STING modulates iron metabolism to promote liver injury and inflammation in acute immune hepatitis.

The pathogenesis of Autoimmune Hepatitis (AIH) is closely associated with perturbations in iron ion metabolism, during which Stimulator of Interferon Genes (STING) plays an important role. However, the precise regulatory mechanism remains elusive. In this study, we investigated the relationship between iron dysregulation and STING activation in Concanavalin A (ConA)-induced AIH liver injury. STING knockout (STING-/-) mice and AAV (Adeno-Associated virus)-Sting1-RNAi-treated mice were involved and subjected in AIH. We observed that increased iron dysregulation was linked with STING activation, but this effect was effectively reversed by the administration of iron chelating agent Desferoxamine (DFO) and the antioxidant Ferrostatin-1 (Fer-1). Notably, the iron transport protein Transferrin (TF) and Transferrin Receptor (TfR) exhibited significant accumulation in AIH along with upregulated expression of ferritin protein. Additionally, the deficiency of STING reduced hepatic iron accumulation, mitigated oxidative stress, and attenuated macrophage activation during ConA treatment. Furthermore, liver-specific knockdown of STING using AAV-Sting1-RNAi significantly ameliorated liver iron dysregulation and oxidative stress response induced by Kupffer cells (KCs). KC-derived STING exacerbates liver damage severity in AIH through promoting disturbances in hepatic iron ion metabolism as well as oxidative stress response. These findings provide valuable insights into the pathogenesis of AIH and may pave the way for potential therapeutic strategies targeting STING and iron metabolism in the future.

Clinical efficacy and tendon integrity of patients with subscapularis tear by the technique of arthroscopic single external row repair.

Background: With the development of arthroscopic technology and equipment, arthroscopy can effectively repair the tear of the subscapular muscle. However, it is difficult to expose the subscapular muscle and operate it under a microscope. In this study, the SwiveLock® C external row anchor under arthroscopy was applied to repair the tear of the subscapular muscle in a single row, which is relatively easy to operate with reliable suture and fixation, and its efficacy was evaluated. Purpose: This study aimed to assess the clinical efficacy and the tendon integrity of patients who had subscapularis tears by adopting the single-row repair technique with a SwiveLock® C external row anchor. Methods: Patients who had the subscapular muscle tear either with or without retraction were included, and their follow-up time was at least 1 year. The degree of tendon injury was examined by magnetic resonance imaging (MRI) and confirmed by arthroscopy. The tendon was repaired in an arthroscopic manner by utilizing the single-row technique at the medial margin of the lesser tuberosity. One double-loaded suture SwiveLock® C anchor was applied to achieve a strong fixation between the footprint and tendon. The range of motion, pain visual simulation score, American Shoulder and Elbow Surgeons (ASES) score, and Constant score of shoulder joint were evaluated for each patient before the operation, 3 months after the operation, and at least 1 year after the operation. Results: In total, 110 patients, including 31 males and 79 females, with an average age of 68.28 ± 8.73 years were included. Arthroscopic repair of the subscapular tendon with SwiveLock® C external anchor can effectively improve the range of motion of the shoulder joint. At the last follow-up, the forward flexion of the shoulder joint increased from 88.97 ± 26.33° to 138.38 ± 26.48° (P < 0.05), the abduction range increased from 88.86 ± 25.27° to 137.78 ± 25.64° (P < 0.05), the external rotation range increased from 46.37 ± 14.48° to 66.49 ± 14.15° (P < 0.05), and the internal rotation range increased from 40.03 ± 9.01° to 57.55 ± 7.43° (P < 0.05). The clinical effect is obvious. The constant shoulder joint score increased from 40.14 ± 15.07 to 81.75 ± 11.00 (P < 0.05), the ASES score increased from 37.88 ± 13.24 to 82.01 ± 9.65 (P < 0.05), and the visual analog scale score decreased from 5.05 ± 2.11 to 1.01 ± 0.85 (P < 0.05). In the 6th month after the operation, two cases (1.81%) were confirmed to have re-tears via MRI. Conclusion: In this study, we repaired the subscapularis muscle with a single-row technique fixed by SwiveLock® C anchor and FiberWire® sutures and evaluated its efficacy. The results showed that the clinical effect of single-row arthroscopic repair was satisfactory and that reliable tendon healing could be achieved.

