Rapid Release of Halocarbons from Saline Water by Iron-Based Photochemistry.

Methyl halides play important roles in stratospheric ozone depletion, but their formation mechanisms are not well defined. This study demonstrated that iron-based photochemistry significantly enhanced alkyl halide production by promoting the reaction of the representative monomer of lignin with halide ions in saline water under solar light irradiation. The methyl chloride (CH3Cl) emission from the light/Fe(III) process was 2 orders of magnitude higher than dark treatment and in the absence of iron. In addition, bromide and iodide showed better reactivity in the formation of the corresponding methyl bromide (CH3Br) and methyl iodide (CH3I). Alkyl halides identified from seawater, brackish water, and salt pan water under sunlight irradiation were positively correlated with the Fe(III) concentrations, indicating that iron-based photochemistry is ubiquitous. This work suggested that the photoinduced formation of methyl radical and redox cycling of iron triggered by the Fenton-like reaction are responsible for the enhanced release of alkyl halides. This study represents an abiotic formation pathway of alkyl halides, which accounts for a portion of the unidentified sources of halocarbons in the ocean.

Enhanced cyanogen chloride formation after UV/PS and UV/H2O2 pre-oxidation and chlorination in natural river water.

Ultraviolet/persulfate (UV/PS) and Ultraviolet/hydrogen peroxide (UV/H2O2) have attracted much attention in recent years as advanced oxidation processes for water treatment. However, it is not all clear how these two methods affect the formation of cyanogen chloride (CNCl) in the subsequent water chlorination process. In this study, it was found that both UV/H2O2 and UV/PS pre-oxidation promoted the formation of CNCl in six actual water samples collected from urban rivers. Glycine, uric acid, arginine and histidine were investigated as the model compounds to explore the effects of different methods on the production of CNCl. The results showed that compared with chlorination alone, pre-oxidation by UV/H2O2 and UV/PS can reduce the production of CNCl for glycine and uric acid by up to 95% during post-chlorination process. However, they can greatly promote the formation of CNCl for arginine and histidine by up to 120-fold. In a more detailed investigation, pre-oxidation of histidine formed highly reactive intermediates to chlorine, leading to increased CNCl formation and chlorine consumption. The results showed that the precursors of CNCl was altered after pre-oxidation, and need to be re-evaluated.

Plaque Distribution Correlates With Morphology of Lenticulostriate Arteries in Single Subcortical Infarctions.

BACKGROUND AND PURPOSE: We aimed to use novel whole-brain vessel-wall magnetic resonance imaging (WB-VWI) to investigate the association between plaque distribution of middle cerebral artery (MCA) and morphological changes of the lenticulostriate arteries (LSAs) in single subcortical infarctions. METHODS: Forty single subcortical infarction patients with no relevant MCA disease on magnetic resonance angiography were prospectively enrolled. Plaque location in the MCA was dichotomized as proximal (located adjacent to the LSA origin) or distal (located distal to the LSA origin) on whole-brain vessel-wall magnetic resonance imaging. The MCAs with proximal plaques were divided into the symptomatic and asymptomatic side, and asymptomatic side MCAs without proximal plaques were the control group. The morphological characteristics of the LSAs and features of proximal plaques were analyzed. RESULTS: A total of 71 MCAs in 40 patients were analyzed (31 on the symptomatic side, 22 on the asymptomatic side, and 18 in the control group). Superior-wall plaques of MCAs were observed more frequently on the symptomatic side than the asymptomatic side (45.2% versus 9.1%, P=0.005). The wall area index, plaque burden, and remodeling index did not differ significantly between the symptomatic and asymptomatic side. The number of LSA branches was smaller (P=0.011) in the symptomatic side (5.48±1.88) compared with the control group (6.83±1.92). The symptomatic side exhibited shorter average length of the LSAs (23.23±3.44 versus 25.75±3.76 mm, P=0.025) and shorter average distance of the LSAs (16.47±3.11 versus 21.53±4.76 mm, P<0.001) compared with the asymptomatic side. CONCLUSIONS: Superiorly distributed MCA plaques at the LSA origin are closely associated with morphological changes of the LSA in symptomatic MCAs, suggesting that the distribution, rather than the inherent features of plaques, determines the occurrence of single subcortical infarctions. Our findings provide insight into the etiologic mechanism of branch atheromatous disease in single subcortical infarctions.

