Nomogram to predict severe retinopathy of prematurity in Southeast China

AIM:To define the predictive factors of severe retinopathy of prematurity(ROP)and develop a nomogram for predicting severe ROP in southeast China.METHODS:Totally 554 infants diagnosed with ROP hospitalized in the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University and hospitalized in Taizhou Women and Children’s Hospital were included.Clinical data and 43 candidate predictive factors of ROP infants were collected retrospectively.Logistic regression model was used to identify predictive factors of severe ROP and to propose a nomogram for individual risk prediction,which was compared with WINROP model and Digirop-Birth model.RESULTS:Infants from the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University(n=478)were randomly allocated into training(n=402)and internal validation group(n=76).Infants from Taizhou Women and Children’s Hospital were set as external validation group(n=76).Severe ROP were found in 52 of 402 infants,12 of 76 infants,and 7 of 76 infants in training group,internal validation group,and external validation group,respectively.Birth weight[odds ratio(OR),0.997;95%confidence interval(CI),0.996-0.999;P<0.001],multiple births(OR,1.885;95%CI,1.013-3.506;P=0.045),and non-invasive ventilation(OR,0.288;95%CI,0.146-0.570;P<0.001)were identified as predictive factors for the prediction of severe ROP,by univariate analysis and multivariate analysis.For predicting severe ROP based on the internal validation group,the areas under receiver operating characteristic curve(AUC)was 78.1(95%CI,64.2-92.0)for the nomogram,32.9(95%CI,15.3-50.5)for WINROP model,70.2(95%CI,55.8-84.6)for Digirop-Birth model.In external validation group,AUC of the nomogram was also higher than that of WINROP model and Digirop-Birth model(80.2 versus 51.1 and 63.4).The decision curve analysis of the nomogram demonstrated better clinical efficacy than that of WINROP model and Digirop-Birth model.The calibration curves demonstrated a good consistency between the actual severe ROP incidence and the predicted probability.CONCLUSION:Birth weight,multiple births,and noninvasive ventilation are independent predictors of severe ROP.The nomogram has a good ability to predict severe ROP and performed well on internal validation and external validation in southeast China.

Basilic vein variation encountered during surgery for arm vein port:A case report

BACKGROUND Venous variations are uncommon and usually hard to identify,and basilic vein variation is particularly rare.Basilic vein variation usually presents without any clinical symptoms and is often regarded as a benign alteration.This case was a patient with congenital basilic vein variation encountered during surgery for an infusion port.CASE SUMMARY We documented and analyzed an uncommon anatomical variation in the basilic vein encountered during arm port insertion.This peculiarity has hitherto remained undescribed in the literature.We offer remedial strategies for addressing this anomaly in the future and precautionary measures to circumvent its occurrence.We conducted a comprehensive review of analogous cases in the literature,offering pertinent therapeutic recommendations and solutions,with the aim of enhancing the efficacy and safety of future arm port implantations.CONCLUSION Venous variation is rare and requires detailed intraoperative and postoperative examination to ensure accuracy,so as not to affect subsequent treatment.

Dialectical study of disulfidptosis and clinical outcome in patients with colorectal cancer

Background:Colorectal cancer(CRC)is a leading cause of cancer mortality globally.This study aims to develop a prognostic model based on disulfidptosis-related genes to assess survival outcomes in CRC,highlighting the tumor microenvironment’s role.Methods:The thought of traditional Chinese medicine syndrome differentiation and treatment runs through the whole study.We analyzed CRC tissue data from The Cancer Genome Atlas and the Gene Expression Omnibus using single-sample gene set enrichment and weighted gene correlation network analyses to identify prognostic markers and evaluate immune infiltration.We also investigated predictive drug sensitivities.Results:We identified seven disulfidptosis-related markers–complement C1q A chain(C1QA),solute carrier family 11 member 1(SLC11A1),cluster of differentiation 36(CD36),cluster of differentiation 6(CD6),interleukin 1 receptor associated kinase 3(IRAK3),S100 calcium binding protein A8(S100A8),and CD8 subunit alpha(CD8A)–that significantly influence prognosis.Patients classified in the low-risk group demonstrated improved overall survival compared to those in the high-risk group across training(P=0.0026)and validation cohorts(P=0.032).Differential gene expression was significant in the high-risk group(P<0.001),and prevalent mutations included APC regulator of WNT signaling pathway(APC),tumor protein P53(TP53),Titin(TTN),and Kirsten rat sarcoma viral oncogene(KRAS).The risk score correlated linearly with tumor microenvironment attributes.The results of drug analysis showed that some traditional drugs may have anticancer effects through the vertical action of disulfidptosis.Conclusion:Our prognostic model,integrating seven disulfidptosis-related genes,categorizes CRC patients by survival probability and underscores these genes as potential biomarkers linked to the tumor microenvironment.These findings support their use in refining therapeutic strategies for CRC.

