Vulvodynia,a chronic pain disorder affecting the vulvar region,represents a significant challenge in both diagnosis and treatment within the field of women’s health.This condition is characterized by chronic pain tha...Vulvodynia,a chronic pain disorder affecting the vulvar region,represents a significant challenge in both diagnosis and treatment within the field of women’s health.This condition is characterized by chronic pain that significantly affects the quality of life of afflicted women.The present perspective paper examines the role of spinal sensitization and microglial activation in vulvodynia.展开更多
Background:Platinum chemotherapy(CT)remains the backbone of systemic therapy for patients with smallcell lung cancer(SCLC).The nucleotide excision repair(NER)pathway plays a central role in the repair of the DNA damag...Background:Platinum chemotherapy(CT)remains the backbone of systemic therapy for patients with smallcell lung cancer(SCLC).The nucleotide excision repair(NER)pathway plays a central role in the repair of the DNA damage exerted by platinum agents.Alteration in this repair mechanism may affect patients’survival.Materials and Methods:We conducted a retrospective analysis of data from 38 patients with extensive disease(ED)-SCLC who underwent platinum-CT at the Clinical Oncology Unit,Careggi University Hospital,Florence(Italy),from 2015 to 2020.mRNA expression analysis and single nucleotide polymorphism(SNP)characterization of three NER pathway genes—namely ERCC1,ERCC2,and ERCC5—were performed on patient tumor samples.Results:Overall,elevated expression of ERCC genes was observed in SCLC patients compared to healthy controls.Patients with low ERCC1 and ERCC5 expression levels exhibited a better median progression-free survival(mPFS=7.1 vs.4.9 months,p=0.39 for ERCC1 and mPFS=6.9 vs.4.8 months,p=0.093 for ERCC5)and overall survival(mOS=8.7 vs.6.0 months,p=0.4 for ERCC1 and mOS=7.2 vs.6.2 months,p=0.13 for ERCC5).Genotyping analysis of five SNPs of ERCC genes showed a longer survival in patients harboring the wild-type genotype or the heterozygous variant of the ERCC1 rs11615 SNP(p=0.24 for PFS and p=0.14 for OS)and of the rs13181 and rs1799793 ERCC2 SNPs(p=0.43 and p=0.26 for PFS and p=0.21 and p=0.16 for OS,respectively)compared to patients with homozygous mutant genotypes.Conclusions:The comprehensive analysis of ERCC gene expression and SNP variants appears to identify patients who derive greater survival benefits from platinum-CT.展开更多
Despite decades of dedicated resea rch,Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disorder for which the mechanisms of onset are sti unc ear.AD is cha racterized by featured histo...Despite decades of dedicated resea rch,Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disorder for which the mechanisms of onset are sti unc ear.AD is cha racterized by featured histological alterations including amyloid-beta (AB) plaque deposition,accumulation of neurofibrillary to ngles of hyperphosphorylated-tau,and neuronal loss,accompanied by progressive cognitive decline and behavioral changes.展开更多
Primary biliary cholangitis is a chronic cholestatic autoimmune liver disease that progressively damages the bile ducts,leading to cholestasis and,in advanced stages,cirrhosis.While it primarily affects middle-aged wo...Primary biliary cholangitis is a chronic cholestatic autoimmune liver disease that progressively damages the bile ducts,leading to cholestasis and,in advanced stages,cirrhosis.While it primarily affects middle-aged women,recent data indicate a rising incidence in men.The interplay between genetic susceptibility,environmental exposures,and gut microbiome alterations is thought to drive disease onset.Diagnosis relies on persistent cholestatic enzyme elevation,diseasespecific autoantibodies,and,in select cases,liver biopsy.Ursodeoxycholic acid remains the cornerstone of treatment,but many patients show an incomplete response.The recent withdrawal of obeticholic acid from the market,due to insufficient evidence of long-term benefit,has highlighted the urgent need for effective second-line therapies.Agonists of peroxisome proliferator-activated receptors,such as elafibranor and seladelpar,have demonstrated promising biochemical improvements and may reshape the therapeutic landscape.Future research is focused on refining risk assessment,optimizing treatment combinations,and addressing symptoms such as fatigue and pruritus to enhance patient well-being.A shift toward early intervention and personalized treatment strategies may further improve long-term outcomes in primary biliary cholangitis.展开更多