Total laparoscopic sigmoid vaginoplasty: a novel therapeutic approach.

BACKGROUND: This study aimed to evaluate the technical feasibility and outcomes of total laparoscopic sigmoid vaginoplasty (TLSV) in women with congenital absence of the vagina. METHODS: We investigated 10 women with congenital absence of the vagina, who underwent TLSV at Guangdong Provincial People's Hospital between April 2013 and July 2016. RESULTS: All 10 women were unmarried, the mean age was 22.8 (range 17-33) years, mean estimated blood loss was 149.2 ± 54.8 (60-170) mL, mean operative time was 108.4 ± 52.6 (130-210) min, mean post-operative hospital stay was 8.0 ± 2.8 (6-12) days and the mean neovaginal length was 13.4 ± 3.0 (12-16) cm. Eight of the 10 women were heterosexually active. Trocar port site infection and neovaginal stenosis occurred 3 months after TLSV in one patient; a vaginal mould was used to relieve the stenosis. CONCLUSION: TLSV is an optimal minimally invasive procedure to treat women with congenital absence of the vagina and is associated with rapid recovery and acceptable cosmetic effects.

Heavy metal exposure, oxidative stress and semen quality: Exploring associations and mediation effects in reproductive-aged men.

BACKGROUND: Heavy metal exposure induces oxidative stress, which is critical for adverse male reproductive health. OBJECTIVE: To explore the mediating effect of oxidative stress on the relationship of heavy metal exposure with semen quality. METHODS: Urinary levels of three oxidative stress markers, semen quality, and urinary arsenic, cadmium and lead were examined among 1020 men. Multivariate linear regression was applied to explore cross-sectional associations, and the role of oxidative stress as mediators was investigated. RESULTS: Quartiles of metals showed significant dose-dependent relationships with increasing levels of 8-hydroxy-2deoxyguanosine (8-OHdG), 8-iso-prostaglandin F2α (8-isoPGF2α) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA). Significant or suggestive associations were also found between urinary 8-OHdG levels and the percentage of normal sperm morphology (ptrend < 0.001), between urinary 8-isoPGF2α levels and total motility (ptrend = 0.052), progressive motility (ptrend = 0.050) respectively. The mediation analysis showed that about 14.59%, 18.06%, 15.35% or 16.49% of the association between arsenic/cadmium exposure and the decreased total motility/progressive motility was mediated by 8-isoPGF2α, respectively. In addition, about 16.47% of the relationship between lead exposure and the decreased percentage of normal sperm morphology was mediated by 8-OHdG. CONCLUSIONS: Our findings suggest that higher urinary arsenic, cadmium and lead levels were associated with increased oxidative stress markers, which also related with altered semen quality. 8-isoPGF2α and 8-OHdG might be the possible mediators of the associations between urinary heavy metals and total motility, progressive motility or the proportion of normal sperm morphology.

Propofol attenuates mast cell degranulation via inhibiting the miR-221/PI3K/Akt/Ca2+ pathway.

The aim of the present study was to investigate the effect of propofol on immunoglobulin (Ig)E-activated mast cell degranulation and explore the underlying mechanisms responsible. RBL-2H3 cells were treated with propofol for at a variety of concentrations and different amounts of time. Cell viability was assessed using an MTT assay and microRNA (miR)-221 expression was quantified using reverse transcription-quantitative polymerase chain reaction. RBL-2H3 cells were transfected with miR-221 mimic or a negative control and degranulation, including the release of ß-hexosaminidase and histamine, was evaluated using an ELISA kit. The effect of miR-221 overexpression on the phosphorylation of protein kinase B (Akt) was detected using western blotting and extracellular Ca2+ influx was measured via afura-2 assay. The phosphoinositide 3-kinase(PI3K) inhibitor LY294002 was used to investigate the association between PI3K/Akt signaling and Ca2+ influx in the presence of propofol. The results demonstrated that propofol treatment suppressed RBL-2H3 cell proliferation in a dose- and time-dependent manner. Propofol inhibited miR-221 expression in a dose-dependent manner compared with the control group; however, the inhibitive effect was significantly abrogated following transfection with miR-221 mimics. Furthermore, ß-hexosaminidase and histamine release, PI3K/Akt signaling and Ca2+ influx were decreased following propofol application. miR-221 overexpression markedly ameliorated the suppressive effect of propofol. Treatment with LY294002 reversed the propofol-induced decrement of Ca2+ influx on IgE-mediated RBL-2H3 cells, suggesting an association between PI3K/Akt signaling and Ca2+ influx. In conclusion, the results of the present study suggest that propofol treatment attenuates mast cell degranulation via inhibiting the miR-221/PI3K/Akt/Ca2+ pathway. These results indicate that propofol may have a potential therapeutic effect as a treatment for allergic diseases.

