.Results:Among the 16 patients, there were 13 males and 3 females, aged from 1 to 31 years. The clinical manifestations included space-occupying lesions of the skull; and imaging showed bone destruction of the skull, with or without involvement of other bones or organs. All patients were pathologically confirmed to have LCH after surgical total resection of the lesions. Routine whole-body bone scanning was performed after surgery: one was found to have local abnormal metabolic activity and received local radiotherapy; 8 were combined with other bone or organ involvement, and received chemotherapy. All the patients were followed up for 1-5 years, and no recurrence was found, and no one died.Conclusion:Good prognosis can be achieved in cranial LCH patients accepted resection by giving additional treatment according to the results of postoperative reexamination and combination use of standardized radiotherapy and chemotherapy.

OBJECTIVE: To explore whether bortezomib and a Bcl-2 inhibitor exhibit synergistic anti-tumor effect in human acute T lymphoblastic leukemia cells. METHODS: MTT assay was used to determine the cytotoxicity of bortezomib in the absence or presence of Bcl-2 inhibitors (obatoclax, AT-101 and ABT-199) in Jurkat cells. The effects of drug treatment on the expression of Bcl-2 family proteins, LC3B, p62, ubiquitin, BiP/Grp78, p-JNK, p-p38 and CHOP proteins were examined by Western blotting. Flow cytometry was used to determine the effects of bortezomib and Bcl-2 inhibitors (obatoclax, AT-101 and ABT-199) on cell apoptosis. Quantitative real-time PCR was used to measure the mRNA expression levels of the key regulatory factors of unfolded protein reaction (UPR). A zebrafish xenograft model was used to study the anti-tumor effect of bortezomib, obatoclax and their combination in vivo. RESULTS: Bortezomib or Bcl-2 inhibitors alone inhibited the cell viability of Jurkat cells, but only obatoclax and bortezomib showed synergistic cytotoxicity and pro-apoptotic effect. Obatoclax, rather than AT-101 and ABT- 199, blocked autophagic flux in the cells evidenced by concomitant accumulation of LC3B-Ⅱ and p62. Both bortezomib and obatoclax alone caused accumulation of polyubiquinated proteins, and their combination showed a synergistic effect, which was consistent with their synergistic cytotoxicity. The dual blockade of proteasome and autophagy by the combination of bortezomib and obatoclax triggered unfolded protein response followed by cell apoptosis. Preventing UPS dysfunction by tauroursodeoxycholic acid (TUDCA) significantly attenuated the cytotoxicity and pro-apoptotic effect of bortezomib in combination with obatoclax. In zebrafish xenograft models, bortezomib combined with obatoclax significantly decreased tumor foci formation. CONCLUSIONS Bortezomib and obatoclax for dual blockade of protein degradation pathways show synergistic anti-tumor effect in human acute T lymphoblastic leukemia cells.
Antineoplastic Agents ; Apoptosis ; Bortezomib ; Cell Line, Tumor ; Drug Synergism ; Humans ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Proteolysis ; Proto-Oncogene Proteins c-bcl-2 ; Pyrroles

Objective To observe changes in relative pituitary hormones after severe traumatic brain injury (STBI) in children and to investigate the short-and long-term effects of mild hypothermia on pituitary function.Methods Included for this study were 81 children who had been admitted to the Brain Hospital of Liaocheng People's Hospital from June 2011 to January 2015 for STBI and abnormal secretion of pituitary-related hormones.They were divided by the wishes of patients and their families into 2 groups,subjected to mild hypothermia treatment (n=42) or conventional treatment (n=41).The levels were examined of growth hormone (GH),prolactin (PRL),adrenocorticotropic hormone (ACTH),free triiodothyronine (FT3),free thyroxine (FT4) and thyroid stimulating hormone (TSH) for both groups unpon admission and in the moming of 1,3,5,7 and 14 days after injury.At 6 months after injury the patients were followed up for Glasgow Outcome Score (GOS) and levels of pituitary-related hormones.Results Of the 83 patients,disturbance of one single hormone was found in 31 (30.10％) and disturbance of 2 or more hormones in 52 (50.48％).The top 3 hormones disturbed were PRL,ACTH and GH.On days 3,5 and 7 after injury,the levels of PRL and ACTH in the mild hypothermia treatment group were significantly lower than in the conventional treatment group (P＜0.05).On day 3 after injury,the level of FT3 in the mild hypothermia treatment group was significantly lower than in the conventional treatment group (P＜0.05).At 6 months after injury,the GOS score for the conventional treatment group was 3.04±0.38,significantly lower than that for the mild hypothermia treatment group (4.56±0.62) (P＜0.05).The incidence of hypopituitarism in the hypothermia treatment group (16.67％) was significantly lower than in the conventional treatment group (46.88％) (P＜0.05).Conclusions Incidence of pituitary dysfunction is high in children following severe traumatic brain injury.Mild hypothermia treatment can effectively alleviate early-stage parasecretion of pituitary hormones,and decrease the incidence of later pituitary dysfunction.