Objective:Nowadays robot-assisted partial nephrectomy(RAPN)represents the standard of care for clinical T1(cT1)renal masses,providing similar oncological outcomes when compared to open or laparoscopic PN with advantag...Objective:Nowadays robot-assisted partial nephrectomy(RAPN)represents the standard of care for clinical T1(cT1)renal masses,providing similar oncological outcomes when compared to open or laparoscopic PN with advantages in terms of functional outcomes and lower perioperative comorbidity,when compared to radical nephrectomy.Methods:We performed an extensive literature review of studies regarding RAPN,its evolution,technical aspects and applications,and new technological tools using different combinations of Medical Subject Headings terms“RAPN”,“partial nephrectomy”,“robot-assisted”,“nephron-sparing surgery”,“renal cell carcinoma”,“complex renal masses”,“endophytic renal masses”,and“bilateral renal tumors”.Results:A consistent body of evidence was selected,including original articles,systematic reviews,meta-analyses,and clinical trials having RAPN as the central focus in adult patients,with all its technical nuances.We started our narrative review with a background on PN and its evolution toward the robotic era with a special spotlight on the extending indications for PN in large and highly complex renal masses.Our review continued with an overview of nephron-sparing surgery in bilateral and recurrent masses.RAPN for bilateral synchronous renal masses represents a challenging scenario with no formal recommendations provided by international guidelines and controversial management and decision-making.Additionally,we reported evidence on redo RAPN which seems to be safe and effective.A final overview of the available technological tools,and in particular on three-dimensional reconstruction was provided.Conclusion:RAPN has been established as the standard of care for cT1 renal masses with an expanding spectrum of applications in different scenarios,including large(cT2),highly complex,and bilateral renal masses,as well as the surgical treatment of local recurrences after nephron-sparing surgery with acknowledged advantages in terms of functional outcomes and perioperative risk profiles while maintaining similar oncological outcomes when compared to open or laparoscopic PN and radical treatment.展开更多
Background:The surgical management of patients with benign prostatic hyperplasia(BPH)has considerably evolved through recent years.Nonetheless,benefits and harms of several laser procedures are still to be determined....Background:The surgical management of patients with benign prostatic hyperplasia(BPH)has considerably evolved through recent years.Nonetheless,benefits and harms of several laser procedures are still to be determined.The study aimed to report perioperative and early functional results of patients treated with anatomical photo vaporization of the prostate(aPVP).Methods:Data from consecutive patients treated with aPVP by using a 180-W XPS GreenLight laser were prospectively collected in a single tertiary center between 2020 and 2023.The surgical procedure was divided into a modular step-by-step fashion.Patients were asked to complete self-administered questionnaires at baseline and during follow-up visits.Results:Overall,176 consecutive patients were enrolled.Median age was 65[interquartile range(IQR)63–72]years.The baseline median prostate volume was 61.2(IQR 52.5–71.0)mL,and the median max flow rate(Qmax)was 9.3(IQR 7.8–11.5)mL/s.Median preoperative International Prostate Symptom Score(IPSS)was 25(IQR 22–29).Overall,the median operative time was 42(IQR 31–47)minutes with a median energy/mL of tissue delivered of 2447 kJ/mL.At 3 month-evaluation,significant improvements were observed,with a median Qmax of 28(IQR:24–32)mL/s and a median IPSS reduction of 15(IQR:11–18)points.A strong inverse correlation was identified between energy delivery during initial procedural steps and the severity of postoperative storage symptoms(all p<0.05),underscoring the importance of precise energy modulation.Multivariate analysis identified increased prostate volume(odds ratio[OR]:1.02;95%confidence interval[CI]1.01–1.11;p=0.001)and higher prostate width-to-length ratio(OR:1.28;95%CI 1.04–1.78;p=0.03)as independent predictors of increased energy requirements.Conclusions:aPVP with 180-W XPS GreenLight laser is a safe and effective technique showing worthy early functional results.The limitation of the energy delivered in some key phases of the procedure may be associated with a significant reduction in postoperative irritative symptoms.The shape and dimensions of the prostate also play a critical role in determining the total energy required for complete adenoma removal.展开更多
