Heat acclimation with probiotics-based ORS supplementation alleviates heat stroke-induced multiple organ dysfunction via improving intestinal thermotolerance and modulating gut microbiota in rats.

Heat stroke (HS) is a critical condition with extremely high mortality. Heat acclimation (HA) is widely recognized as the best measure to prevent and protect against HS. Preventive administration of oral rehydration salts III (ORSIII) and probiotics have been reported to sustain intestinal function in cases of HS. This study established a rat model of HA that was treated with probiotics-based ORS (ORSP) during consecutive 21-day HA training. The results showed that HA with ORSP could attenuate HS-induced hyperthermia by regulating thermoregulatory response. We also found that HA with ORSP could significantly alleviate HS-induced multiple organ injuries. The expression levels of a series of heat-shock proteins (HSPs), including HSP90, HSP70, HSP60, and HSP40, were significantly up-regulated from the HA training. The increases in intestinal fatty acid binding protein (I-FABP) and D-Lactate typically seen during HS were decreased through HA. The representative TJ proteins including ZO-1, E-cadherin, and JAM-1 were found to be significantly down-regulated by HS, but sustained following HA. The ultrastructure of TJ was examined by TEM, which confirmed its protective effect on the intestinal barrier protection following HA. We also demonstrated that HA raised the intestinal levels of beneficial bacteria Lactobacillus and lowered those of the harmful bacteria Streptococcus through 16S rRNA gene sequencing. These findings suggest that HA with ORSP was proven to improve intestinal thermotolerance and the levels of protective gut microbiota against HS.

[Progress on application of hydrogels in the field of peripheral nerve injury repair].

As one of the common traumatic diseases in clinical practice, peripheral nerve injury (PIN) often causes nerve pain, abnormal reflexes, autonomic disorders, and even sensorimotor disorders due to the slow regeneration rate after injury, which seriously affects body function. Even as the gold standard of treatment, autologous nerve transplantation has limitations such as limited donor area and donor injury, which greatly limits its clinical application effect. Therefore, the preparation of artificial nerve grafts suitable for clinical practice has become the future development trend of peripheral nerve injury treatment, and the repair of injury defects and the promotion of nerve regeneration have also become research hotspots in tissue engineering and regenerative medicine. In recent years, extensive research has been carried out on nerve guidance conduits (NGCs) in the field of nerve regeneration and repair, in which scaffold materials and internal fillers have also become the focus of research as the core elements of neural catheters, and a series of achievements have been made in the application of new materials, embedding stem cells/precursor cells, and developing trophic factors and drug-loaded sustained-release systems. Therefore, this paper focuses on the application progress of hydrogel and its related derivative materials in the field of peripheral nerve injury repair, and provides new ideas for promoting the related research of tissue engineering and clinical medicine.

Mechanisms of the Masquelet technique to promote bone defect repair and its influencing factors.

The Masquelet technique, also known as the induced membrane technique, is a surgical technique for repairing large bone defects based on the use of a membrane generated by a foreign body reaction for bone grafting. This technique is not only simple to perform, with few complications and quick recovery, but also has excellent clinical results. To better understand the mechanisms by which this technique promotes bone defect repair and the factors that require special attention in practice, we examined and summarized the relevant research advances in this technique by searching, reading, and analysing the literature. Literature show that the Masquelet technique may promote the repair of bone defects through the physical septum and molecular barrier, vascular network, enrichment of mesenchymal stem cells, and high expression of bone-related growth factors, and the repair process is affected by the properties of spacers, the timing of bone graft, mechanical environment, intramembrane filling materials, artificial membrane, and pharmaceutical/biological agents/physical stimulation.

Activation of Piezo1 increases the sensitivity of breast cancer to hyperthermia therapy.

