Acute Laceration in the Transverse Mesocolon After a Colonoscopy: A Case Report.

Colonoscopy is a widely used examination for colonic diseases with low risk. Hemoperitoneum due to injury of transverse mesocolon is an extremely rare but potentially lethal complication. We present a case of an elderly woman who complained of continuous abdominal pain after a colonoscopy, with progressive anemia. An emergency exploratory laparoscopy revealed a laceration of the transverse mesocolon. The underlying mechanism is unclear due to its rarity. Old age, atherosclerotic disease, the long operating time of colonoscopy, and manual compression on the abdomen during the procedure may be risk factors for transverse mesenteric laceration during colonoscopy.

Systemic immune-inflammation index predicts short-term mortality in acute ischemic stroke with severe stenosis of internal carotid artery associated pneumonia.

BACKGROUND: We aimed to investigate the relationship between systemic immune-inflammation index (SII) and short-term mortality in acute ischemic stroke (AIS) with internal carotid artery (ICA) severe stenosis and stroke associated pneumonia (SAP) patients. METHODS: Information on general demographic, laboratory data, CT angiography, magnetic resonance angiography, or digital subtraction angiography were obtained. The predictive power was evaluated by assessing the area under the receiver operating characteristic (ROC) curve. The logistic regression was performed to assess the association of SII and short-term mortality in severe stenosis ICA-AIS and SAP patients. RESULT: Among 342 patients with severe stenosis ICA-AIS and SAP, death occurred in 66 patients during 120 days follow-up. Multivariate regression analyses indicated that increased SII predicts higher mortality in 120 days follow-up, and the risk of short-term mortality in SII > 666.31 × 109/L group is increased 4.671-fold. Patients with SII > 666.31 × 109/L had higher proportion of male, hypertension, smoking, higher admission NIHSS score, higher systolic blood pressure, and higher proportion of 120 days mortality. Higher SII predicted a worse 120 days mortality was worked out by Kaplan-Meier methods. CONCLUSION: An elevated SII was remarkably associated with 120 days mortality in severe stenosis ICA-AIS and SAP patients.

Copper Vanadium Oxide Yolk-Shell Microspheres with Excellent Capacitance and Cycling Performance for Electrochromic Supercapacitor.

Vanadium pentoxide (V2O5) is considered a promising material for electrochromic supercapacitors due to its rich color transitions and excellent electrochemical capacity. However, V2O5 exhibits low electrical conductivity, and its volume changes dramatically during charge-discharge cycles, leading to structural collapse and poor long-term cyclability. These issues have hindered the development and application of V2O5. In this study, copper vanadium oxide yolk-shell microspheres (CVO) were synthesized through a one-step solvent heat treatment with an annealing process. With the doping of copper element, the capacitance, conductivity, and cyclic stability of CVO microspheres were significantly enhanced. Subsequently, the sphere-wire network structure was formed by blending Na2V6O16·3H2O nanowires (NVO), resulting in the formation of CVO/NVO composites. The three-dimensional sphere-wire network efficiently facilitates the acquisition of additional redox sites and strengthens the material-to-substrate bonding. Under the combined influence of these favorable factors, CVO/NVO achieved a high specific capacitance of 39.2 mF cm-2, with a capacitance retention of 84% after 7500 cycles at a current density of 0.7 mA cm-2. The fully inorganic solid-state electrochromic supercapacitor (ECSC), assembled on the basis of CVO/NVO, demonstrates a vivid and clearly distinguishable color change (ΔE* = 37). Even more impressive is the energy storage capacity (18.4 mF·cm-2) and the cycling stability (up to 89% retention after 10,000 cycles) exhibited by the devices. These key performances are superior to those of most of the previously reported V2O5-based ECSCs, opening a promising avenue for the development of V2O5-based electrochromic energy storage devices.

A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled 14-Week Study of Mirogabalin in Chinese Patients with Diabetic Peripheral Neuropathic Pain.

