A cross-sectional evaluation of knowledge among Chinese dentists regarding the treatment of traumatic injuries in primary teeth.

BACKGROUND/AIM: Injuries to the primary dentition affect children's esthetics, function, and mental health. They may also affect the development of the permanent teeth. The knowledge of dentists about deciduous tooth trauma is rarely evaluated. The aim of this study was to evaluate the knowledge and attitude of dentists in China regarding traumatic dental injuries to primary teeth. MATERIAL AND METHODS: A self-administered online questionnaire containing questions on demographic data and knowledge based on a clinical scenario was given to a purposive sample of dentists, recruited by a non-probability convenience sampling method. The chi-square test was used for statistical analysis, with the significance level set at P <.05. RESULTS: A total of 394 out of 409 dentists provided valid data. There was no significant difference in demographic data. Questions about the treatment of hard dental tissue injuries in primary teeth presented a correct-response rate of 66.4%, with the highest correct-response rate for enamel fracture (n = 368, 93.4%) and lowest for complicated crown-root fracture with pulp exposure (n = 104, 26.4%). Questions about treatment of luxation injuries in primary teeth presented a correct-response rate of 66.6%, with subluxation presenting the highest correct-response rate (n = 391, 99.2%). Factors associated with higher correct-response rates were specialist disciplines, educational qualifications, workplaces, experience of injured teeth treated, and educational experience about primary tooth trauma. No significant differences were found in the correct-response rates of dentists with different years of work experience. Lack of cooperation from children was considered a major obstacle for treatment. Special lectures and Internet courses were the most preferred methods of obtaining knowledge. CONCLUSION: The results suggest that it is necessary to enhance dental trauma education for dentists in China. More attention needs to be paid to trauma in primary dentition to ensure adequate treatment for traumatized primary teeth.

Step-by-step teaching method: improving learning outcomes of undergraduate dental students in layering techniques for direct composite resin restorations.

BACKGROUND: Layering techniques for direct composite resin restorations might be complicated for inexperienced learners, as a number of materials and instruments are required at each step. The present study aimed to compare and assess the teaching effect of step-by-step and all-in-one teaching methods in layering techniques for direct composite resin restorations among undergraduate dental students. METHODS: A total of 68 junior dental students participated in this study, which was a prospective and single-blind trial. The students were randomly divided into a step-by-step group (experimental group, n = 34) and all-in-one group (control group, n = 34). The same teacher taught the two groups, ensuring a comparable teaching effect. The final score of each student was an average of scores by two experts who were blinded to the grouping. The scoring system was consisted by five parts. Each part was assigned scores of 3.0, 1.5, or 0. The total maximum score was 15 and minimum was 0. The total time taken by each group was also calculated. RESULTS: The values of the quality of tooth restorations evaluated by experts for step-by-step and all-in-one groups were 11.29 ± 2.13 from 15 and 9.00 ± 2.71 from 15 (t = 3.88, P < 0.001), respectively. In addition, the time spent by the experimental group was significantly lesser than that spent by the control group, which was 122.47 ± 2.82 and 137.18 ± 6.75 min, respectively (t = 11.72, p < 0.001). CONCLUSION: With regard to the layering techniques for direct composite resin restorations, the outcomes were better in the step-by-step group than in the all-in-one group.

[Technical scheme of real-time evaluation of traditional Chinese medicine orally disintegrating tablets].

Orally disintegrating tablets (ODT), a kind of new solid tablet that rapidly disintegrates to work in the mouth, has became the hot form of new drug research in recent years with many advantages, such as the convenient taking, a widely applicable people, fast acting, high bioavailability, good compliance, and so on. ODT has been widely used in chemical medicines, while the application of it in traditional Chinese medicines (TCMs) is still in the stage of development The development of TCMs ODT provides a new direction for the research of Chinese medicine new dosage, accelerates the pace of connecting to the world and modernization of Chinese medicine. This dosage has a broad market prospect, and its quality control and assessment standards, taste, the disintegration time in vitro and evaluation method are the key factors that affect the industrialization, standardization of Chinese medicine ODT. Therefore, this paper reviewed the characteristics, preparation, taste masking technology and quality evaluation with new technology of ODT. Meantime, numerous application examples of ODT used in traditional Chinese medicine were described. We expect to provide the reference and utilization for the development of traditional Chinese medicine orally disinteeratine tablets.