Panoramic heat map for spatial distribution of necrotic lesions.

Aims: In this study, we aimed to visualize the spatial distribution characteristics of femoral head necrosis using a novel measurement method. Methods: We retrospectively collected CT imaging data of 108 hips with non-traumatic osteonecrosis of the femoral head from 76 consecutive patients (mean age 34.3 years (SD 8.1), 56.58% male (n = 43)) in two clinical centres. The femoral head was divided into 288 standard units (based on the orientation of units within the femoral head, designated as N[Superior], S[Inferior], E[Anterior], and W[Posterior]) using a new measurement system called the longitude and latitude division system (LLDS). A computer-aided design (CAD) measurement tool was also developed to visualize the measurement of the spatial location of necrotic lesions in CT images. Two orthopaedic surgeons independently performed measurements, and the results were used to draw 2D and 3D heat maps of spatial distribution of necrotic lesions in the femoral head, and for statistical analysis. Results: The results showed that the LLDS has high inter-rater reliability. As illustrated by the heat map, the distribution of Japanese Investigation Committee (JIC) classification type C necrotic lesions exhibited clustering characteristics, with the lesions being concentrated in the northern and eastern regions, forming a hot zone (90% probability) centred on the N4-N6E2, N3-N6E units of outer ring blocks. Statistical results showed that the distribution difference between type C2 and type C1 was most significant in the E1 and E2 units and, combined with the heat map, indicated that the spatial distribution differences at N3-N6E1 and N1-N3E2 units are crucial in understanding type C1 and C2 necrotic lesions. Conclusion: The LLDS can be used to accurately measure the spatial location of necrotic lesions and display their distribution characteristics.

Interaction of human genes WT1 and CML28 in leukemic cells.

The molecular pathogenesis of leukemia is poorly understood. Earlier studies have shown both Wilms' tumor 1 suppressor gene (WT1) and CML28 abnormally expressed in malignant diseases of the hematopoietic system and WT1 played an important role in leukemogenesis. However, the relationship between molecular CML28 and WT1 has not been reported. Here we described the use of small interfering RNA (siRNA) against WT1 and CML28 in leukemic cell line K562 to examine the interaction between CML28 and WT1. WT1 and CML28 gene expression in transfected K562 cells was detected by using RQ-PCR and Western blotting. K562 cells transfected with WT1-siRNA could greatly decrease both mRNA and protein expression levels of WT1 and CML28. In contrast, CML28-siRNA did not exert effect on WT1. Further, subcellular co-localization assay showed that the two proteins could co-localize in the cytoplasm of K562 cells, but WT1/CML28 complexes were not detected by using immunoprecipitation. It was suggested that there exists the relationship between CML28 and WT1. CML28 may be a downstream target molecule of WT1 and regulated by WT1, which will provide important clues for further study on the role of CML28 and WT1 in leukemic cells.

Biomechanics evaluation of sacroiliac joint pain after lumbosacral fusion: A finite element analysis.

The sacroiliac joint (SIJ) constitutes the predominant pain source following lumbar or lumbosacral fusion. Although studies have investigated the biomechanical patterns of SIJ behaviors after lumbosacral fusion, the relationship between ligament strain and SIJ pain following lumbosacral fusion remains unclear. The present study developed a three-dimensional finite element model including L4, L5, sacrum, ilium, SIJ, and seven mainly ligaments. After successful validation, the model was used to investigate the biomechanics of SIJ and ligaments in simulating lumbosacral fusion process. Our results showed that small motion in a stable SIJ may significantly increases the contact pressure and stress of the SIJ, which increase the maximum contact pressure by 171%, 676%, 199%, and 203% and stress by 130%, 424%, 168%, and 241% for flexion, extension, bending, and axial rotation, respectively. An increase in contact pressure and stress in SIJ possibly causes pain at the SIJ, especially in extension and axial rotation. A comparison between the lumbosacral and intact models exhibited the maximum strain increase in the iliosacral ligament (ISL) and the ileal ligament (IL) under all loading conditions. The present study suggests that after lumbosacral fusion process, the ligament sudden increase or decrease is likely to lead sprain or strain ligament, especially ISL and IL thereby causing SIJ pain. This study may contribute to understand the relationship between SIJ ligaments and SIJ pain.