INTRODUCTION: There is no approved effective drug for diabetic peripheral neuropathic pain (DPNP) in China. Gabapentinoids including mirogabalin have shown promise, although data in Chinese patients are scarce. METHODS: This phase 3, multicenter, randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of mirogabalin for treating DPNP in China. Mirogabalin was administered at 5 mg twice daily for the first week and uptitrated to 15 mg twice daily for a total duration of 14 weeks. The primary efficacy endpoint was the change from baseline in weekly average daily pain score (ADPS) at week 14; secondary endpoints included the ADPS responder rate, Short-Form McGill Pain Questionnaire visual analogue scale score, patient global impression of change (PGIC), average daily sleep interference score (ADSIS), EuroQol 5-dimensions 5-levels (EQ-5D-5L), and incidence of treatment-emergent adverse events (TEAEs). RESULTS: Of 393 patients (mirogabalin, n = 196; placebo n = 197), the mean age was 58.2 years (mirogabalin, 58.7 years; placebo, 57.7 years) and 54.2% were male (mirogabalin, 56.1%; placebo, 52.3%). Mirogabalin elicited a greater change from baseline in the weekly ADPS vs. placebo at week 14: least-squares mean difference (95% confidence interval) vs. placebo - 0.39 (- 0.74, - 0.04), p = 0.0301. PGIC, ADSIS, and EQ-5D-5L data reflected significantly better improvements for patients receiving mirogabalin vs. placebo. The incidence of TEAEs was 75.0% and 75.1% in the mirogabalin and placebo groups, respectively. Most TEAEs were mild or moderate, and the incidence of TEAEs leading to treatment discontinuation was 2.6% in the mirogabalin group and 1.5% in the placebo group. CONCLUSIONS: Although the effect size of mirogabalin was reduced due to the placebo effect, mirogabalin is a safe and effective treatment option for Chinese patients with DPNP. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04094662.

Nano-based drug delivery systems for active ingredients from traditional Chinese medicine: Harnessing the power of nanotechnology.

Introduction: Traditional Chinese medicine (TCM) is gaining worldwide popularity as a complementary and alternative medicine. The isolation and characterization of active ingredients from TCM has become optional strategies for drug development. In order to overcome the inherent limitations of these natural products such as poor water solubility and low bioavailability, the combination of nanotechnology with TCM has been explored. Taking advantage of the benefits offered by the nanoscale, various drug delivery systems have been designed to enhance the efficacy of TCM in the treatment and prevention of diseases. Methods: The manuscript aims to present years of research dedicated to the application of nanotechnology in the field of TCM. Results: The manuscript discusses the formulation, characteristics and therapeutic effects of nano-TCM. Additionally, the formation of carrier-free nanomedicines through self-assembly between active ingredients of TCM is summarized. Finally, the paper discusses the safety behind the application of nano-TCM and proposes potential research directions. Discussion: Despite some achievements, the safety of nano-TCM still need special attention. Furthermore, exploring the substance basis of TCM formulas from the perspective of nanotechnology may provide direction for elucidating the scientific intension of TCM formulas.

Increased TMEM166 Level in Patients with Postoperative Stroke after Carotid Endarterectomy.

Postoperative stroke is a challenging and potentially devastating complication after elective carotid endarterectomy (CEA). We previously demonstrated that transmembrane protein 166 (TMEM166) levels were directly related to neuronal damage after cerebral ischemia-reperfusion injury in rats. In this subsequent clinical study, we aimed to evaluate the prognostic value of TMEM166 in patients suffering from post-CEA strokes. Thirty-five patients undergoing uncomplicated elective CEA and 8 patients who suffered ischemic strokes after CEA were recruited. We evaluated the protein level and expression of TMEM166 in patients diagnosed with postoperative strokes and compared it to those in patients who underwent uncomplicated elective CEA. Blood samples and carotid artery plaques were collected and analyzed. High expressions of TMEM166 were detected by immunofluorescence staining and Western Blot in carotid artery plaques of all patients who underwent CEA. Furthermore, circulating TMEM166 concentrations were statistically higher in post-CEA stroke patients than in patients allocated to the control group. Mean plasma concentrations of inflammatory markers, including interleukin 6 (IL-6) and C-reactive protein (CRP), were also elevated in patients with postoperative strokes. Therefore, based on these findings, we hypothesize that elevated TMEM166 levels, accompanied by a strong inflammatory response, serve as a useful biomarker for risk assessment of postoperative stroke following CEA.