Gingival-derived mesenchymal stem cells alleviate allergic asthma inflammation via HGF in animal models.

Allergic asthma is a chronic non-communicable disease characterized by lung tissue inflammation. Current treatments can alleviate the clinical symptoms to some extent, but there is still no cure. Recently, the transplantation of mesenchymal stem cells (MSCs) has emerged as a potential approach for treating allergic asthma. Gingival-derived mesenchymal stem cells (GMSCs), a type of MSC recently studied, have shown significant therapeutic effects in various experimental models of autoimmune diseases. However, their application in allergic diseases has yet to be fully elucidated. In this study, using an OVA-induced allergic asthma model, we demonstrated that GMSCs decrease CD11b+CD11c+ proinflammatory dendritic cells (DCs), reduce Th2 cells differentiation, and thus effectively diminish eosinophils infiltration. We also identified that the core functional factor, hepatocyte growth factor (HGF) secreted by GMSCs, mediated its effects in relieving airway inflammation. Taken together, our findings indicate GMSCs as a potential therapy for allergic asthma and other related diseases.

Infusion of GMSCs relieves autoimmune arthritis by suppressing the externalization of neutrophil extracellular traps via PGE2-PKA-ERK axis.

INTRODUCTION: Rheumatoid arthritis (RA) is a systemic autoimmune disease with limited treatment success, characterized by chronic inflammation and progressive cartilage and bone destruction. Accumulating evidence has shown that neutrophil extracellular traps (NETs) released by activated neutrophils are important for initiating and perpetuating synovial inflammation and thereby could be a promising therapeutic target for RA. K/B × N serum transfer-induced arthritis (STIA) is a rapidly developed joint inflammatory model that somehow mimics the inflammatory response in patients with RA. Human gingival-derived mesenchymal stem cells (GMSCs) have been previously shown to possess immunosuppressive effects in arthritis and humanized animal models. However, it is unknown whether GMSCs can manage neutrophils in autoimmune arthritis. OBJECTIVES: To evaluate whether infusion of GMSCs can alleviate RA by regulating neutrophils and NETs formation. If this is so, we will explore the underlying mechanism(s) in an animal model of inflammatory arthritis. METHODS: The effects of GMSCs on RA were assessed by comparing the symptoms of the K/B × N serum transfer-induced arthritis (STIA) model administered either with GMSCs or with control cells. Phenotypes examined included clinical scores, rear ankle thickness, paw swelling, inflammation, synovial cell proliferation, and immune cell frequency. The regulation of GMSCs on NETs was examined through immunofluorescence and immunoblotting in GMSCs-infused STIA mice and in an in vitro co-culture system of neutrophils with GMSCs. The molecular mechanism(s) by which GMSCs regulate NETs was explored both in vitro and in vivo by silencing experiments. RESULTS: We found in this study that adoptive transfer of GMSCs into STIA mice significantly ameliorated experimental arthritis and reduced neutrophil infiltration and NET formation. In vitro studies also showed that GMSCs inhibited the generation of NETs in neutrophils. Subsequent investigations revealed that GMSCs secreted prostaglandin E2 (PGE2) to activate protein kinase A (PKA), which ultimately inhibited the downstream extracellular signal-regulated kinase (ERK) pathway that is essential for NET formation. CONCLUSION: Our results demonstrate that infusion of GMSCs can ameliorate inflammatory arthritis mainly by suppressing NET formation via the PGE2-PKA-ERK signaling pathway. These findings further support the notion that the manipulation of GMSCs is a promising stem cell-based therapy for patients with RA and other autoimmune and inflammatory diseases.

miRNA-148a-containing GMSC-derived EVs modulate Treg/Th17 balance via IKKB/NF-κB pathway and treat a rheumatoid arthritis model.