The integrative effect of periphyton biofilm and tape grass (Vallisneria natans) on internal loading of shallow eutrophic lakes.

The response of periphyton biofilm and the submerged macrophyte tape grass (Vallisneria natans) to internal loading from eutrophic lake sediments were evaluated in microcosms. The sediments from the littoral zone and center of a lake were selected to carry out the microcosm experiment. To determine how the differences in the periphyton biofilm and V. natans growth alone or in combination, we measured changes in water quality, growth, and TP in the periphyton biofilm and V. natans in microcosms containing these sediments. The results showed that the average daily TN and TP removal rates were 32.6 and 35.4%, respectively, in the microcosms containing the lake center sediments by V. natans and the periphyton biofilm. The presence of the periphyton biofilm and V. natans increased the pH, dissolved oxygen, and redox potential and decreased the conductivity in the overlying water in all treatments. Compared to the state before the treatments, V. natans grew well, with a significant increase in biomass (3.1- to 5.5-fold growth) and TP amount (5.1- to 8.8-fold) in all treatments after 48 days. However, the growth of V. natans that combined with the periphyton biofilm was better than that of V. natans alone, as reflected by the dry weight, chlorophyll a content, malondialdehyde content, and TP amount. In conclusion, the periphyton biofilm was beneficial for the growth of V. natans, and the appropriate combination of V. natans and periphyton biofilm would be a potential method for the ecological restoration of eutrophic lakes.

In situ forming hydrogels with long-lasting miR-21 enhances the therapeutic potential of MSC by sustaining stimulation of target gene.

Regulating stem cells by microRNA (miRNA) is promising in regenerative medicine. However, non-viral transfection is usually transient while stably lentiviral transfection is accompanied with oncogenic risk. In the study, we explored the feasibility to retain the microRNAs within biopolymer hydrogels for their long-lasting working and sustaining stimulation of target gene. miRNA-21 (MiR-21), a reported microRNA enhancing the therapeutic potential of mesenchymal stem cells (MSCs) was used. We demonstrated that miR-21 could be efficiently retained within collagen hydrogel after forming complex with cationic polymer polyethylenimine (PEI). Due to the electronic interaction with positively charged PEI, the release of miR-21 was largely prevented during 2 week incubation (<20%), while free miR-21 encapsulated in hydrogels was largely released (>50%). When MSCs were cultivated in the PEI/miR-21-incorporated hydrogels, the sustained activation of targeted gene HIF-1α was observed, resulting in the sustaining up-regulation of several downstream therapeutic cytokines. Then, the hydrogels encapsulating miR-21/PEI were coated onto tissue plate for MSC cultivation, which further confirmed the long-lasting retention and efficacy of miR-21 on the plate surface. In addition, under H2O2-simulated stress condition, we also demonstrated that the anti-apoptotic capacity of MSCs was significantly improved when growing on miR-21-retained hydrogels. Our study provided a safe and promising method for long-lasting stem cell regulation with miRNAs.

[Evaluation of a heart-type fatty acid-binding protein detection kit for diagnosis of acute coronary syndrome].