Alkyl halide formation from degradation of carboxylic acids in the presence of Fe(III) and halides under light irradiation.

Advanced oxidation processes (AOPs) have been widely used in water and wastewater treatment and have shown excellent performance in remediating contaminated water. However, their oxidation byproducts, including halogenated organics, have recently attracted increasing attention. Alkyl halides are among the most important environmental pollutants in nature. Here, we report a Fenton-like reaction in which alkyl halides can form during the photodegradation of aliphatic carboxylic acids in the presence of Fe(III) and halides. Chloromethane, chloroethane, and 1-chloropropane were produced from the degradation of acetic acid, propionic acid and n-butyric acid, respectively. CH3Cl, CH2Cl2 and CHCl3 were all identified as the products of acetic acid with the yields of approximately 5.1%, 0.2% and 0.005%, respectively. It was demonstrated that hydroxyl radicals, halogen radicals and alkyl radicals were involved in the formation of alkyl halides. A possible mechanism of chloromethane formation was proposed based on the results. In real samples of saline water, the addition of carboxylic acid and Fe(III) significantly promoted the generation of CH3Cl under xenon lamp irradiation. The results indicated that the coexistence of Fe(III), halides and carboxylic acids enhanced the photochemical release of alkyl halides. The reactions described in this paper may contribute to knowledge on the mechanism of halogenated byproduct formation during AOPs.

Mechanical upside of PAO mainstream fixations: co-simulation based on early postoperative gait characteristics of DDH patients.

Purpose: To investigate the early postoperative gait characteristics of patients who underwent periacetabular osteotomy (PAO) and predict the biomechanical performance of two commonly used PAO fixation methods: iliac screw (IS) and transverse screw (TS). Methods: A total of 12 patients with unilateral developmental dysplasia of the hip (DDH) (mean age 27.81 ± 4.64 years, 42% male) that were scheduled to undergo PAO surgery were included in this study. Their preoperative CT images and pre- and postoperative gait data were used to create subject-specific musculoskeletal models and complete the inverse dynamics analysis (IDA). Two patients with typical gait characteristics were selected using clustering analysis, and their IDA data were incorporated into finite element (FE) models of IS and TS fixations. Failure simulation was performed by applying iterative steps with increasing gait load to predict yield load. Stress results and yield loads were calculated for each FE model at different phases of the gait cycle. Results: Postoperative gait showed improvement compared to preoperative gait but remained inferior to that of healthy individuals. Postoperative gait was characterized by a lower hip range of motion, lower peri-ilium muscle forces, particularly in the abductors, and a sharper initial peak and flatter second peak of hip joint reaction force (HRF). Finite element analysis (FEA) showed a trend of increasing stress during the second-fourth phases of the gait cycle, with lower stress levels in other phases. At high-stress gait phases, the mean stress of maximum p¯100 differed significantly between IS and TS (p < 0.05) and between coupled and uncoupled muscle forces (p < 0.05). Failure analysis predicted a slightly larger yield load for TS configurations (6.21*BW) than that for IS (6.16*BW), but both were well above the gait load. Coupled and uncoupled groups showed similar results, but uncoupled groups had lower yield loads (5.9*BW). Conclusion: PAO early postoperative gait shows a normalized trend, but abnormalities persist. IS and TS are both capable of resisting mechanical strain failure, with no significant mechanical advantage found for transverse screw fixation during PAO early postoperative gait. Additionally, it is important to note that the TS may have a higher risk of cyclic fatigue failure due to the localized greater stress concentration. Furthermore, the most medial screw is crucial for pelvic stability.

PDGF-BB prevents destructive repair and promotes reparative osteogenesis of steroid-associated osteonecrosis of the femoral head in rabbits.