Mesenchymal stem cells (MSCs) have demonstrated potent immunomodulatory properties that have shown promise in the treatment of autoimmune diseases, including rheumatoid arthritis (RA). However, the inherent heterogeneity of MSCs triggered conflicting therapeutic outcomes, raising safety concerns and limiting their clinical application. This study aimed to investigate the potential of extracellular vesicles derived from human gingival mesenchymal stem cells (GMSC-EVs) as a therapeutic strategy for RA. Through in vivo experiments using an experimental RA model, our results demonstrate that GMSC-EVs selectively homed to inflamed joints and recovered Treg and Th17 cell balance, resulting in the reduction of arthritis progression. Our investigations also uncovered miR-148a-3p as a critical contributor to the Treg/Th17 balance modulation via IKKB/NF-κB signaling orchestrated by GMSC-EVs, which was subsequently validated in a model of human xenograft versus host disease (xGvHD). Furthermore, we successfully developed a humanized animal model by utilizing synovial fibroblasts obtained from patients with RA (RASFs). We found that GMSC-EVs impeded the invasiveness of RASFs and minimized cartilage destruction, indicating their potential therapeutic efficacy in the context of patients with RA. Overall, the unique characteristics - including reduced immunogenicity, simplified administration, and inherent ability to target inflamed tissues - position GMSC-EVs as a viable alternative for RA and other autoimmune diseases.

One-year clinical outcome of a randomized trial of polymer-free paclitaxel-eluting stents versus biodegradable polymer-based rapamycin-eluting stents in patients with coronary heart disease.

BACKGROUND: More widespread use of drug-eluting stents (DES) to treat coronary heart disease (CHD) has recently generated more attention to thrombosis, which was relative to the polymer. Polymer-free and biodegradable polymer-based stents are more frequently studied, but their efficacy on preventing detrimental clinical events is unclear. METHODS AND RESULTS: To assess whether polymer-free paclitaxel-eluting stent (YINYI stent) was noninferior or equivalent to biodegradable polymer-based rapamycin-eluting stents (EXCEL stent) in preventing detrimental clinical cardiovascular events, a total of 167 consecutive CHD patients requiring DES implantation were randomly divided into the YINYI group (n = 82) and the EXCEL group (n = 85). The primary end-point was major adverse cardiac events (MACE). The secondary end-points included stent thrombosis events, all-cause mortality, and rehospitalization. The study was designed to test the noninferiority or equivalence of the YINYI stent compared with the EXCEL stent with respect to one-year MACE according to a noninferiority or equivalence margin of 0.1. One-year MACE was 6.10% in the YINYI group versus 5.88% in the EXCEL group. The lower limit of the one-sided 95% confidence interval was -0.0582 (P = 0.002 from the test for noninferiority). The 95% confidence interval for the equivalence test was [-0.0698, 0.0742] (P1 =0.004 and P2 =0.007 from 2 times the 1-sided test for equivalence). There was no statistically significant difference in thrombosis events, all-cause death, and rehospitalization (all P > 0.05). CONCLUSIONS: In this small randomized trial, polymer-free paclitaxel-eluting stents appear to be noninferior or equivalent to biodegradable polymer-based rapamycin-eluting stents.

Genome sequencing identified a novel exonic microdeletion in the RUNX2 gene that causes cleidocranial dysplasia.

BACKGROUND AND AIMS: Cleidocranial dysplasia (CCD) represents a rare autosomal dominant skeletal dysplasia caused by mutations that induce haploinsufficiency in RUNX2, the important transcription factor of osteoblasts related to bone/cartilage development and maintenance. Clavicular hypoplasia, which involves aberrant tooth/craniofacial bone/skeletal formation, is a feature of classic CCD. RUNX2 mutations can be found in approximately 60-70% of patients with CCD, and around ∼10% of these mutations are microdeletions. The present paper describes the radiological and clinical characteristics of a 5-year-old girl who showed representative CCD features, including extra teeth, aplasia of clavicles, sloping shoulders, marked calvarial hypomineralization, and osteoporosis. MATERIALS AND METHODS: We obtained genomic DNA of her family members and performed whole-genome sequencing (WGS) for samples collected from the proband. Quantitative fluorescent PCR (QF-PCR) and specific PCR plus electrophoresis were then performed as validation assays for all participants. In vitro analysis was performed. Luciferase assay for Runx2 transcription activity and evaluation of mRNA levels of Runx2 downstream osteogenic markers were conducted. RESULTS: WGS identified a 11.38-kb microdeletion in RUNX2 comprising 8-9 exons, which was validated by QF-PCR and specific PCR plus electrophoresis. In vitro experiments confirmed the pathogenicity of this variation. CONCLUSION: The present study identified a 11.38-kb microdeletion in RUNX2 that causes CCD. The deletion in the PST domain of RUNX2 reduces its transcription activity and reduces osteogenic marker levels, eventually decreasing the differentiation of osteoblasts. These findings clarify the role of the CCD-related mechanism in the development of CCD and suggest that it is important to consider copy number variation for the suspected familial patients early.