Photothermal therapy (PTT) of nanomaterials is an emerging novel therapeutic strategy for breast cancer. However, there exists an urgent need for appropriate strategies to enhance the antitumor efficacy of PTT and minimize damage to surrounding normal tissues. Piezo1 might be a promising novel photothermal therapeutic target for breast cancer. This study aims to explore the potential role of Piezo1 activation in the hyperthermia therapy of breast cancer cells and investigate the underlying mechanisms. Results showed that the specific agonist of Piezo1 ion channel (Yoda1) aggravated the cell death of breast cancer cells triggered by heat stress in vitro. Reactive oxygen species (ROS) production was significantly increased following heat stress, and Yoda1 exacerbated the rise in ROS release. GSK2795039, an inhibitor of NADPH oxidase 2 (NOX2), reversed the Yoda1-mediated aggravation of cellular injury and ROS generation after heat stress. The in vivo experiments demonstrate the well photothermal conversion efficiency of TiCN under the 1,064 nm laser irradiation, and Yoda1 increases the sensitivity of breast tumors to PTT in the presence of TiCN. Our study reveals that Piezo1 activation might serve as a photothermal sensitizer for PTT, which may develop as a promising therapeutic strategy for breast cancer.

The prediction of the survival in patients with severe trauma during prehospital care: Analyses based on NTDB database.

PURPOSE: Traumas cause great casualties, accompanied by heavy economic burdens every year. The study aimed to use ML (machine learning) survival algorithms for predicting the 8-and 24-hour survival of severe traumas. METHODS: A retrospective study using data from National Trauma Data Bank (NTDB) was conducted. Four ML survival algorithms including survival tree (ST), random forest for survival (RFS) and gradient boosting machine (GBM), together with a Cox proportional hazard model (Cox), were utilized to develop the survival prediction models. Following this, model performance was determined by the comparison of the C-index, integrated Brier score (IBS) and calibration curves in the test datasets. RESULTS: A total of 191,240 individuals diagnosed with severe trauma between 2015 and 2018 were identified. Glasgow Coma Scale (GCS), trauma type, age, SaO2, respiratory rate (RR), systolic blood pressure (SBP), EMS transport time, EMS on-scene time, pulse, and EMS response time were identified as the main predictors. For predicting the 8-hour survival with the complete cases, the C-indexes in the test sets were 0.853 (0.845, 0.861), 0.823 (0.812, 0.834), 0.871 (0.862, 0.879) and 0.857 (0.849, 0.865) for Cox, ST, RFS and GBM, respectively. Similar results were observed in the 24-hour survival prediction models. The prediction error curves based on IBS also showed a similar pattern for these models. Additionally, a free web-based calculator was developed for potential clinical use. CONCLUSION: The RFS survival algorithms provide non-parametric alternatives to other regression models to be of clinical use for estimating the survival probability of severe trauma patients.

Hypoxia preconditioning of adipose stem cell-derived exosomes loaded in gelatin methacryloyl (GelMA) promote type H angiogenesis and osteoporotic fracture repair.

The challenges posed by delayed atrophic healing and nonunion stand as formidable obstacles in osteoporotic fracture treatment. The processes of type H angiogenesis and osteogenesis emerge as pivotal mechanisms during bone regeneration. Notably, the preconditioning of adipose-derived stem cell (ADSC) exosomes under hypoxic conditions has garnered attention for its potential to augment the secretion and functionality of these exosomes. In the present investigation, we embarked upon a comprehensive elucidation of the underlying mechanisms of hypo-ADSC-Exos within the milieu of osteoporotic bone regeneration. Our findings revealed that hypo-ADSC-Exos harboured a preeminent miRNA, namely, miR-21-5p, which emerged as the principal orchestrator of angiogenic effects. Through in vitro experiments, we demonstrated the capacity of hypo-ADSC-Exos to stimulate the proliferation, migration, and angiogenic potential of human umbilical vein endothelial cells (HUVECs) via the mediation of miR-21-5p. The inhibition of miR-21-5p effectively attenuated the proangiogenic effects mediated by hypo-ADSC-Exos. Mechanistically, our investigation revealed that exosomal miR-21-5p emanating from hypo-ADSCs exerts its regulatory influence by targeting sprouly1 (SPRY1) within HUVECs, thereby facilitating the activation of the PI3K/AKT signalling pathway. Notably, knockdown of SPRY1 in HUVECs was found to potentiate PI3K/AKT activation and, concomitantly, HUVEC proliferation, migration, and angiogenesis. The culminating stage of our study involved a compelling in vivo demonstration wherein GelMA loaded with hypo-ADSC-Exos was validated to substantially enhance local type H angiogenesis and concomitant bone regeneration. This enhancement was unequivocally attributed to the exosomal modulation of SPRY1. In summary, our investigation offers a pioneering perspective on the potential utility of hypo-ADSC-Exos as readily available for osteoporotic fracture treatment.