Destructive repair characterized by inadequate angiogenesis and osteogenesis is the main pathological progression in steroid-associated osteonecrosis of the femoral head (SONFH). Platelet-derived growth factor-BB (PDGF-BB) is an "angiogenesis and osteogenesis coupling" factor that has been used for the treatment of bone defects in clinic. This study was designed to analyze the ability of PDGF-BB for preventing destructive repair and promoting reparative osteogenesis in SONFH. Steroid-associated osteonecrosis (SAON) was induced and triggered destructive repair of the femoral head by repeated lipopolysaccharide (LPS) and methylprednisolone (MPS) injections in rabbits. At 2, 4, and 6 weeks after induction, recombinant human PDGF-BB, neutralizing PDGF-BB antibody, or saline was intramedullary injected into the proximal femora. At week 6 after SAON induction, the proximal femora were dissected for bone architecture and histological analysis. C3H10T1/2 cells and HUVECs were used for further mechanistic investigation. After PDGF-BB treatment, type H vessels and leptin receptor-positive (LepR+) mesenchymal stem cells (MSCs) increased in the affected femoral head, and more osteoblastic osteogenesis along the bone surfaces but scattered adipocytes in bone marrow tissue than that in the SAON group. PDGF-BB treatment prevented destructive repair progression and led to 50-70 % of osteonecrotic femoral heads undergoing reparative osteogenesis. In particular, we found that PDGF-BB could mediate MSC self-renewal and maintain their osteogenic potency by activating PDGFR/Akt/GSK3ß/CERB signaling in the presence of steroids. Moreover, PDGF-BB also stabled the newly formed vascular tubes by recruiting MSCs for improving intraosseous vascular integration. PDGF-BB may be a candidate for the promotion of reparative osteogenesis in SONFH.

Astragaloside IV as a novel CXCR4 antagonist alleviates osteoarthritis in the knee of monosodium iodoacetate-induced rats.

BACKGROUND AND PURPOSE: C-X-C chemokine receptor type 4 (CXCR4) inhibition protects cartilage in osteoarthritis (OA) animal models. Therefore, CXCR4 has becoming a novel target for OA drug development. Since dietary and herbal supplements have been widely used for joint health, we hypothesized that some supplements exhibit protective effects on OA cartilage through inhibiting CXCR4 signaling. METHODS: The single-cell RNA sequencing data of OA patients (GSE152805) was re-analyzed by Scanpy 1.9.0. The docking screening of CXCR4 antagonists was conducted by Autodock Vina 1.2.0. The CXCR4 antagonistic activity was evaluated by calcium response in THP-1 cells. Signaling pathway study was conducted by bulk RNA sequencing and western blot analysis in human C28/I2 chondrocytes. The anti-OA activity was evaluated in monosodium iodoacetate (MIA)-induced rats. RESULTS: Astragaloside IV (ASN IV), the predominate phytochemical in Astragalus membranaceus, has been identified as a novel CXCR4 antagonist. ASN IV reduced CXCL12-induced ADAMTS4,5 overexpression in chondrocytes through blocking Akt signaling pathway. Furthermore, ASN IV administration significantly repaired the damaged cartilage and subchondral bone in MIA-induced rats. CONCLUSION: The blockade of CXCR4 signaling by ASN IV could explain anti-OA activities of Astragalus membranaceus by protection of cartilage degradation in OA patients. Since ASN IV as an antiviral has been approved by China National Medical Products Administration for testing in people, repurposing of ASN IV as a joint protective agent might be a promising strategy for OA drug development.