Brij-functionalized chitosan nanocarrier system enhances the intestinal permeability of P-glycoprotein substrate-like drugs.

The highly expressed P-glycoprotein (Pgp) in the intestine plays a key role in preventing drugs across the intestinal epithelium, which linked by tight junctions (TJs). Thus increasing the oral bioavailability of Pgp substrate-like drugs (PSLDs) remains a great challenge. Herein, we construct a nanocarrier system derived from Brij-grafted-chitosan (BC) to enhance the oral bioavailability and therapeutic effect of berberine (BBR, a typical PLSD) against diabetic kidney disease. The developed BC nanoparticles (BC-NPs) are demonstrated to improve the intestinal permeability of BBR via transiently and reversibly modulating the intercellular TJs (paracellular pathway) and Pgp-mediated drug efflux (transcellular pathway). As compared to free BBR and chitosan nanoparticles, the BC-NPs enhanced the relative oral bioavailability of BBR in rats (4.4- and 2.7-fold, respectively), and the therapeutic potency of BBR in renal function and histopathology. In summary, such strategy may provide an effective nanocarrier system for oral delivery of BBR and PSLDs.

Detection of Treponema denticola in Chronic Periodontitis by Quantitative Real-Time Polymerase Chain Reaction.

Chronic periodontitis constitutes a significant public health issue, particularly in China. Treponema denticola is one of the bacterial species critically involved in the development of this disease. Therefore, an effort was made in this study to design a technique for isolation of DNA from gingival fluid and detection of T. denticola genes by PCR methodology. For this purpose, samples were collected from 30 patients with severe periodontitis and 20 patients with mild periodontitis. A group of 50 healthy individuals served as a control. Following the isolation of DNA from the gingival fluid by magnetic microbeads, the material was analyzed for the presence of 16S rRNA by conventional and quantitative real-time PCR protocols. This newly developed methodology identified the presence of T. denticola in all samples from periodontitis patients. Quantitative analysis of copy numbers demonstrated that the bacterial count was highest in the severe periodontitis group and intermediate in the mild periodontitis group. The smallest number of bacteria were present in healthy controls. Besides being rapid, accurate and specific, the proposed method eliminates the need for anaerobic bacterial cultures, making it applicable in a typical clinical setting.

[Combined rapamycin eye drop in nanometer vector and poly (lactic acid) wafers of cyclosporine A effectively prevents high-risk corneal allograft rejection in rabbits].