Designing Bioorthogonal Reactions for Biomedical Applications

Bioorthogonal reactions are a class of chemical reactions that can be carried out in living organisms without interfering with other reactions, possessing high yield, high selectivity, and high efficiency. Since the first proposal of the conception by Professor Carolyn Bertozzi in 2003, bioorthogonal chemistry has attracted great attention and has been quickly developed. As an important chemical biology tool, bioorthogonal reactions have been applied broadly in biomedicine, including bio-labeling, nucleic acid functionalization, drug discovery, drug activation, synthesis of antibody–drug conjugates, and proteolysis-targeting chimeras. Given this, we summarized the basic knowledge, development history, research status, and prospects of bioorthogonal reactions and their biomedical applications. The main purpose of this paper is to furnish an overview of the intriguing bioorthogonal reactions in a variety of biomedical applications and to provide guidance for the design of novel reactions to enrich bioorthogonal chemistry toolkits.

Association between UCP3 gene polymorphisms and nonalcoholic fatty liver disease in Chinese children

AIM:To confirm the hypothesis that polymorphisms of the uncoupling protein 3(UCP3)gene are associated with the occurrence of nonalcoholic fatty liver disease(NAFLD).METHODS:A total of 250 NAFLD patients(147 malesand 103 females)and 200 healthy individuals who served as controls(control,109 males and 91 females),aged between 6 and 16 years were enrolled in this study.The four non-synonymous single nucleotide polymorphisms(SNPs)in the UCP3 gene polymorphisms of rs1726745,rs3781907,rs11235972 and rs1800849,were genotyped using MassArray.Body mass index(BMI),waist and hip circumference,blood pressure(BP),fasting blood glucose(FBG),insulin and lipid profiles were measured and B-ultrasound examination was performed in all subjects.RESULTS:NAFLD patients showed risk factors for metabolic syndrome:elevated BMI,waist-to-hip ratio,BP,FBG,homeostasis model assessment-estimated insulin resistance,total triglyceride,total cholesterol and low-density lipoprotein-cholesterol,while decreased high-density lipoprotein-cholesterol level compared with the control group.The GG genotype distributions of rs11235972 in the NAFLD group differed significantly from that in the control group.We found that waist circumference between CC(58.76±6.45 cm)and CT+TT(57.00±5.59 cm),and hip circumference between CC(71.28±7.84 cm)and CT+TT genotypes(69.06±7.75 cm)were significantly different with and without rs1800849 variation(P<0.05).CONCLUSION:A higher prevalence of rs11235972 GG genotype was observed in the NAFLD group compared with the control group.No differences were observed for the other SNPs.However,there was a significant difference in body height in addition to waist and hip circumference between the CC(mutant type group)and CT+TT group with and without rs1800849 variation.

The role of transporters in cancer redox homeostasis and cross-talk with nanomedicines

Tumor cell usually exhibits high levels of reactive oxygen species and adaptive antioxidant system due to the metabolic,genetic,and microenvironment-associated alterations.The altered redox homeostasis can promote tumor progression,development,and treatment resistance.Several membrane transporters are involved in the resetting redox homeostasis and play important roles in tumor progression.Therefore,targeting the involved transporters to disrupt the altered redox balance emerges as a viable strategy for cancer therapy.In addition,nanomedicines have drawn much attention in the past decades.Using nanomedicines to target or reset the redox homeostasis alone or combined with other therapies has brought convincing data in cancer treatment.In this review,we will introduce the altered redox balance in cancer metabolism and involved transporters,and highlight the recent advancements of redox-modulating nanomedicines for cancer treatment.