OBJECTIVE: To evaluation the performance of a heart-type fatty acid-binding protein (H-FABP) ELISA detection kit in the clinical diagnosis of acute coronary syndrome (ACS). METHODS: Plasma or serum samples from 160 suspected ACS patients hospitalized in General Hospital of PLA were examined using Lanzhou H-FABP reagent kit and Holland H-FABP kit. Correlation of the two kits was evaluated and Kappa test was used to examine the consistency of the results of the two products. RESULTS: The sensitivity of H-FABP diagnosis of ACS detection Lanzhou kit was 91.8%, the specificity was 88.7%, and the total diagnostic rate was 90.42%. The sensitivity of H-FABP diagnosis of ACS detection Holland kit was 90.3%, the specificity was 86.8%, and the total diagnostic rate was 88.75%. The test results showed that two products yielded comparable results (P=0.668, >0.05) with a good consistency (Kappa=0.726, P<0.01). CONCLUSIONS: H-FABP ELISA detection kit produccted by LanZhou biological research institute has a good correlation with H-FABP detection kit produced by HBT company of Holland and has the potential for clinical application.

ShaoYao decoction ameliorates colitis-associated colorectal cancer by downregulating proinflammatory cytokines and promoting epithelial-mesenchymal transition.

BACKGROUND: Shaoyao decoction (SYD) is a traditional Chinese medicine prescription formulated by Liu Wan-Su, a master of traditional Chinese medicine in Jin-Yuan Dynasty. SYD is effective in treating ulcerative colitis. Paeonol, a component of SYD, inhibits colorectal cancer (CRC) cell proliferation and induces CRC cell apoptosis. In this study, azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated CRC (caCRC) model and CRC cell lines were used to examine the effects of SYD on CRC in vivo and in vitro. METHODS: A translational medicine strategy based on phytomics quality control was adopted. Liquid chromatography was employed for the chemical characterization and chemical fingerprinting of SYD. Protein expression and macrophage existence were determined by immunohistochemistry and western blot. Serum cytokines were quantified by Luminex assay. RESULTS: AOM/DSS-induced caCRC phenotypically resembled human caCRC. SYD significantly increased the survival rate of the mice, ameliorated the general well-being of the mice, and reduced the incidence and multiplicity of colonic neoplasms. SYD inhibited epithelial-mesenchymal transition (EMT), as indicated by upregulated epithelia cadherin and downregulated neuronal cadherin, fibronectin, vimentin, and transcription factor Snail. SYD reduced the expression levels of serum interleukin 1ß, interleukin-6, tumor necrosis factor α, tumor-associated macrophages, and p65. These results showed that SYD can attenuate proinflammatory cytokines and inhibit EMT. CONCLUSIONS: SYD ameliorates caCRC by suppressing inflammation and inhibiting EMT. SYD might be an alternative therapy for caCRC.

Temperature-dependent gelation process in colloidal dispersions by diffusing wave spectroscopy.

Temperature-dependent microrheology of a concentrated charge-stabilized poly(methyl methacrylate) colloidal dispersion with different salt concentrations was investigated by diffusing wave spectroscopy in backscattering mode. The critical temperature where the system undergoes aggregation and gelation depends upon the particle volume fraction or salt concentration. The viscoelastic properties of the systems have been discussed using Maxwell and Kelvin-Voigt models. Temperature-dependent crossover (G' = G″) frequency has been used to calculate activation energies representing a critical energy of interaction of gel formation.

Prognostic value of ultra-sensitive pregnancy associated plasma protein-A in patients with acute coronary syndrome.

OBJECTIVE: To investigate the prognostic value of ultra-sensitive pregnancy associated plasma protein-A (PAPP-A) level in the early phase of acute coronary syndrome (ACS) attack. METHODS: Patients diagnosed as ACS were enrolled and the level of circulatory PAPP-A was measured within 12 hours after ACS attack. The patients were followed at the time of 1st, 6th, and 12th months post-ACS attack in order to observe the incidence of the cardiovascular adverse events. According to the highest quintile, the patients were divided into 2 groups: high level (≥26.08 µg/L) group and low level (<26.08 µg/L) group, to evaluate the association between the level of PAPP-A and the incidence of the cardiovascular events. RESULTS: Compared with the low level group, the incidence of the composite outcome is significantly increased in the high level group, and the values of OR are 4.76, 4.38, 3.75 for 1st, 6th, 12th months respectively (P=0.000). For myocardial infarction (MI) + cardiac death (CD) the values of OR were 9.81, 6.08, 4.12 (P<0.01). Multivariate logistic regression analysis demonstrates that PAPP-A was an independent risk factor for the cardiovascular adverse events in the early, median, and late phase of ACS (P<0.05). CONCLUSION: In the early phase of ACS attack, the elevation of PAPP-A is an independent risk factor for the occurrence of cardiovascular adverse events.