DNAJA1­knockout alleviates heat stroke­induced endothelial barrier disruption via improving thermal tolerance and suppressing the MLCK­MLC signaling pathway.

Endothelial barrier disruption plays a key role in the pathophysiology of heat stroke (HS). Knockout of DNAJA1 (DNAJA1­KO) is thought to be protective against HS based on a genome­wide CRISPR­Cas9 screen experiment. The present study aimed to illustrate the function of DNAJA1­KO against HS in human umbilical vein endothelial cells. DNAJA1­KO cells were infected using a lentivirus to investigate the role of DNAJA1­KO in HS­induced endothelial barrier disruption. It was shown that DNAJA1­KO could ameliorate decreased cell viability and increased cell injury, according to the results of Cell Counting Kit­8 and lactate dehydrogenase assays. Moreover, HS­induced endothelial cell apoptosis was inhibited by DNAJA1­KO, as indicated by Annexin V­FITC/PI staining and cleaved­caspase­3 expression using flow cytometry and western blotting, respectively. Furthermore, the endothelial barrier function, as measured by transepithelial electrical resistance and FITC­Dextran, was sustained during HS. DNAJA1­KO was not found to have a significant effect on the expression and distribution of cell junction proteins under normal conditions without HS. However, DNAJA1­KO could effectively protect the HS­induced decrease in the expression and distribution of cell junction proteins, including zonula occludens­1, claudin­5, junctional adhesion molecule A and occludin. A total of 4,394 proteins were identified using proteomic analysis, of which 102 differentially expressed proteins (DEPs) were activated in HS­induced wild­type cells and inhibited by DNAJA1­KO. DEPs were investigated by enrichment analysis, which demonstrated significant enrichment in the 'calcium signaling pathway' and associations with vascular­barrier regulation. Furthermore, the 'myosin light­chain kinase (MLCK)­MLC signaling pathway' was proven to be activated by HS and inhibited by DNAJA1­KO, as expected. Moreover, DNAJA1­KO mice and a HS mouse model were established to demonstrate the protective effects on endothelial barrier in vivo. In conclusion, the results of the present study suggested that DNAJA1­KO alleviates HS­induced endothelial barrier disruption by improving thermal tolerance and suppressing the MLCK­MLC signaling pathway.

Therapeutic potential of traditional Chinese medicine on heat stroke.

As global warming progresses, heat waves are becoming increasingly frequent and intense, meanwhile the incidence of heat stroke (HS) has increased sharply during the past decades. HS is typically associated with significant morbidity and mortality, and there is an urgent need for further research to solve this difficult issue. There currently exists difficulties regarding on-site emergency treatment methods and limited in-hospital treatment approaches, and better treatments are required as soon as possible. Theories and therapies from various traditional Chinese medicine (TCM) academic groups have been widely reported. Therefore, an exploration of prevention and protection methods should consider TCM experiences as an alternative. This article primarily reviews TCM herbal therapies and external therapies that have been described in various clinical reports and demonstrated in relevant studies. Herbal therapies, including herbal formulas, Chinese patent medicines (CPMs), single Chinese herbs, and associated extracts or monomers, are summarized based on the shared perspectives of the underlying mechanisms from TCM. In addition, external therapies including acupuncture, bloodletting, cupping, Gua sha and Tui na that have rarely been rarely mentioned and considered in most cases, are introduced and discussed to offer a unique perspective in the search for novel interventions for HS. In summary, TCM may provide abundant potential clinical benefits and research directions in the fight against HS.

Metabolomics provides insights into acceleration of bone healing in fractured patients with traumatic brain injuries.