Chlorogenic acid alleviates hypoxic-ischemic brain injury in neonatal mice

Recent studies have shown that chlorogenic acid(CGA),which is present in coffee,has protective effects on the nervous system.However,its role in neonatal hypoxic-ischemic brain injury remains unclear.In this study,we established a newborn mouse model of hypoxic-ischemic brain injury using a modified Rice-Vannucci method and performed intraperitoneal injection of CGA.We found that CGA intervention effectively reduced the volume of cerebral infarct,alleviated cerebral edema,restored brain tissue structure after injury,and promoted axon growth in injured brain tissue.Moreover,CGA pretreatment alleviated oxygen-glucose deprivation damage of primary neurons and promoted neuron survival.In addition,changes in ferroptosis-related proteins caused by hypoxic-ischemic brain injury were partially reversed by CGA.Furthermore,CGA intervention upregulated the expression of the key ferroptosis factor glutathione peroxidase 4 and its upstream glutamate/cystine antiporter related factors SLC7A11 and SLC3A2.In summary,our findings reveal that CGA alleviates hypoxic-ischemic brain injury in neonatal mice by reducing ferroptosis,providing new ideas for the treatment of neonatal hypoxic-ischemic brain injury.

Reperfusion after hypoxia-ischemia exacerbates brain injury with compensatory activation of the antiferroptosis system:based on a novel rat model

Hypoxic-ischemic encephalopathy,which predisposes to neonatal death and neurological sequelae,has a high morbidity,but there is still a lack of effective prevention and treatment in clinical practice.To better understand the pathophysiological mechanism underlying hypoxic-ischemic encephalopathy,in this study we compared hypoxic-ischemic reperfusion brain injury and simple hypoxic-ischemic brain injury in neonatal rats.First,based on the conventional RiceVannucci model of hypoxic-ischemic encephalopathy,we established a rat model of hypoxic-ischemic reperfusion brain injury by creating a common carotid artery muscle bridge.Then we performed tandem mass tag-based proteomic analysis to identify differentially expressed proteins between the hypoxic-ischemic reperfusion brain injury model and the conventional Rice-Vannucci model and found that the majority were mitochondrial proteins.We also performed transmission electron microscopy and found typical characteristics of ferroptosis,including mitochondrial shrinkage,ruptured mitochondrial membranes,and reduced or absent mitochondrial cristae.Further,both rat models showed high levels of glial fibrillary acidic protein and low levels of myelin basic protein,which are biological indicators of hypoxic-ischemic brain injury and indicate similar degrees of damage.Finally,we found that ferroptosis-related Ferritin(Fth1)and glutathione peroxidase 4 were expressed at higher levels in the brain tissue of rats with hypoxic-ischemic reperfusion brain injury than in rats with simple hypoxic-ischemic brain injury.Based on these results,it appears that the rat model of hypoxic-ischemic reperfusion brain injury is more closely related to the pathophysiology of clinical reperfusion.Reperfusion not only aggravates hypoxic-ischemic brain injury but also activates the anti-ferroptosis system.