Shang-Ke-Huang-Shui and coptisine alleviate osteoarthritis in the knee of monosodium iodoacetate-induced rats through inhibiting CXCR4 signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Shang-Ke-Huang-Shui (SKHS) is a classic traditional Chinese medicine formula originally from the southern China city of Foshan. It has been widely used in the treatment of osteoarthritis (OA) but underlying molecular mechanisms remain unclear. AIM OF STUDY: Recently, activation of C-X-C chemokine receptor type 4 (CXCR4) signaling has been reported to induce cartilage degradation in OA patients; therefore, inhibition of CXCR4 signaling has becoming a promising approach for OA treatment. The aim of this study was to validate the cartilage protective effect of SKHS and test whether the anti-OA effects of SKHS depend on its inhibition on CXCR4 signaling. Additionally, CXCR4 antagonist in SKHS should be identified and its anti-OA activity should also be tested in vitro and in vivo. METHODS: The anti-OA effects of SKHS and the newly identified CXCR4 antagonist was evaluated by monosodium iodoacetate (MIA)-induced rats. The articular cartilage surface was examined by hematoxylin and eosin (H&E) staining and Safranin O-Fast Green (S-F) staining whereas the subchondral bone was examined by micro-CT. CXCR4 antagonist screenings were conducted by molecular docking and calcium response assay. The CXCR4 antagonist was characterized by UPLC/MS/MS. The bulk RNA-Seq was conducted to identify CXCR4-mediated signaling pathway. The expression of ADAMTS4,5 was tested by qPCR and Western blot. RESULTS: SKHS protected rats from MIA-induced cartilage degradation and subchondral bone damage. SKHS also inhibited CXCL12-indcued ADAMTS4,5 overexpression in chondrocytes through inhibiting Akt pathway. Coptisine has been identified as the most potent CXCR4 antagonist in SKHS. Coptisine reduced CXCL12-induced ADAMTS4,5 overexpression in chondrocytes. Furthermore, in MIA-induced OA model, the repaired cartilage and subchondral bone were observed in the coptisine-treated rats. CONCLUSION: We first report here that the traditional Chinese medicine formula SKHS and its predominate phytochemical coptisine significantly alleviated cartilage degradation as well as subchondral bone damage through inhibiting CXCR4-mediated ADAMTS4,5 overexpression. Together, our work has provided an important insight of the molecular mechanism of SKHS and coptisine for their treatment of OA.

[Evaluation of acetabular cup placement precision in Stryker computer-assisted navigated total hip arthroplasty].

To contrast the methodology of measuring cup placement precision utilizing Mimics and Matlab programming, based on clinical CT images of primary THA cases with computer assisted navigated surgery (CANS) and with the traditional manual method (MANS). The method was applied and analyzed to measure cup anteversion, cup abduction of 50 clinical cases with CANS and MANSThe results show that, cup placement precision differences exits between primary THA cases with CANS and MANS; more cases with CANS are within the safe zone contrasting MANS, and there was less variation and less placement error in CANS cases. CANS can improve cup placement precision and reduce the chance of dislocation efficiently.

The association between the severity and distribution of white matter lesions and hemorrhagic transformation after ischemic stroke: A systematic review and meta-analysis.

Background and purpose: As a part of the natural course of ischemic stroke, hemorrhagic transformation (HT) is a serious complication after reperfusion treatment, which may affect the prognosis of patients with ischemic stroke. White matter lesions (WMLs) refer to focal lesions on neuroimaging and have been suggested to indicate a high risk of HT. This systematic review and meta-analysis aimed to summarize current evidence on the relation between WML and HT. Methods: This systematic review was prepared with reference to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched PubMed, Embase, Web of Science, and Cochrane Library databases for publications on WML and HT in patients with ischemic stroke. Odds ratios (ORs) and 95% confidence intervals (CIs) from eligible studies were combined to quantify the association between the severity of WML and the risk of HT. In addition, the descriptive analysis was adopted to evaluate the influence of different WML distributions on predicting HT. Results: A total of 2,303 articles were identified after removing duplicates through database searching, and 41 studies were included in our final analysis. The meta-analysis showed that the presence of WML was associated with HT (OR = 1.62, 95%CI 1.08-2.43, p = 0.019) and symptomatic intracerebral hemorrhage (sICH) (OR = 1.64, 95%CI 1.17-2.30, p = 0.004), and moderate-to-severe WML indicated a high risk of HT (OR = 2.03, 95%CI 1.33-3.12, p = 0.001) and sICH (OR = 1.92, 95%CI 1.31-2.81, p < 0.001). The dose-response meta-analysis revealed risk effects of increasing the severity of WML on both HT and ICH. In addition, both periventricular WML (PWML) (five of seven articles) and deep WML (DWML) (five of six articles) were shown to be associated with HT. Conclusions: White matter lesions are associated with overall HT and sICH in patients with ischemic stroke, and more severe WMLs indicate a high risk of HT and sICH. In addition, both PWML and DWMLs could be risk factors for HT. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: PROSPERO CRD42022313467.