While clinical surveys have frequently reported that patients with traumatic brain injuries (TBIs) and comorbidities experience faster healing, the underlying mechanisms have been investigated but remain unclear. As a comprehensive comparison and analysis of the metabolic characteristics of these two pathologies have not been undertaken, we developed a rat model of fracture and TBI and collected serum samples for metabolomic analysis using ultra-high performance liquid chromatography-quadrupole time-of-flight MS (UHPLC-Q-TOF/MS). In total, we identified 40 differential metabolites and uncovered related pathways and potential mechanisms, including aminoacyl-transfer RNA biosynthesis; differential amino acids such as leucine, cholylhistidine, aspartyl-lysine; and related lipid metabolism, and discussed their impacts on bone formation in detail. This study highlights that the UHPLC-Q-TOF/MS-based metabolomics approach offers a better understanding of the metabolic links between TBI and accelerated bone recovery.

Biodegradable composites of poly(propylene carbonate) mixed with silicon nitride for osteogenic activity of adipose-derived stem cells and repair of bone defects.

Absorbable polymers have attracted increasing attention in the field of bone regeneration in recent years for their degradation. Compared with other degradable polymers, polypropylene carbonate (PPC) has several advantages such as biodegradation and relatively cheap raw materials. Most importantly, PPC can degrade into water and carbon dioxide totally which does not give rise to local inflammation and bone resorption in vivo. However, pure PPC has not presented excellent osteoinductivity properties. In order to enhance the osteoinductivity of PPC, silicon nitride (SiN) was employed due to its excellent mechanical properties, biocompatibility and osteogenesis compared with the other common materials such as hydroxyapatite and calcium phosphate ceramics. In this study, composites of PPC mixed with different contents of SiN were prepared successfully (PSN10 with 10 wt% SiN content, and PSN20 with 20 wt% SiN content). The characterization of the composites suggested that PPC mixed with SiN evenly and PSN composites presented stable properties. The results in vitro revealed that the PSN20 composite possessed satisfactory biocompatibility and exerted better osteogenic differentiation effects on adipose-derived stem cells (ADSCs). In particular, the PSN20 composite accelerated the healing of bone defects better and degraded with the process of bone healing in vivo. Overall, the PSN20 composite exhibited better biocompatibility, induced osteogenic differentiation of ADSCs and promoted healing of bone defects, due to which the PSN composite is considered as a potential candidate for treating bone defects in the field of bone tissue engineering.

Premature death patterns and trends in diseases of the musculoskeletal system and connective tissue in Shanghai China from 1973 to 2019.

OBJECTIVES: The long-term trends in crude mortality rates (CMRs) and age-standardized mortality rates characterized by Segi's world standard population (ASMRWs) of DMSCT in Pudong New Area (PNA), Shanghai, were evaluated from 1973 to 2019, and the role of demographic and non-demographic factors in the mortality of diseases of the musculoskeletal system and connective tissue (DMSCT) was explored. METHODS: The PNA district has the largest population and area in Shanghai. Therefore, the mortality registration system of the PNA district was used to calculate and verify the number of deaths. Then, the Joinpoint Regression Program was used to analyze the time trend of mortality. The difference decomposition method was used to visualize the mortality of population and non-population factors, and GraphPad Prism was used for image visualization. RESULTS: A total of 2260 deaths from DMSCT occurred from 1973 to 2019. The CMR and ASMRW of DMSCT were 2.56/105 person-years and 1.57/105 person-years, respectively. The number of people aged ≥80 (696 deaths) who died of DMSCT was the highest among total deaths, the highest number of years of life lost (YLL) was observed in the 45-59 age group, and the YLL rate in the ≥80 age group was the highest. The CMR and YLL rates of DMSCT showed upward trends in the total population from 1973 to 2019. CONCLUSION: The CMR and YLL rates of DMSCT showed upward trends in the total population from 1973 to 2019 in PNA, Shanghai, and age was closely related to the occurrence of DMSCT. Similarly, demographic factors played a role in this process.

Nickel-titanium shape memory alloy embracing fixator benefits the determination of the implantation angle of prosthesis stem in tumor-type artificial joint replacement.