Bexarotene improves motor function after spinal cord injury in mice

Spinal cord injury is a challenge in orthopedics because it causes irreversible damage to the central nervous system.Therefore,early treatment to prevent lesion expansion is crucial for the management of patients with spinal cord injury.Bexarotene,a type of retinoid,exerts therapeutic effects on patients with cutaneous T-cell lymphoma and Parkinson's disease.Bexarotene has been proven to promote autophagy,but it has not been used in the treatment of spinal cord injury.To investigate the effects of bexarotene on spinal cord injury,we established a mouse model of T11–T12 spinal cord contusion and performed daily intraperitoneal injection of bexarotene for 5 consecutive days.We found that bexarotene effectively reduced the deposition of collagen and the number of pathological neurons in the injured spinal cord,increased the number of synapses of nerve cells,reduced oxidative stress,inhibited pyroptosis,promoted the recovery of motor function,and reduced death.Inhibition of autophagy with 3-methyladenine reversed the effects of bexarotene on spinal cord injury.Bexarotene enhanced the nuclear translocation of transcription factor E3,which further activated AMP-activated protein kinase-S-phase kinase-associated protein 2-coactivator-associated arginine methyltransferase 1 and AMP-activated protein kinase-mammalian target of rapamycin signaling pathways.Intravenous injection of transcription factor E3 sh RNA or intraperitoneal injection of compound C,an AMP-activated protein kinase blocker,inhibited the effects of bexarotene.These findings suggest that bexarotene regulates nuclear translocation of transcription factor E3 through the AMP-activated protein kinase-Sphase kinase-associated protein 2-coactivator-associated arginine methyltransferase 1 and AMP-activated protein kinase-mammalian target of rapamycin signal pathways,promotes autophagy,decreases reactive oxygen species level,inhibits pyroptosis,and improves motor function after spinal cord injury.

Functions and mechanisms of cytosolic phospholipase A_(2)in central nervous system trauma

Central nervous system(CNS)trauma,including traumatic brain injury and spinal cord injury,has a high rate of disability and mortality,and effective treatment is currently lacking.Previous studies have revealed that neural inflammation plays a vital role in CNS trauma.As the initial enzyme in neuroinflammation,cytosolic phospholipase A_(2)(cPLA2)can hydrolyze membranous phosphatides at the sn-2 position in a preferential way to release lysophospholipids andω3-polyunsaturated fatty acid dominated by arachidonic acid,thereby inducing secondary injuries.Although there is substantial fresh knowledge pertaining to cPLA2,in-depth comprehension of how cPLA2 participates in CNS trauma and the potential methods to amelio rate the clinical res ults after CNS trauma are still insufficient.The present review summarizes the latest understanding of how cPLA2 participates in CNS trauma,highlighting novel findings pertaining to how cPLA2 activation initiates the potential mechanisms specifically,neuroinflammation,lysosome membrane functions,and autophagy activity,that damage the CNS after trauma.Moreover,we focused on testing a variety of drugs capable of inhibiting cPLA2 or the upstream pathway,and we explored how those agents might be utilized as treatments to improve the results following CNS trauma.This review aimed to effectively understand the mechanism of cPLA2 activation and its role in the pathophysiological processes of CNS trauma and provide clarification and a new referential framework for future research.

Sepsis-induced immunosuppression:mechanisms,diagnosis and current treatment options

Sepsis is a common complication of combat injuries and trauma,and is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection.It is also one of the significant causes of death and increased health care costs in modern intensive care units.The use of antibiotics,fluid resuscitation,and organ support therapy have limited prognostic impact in patients with sepsis.Although its pathophysiology remains elusive,immunosuppression is now recognized as one of the major causes of septic death.Sepsis-induced immunosuppression is resulted from disruption of immune homeostasis.It is characterized by the release of antiinflammatory cytokines,abnormal death of immune effector cells,hyperproliferation of immune suppressor cells,and expression of immune checkpoints.By targeting immunosuppression,especially with immune checkpoint inhibitors,preclinical studies have demonstrated the reversal of immunocyte dysfunctions and established host resistance.Here,we comprehensively discuss recent findings on the mechanisms,regulation and biomarkers of sepsis-induced immunosuppression and highlight their implications for developing effective strategies to treat patients with septic shock.