Transcriptome Analysis Reveals Dynamic Microglial-Induced A1 Astrocyte Reactivity via C3/C3aR/NF-κB Signaling After Ischemic Stroke.

Microglia and astrocytes are key players in neuroinflammation and ischemic stroke. A1 astrocytes are a subtype of astrocytes that are extremely neurotoxic and quickly kill neurons. Although the detrimental A1 astrocytes are present in many neurodegenerative diseases and are considered to accelerate neurodegeneration, their role in the pathophysiology of ischemic stroke is poorly understood. Here, we combined RNA-seq, molecular and immunological techniques, and behavioral tests to investigate the role of A1 astrocytes in the pathophysiology of ischemic stroke. We found that astrocyte phenotypes change from a beneficial A2 type in the acute phase to a detrimental A1 type in the chronic phase following ischemic stroke. The activated microglial IL1α, TNF, and C1q prompt commitment of A1 astrocytes. Inhibition of A1 astrocytes induction attenuates reactive gliosis and ameliorates morphological and functional defects following ischemic stroke. The crosstalk between astrocytic C3 and microglial C3aR contributes to the formation of A1 astrocytes and morphological and functional defects. In addition, NF-κB is activated following ischemic stroke and governs the formation of A1 astrocytes via direct targeting of inflammatory cytokines and chemokines. Taken together, we discovered that A2 astrocytes and A1 astrocytes are enriched in the acute and chronic phases of ischemic stroke respectively, and that the C3/C3aR/NF-κB signaling leads to A1 astrocytes induction. Therefore, the C3/C3aR/NF-κB signaling is a novel therapeutic target for ischemic stroke treatment.

Rimegepant orally disintegrating tablet 75 mg for acute treatment of migraine in adults from China: a subgroup analysis of a double-blind, randomized, placebo-controlled, phase 3 clinical trial.

BACKGROUND: Rimegepant orally disintegrating tablet (ODT), an oral small-molecule calcitonin gene-related peptide receptor antagonist, is indicated for acute and preventive treatment of migraine in the United States and other countries. Previously, a large clinical trial assessed the efficacy and safety of rimegepant ODT 75 mg for the acute treatment of migraine in adults living in China or South Korea. A post hoc subgroup analysis of this trial was performed to evaluate the efficacy and safety of rimegepant for acute treatment of migraine in adults living in China. METHODS: Eligible participants were ≥ 18 years of age and had a ≥ 1-year history of migraine, with 2 to 8 attacks of moderate or severe pain intensity per month and < 15 headache days per month during the 3 months before screening. Participants self-administered rimegepant ODT 75 mg or matching placebo to treat a single migraine attack of moderate or severe pain intensity. The co-primary endpoints were pain freedom and freedom from the most bothersome symptom (MBS) at 2 h post-dose. Key secondary endpoints included pain relief at 2 h post-dose, ability to function normally at 2 h post-dose, use of rescue medication within 24 h post-dose, and sustained pain freedom from 2 to 24 h and 2 to 48 h post-dose. All p values were nominal. Safety was assessed via treatment-emergent adverse events (TEAEs), electrocardiograms, vital signs, and routine laboratory tests. RESULTS: Overall, 1075 participants (rimegepant, n = 538; placebo, n = 537) were included in the subgroup analysis. Rimegepant was more effective than placebo for the co-primary endpoints of pain freedom (18.2% vs. 10.6%, p = 0.0004) and freedom from the MBS (48.0% vs. 31.8%, p <  0.0001), as well as all key secondary endpoints. The incidence of TEAEs was comparable between the rimegepant (15.2%) and placebo (16.4%) groups. No signal of drug-induced liver injury was observed, and no study drug-related serious TEAEs were reported in the rimegepant group. CONCLUSIONS: A single dose of rimegepant 75 mg rimegepant was effective for the acute treatment of migraine in adults living in China, with safety and tolerability similar to placebo. TRIAL REGISTRATION: Clinicaltrials.gov NCT04574362 Date registered: 2020-10-05.