BACKGROUND: Hip tumors often require tumor-type artificial joint replacement. The selection of the prosthesis stem (hip tumor prosthesis stem) implantation angle during the operation is important to prevent the complication of postoperative prosthesis dislocation. The aim of this study was to evaluate the role of a nickel-titanium (Ni-Ti) shape memory alloy embracing fixator in determination of the implantation angle of a hip tumor prosthesis stem and analyze its efficacy. METHODS: 36 patients with proximal femur tumor were treated with extended tumor resection and prosthetic replacement. 14 patients received prosthetic replacements with the embracing fixators fixing between the junction of the prosthesis stem and the femur temporarily, while the other 22 patients received the same replacements but without the fixators. The two groups were compared regarding occurrence of complications, limb function, and active hip range of motion (ROM). RESULTS: There was no case of hip dislocation in the group that received prosthetic replacements with the use of embracing fixators. Occurrence of deep infection had no difference between the two groups. However, better limb function and higher active (ROM) on abduction or flexion were observed in the group using embracing fixators. CONCLUSION: Ni-Ti shape memory alloy embracing fixator plays a key role in assisting the accurate implantation angle of the prosthesis stem in prosthetic replacement. The prosthesis stem can be adjusted to the optimal angle with the help of the embracing fixator. Patients have a lower risk of dislocation, better limb function, and higher active hip ROM.

CCL25 Inhibition Alleviates Sepsis-Induced Acute Lung Injury and Inflammation.

Purpose: Acute lung injury (ALI) is a common clinical syndrome with high mortality. The chemokine ligand 25 (CCL25) is involved in inflammation, leukocyte trafficking and immunoregulation. However, the role and mechanism of CCL25 in ALI are not fully understood yet. The aim of this study was to explore the relationship between acute lung injury and CCL25. Patients and Methods: In this study, we first examined chemokine expression in sepsis patients and found that serum CCL25 expression levels were relatively high in sepsis patients compared to healthy individuals. Based on this, we designed in vitro and in vivo experiments to verify the validity of the theory. In vitro, we used lipopolysaccharide-stimulated human pulmonary microvascular endothelial cells (HPMECs). In vivo, we established male C57BL/6 mice cecal ligation puncture (CLP) model of sepsis. Results: In vitro, we used lipopolysaccharide-stimulated human pulmonary microvascular endothelial cells (HPMECs) and found significantly higher expression of CCL25 by enzyme-linked immunosorbent assay. Inhibition of CCL25 resulted in a significant decrease in the expression of inflammatory cytokines in HPMECs. In addition, we found that CCL25 promoted increased endothelial permeability by reducing the expression of tight junction proteins and was associated with activation of the P38 MAPK pathway by measuring the transepithelial electrical resistance and fluorescence intensity of fluorescein isothiocyanate. Results from luciferase assays and chromatin immunoprecipitation assays showed that inhibition of NF-κB activity in HPMECs decreased CCL25 expression, but addition of recombinant CCL25 increased cell permeability and inflammatory cytokine expression. In vivo, we established male C57BL/6 mice cecal ligation puncture (CLP) model of sepsis. We found that inhibition of CCL25 significantly reduced inflammatory cytokine expression in a CLP-induced sepsis model, thereby alleviating lung tissue damage in mice. Conclusion: Our study suggests that CCL25 contributed to the development of ALI by modulating the functions of microvascular endothelial cells.

Application of an arched, Ni-Ti shape-memory connector in repairing distal tibiofibular syndesmosis ligament injury.

OBJECTIVE: To investigate the clinical effect of internal fixation of a Ni-Ti arched shape-memory connector in the treatment of distal tibiofibular syndesmosis ligament injury. METHODS: From January 2013 to January 2016, 108 cases of ankle fracture with distal tibiofibular syndesmosis ligament injury in our hospital were selected, and all of them were fixed with ASCs or screw fixation. The functional evaluation and efficacy evaluation were performed according to the Olerud Molander Ankle Score (Omas) and SF-36. At the same time, follow-ups recorded the incidence of postoperative complications: osteoarthritis, superficial infection, symptomatic hard and soft tissue irritation, early removal and poor reduction of internal fixation, and later loss of reduction. RESULTS: In the ASC(Ni-Ti Arched shape-memory Connector) group, the incidence of symptomatic hardware, soft tissue or superficial infection decreased to 2.77%(from 13.8% or 11.1% in SCREW group). The early removal rate(2.77%) of internal fixation was also lower than that of the screw group. While the incidence of osteoarthritis is 13.8% in SCREW group, the incidence of osteoarthritis in the later follow-up was also as low as 1.38% in ASC group. Loss of fracture reduction due to removal of the fixation device for the distal tibiofibular syndesmosis ligament was not observed in the ASC group. With two postoperative scoring systems (OMAS and SF-36), patients in the ASC group significantly get higher score than that in SCREW group. CONCLUSION: The design of the Ni-Ti arched shape-memory connector can be adapted to the irregular anatomical structure of the malleolus and the ability to continue to contract by body temperature. The use of ASCs in fixation of articular ligaments can preserve a slight range of motion, and the results suggest that ASCs can effectively reduce the incidence of fixation looseness, fracture, infection and other complications.