OBJECTIVE: To evaluate the combined effect of topical rapamycin (RAPA) eye drop in nanometer vector and poly (lactic acid) (PLA) wafers of cyclosporine A (CsA) in the prevention of acute allograft rejection after rabbit corneal transplantation. Methods It was an experimental study. RAPA was incorporated into the nanometer particles and CsA was incorporated into PLA wafers. A was syngeneic control whose both donor and recipient are New Zealand rabbit. Gray donor corneas were implanted into the 102 recipients of New Zealand albino rabbits with corneal neovascularization who were randomly divided into B, C, D, E, F, G 6 groups to receive the different types of therapy: B was no therapy control; C was eye drop of nanometer vector but no RAPA twice a day, 28 days; D was PLA wafers in the anterior chamber of rabbit eyes but no drugs; E was 0.5% RAPA eye drop of nanometer vector twice a day, 28 days; F was PLA wafers of CsA in the anterior chamber of rabbit eyes; G was PLA wafers of CsA in the anterior chamber of rabbit eyes and 0.5% RAPA eye drop of nanometer vector eye drop twice a day for 28 days together. Postoperative evaluation included slit-lamp biomicroscopy, histopathology and immunohistology, Cytokines related with neovascularization and immunosuppression in the corneal tissue by RT-PCR. The graft survival was assessed by One-Way ANOVA and q test. RESULTS: Corneal allograft survival time: A (100.00 +/- 0.00), B (8.44 +/- 1.24), C (8.89 +/- 2.57), D (8.56 +/- 2.30), E (43.11 +/- 5.58), F (43.67 +/- 9.54), G (72.00 +/- 15.34) d. Group G led to a statistically significant prolongation of transplant survival and was superior than group E and F which was a statistical prolongation compared with group B, C and D (qGE = 11.42, qGF = 11.24, qEB = 13.64, qEC = 13.38, qED = 13.46, qFB = 13.82, qFC = 13.56, qFD = 13.64; P < 0.01). Immunohistopathologically, the grafts were subjected to an immune response contained a dense infiltrate of neutrophils, CD4+ and CD8+ T lymphocytes in the group B, C and D. This cellular infiltrate was a significant reduction in group E,F,G. RT-PCR showed that the gene expression of IL-2 was inhibited earlier (3 days) in group F, G and VEGF gene expression being suppressed later (14 days) in group E, G. CONCLUSIONS: Combined therapy with topical application of RAPA eye drop of nanometer vector and CsA PLA wafers can significantly prolong the survival of allograft at high-risk. Moreover, topical combined treatment of them is more effective, lower dosage, less side-effects and cheaper than the treatment with topical individual immunosuppressive drug.

Human gingival tissue-derived MSC suppress osteoclastogenesis and bone erosion via CD39-adenosine signal pathway in autoimmune arthritis.

BACKGROUND: Bone destruction is one of many severe complications that occurs in patients with rheumatoid arthritis (RA) and current therapies are unable to cure this manifestation. This study here aims to determine whether GMSC can directly inhibit osteoclast formation and eventually attenuate osteoclastogenesis and bone erosion in an inflammatory milieu. METHOD: GMSC were co-cultured with osteoclast precursors with or without CD39 inhibitor, CD73 inhibitor or adenosine receptors inhibitors pretreatment and osteoclast formation were evaluated in vitro. 2×10^6 GMSC per mouse were transferred to CIA mice and pathology scores, the frequency of osteoclasts, bone erosion in joints were assessed in vivo. FINDING: GMSC but not control cells, markedly suppressed human or mice osteoclastogenesis in vitro. GMSC treatment also resulted in a dramatically decreased level of NF-κB p65/p50 in osteoclasts in vitro. Infusion of GMSC to CIA significantly attenuated the severity of arthritis, pathology scores, frequency of osteoclasts, particularly bone erosion, as well as a decreased expression of RANKL in synovial tissues in vivo. Blockade of CD39/CD73 or adenosine receptors has significantly abrogated the suppressive ability of GMSC in vitro and therapeutic effect of GMSC on bone erosion during CIA in vivo. INTERPRETATION: GMSC inhibit osteoclast formation in vitro and in vivo partially via CD39-CD73-adenosine signals. Manipulation of GMSC may have a therapeutic implication on rheumatoid arthritis and other bone erosion related diseases. FUND: This study was supported by grants from the National Key R&D Program of China (2017YFA0105801 to F.H); the Zhujiang Innovative and Entrepreneurial Talent Team Award of Guangdong Province (2016 ZT 06S 252 to F·H) and National Institutes of Health (R01 AR059103, R61 AR073409 and NIH Star Award to S.G.Z).

Human Gingiva-Derived Mesenchymal Stem Cells Modulate Monocytes/Macrophages and Alleviate Atherosclerosis.

Atherosclerosis is the major cause of cardiovascular diseases. Current evidences indicate that inflammation is involved in the pathogenesis of atherosclerosis. Human gingiva-derived mesenchymal stem cells (GMSC) have shown anti-inflammatory and immunomodulatory effects on autoimmune and inflammatory diseases. However, the function of GMSC in controlling atherosclerosis is far from clear. The present study is aimed to elucidate the role of GMSC in atherosclerosis, examining the inhibition of GMSC on macrophage foam cell formation, and further determining whether GMSC could affect the polarization and activation of macrophages under different conditions. The results show that infusion of GMSC to AopE-/- mice significantly reduced the frequency of inflammatory monocytes/macrophages and decreased the plaque size and lipid deposition. Additionally, GMSC treatment markedly inhibited macrophage foam cell formation and reduced inflammatory macrophage activation, converting inflammatory macrophages to anti-inflammatory macrophages in vitro. Thus, our study has revealed a significant role of GMSC on modulating inflammatory monocytes/macrophages and alleviating atherosclerosis.