Mesoporous polydopamine Targeting CDK4/6 Inhibitor toward Brilliant Synergistic Immunotherapy of Breast Cancer.

Immunotherapy utilizing anti-PD-L1 blockade has achieved dramatic success in clinical breast cancer management but is often hampered by the limited immune response. Increasing evidence shows that immunogenic cell death (ICD) recently arises as a promising strategy for enlarging tumor immunogenicity and eliciting systemic anti-tumor immunity effectively. However, developing simple but versatile, highly efficient but low-toxic, biosafe, and clinically available transformed ICD inducers remains a huge demand and is highly desirable. Herein, a multifunctional ICD inducer is purposefully developed A6-MPDA@PAL by integrating photothermal therapy (PTT) nanoplatforms mesoporous polydopamine (MPDA), CDK4/6 inhibitor palbociclib (PAL), and CD44-specific targeting A6 peptide in a simple way for augmenting the immune antitumor efficacy of anti-PD-L1 therapy. Remarkably, the light-inducible nanoplatforms exhibit multiple favorable therapeutic features ensuring a superior and biosafe PTT/chemotherapy efficacy. Together with stronger accumulative ICD induction, single administration of A6-MPDA@PAL can trigger robust systemic antitumor immunity and abscopal effect with the assistance of anti-PD-L1 blockade by fascinating the intratumoral infiltration of T lymphocytes and reversing the immunosuppressive tumor microenvironment simultaneously, therapy achieving brilliant synergistic immunotherapy with effective tumor ablation. This study presents a simple and smart ICD inducer opening up attractive clinical possibilities for reinforcing the anti-PD-L1 therapy against breast cancer.

Bifico Ameliorates Neurological Deficits After Ischemic Stroke in Mice: Transcriptome Profiling.

BACKGROUND/AIM: Evidence suggests that gut microbiota can affect various neurological diseases, including stroke. Stroke patients have an increase in harmful gut bacteria and a decrease in beneficial bacteria. This increases intestinal permeability, increases the risk of infection, and even affects many inflammatory factors. While probiotics may affect stroke prognosis by improving the gut environment. This study aimed to investigate the effect of probiotic Bifico on the neural function in mice after focal cerebral ischemia and explore its mechanisms of action. MATERIALS AND METHODS: A focal cerebral ischemia model was established in mice. Four weeks before modeling, animals were divided into three groups: Stroke plus Vehicle group, Stroke plus Pre-Bifico group and Bifico group. The infarct volume and neurobehaviors were evaluated. Whole-gene expression profiling was performed at different days after treatment (D1, D7, D14, D28) by RNA-seq. Differentially expressed genes (DEGs) were the processed for Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG). Some inflammation and immune related genes were screened and their expression was analyzed. RESULTS: Compared to the Stroke plus Vehicle group and Bifico group, the infarct volume and neurological score were significantly reduced in the Pre-Bifico group. There were 2 DEGs at D1, 193 DEGs at D7, 70 DEGs at D28 between Stroke plus Pre-Bifico group and Stroke plus Vehicle group. For GO analysis, there were 139 significant terms at D7 and 195 at D28. For KEGG, there were 2 significant pathways at D7 and 9 at D28. Among 87 genes related to inflammation and immunity, 6 DEGs were identified. The expression of CCL9 was significantly elevated at most time points after stroke compared to the Stroke plus Vehicle group, while that of CCL6, CXCL10, CD48, CD72 and CLEC7A was highly expressed only in the recovery stage of stroke. CONCLUSION: Oral pre-treatment with Bifico for 28 days can reduce cerebral infarction and promote recovery of neurological function in stroke mice, which may be ascribed to the regulation of immunity and inflammation in the brain.