Effect of solvent annealing on the tensile deformation mechanism of a colloidal crystalline polymeric latex film.

The influence of solvent annealing on microscopic deformational behavior of a styrene/n-butyl acrylate copolymer latex film subjected to uniaxial tensile deformation was studied by small-angle X-ray scattering. It was demonstrated that the microscopic deformation mechanism of the latex films transformed from a nonaffine deformation behavior to an affine deformation behavior after solvent annealing. This was attributed to the interdiffusion of polymeric chains between adjacent swollen latex particles in the film. It turns out that solvent annealing is much more efficient than thermal annealing due to a much slow evaporation process after solvent annealing.

Structural reorganization of a polymeric latex film during dry sintering at elevated temperatures.

Structural rearrangement in a latex powder during dry sintering at temperatures higher than the minimum film formation temperature was investigated by means of synchrotron small-angle X-ray scattering. Two major effects were identified: (1) Deformation of latex particles leads to a closure of voids between them and an extensive perfectioning of the face centered cubic colloidal crystalline ordering. Such an improvement of the colloidal crystalline structure involves preferential crystal growth along certain crystallographic directions as was evidenced by the measured unmatched relative diffraction intensity distribution of the crystallographic (111) and (220) planes. (2) Interdiffusion of polymeric chains between adjacent particles promotes a nanometer sized aggregation of nonpolymeric materials previously located in the interstices between particles. Size and size distribution of the aggregates at different dry sintering conditions were evaluated by using a model considering spheres dispersed in the system.

Structural evolution of a colloidal crystal fiber during heating and annealing studied by in situ synchrotron small angle X-ray scattering.

The structural evolution of a colloidal crystal fiber during heating and annealing was followed by in situ synchrotron small-angle X-ray scattering. The polymer dispersion (with a particle size of 118 nm) from which the fibers were formed by directed drying contained emulsifier and salt. A cellular structure formed upon drying in which the percolating phase (the "membrane phase") is composed from these components; this membrane phase gives rise to the scattering contrast on which the present observations build. Changes of the lattice constant of the colloidal crystallites and the intensity evolution of the scattering from the crystalline and the amorphous phases during heating and annealing indicate characteristic temperatures where the system exhibits pronounced structural changes. The first characteristic temperature was identified as 125 degrees C above which residue water in the membrane material was evaporated leading to shrinkage of the colloidal crystalline lattice. At a temperature above about 140 degrees C the membrane material was expelled out of the crystalline domains. This effect is accompanied by the progressive interdiffusion of polymer chains between adjacent latex particles and leads to further thermal shrinkage of the colloidal crystals. The second characteristic temperature is defined by a rapid increase in isotropic scattering. This effect is attributed to the formation of increasingly large domains of the membrane material and the concomitant disappearance of the membrane phase from the former crystal domains.

Steady-state pharmacokinetic properties of aripiprazole 10 mg PO g12h in Han Chinese adults with schizophrenia: A prospective, open-label, pilot study.