Dual-functional Brij-S20-modified nanocrystal formulation enhances the intestinal transport and oral bioavailability of berberine.

INTRODUCTION: Berberine (BBR) is a plant-derived benzylisoquinoline alkaloid and has been demonstrated to be a potential treatment for various chronic diseases. The poor water solubility and P-glycoprotein (Pgp)-mediated drug efflux are the main challenges for its further application in a clinical setting. MATERIALS AND METHODS: In this study, a Brij-S20 (BS20)-modified nanocrystal formulation (BBR-BS20-NCs) has been developed and investigated with the purpose of improving the intestinal absorption of BBR. The physicochemical properties of the developed BBR-BS20-NCs were characterized and the enhancement of the BBR-BS20-NCs on BBR absorption were investigated both in vitro and in vivo. RESULTS: The results indicated that BS20 could significantly enhance the intracellular uptake of BBR in MDCK-MDR1 cells via a short-term and reversible modulation on the Pgp function, accompanied by a marked increase in Pgp mRNA expression but without significant influence on the Pgp protein expression. Moreover, the morphology of the prepared BBR-BS20-NCs was observed to be prism-like, with a smooth surface and an average diameter of 148.0 ± 3.2 nm. Compared to raw BBR and physical mixture, BBR-BS20-NCs facilitated the dissolution rate and extent of release of BBR in aqueous solution, and further increased the absorption of BBR in MDCK-MDR1 monolayer by overcoming the Pgp-mediated secretory transport (Papp[BL-AP] values of 2.85 ± 0.04 × 10-6 cm/s, 2.21 ± 0.14 × 10-6 cm/s, and 2.00 ± 0.07 × 10-6 cm/s for pure BBR, physical mixture, and BBR-BS20-NCs, respectively). Significant improvements in the maximum concentration observed (Cmax) and area under drug concentration-time curve (AUC0-t) of BBR-BS20-NCs were obtained in pharmacokinetic studies compared to pure BBR, and the relative bioavailability of BBR-BS20-NCs to pure BBR was 404.1%. CONCLUSION: The developed BBR-BS20-NCs combine the advantages of nanocrystal formulation and functional excipient. The novel pharmaceutical design provides a new strategy to improve the oral bioavailability of those drugs with both poor water solubility and Pgp-mediated efflux.

[Effects and influential factors of rapid prototyping technology in dental restorations].

PURPOSE: To explore the effects and influential factors of rapid prototyping technology in dental restorations. METHODS: From May 2013 to November 2014 in our hospital, 120 patients were divided into experimental group and conventional group. Patients in the experimental group were treated by rapid prototyping technology, while patients in the conventional group were treated by routine methods. The effects of the two groups were compared using SPSS 17.0 software package. RESULTS: The effective rate of the experimental group was significantly higher than that of the conventional group (P<0.05). Complications in the experimental group were significantly lower than those in the conventional group (P<0.05). CONCLUSIONS: Rapid prototyping technology can be used in the treatment of patients with dentition defects with satisfactory results and fewer adverse reactions.

Human Gingiva-Derived Mesenchymal Stem Cells Inhibit Xeno-Graft-versus-Host Disease via CD39-CD73-Adenosine and IDO Signals.