Predictive Factors of Intestinal Ischaemia in Adhesive Small Bowel Obstruction.

OBJECTIVE: To identify the predictive factors of intestinal ischaemia in adhesive small bowel obstruction (ASBO) and develop an intestinal ischaemia risk score. STUDY DESIGN: Observational study. Place and Duration of the Study: Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China, from January 2017 to February 2022. METHODOLOGY: ASBO was determined by findings at laparotomy. The assessment of small bowel's viability was conducted through surgical inspection and subsequent histological examination of the surgical specimen. Univariate and multivariate analyses were conducted to ascertain the risk factors associated with intestinal ischaemia. RESULTS: In total, 79 patients were included. Factors entered into multivariate analysis associated with intestinal ischaemia were; rebound tenderness (odds ratio (OR): 7.8, 95% confidence interval (CI):1.7-35.3; p=0.008), procalcitonin (PCT) >0.5 ng/mL (OR: 11.7, 95% CI: 2.3-58.1; p=0.003), and reduced bowel wall enhancement on computerised tomography (CT) scan (OR: 12.2, 95% CI:2.4-61.5; p=0.003). Among patients with 0, 1, 2, and 3 factors, the rate of intestinal ischaemia increased from 0% to 49%, 72%, and 100%, respectively. According to the number of risk factors, the area under the receiver operating characteristic curve for the determination of intestinal ischaemia was 0.848 (95% CI: 0.764-0.932). CONCLUSION: Rebound tenderness, PCT levels >0.5 ng/mL, and reduced bowel wall enhancement are risk factors of intestinal ischemic injury that require surgery within the context of ASBO. These factors need to be closely monitored that could assist clinicians in avoiding unnecessary laparotomies and selecting patients eligible for surgery. KEY WORDS: Intestinal obstruction, Ischaemia, Adhesions.

Regulating pyroptosis by mesenchymal stem cells and extracellular vesicles: A promising strategy to alleviate intervertebral disc degeneration.

Intervertebral disc degeneration (IVDD) is a main cause of low back pain (LBP), which can lead to disability and thus generate a heavy burden on society. IVDD is characterized by a decrease in nucleus pulposus cells (NPCs) and endogenous mesenchymal stem cells (MSCs), degradation of the extracellular matrix, macrophage infiltration, and blood vessel and nerve ingrowth. To date, the therapeutic approaches regarding IVDD mainly include conservative treatment and surgical intervention. However, both can only relieve symptoms rather than stop or revert the progression of IVDD, since the pathogenesis of IVDD is not yet clear. Pyroptosis, which is characterized by Caspase family dependence and conducted by the Gasdermin family, is a newly discovered mode of programmed cell death. Pyroptosis has been observed in NPCs, annulus fibrosus cells (AFCs), chondrocytes, MSCs, macrophages, vascular endothelial cells and neurons and may contribute to IVDD. MSCs are a kind of pluripotent stem cell that can be found in almost all tissues. MSCs have a strong ability to secrete extracellular vesicles (EVs), which contain exosomes, microvesicles and apoptotic bodies. EVs derived from MSCs play an important role in pyroptosis regulation and could be beneficial for alleviating IVDD. This review focuses on clarifying the regulation of pyroptosis to improve IVDD by MSCs and EVs derived from MSCs.

Recent advances in light energy biotherapeutic strategies with photobiomodulation on central nervous system disorders.