Knowledge,attitude,and practice of patients living with inflammatory bowel disease:A cross-sectional study

BACKGROUND Patients with inflammatory bowel diseases(IBDs)generally have poor knowledge,attitude,and practice of their disease,while the data from China are lacking.AIM To address this knowledge disparity among Chinese patients with IBD.METHODS This web-based,cross-sectional study was conducted on a cohort of IBD patients who visited the Second Affiliated Hospital of Wenzhou Medical University between December 2022 and February 2023.Their socio-demographic information and the knowledge,attitude,and practice scores were collected and estimated using a self-designed questionnaire.Pearson’s correlation analysis was used to determine the pairwise correlations among knowledge,attitude,and practice scores.A multivariate logistic regression analysis was further performed to determine the independent factors associated with their knowledge,attitude,and practice scores.RESULTS A total of 353 patients(224 males)with IBD completed the questionnaires.The mean knowledge,attitude,and practice scores were 10.05±3.46(possible range:0-14),41.58±5.23(possible range:0-56),44.20±7.39(possible range:0-56),respectively,indicating good knowledge,positive attitude,and proactive practice toward IBD.Pearson’s correlation analysis showed that the knowledge score had significant positive correlations with the attitude score(r=0.371,P<0.001)and practice score(r=0.100,P<0.001).The attitude score had a significant positive correlation with the practice score(r=0.452,P<0.001).Moreover,multivariate logistic regression analysis showed that aged 30-40 years[odds ratio(OR)=4.06,95%confidence interval(CI):1.04-15.82,P=0.043],middle school education(OR=3.98,95%CI:1.29-12.33,P=0.017),high school/technical secondary school education(OR=14.06,95%CI:3.92-50.38,P<0.001),and junior college/bachelor’s degree and above education(OR=15.20,95%CI:4.15-55.650,P<0.001)were independently associated with good knowledge.The higher knowledge score was independently associated with a positive attitude(OR=1.23,95%CI:1.11-1.36,P<0.001).The higher attitude score was independently associated with proactive practice(OR=1.20,95%CI:1.11-1.30,P<0.001).CONCLUSION Chinese patients with IBD might have good knowledge,a positive attitude,and proactive practice toward their disease.However,a small number of specific items require education.

Water-responsive gel extends drug retention and facilitates skin penetration for curcumin topical delivery against psoriasis

Psoriasis is a chronic inflammatory skin disease characterized by erythema,scaling,and skin thickening.Topical drug application is recommended as the first-line treatment.Many formulation strategies have been developed and explored for enhanced topical psoriasis treatment.However,these preparations usually have low viscosity and limited retention on the skin surface,resulting in low drug delivery efficiency and poor patient satisfaction.In this study,we developed the first water-responsive gel(WRG),which has a distinct water-triggered liquid-to-gel phase transition property.Specifically,WRG was kept in a solution state in the absence of water,and the addition of water induced an immediate phase transition and resulted in a high viscosity gel.Curcumin was used as a model drug to investigate the potential of WRG in topical drug delivery against psoriasis.In vitro and in vivo data showed that WRG formulation could not only extend skin retention but also facilitate the drug permeating across the skin.In a mouse model of psoriasis,curcumin loaded WRG(CUR-WRG)effectively ameliorated the symptoms of psoriasis and exerted a potent anti-psoriasis effect by extending drug retention and facilitating drug penetration.Further mechanism study demonstrated that the anti-hyperplasia,anti-inflammation,anti-angiogenesis,anti-oxidation,and immunomodulation properties of curcumin were amplified by enhanced topical drug delivery efficiency.Notably,neglectable local or systemic toxicity was observed for CUR-WRG application.This study suggests that WRG is a promising formulation for topically psoriasis treatment.

Iatrogenic flexor tendon rupture caused by misdiagnosing sarcoidosis-related flexor tendon contracture as tenosynovitis: A case report

BACKGROUND Sarcoidosis is a multisystem disease characterized by granuloma formation in various organs.Sarcoidosis-related flexor tendon contractures are uncommon in clinical settings.This contracture is similar to stenosing tenosynovitis and po-tentially leads to misdiagnosis and mistreatment.Herein,we report a rare case of sarcoidosis-related finger flexor tendon contracture that was misdiagnosed as tenosynovitis.A 44-year-old woman presented to our department with flexion contracture of the right ring and middle fingers.The patient was misdiagnosed with tenosynovitis and underwent acupotomy release of the A1 pulley of the middle finger in an-other hospital that resulted in iatrogenic rupture of both the superficial and profundus flexors.Radiological presentation showed multiple sarcoid involve-ments in the pulmonary locations and ipsilateral forearm.A diagnosis of sar-coidosis was made based on the presence of non-caseating granulomas with tubercles consisting of Langhans giant cells with lymphocyte infiltration on biopsy,and the patient underwent surgical repair for the contracture.After 2 mo,the patient experienced another spontaneous rupture of the repaired middle finger tendon and underwent surgical re-repair.Satisfactory results were achieved at the 10 mo follow-up after reoperation.CONCLUSION Sarcoidosis-related finger contractures are rare;thus,caution should be exercised when dealing with such patients to avoid incorrect treatment.