Mesenchymal stem cells have the capacity to maintain immune homeostasis and prevent autoimmunity. We recently reported that human-derived gingival mesenchymal stem cells (GMSCs) have strong capacity to suppress immune responses and T cell-mediated collagen-induced arthritis in animals. However, it is unclear whether these cells can suppress human T cell-mediated diseases. Here, we used a xenogenic GVHD model in the NOD/SCID mouse, which is a useful preclinical construct for evaluating the therapeutic and translational potential of this approach for applications in human disease. We found that GMSCs potently suppressed the proliferation of PBMC and T cells in vitro. Co-transfer of GMSC with human PBMC significantly suppressed human cell engraftment and markedly prolonged the mouse survival. Moreover, we demonstrated that GMSCs inhibited human PBMC-initiated xenogenic responses via CD39/CD73/adenosine and IDO signals. These findings suggest the potential for GMSCs to suppress human immune responses in immune system-mediated diseases, offering a potential clinical option to be used for modulating GVHD and autoimmune diseases.

Human Gingiva-Derived Mesenchymal Stem Cells Ameliorate Streptozoticin-induced T1DM in mice via Suppression of T effector cells and Up-regulating Treg Subsets.

There is yet no cure for type 1 diabetes (T1DM) so far. A significant body of evidence has demonstrated that bone marrow-derived mesenchymal stem cells (BMSCs) showed great potential in controlling T1DM. But there exists much difficulty in using BMSCs as a clinical therapy. We here test whether a new population of mesenchymal stem cells from human gingiva (GMSCs), which has many advantages over BMSCs, can delay or prevent progress of T1DM. GMSCs were adoptively transferred to multiple low-dose streptozotocin (STZ)-induced T1DM. Blood glucose levels and disease severities were analyzed. T cells subsets in blood, spleen and lymph nodes were detected dynamically by flow cytometry. GMSC distribution was dynamically analyzed. We found that infusion of GMSCs but not fibroblast cells significantly controlled blood glucose levels, delayed diabetes onset, ameliorated pathology scores in pancreas, and down-regulated production of IL-17 and IFN-γ in CD4+ and CD8+ T cells in spleens, pancreatic lymph nodes (pLN) and other lymph nodes. GMSCs also up-regulated the levels of CD4+ Treg induced in the periphery. Mechanismly, GMSCs could migrate to pancreas and local lymph node and function through CD39/CD73 pathway to regulate effector T cells. Thus, GMSCs show a potential promise in treating T1DM in the clinic.

Two-year clinical outcomes of different drug-eluting stents with different polymer coating strategies in coronary artery heart disease: a multi-centre, randomised, controlled clinical trial.

BACKGROUND: The persistence of polymer may be related to late and very late stent thrombosis. Recently, biodegradable polymer (BD) and polymer-free (PF) stents have become a focus for prevention of detrimental clinical events. However, the long-term efficacy of these types of stent compared to that of permanent polymer (PP) stents is unclear. METHODS AND RESULTS: A total of 989 consecutive coronary heart disease (CHD) patients from five centres who required the implantation of drug-eluting stents (DES) were randomly divided into the PP (n = 321), PF (n = 327) and BD groups (n = 341). The primary endpoint was major adverse cardiac events (MACE). The secondary endpoints were stent thrombosis events, all-cause death and rehospitalisation. The study was designed to test the noninferiority of the PF and BD stents compared with that of the PP stent with respect to two-year MACE, using a noninferiority margin of 0.05. After clinical follow-up for 26.96 ± 12.99 months, the 2-year MACE rates were 6.17% in the PF group, 6.58% in the BD group and 7.24% in the PP group. The noninferiority testing produced lower limits of the one-sided 95% confidence interval of -0.0435 (P = 0.024) for the PF group and -0.0401 (P = 0.017) for the BD group. There were no significant differences in stent thrombosis events, all-cause death and rehospitalisation among the three groups (all P>0.05). CONCLUSION: In this multicentre, randomised, controlled clinical trial, PF paclitaxel-eluting stents and BD rapamycin-eluting stents were shown to be noninferior to PP rapamycin-eluting stents in two-year clinical outcomes for the treatment for CHD.

Transjugular intrahepatic portosystemic shunt vs endoscopic therapy in preventing variceal rebleeding.