Free chlorine formation in the process of the chlorine dioxide oxidation of aliphatic amines.

Chlorine dioxide (ClO2) is commonly used as an alternative disinfectant to chlorine because it has a high bactericidal effect and may produce limited concentrations of halogenated disinfection byproducts (DBPs). However, previous studies have reported that free available chlorine (FAC) was produced when ClO2 reacted with some compounds, such as phenol, leading to the formation of halogenated DBPs. In this study aliphatic amines was found to react rapidly with ClO2 to form significant amount of FAC and its related DBPs. This study investigated the formation of FAC when ClO2 reacts with six model aliphatic amines (including primary amines, secondary amines and tertiary amines). FAC was formed immediately as ClO2 was added to the precursor solution. The maximum yield of FAC even reached 45% (based on consumed ClO2) when ClO2 reacted with 20 µM methylamine at a dose of 10 µM, which is close to a realistic maximum dose (about 0.8 mg/L) in the U.S.. The reactivity of amines to result FAC follows the sequence tertiary amines < secondary amines < primary amines. It was verified that the addition of aliphatic amines may enhance the formation of FAC during ClO2 oxidation in actual water samples. Organic chloramines and other chlorinated DBPs, such as cyanogen chloride, were detected when ClO2 was used as the sole oxidant of real water samples. This study demonstrated that chlorine-related byproducts may also be formed in the presence of organic amines during ClO2 treatment.

Association Between Systemic Immune-Inflammation Index and Symptomatic Intracranial Hemorrhage in Acute Ischemic Stroke Patients Undergoing Endovascular Treatment.

BACKGROUND/OBJECTIVE: Systemic immune-inflammation index (SII) is a novel inflammatory factor, which may be involved in the destruction of the blood-brain barrier (BBB) after acute ischemic stroke (AIS); however, the association between SII and symptomatic intracranial hemorrhage (sICH) in AIS patients undergoing endovascular treatment (EVT) remains unclear. METHODS: Patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO) who underwent EVT were consecutively enrolled. Blood samples were collected in the emergency room and SII was calculated by neutrophils × platelets/lymphocytes. Participants were categorized into tertiles according to admission SII. The main outcome was defined as the occurrence of sICH, following the European Cooperative Acute Stroke Study III (ECASS-III) criteria. RESULTS: A total of 379 AIS-LVO patients with EVT were enrolled (median age = 71 years, 52.5% males). The median baseline National Institutes of Health Stroke Scale (NIHSS) score was 15 (IQR, 12-18). The median of SII was 820.9 × 109/L (IQR, 473.1-1345.2). Forty-three (11.3%) patients developed sICH. SII was found to be independently associated with sICH after EVT (adjusted odd ratio (OR) = 1.005 (per 10 units increase); 95% confidence interval (CI): 1.002-1.008; p = 0.002). Compared to patients in the lowest SII tertile, patients in the highest tertile had a higher risk of sICH (adj-OR 3.379; 95% CI 1.302-8.768; p = 0.012). The risk of sICH increased with the increase of SII in a dose-dependent manner (p for trend = 0.004). There was no interaction between potential modifiers and SII on sICH. CONCLUSION: Admission SII is positively associated with sICH in AIS-LVO patients treated with EVT. These results need to be confirmed in future studies.

Promoting osteointegration effect of Cu-alloyed titanium in ovariectomized rats.