OBJECTIVES: The aims of this study were to investigate the pharmacokinetic (PK) properties of aripiprazole in the steady state in Han Chinese adults with schizophrenia and to compare them between Han Chinese and white populations described in the literature. METHODS: This prospective, open4abel, pilot study was conducted at the Mental Health Institute, Xiang-ya Second Hospital, Central South University, Changsha, China. Male and female hospitalized patients aged 18 to 45 years diagnosed with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-defined schizophrenia, with a Positive and Negative Syndrome Scale (PANSS) total score ⩾60 (indicating schizophrenia of at least mild severity) were eligible. On study days 1 and 2, patients were pretreated with aripiprazole 10 mg PO QD, followed by 10 mg g12h on days 3 to 21. Blood samples were drawn for analysis on day 21 before dosing and 1, 3, 4, 5, 12, 24, 48, 72, 96, 144, and 192 hours after the morning dosing of aripiprazole on day 21. Patients received low-dose (25-100 mg/d) clozapine on day 25 until day 28. The samples were assessed using high-performance liquid chromatography-mass spectrometry and compartment model analysis for aripiprazole. PK properties included mean residence time (MRT) steady-state Cmax (Css max), time to Css max (Tmax), elimination t/12, apparent oral clearance (CL/F), and apparent volume of distribution (V/F). Adverse effects were monitored using physical examination (including vital sign measurements), electrocardiography, electroencephalography, and clinical laboratory testing (including biochemistry, hematology, and urinalysis) at baseline and at the end of the study. Patients were asked about adverse events on days 1 to 7 and at random intervals thereafter. Patients were also instructed to report any spontaneous symptoms they experienced. RESULTS: Twelve patients were enrolled (6 men, 6 women; mean [SD] age, 26.1 [7.0] years; mean [SD] weight, 56.6 [9.0] kg; mean [SD] PANSS score, 116.8 [12.2]). Aripiprazole exhibited linear kinetic characteristics on a 2-compartment model. After multiple oral doses (10 mg g12h), the mean (SD) t1/2, Css max, Tmax, MRT, V/F, and CL/F were 62.2 (9.0) hours, 557.3 (135.5) ng/mL, 2.6 (1.1) hours, 84.5 (11.2) hours, 173 (48) L, and 1.9 (0.5) L/h, respectively. In Chinese patients, the t/12 values were numerically similar (62.2 [9.0] vs 68.1 [22.9] hours); Css max values were numerically higher (557.3 [135.5] vs 393 [181 ] ng/mL); and V/F and CL/F values were numerically lower (V/F: 173 [48] vs 196 [66] L; CL/F: 1.9 [0.5] vs 3.4 [1.6] L/h) compared with healthy white male volunteers. Adverse effects were mild to moderate: lightheadedness (5 of 12 patients), somnolence (3), tachycardia (3), hypodynamia (2), and extrapyramidal symptoms (EPS) (1). The EPS (convulsive movement of the muscles related to the larynx) led to one patient's discontinuation of the study. CONCLUSIONS: In this small pilot study of the PK properties of aripiprazole 10 mg PO g12h in Han Chinese patients with schizophrenia, the mean t1/2 value was numerically similar to that previously reported in a population of healthy white male volunteers. However, the mean Css max value was numerically higher, and V/F and CL/F values were numerically lower, compared with those in healthy white male volunteers.

[Cigarette smoking and Parkinson's disease: a population based case-control study].

OBJECTIVE: To explore the association with cigarette smoking for Parkinson's disease (PD). METHODS: One hundred and fourteen PD cases and 205 controls matched on gender and race were recruited from ongoing PD prevalence survey and identified at the neurological clinic of Peking Union Medical College Hospital. Face to face questionnaire interview was carried out and data on smoking and alcohol consumption were analyzed in a population-based case control study. RESULTS: With never-smokers as the reference category, we observed reduced risk for PD among ever smokers (OR = 0.49, 95% CI: 0.30 - 0.79) current smokers (OR = 0.44, 95% CI: 0.23 - 0.86) and ex-smokers (OR = 0.54, 95% CI: 0.30 - 0.96). When comparing with non-smokers, the ever smokers stratified by years of smoking had an inverse association with those whose smoking history longer than 20 years (OR = 0.35, 95% CI: 0.18 - 0.70) and an mild protective association with those who smoked less than 20 years (OR = 0.61, 95% CI: 0.35 - 1.07). Those who had quitted smoking for more than 20 years were less likely to have the disease than never smokers, and those who had quitted for less than 20 years were least likely to have PD. Those current smokers were still least likely to have the disease. Significant inverse gradient with pack-day smoker (trend P < 0.05), and the inverse association for cigarette smoking and PD were found not bing confounded by alcohol consumption. CONCLUSION: The inverse association between PD and cigarette smoking and history of cessation was found. Further studies need to provide biochemical evidence on the relation between smoking and its protective effect on PD.