Objective To establish WeChat official account-based platform for evidence dissemination,and to evaluate the effects of the platform.Methods The WeChat official account-based platform for evidence dissemination was established,and big data analysis and sampling survey were adopted to analyze information and its communication effects published from December,2014 to September,2016.Results Totally 22 369 followers used the platform and conducted 404 232 hits on its pages in total.The most frequent searches were Evidence and Knowledge of evidence-based nursing.The WeChat Communication Index was 433.07.The overall evaluation score was 4.34± 0.67.Conclusion WeChat official account-based platform for evidence dissemination can promote the accessibility of evidence and receives high evaluation score from followers.

The medical and health reform at grass-root level was monitored during the NPC and CPPCC from 2015-2017 . The public sentiment on medical and health reform at grass-root level in recent years was thus as-sessed according to the text mining and data analysis using the R language and Python method from the aspects ofnow rural cooperative medical care,comprehensive health reform at grass-root level,health service develop-ment at grass-root level and Internet + medical care in order to provide reference for the effective feedback of achievements and development in policies of medical and health reform at grass-root level.

OBJECTIVE:To establish a method for the determination of drug loading and encapsulation efficiency of Epirubi-cin hydrochloride-sorafenib-loaded Polylactic Acid-glycolic Acid Polymer(PLGA)embolic microspheres. METHODS:HPLC meth-od was adopted to determine the contents of epirubicin hydrochloride and sorafenib in the preparation,and then drug loading and encapsulation efficiency were calculated by formula. The determination was performed on Phenomenex Luna 5u C8(2) 100A col-umn with mobile phase consisted of methanol-water(containing 0.05% trifluoroacetic acid and 0.14% dium dodecyl sulfate)(75:25,V/V)at the flow rate of 1.0 mL/min. The detection wavelength was set at 252 nm,and the column temperature was maintained at 25℃. The injection volume was 10μL. RESULTS:The linear ranges were 2.020-101.00μg/mL for epirubicin hydrochloride(r=0.9998)and 2.048-102.40 μg/mL for sorafenib(r=0.9997),respectively. The limits of quantification were 3.2970,2.5468 μg/mL, respectively. The detection limits were 0.9891,0.7641 μg/mL,respectively. RSDs of precision,stability and repeatability tests were all less than 2.0%. The recoveries were 96.41%-101.80%(RSD=1.64%,n=9),99.46%-101.45%(RSD=0.70%,n=9),re-spectively. Drug loading of two components in 3 batches of samples were no lower than 1.17%,encapsulation efficiency no lower than 58%. CONCLUSIONS:The method is simple,accurate,can be used to determine drug loading and encapsulation efficiency of Epirubicin hydrochloride-sorafenib PLGA embolic microspheres.

Objective To observe the curative effect and safety of operation combined with recombinant human erythropoietin on patients with severe intracerebral hemorrhage. Methods Seventy-six surgery patients with severe intracerebral hemorrhage were divided into rHu-EPO group (40 cases) and control group (36 cases) by random digits table method. The rHu-EPO group was injected subcutaneously with rHu-EPO, and the control group was treated with placebo. Neurologic impairment (National Institute of Health Stroke Scale, NIHSS score) and activities of daily living (Barthel index) were evaluated 1 month and 3 months after treatment respectively. Moreover, blood pressure, hemoglobin, and adverse reaction were also observed. Results The scores of NIHSS and Barthel index in two groups before treatment had no significant differences (P>0.05). One month and 3 months after treatment, the scores of NIHSS and Barthel index in rHu-EPO group were significantly better: (12.27±5.26) scores vs. (15.36±4.34) scores and (8.17±2.40) scores vs. (13.90±2.54) scores, (54.36±21.87) scores vs. (43.47±20.29) scores and (69.71±23.08) scores vs. (52.56±21.32) scores, there were statistical differences(P<0.05). There were no statistical differences in systemic blood pressure, diastolic blood pressure and hemoglobin between 2 groups (P>0.05). There were no apparente adverse reactions such as fever, erythra, itching and deep venous thrombosis in rHu-EPO group. Conclusions Operation combined with recombinant human erythropoietin has nerve protective effect, and might be an effective and safe therapy target in severe intracerebral hemorrhage.

Objective To observe the short-term curative effect and safety of recombinant human erythropoietin(rHu-EPO)on patients with primary brain stem injury. Methods Sixty patients with primary brain stem injury were recruited at Liaocheng People' Hospital from July 2010 to July 2013. All cases were randomly divided into EPO group and control group. The patients in EPO group were injected subcutaneous with rHu-EPO five times at dose of 6 000 U,while patients in the control group were treated with placebo in 2 weeks. All other conventional treatments were the same. NIHSS score and GOS score were evaluated in two weeks and three months respectively. Moreover,blood pressure and hemoglobin were also measured. Results NIHSS score in EPO group was 11. 37 ± 7. 78,significant higher than that of control group after two weeks(19. 41 ± 8. 26,P = 0. 019). GOS score in EPO group was also significant differences in two groups after three months (Z = - 2. 367,P = 0. 009 ). However,no significant difference was observed in the followed-up blood tests. Conclusion Recombinant human erythropoietin could be the exact nerve protective effect,and might be an effective therapy for patients with primary brain stem injury.

In order to show the social situation and public opinions for the decision-makers of medical reform, the viewpoints of main media, NPC and PCC members, and Internet users were analyzed according to the real-time monitoring data of public opinions on health-related topics ( new rural cooperative medical system, basic public health service, and rural medical workers) during the NPC and PCC, which showed the public awareness of health reform in grass-roots units of China.