Osteoporosis is a common skeletal disease making patients be prone to the osteoporotic fracture. However, the clinical implants made of titanium and its alloys with a poor osseointegration need a long time for healing and easily to loosening. Thus, a new class of Cu-alloyed titanium (TiCu) alloys with excellent mechanical properties and bio-functionalization has been developed. In this study, the osteoporosis modeled rats were used to study the osteointegration effect and underlying mechanism of TiCu. The results showed that after implantation for 4 weeks, TiCu alloy could promote the reconstruction of vascular network around the implant by up-regulating vascular endothelial growth factor expression. After 8 weeks, it could further promote the proliferation and differentiation of osteoblasts, mineralization and deposition of collagens, and then significantly increasing bone mineral density around the implant. In conclusion, TiCu alloy would enhance the fixation stability, accelerate the osteointegration, and thus reduce the risk of aseptic loosening during the long-term implantation in the osteoporosis environment. This study was the first to report the role and mechanism of a Cu-alloyed metal in promoting osteointegration in osteoporosis environment, which provides a new attractive support for the improvement of future clinical applications of Cu-alloyed antibacterial titanium alloys.

Treatment of collagen-induced arthritis rat model by using Notch signalling inhibitor.

BACKGROUND: The Notch signalling pathway has been reported to play a key role in rheumatoid arthritis (RA) development. Thus, inhibition of the activation of this signalling pathway may be a promising approach to the treatment of RA. In this study, the Notch signalling inhibitor LY411575, which can inhibit both Notch1 and Notch3, was used for the treatment of collagen-induced arthritis (CIA) rats. METHODS: Wistar rats were immunised with bovine type II collagen (CII) to establish rats CIA model. The inhibitory effects of LY411575 on Notch1 intracellular domain (N1ICD) and Notch3 intracellular domain (N3ICD) protein was verified by western blot (WB) in vitro. CIA rats were treated with different doses of LY411575 for 15 and 28 days, respectively. Methotrexate and sodium carboxymethyl cellulose (CMC-Na) were used as positive and negative (vehicle) control respectively. Destruction of the rat ankle joint and the bone loss on the periarticular side were evaluated by micro-computed tomography (Micro-CT). In addition, destruction of the ankle articular cartilage and the osteoclast numbers were determined by histology. Expression of N1ICD and N3ICD in the ankle joint was detected by immunohistochemistry. RESULTS: LY411575 could significantly inhibit the expression of N1ICD and N3ICD in vitro. Micro-CT test showed that the ankle joint destruction significantly improved after treatment with LY411575 (5 â€‹mg/kg and 10 â€‹mg/kg, respectively). The bone quality in the LY411575 (5 â€‹mg/kg and 10 â€‹mg/kg, respectively) groups were improved compared with the vehicle group. Histological analysis showed that LY411575 (5 â€‹mg/kg and 10 â€‹mg/kg, respectively) treatment reduced the severity of ankle joint inflammation in CIA rats (including ankle joint destruction, pannus formation, and cartilage damage) and reduced the expression of N1ICD and N3ICD in CIA rats ankle joints significantly. CONCLUSION: The inhibitor of Notch signalling LY411575 is an effective treatment for CIA. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: Our study provides new evidence to support the potential clinical application of Notch signalling pathway inhibitor LY411575 as a drug candidate for the treatment of RA.

Formation of organic chloramines during chlorination of 18 compounds.

Organic chloramines have attracted considerable attention because of their potential toxicity and reactivity. However, the lack of suitable and effective analytical methods has limited the study of organic chloramines due to their volatile and unstable properties. In this study, membrane introduction mass spectrometry (MIMS) combined with DPD/FAS titration was used to monitor the formation of organic chloramines. N-chlorodimethylamine [(CH3)2NCl] and N-chlorodiethylamine [(C2H5)2NCl] were detected and identified as the dominant volatile DBPs during chlorination of 18 organic compounds with dimethylamine or diethylamine functional groups, with yields ranging from 0.3% to 51.1% at a chlorine to precursor (Cl/P) molar ratio of 8.0. (CH3)2NBr was formed in the presence of bromide, while the formation of (CH3)2NCl was decreased. The reaction of phenol with (CH3)2NCl combined with theoretical calculations confirmed that the reactivity of (CH3)2NCl was similar to that of monochloramine. Moreover, (CH3)2NCl and (C2H5)2NCl were observed at the ppb level during chlorination of actual water samples collected from different areas. The results suggest that (CH3)2NCl and (C2H5)2NCl are important organic chloramines during chlorination, which may lead to the occurrence of further oxidation reactions and promote the formation of other disinfection byproducts simultaneously and should be of concern.