Polydopamine and hyaluronic acid immobilisation on vancomycin-loaded titanium nanotube for prophylaxis of implant infections.

Titanium nanotube (Ti-NT) is an attractive substrate for local drug delivery, however, it is difficult to control the burst drug release and achieve sustained release from these nanotubes. In the present study, we investigated the feasibility of controlling drug release from Ti-NT within polydopamine and hyaluronic acid films, to achieve antibacterial activity and osteogenic promotion. Vancomycin was loaded into the Ti-NT by lyophilisation. Dopamine and hyaluronic acid were immobilized on the vancomycin-loaded Ti-NT surface through alternate deposition technique. The anti-infective and osteogenic abilities of the polydopamine and hyaluronic acid-modified Ti-NT were then investigated. Our results demonstrated that polydopamine and hyaluronic acid-modified Ti-NT exhibited improved drug loading and release control for 7 days. Compared with the vancomycin-loaded Ti-NT, the polydopamine and hyaluronic acid-modified Ti-NT exhibited better antibacterial ability, and the hyaluronic acid-modified Ti-NT promoted the osteogenic differentiation of rat bone marrow stem cells. Our results demonstrated that Ti-NT biofunctionalized with polydopamine and hyaluronic acid can help overcome the limitations of Ti-NT, by improving drug loading, antibacterial activity and osteogenic ability.

Bovine Lactoferrin Alleviates Pulmonary Lipid Peroxidation and Inflammatory Damage in Heat Stroke Rats.

Lung injury occurring in the early stage of heat stroke (HS) leads to hypoxia and further aggravation of other organic damage. Lactoferrin (LF) is an iron binding protein with anti-inflammatory and antioxidant effects. This study focuses on the protection of preadministration of bovine lactoferrin (BLF) against lung injury in rats with HS. Sixty-four Sprague-Dawley male rats were divided into four groups randomly: control (CON)+phosphate-buffered saline (PBS) (n = 16), HS+PBS (n = 16), HS+low-dose BLF (LBLF) (n = 16), and HS+high-dose BLF (HBLF) (n = 16). CON+PBS and HS+PBS were preadministered 10 mL/kg PBS for 1 week. HS+LBLF and HS+HBLF were preadministered 100 and 200 mg/kg BLF for 1 week, respectively. The HS onset time and the survival rate were recorded, and bronchoalveolar lavage fluid was obtained to measure protein concentration. Lung was obtained for pathological analysis and wet/dry weight ratio measurement; later, the content of malondialdehyde (MDA), activity of myeloperoxidase (MPO), and superoxide dismutase (SOD) were measured in lung tissue homogenate. The results indicated that BLF preadministration could delay the HS onset time, enhance the survival rate, the levels of serum inflammatory cytokine and MDA content in HS+LBLF and HS+HBLF showed significant reduction compared with HS+PBS, while a significant elevation of SOD activity and reduction of MPO activity in HS+HBLF. Our results demonstrate that BLF preadministration could relieve lung injury in HS rats by enhancing thermal endurance, and alleviating serum inflammatory response and pulmonary oxidative stress damage.

[Development of Novel Guide Device for Cannulated Screws Implantation in Femoral Neck Fracture Surgery].

Cannulated Screw is a common internal fixation for the treatment of femoral neck fractures. However, the traditional implantation method has disadvantages such as inaccuracy and large radiation exposure. Based on the anatomical characteristics of the femoral neck and geometric principles, we develop a novel guide device for cannulated screws insertion. The cadaver experiment showed that it can improve the accuracy of cannulated screws implantation, reduce puncture attempts and the radiation exposure of doctors and patients.