Biliary hemorrhage caused by a malignant small round cell tumor in the common bile duct:A case report

BACKGROUND Malignant small round cell tumor(MSRCT)metastasis to the common bile duct associated with recurrent biliary hemorrhage is extremely rare.Thus far,there have been no reports of metastatic small round cell tumors of the common bile duct.CASE SUMMARY Herein,we report the case of a 77-year-old female patient with an MSRCT in the common bile duct.The patient was admitted to hospital due to gastrointestinal hemorrhage and abdominal pain.We found a neoplasm in the common bile duct with active bleeding through a spyglass.We performed biopsy through the spyglass and placed a metal stent to stop bleeding.The pathological result suggested that it was an MSRCT metastasized from the back to the common bile duct.Later,we found using fluorescence in situ hybridization that the SS18 gene break test was negative,ruling out the diagnosis of synovial sarcoma.CONCLUSION MSRCT is a group of tumors with similar cell morphology and diffuse histological structure.Complete tumor resection results in improved survival in patients with MSRCT.Roux-en-Y cholangiojejunostomy was performed.After excision of the common bile duct tumor,the patient felt that the abdominal pain improved and hemorrhage disappeared.The patient underwent routine fecal examination one month after surgery,indicating a negative fecal occult blood test.On May 22,2023,the patient was reexamined by abdominal computed tomography,and no abdominal space occupying lesions or abdominal lymphadenopathy was found.

Modified procedure for prolapse and hemorrhoids: Lower recurrence, higher satisfaction

BACKGROUND Hemorrhoidal prolapse is a common benign disease with a high incidence.The treatment procedure for prolapse and hemorrhoids(PPH)remains an operative method used for internal hemorrhoid prolapse.Although it is related to less posoperative pain,faster recovery and shorter hospital stays,the postoperative recurrence rate is higher than that of the Milligan-Morgan hemorrhoidectomy(MMH).We have considered that recurrence could be due to shortage of the pulling-up effect.This issue may be overcome by using lower purse-string sutures[modified-PPH(M-PPH)].AIM To compare the therapeutic effects and the patients’satisfaction after M-PPH,PPH and MMH.METHODS This retrospective cohort study included 1163 patients(M-PPH,461;original PPH,321;MMH,381)with severe hemorrhoids(stage III/IV)who were admitted to The 2nd Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University from 2012 to 2014.Early postoperative complications,efficacy,postoperative anal dysfunction and patient satisfaction were compared among the three groups.Established criteria were used to assess short-and long-term postoperative complications.A visual analog scale was used to evaluate postoperative pain.Follow-up was conducted 5 years postoperatively.RESULT Length of hospital stay and operating time were significantly longer in the MMH group(8.05±2.50 d,19.98±4.21 min;P<0.0001)than in other groups.The incidence of postoperative anastomotic bleeding was significantly lower after MPPH than after PPH or MMH(1.9%,5.1%and 3.7%;n=9,16 and 14;respectively).There was a significantly higher rate of sensation of rectal tenesmus after M-PPH than after MMH or PPH(15%,8%and 10%;n=69,30 and 32;respectively).There was a significantly lower rate of recurrence after M-PPH than after PPH(8.7%and 18.8%,n=40 and 61;P<0.0001).The incidence of postoperative anal incontinence differed significantly only between the MMH and M-PPH groups(1.3%and 4.3%,n=5 and 20;P=0.04).Patient satisfaction was significantly greater after M-PPH than after other surgeries.CONCLUSION M-PPH has many advantages for severe hemorrhoids(Goligher stage III/IV),with a low rate of anastomotic bleeding and recurrence and a very high rate of patient satisfaction.