Transcranial photobiomodulation refers to irradiation of the brain through the skull using low-intensity red or near-infrared light, which is the most commonly studied method of light energy biotherapy for central nervous system disorders. The absorption of photons by specific chromophores within the cell elevates ATP synthesis, reduces oxidative stress damage, alleviates inflammation or mediates the activation of transcription factors and signaling mediators through secondary mediators, which in turn trigger downstream signaling pathways to cause a series of photobiological effects including upregulation of neurotrophic factors. Multiple mechanisms are simultaneously involved in the pathological process of central nervous system disorders. The pleiotropic treatment of transcranial photobiomodulation towards multiple targets plays a beneficial role in improving hemodynamics, neural repair and improving behaviors in central nervous system disorders such as ischemic stroke, traumatic brain injury, neurodegenerative diseases, epilepsy and depression. This review mainly introduces the mechanism and recent preclinical and clinical advances of transcranial photobiomodulation for central nervous system disorders, which will provide a reference for clinicians to understand and engage in related studies, and calls for more and larger studies to validate and develop a wider application of transcranial photobiomodulation in central nervous system.

Serum Pentaxin 3 (PTX3) Promotes NLRP3 Inflammasome and Pyroptosis in Patients with Up-Regulated Myasthenia Gravis.

BACKGROUND: Myasthenia gravis (MG) is an autoantibodies-mediated autoimmune disease with the complications of neuromuscular junction transmission. In this study, we aimed to investigate the molecular regulatory roles of pentaxin 3 (PTX3) in patients and in animal model with MG and to explore its underlying mechanism. METHODS: Patients with MG were identified and enrolled at our designated hospital and animal model was utilized for the proposed study. Enzyme-linked immunosorbent assay (ELISA) kit were used to quantify the IL-1ß, IL-6, INF-γ, IL-17, TNF-α, anti-TAChR IgG/IgG1/IgG2b/IgG2c levels. RESULTS: Serum PTX3 expression level in patients with MG was up-regulated as compared to normal. Furthermore, we found increased expression level of mRNA and protein product of PTX3 in the mice with MG. PTX3 promoted inflammation, pyroptosis in patients as well as in the MG mouse model. In addition, PTX3 induced the STAT3/NLRP3 inflammasome and promoted gene synthesis of STAT3. We found that METTL3-mediated m6A modification decreases PTX3 stability. CONCLUSIONS: Our study suggests that the PTX3 is associated with the enhancement of inflammation and pyroptosis through regulating the STAT3/NLRP3 inflammasome signaling pathway at the early stage of the disease. The pro-inflammatory PTX3 facilitates the development of MG and it can be used as a potantial MG-associated diagnostic biomarker for MG.

Mesenchymal stromal cell biotherapy for Parkinson's disease premotor symptoms.

Parkinson's disease (PD) is a neurodegenerative disorder with motor deficits due to nigrostriatal dopamine depletion and with the non-motor/premotor symptoms (NMS) such as anxiety, cognitive dysfunction, depression, hyposmia, and sleep disorders. NMS is presented in at least one-fifth of the patients with PD. With the histological information being investigated, stem cells are shown to provide neurotrophic supports and cellular replacement in the damaging brain areas under PD conditions. Pathological change of progressive PD includes degeneration and loss of dopaminergic neurons in the substantia nigra of the midbrain. The current stem cell beneficial effect addresses dopamine boost for the striatal neurons and gliovascular mechanisms as competing for validated PD drug targets. In addition, there are clinical interventions for improving the patient's NMS and targeting their autonomic dysfunction, dementia, mood disorders, or sleep problems. In our and many others' research using brain injury models, multipotent mesenchymal stromal cells demonstrate an additional and unique ability to alleviate depressive-like behaviors, independent of an accelerated motor recovery. Intranasal delivery of the stem cells is discussed for it is extensively tested in rodent animal models of neurological and psychiatric disorders. In this review, we attempt to discuss the repairing potentials of transplanted cells into parkinsonism pathological regions of motor deficits and focus on preventive and treatment effects. From new approaches in the PD biological therapy, it is believed that it can as well benefit patients against PD-NMS.