AIM: To compare early use of transjugular intrahepatic portosystemic shunt (TIPS) with endoscopic treatment (ET) for the prophylaxis of recurrent variceal bleeding. METHODS: In-patient data were collected from 190 patients between January 2007 and June 2010 who suffured from variceal bleeding. Patients who were older than 75 years; previously received surgical treatment or endoscopic therapy for variceal bleeding; and complicated with hepatic encephalopathy or hepatic cancer, were excluded from this research. Thirty-five cases lost to follow-up were also excluded. Retrospective analysis was done in 126 eligible cases. Among them, 64 patients received TIPS (TIPS group) while 62 patients received endoscopic therapy (ET group). The relevant data were collected by patient review or telephone calls. The occurrence of rebleeding, hepatic encephalopathy or other complications, survival rate and cost of treatment were compared between the two groups. RESULTS: During the follow-up period (median, 20.7 and 18.7 mo in TIPS and ET groups, respectively), rebleeding from any source occurred in 11 patients in the TIPS group as compared with 31 patients in the ET group (Kaplan-Meier analysis and log-rank test, P = 0.000). Rebleeding rates at any time point (6 wk, 1 year and 2 year) in the TIPS group were lower than in the ET group (Bonferroni correction α' = α/3). Eight patients in the TIPS group and 16 in the ET group died with the cumulative survival rates of 80.6% and 64.9% (Kaplan-Meier analysis and log-rank test χ(2) = 4.864, P = 0.02), respectively. There was no significant difference between the two groups with respect to 6-wk survival rates (Bonferroni correction α' = α/3). However, significant differences were observed between the two groups in the 1-year survival rates (92% and 79%) and the 2-year survival rates (89% and 64.9%) (Bonferroni correction α' = α/3). No significant differences were observed between the two treatment groups in the occurrence of hepatic encephalopathy (12 patients in TIPS group and 5 in ET group, Kaplan-Meier analysis and log-rank test, χ(2) = 3.103, P = 0.08). The average total cost for the TIPS group was higher than for ET group (Wilcxon-Mann Whitney test, 52 678 RMB vs 38,844 RMB, P < 0.05), but hospitalization frequency and hospital stay during follow-up period were lower (Wilcxon-Mann Whitney test, 0.4 d vs 1.3 d, P = 0.01; 5 d vs 19 d, P < 0.05). CONCLUSION: Early use of TIPS is more effective than endoscopic treatment in preventing variceal rebleeding and improving survival rate, and does not increase occurrence of hepatic encephalopathy.

Redox/pH dual stimuli-responsive biodegradable nanohydrogels with varying responses to dithiothreitol and glutathione for controlled drug release.

A new type of redox/pH dual stimuli-responsive poly(methacrylic acid) (PMAA)-based nanohydrogels was prepared from methacrylic acid and N,N-bis(acryloyl)cystamine crosslinker via distillation-precipitation polymerization. The nanohydrogels could be easily degraded into individual linear short chains (M(n) ≈ 1200, M(w)/M(n) < 1.1) in the presence of 10 mM dithiothreitol (DTT) or glutathione (GSH). Doxorubicin (DOX) as a model anti-cancer drug was high efficiently loaded into the nanohydrogels (up to 42.3 wt%) due to the strong electrostatic interactions between the amine group in doxorubicin (DOX) and the carboxyl groups in the nanohydrogels at a physiological pH. The cumulative release profile of the DOX-loaded nanohydrogels showed a low level of drug release (less than 15 wt% in 24 h) at pH 7.4, and was significantly accelerated at a lower pH (5.0) and reducing environment (over 91 wt% in 5 h), exhibiting an obvious pH/redox dual-responsive controlled drug release capability. The drug release behavior of the DOX-loaded nanohydrogels in the presence of GSH was very different from the DTT as the loaded DOX could be quickly released in the presence of GSH, but not in DTT. The possible reason is the synergic effect of reduction and charge exchange of GSH at a low pH. The dose-dependent cytotoxicity of the DOX-loaded nanohydrogels was studied by the CCK-8 assay; the DOX-loaded nanohydrogels could be taken up quickly by human glioma (U251MG cells) via endocytosis, and then biodegraded to release the loaded drugs, which exhibited a comparably anti-tumor efficacy. These nanohydrogels possess many favorable traits, such as excellent biocompatibility and biodegradability, adequate drug loading capacity, minimal drug release under an extracellular condition (non-reductive), and rapid drug release in response to the intracellular level of pH and reducing potential, which endow them as a promise candidate for delivering anti-cancer drugs.