Notch-1 and Notch-3 Mediate Hypoxia-Induced Activation of Synovial Fibroblasts in Rheumatoid Arthritis.

OBJECTIVE: To investigate the molecular mechanism of hypoxia-induced rheumatoid arthritis synovial fibroblast (RASF) activation via Notch-1 and Notch-3 signaling, and to evaluate its potential as a therapeutic target. METHODS: Expression of Notch-1 intracellular domain (N1ICD), N3ICD, and hypoxia-inducible factor 1α (HIF-1α) was assessed by immunhistology in synovial tissue from patients with RA. RASFs were cultured under hypoxic conditions and normoxic conditions with or without small interfering RNAs (siRNAs), and N1ICD and N3ICD were overexpressed under normoxic conditions. Rats with collagen-induced arthritis (CIA) were administered LY411575 (inhibitor of N1ICD and N3ICD) for 15 days and 28 days, and its therapeutic efficacy was assessed by histologic and radiologic evaluation of the rat synovial tissue, and by analysis of inflammatory cytokine production in the serum of rats. RESULTS: N1ICD, N3ICD, and HIF-1α were expressed abundantly in the synovial tissue of RA patients. HIF-1α was shown to directly regulate the expression of Notch-1 and Notch-3 genes under hypoxic conditions. Moreover, hypoxia-induced N1ICD and N3ICD expression in RASFs was blocked by HIF-1α siRNA. Notch-1 siRNA and Notch-3 siRNA inhibited hypoxia-induced RASF invasion and angiogenesis in vitro, whereas overexpression of N1ICD and N3ICD promoted these processes. In addition, Notch-1 was shown to regulate RASF migration and epithelial-mesenchymal transition under hypoxic conditions, whereas Notch-3 was shown to regulate the processes of anti-apoptosis and autophagy. Furthermore, in vivo studies in rats with CIA showed that the N1ICD and N3ICD inhibitor LY411575 had a therapeutic effect in terms of ameliorating the symptoms and severity of the disease. CONCLUSION: This study identified a functional link between HIF-1α, Notch-1, and Notch-3 signaling in regulating activation of RASFs and the processes involved in the pathogenesis of RA.

Association Between Neutrophil to Lymphocyte Ratio and Malignant Brain Edema in Patients With Large Hemispheric Infarction.

INTRODUCTION: Malignant brain edema (MBE) is a life-threatening complication for patients with large hemispheric infarction (LHI). Stroke-related inflammatory responses may cause secondary brain injury and lead to brain edema. The neutrophil to lymphocyte ratio (NLR) is a well-known systemic inflammatory biomarker. The aim of this study was to evaluate if NLR is associated with MBE in patients with LHI. METHODS: A retrospective analysis was performed of LHI patients within 24 h from stroke onset admitted to the Department of Neurology, West China Hospital from January 1, 2017 to December 31, 2018. Blood samples were collected upon admission. MBE was diagnosed by any neurological deterioration accompanied by brain edema in follow-up images. Patients were categorized according to NLR tertiles. Univariate analyses were performed to identify potential confounding variables and a multivariate logistic regression analysis was conducted to determine the correlation between NLR and MBE. RESULTS: A total of 257 patients with a mean age of 68.6 ± 14.0 years were identified. Among them, 83 (32.3%) patients developed MBE with a median time of one day (interquartile range [IQR] 0-2 days) from hospital admission. An elevated NLR was related to an increased risk of MBE when the lowest and highest tertiles were compared (odds ratio 2.27, 95% confidence interval 1.11-4.62, p = 0.024). The risk of MBE increased with the increase of NLR in a dosedependent manner (p for trend = 0.029). No interaction between potential modifiers and NLR on MBE was observed. CONCLUSIONS: Higher NLR was associated with an increased risk of MBE in patients with LHI.