Comparative Genomic Analysis of Enterovirus 71 Revealed Six New Potential Neurovirulence-associated Sites

In the present study,the complete genomes of four common（4/EV71/Wenzhou/CHN/2014,15/EV71/Wenzhou/CHN/2014,116/EV71/Wenzhou/CHN/2014,and 120/EV71/Wenzhou/CHN/2014）and two virulent（11/EV71/Wenzhou/CHN/2014and 109/EV71/Wenzhou/CHN/2014）enterovirus 71（EV71）isolates were sequenced and described.They are 7405 bp in length and belong to EV71 sub-genotype C4 （C4a cluster）.

Pathological mechanisms and therapeutic outlooks for arthrofibrosis

Arthrofibrosis is a fibrotic joint disorder that begins with an inflammatory reaction to insults such as injury,surgery and infection.Excessive extracellular matrix and adhesions contract pouches,bursae and tendons,cause pain and prevent a normal range of joint motion,with devastating consequences for patient quality of life.Arthrofibrosis affects people of all ages,with published rates varying.The risk factors and best management strategies are largely unknown due to a poor understanding of the pathology and lack of diagnostic biomarkers.However,current research into the pathogenesis of fibrosis in organs now informs the understanding of arthrofibrosis.The process begins when stress signals stimulate immune cells.The resulting cascade of cytokines and mediators drives fibroblasts to differentiate into myofibroblasts,which secrete fibrillar collagens and transforming growth factor-β(TGF-β).Positive feedback networks then dysregulate processes that normally terminate healing processes.We propose two subtypes of arthrofibrosis occur:active arthrofibrosis and residual arthrofibrosis.In the latter the fibrogenic processes have resolved but the joint remains stiff.The best therapeutic approach for each subtype may differ significantly.Treatment typically involves surgery,however,a pharmacological approach to correct dysregulated cell signalling could be more effective.Recent research shows that myofibroblasts are capable of reversing differentiation,and understanding the mechanisms of pathogenesis and resolution will be essential for the development of cell-based treatments.Therapies with significant promise are currently available,with more in development,including those that inhibit TGF-βsignalling and epigenetic modifications.This review focuses on pathogenesis of sterile arthrofibrosis and therapeutic treatments.

Bacterial colonization and intestinal mucosal barrier development

The intestinal tract is colonized soon after birth with a variety of ingested environmental and maternal microflora. This process is influenced by many factors including mode of delivery, diet, environment, and the use of antibiotics. Normal intestinal microflora provides protection against infection, ensures tolerance to foods, and contributes to nutrient digestion and energy harvest. In addition, enteral feeding and colonization with the normal commensal flora are necessary for the maintenance of intestinal barrier function and play a vital role in the regulation of intestinal barrier function. Intestinal commensal microorganisms also provide signals that foster normal immune system development and influence the ensuing immune responses. There is increasingly recognition that alterations of the microbial gut flora and associated changes in intestinal barrier function may be related to certain diseases of the gastrointestinal tract. This review summarizes recent advances in understanding the complex ecosystem of intestinal microbiota and its role in regulating intestinal barrier function and a few common pediatric diseases. Disruption in the establishment of a stable normal gut microflora may contribute to the pathogenesis of diseases including inflammatory bowel disease, nosocomial infection, and neonatal necrotizing enterocolitis.

Exosomes-the enigmatic regulators of bone homeostasis

Exosomes are a heterogeneous group of cell-derived membranous structures, which mediate crosstalk interaction between cells.Recent studies have revealed a close relationship between exosomes and bone homeostasis. It is suggested that bone cells can spontaneously secret exosomes containing proteins, lipids and nucleic acids, which then to regulate osteoclastogenesis and osteogenesis. However, the network of regulatory activities of exosomes in bone homeostasis as well as their therapeutic potential in bone injury remain largely unknown. This review will detail and discuss the characteristics of exosomes, the regulatory activities of exosomes in bone homeostasis as well as the clinical potential of exosomes in bone injury.