BACKGROUND Barrett esophagus(BE),a metaplastic adaptive process to gastrointestinal reflux,is associated with a higher risk of developing esophageal adenocarcinoma.However,the factors and mechanism that drive the mali...BACKGROUND Barrett esophagus(BE),a metaplastic adaptive process to gastrointestinal reflux,is associated with a higher risk of developing esophageal adenocarcinoma.However,the factors and mechanism that drive the malignant progression of BE is not well understood.AIM To investigate the role of bile acids,a component of the reflux fluid,in the malignant progression of BE.METHODS Using engineered green fluorescent protein-labeled adult tissue-resident stem cells isolated from BE clinical biopsies(BE-ASCs)as the target,we studied the effect of hydrophobic deoxycholic acid(DCA)and hydrophilic tetrahydroxylated bile acids(THBA)on cell viability by fluorescence intensity analysis,mucin production by dark density measurement,tissue structure by pathology analysis,expression of different pro-inflammatory factors gene by quantitative polymerase chain reaction and proteins by Western blot.RESULTS We found that hydrophobic DCA has cytotoxic and proinflammatory effects through activation of interleukin-1β(IL-1β)-nuclear factor kappa-B(NF-κB)inflammatory pathway on BE-ASCs.This action results in impaired cell viability,tissue intactness,reduced mucin production,and increased transition to disorganized atypical cells without intestinal features.In contrast,co-culture with hydrophilic THBA inhibited the IL-1β-NF-κB inflammatory pathway with maintenance of mature intestinal type cellular and histomorphology.CONCLUSION Our data indicates that the hydrophilic bile acid THBA can counteract the cytotoxic and proinflammatory effect of hydrophobic DCA and prevent the malignant progression of BE by inhibiting the IL-1β-NF-κB pathway.展开更多
Background Non-suicidal self-injury(NSSI)is a significant health concern among adolescents and young adults,often resulting from adverse childhood experiences(ACEs).Dissociation,post-traumatic symptoms and attachment ...Background Non-suicidal self-injury(NSSI)is a significant health concern among adolescents and young adults,often resulting from adverse childhood experiences(ACEs).Dissociation,post-traumatic symptoms and attachment style may have a role in shaping such associations.Aims This study aims to provide a unified model of the impact of ACEs on NSSI,exploring complex post-traumatic stress disorder(cPTSD)symptoms and dissociation as potential mediators and the role of the predominant attachment style in affecting such associations.Methods 1010 young individuals attending the last year of high school participated in this cross-sectional study.ACEs,cPTSD,dissociation and NSSI were evaluated using self-report questionnaires.We fitted a path model of NSSI,with ACEs as exogenous variables and cPTSD and dissociation as sequential mediators.Secure,fearful and preoccupied attachment styles were modelled as grouping variables.Results Our findings showed that dissociation mediated the impact of ACEs on NSSI in subjects with a fearful attachment style,as opposed to those with a preoccupied attachment for whom cPTSD symptoms mediated the ACEs-NSSI association.Conclusions Attachment styles moderate the relationship between ACEs and NSSI,with either dissociation or post-traumatic symptomatology mediating the impact of ACEs on NSSI,depending on the predominant attachment style.Our results highlight the importance of attachment as a pathway modifier in the relationships between different psychopathology dimensions,providing a useful framework to better conceptualise the ACEs-NSSI association.展开更多
Different forms of programmed cell death have been described to participate in the degeneration of dopaminergic neurons in Parkinson’s disease(PD).Given the critical role that disturbance of mitochondrial homeostasis...Different forms of programmed cell death have been described to participate in the degeneration of dopaminergic neurons in Parkinson’s disease(PD).Given the critical role that disturbance of mitochondrial homeostasis plays in the pathogenesis of PD,apoptosis can be reasonably considered as one of the cell death pathways involved in neuronal loss(Schon and Przedborski,2011).Multiple lines of evidence support that proposal such as the observations in postmortem human brain samples of PD patients including mitochondrial complex I deficiency,reactive oxygen species generation,and oxidative damage to lipids,proteins,and DNA,among others.展开更多
1 MHC-I Loss in the Immune Evasion of Cancer Cells Pancreatic ductal adenocarcinoma(PDAC)is a lethal cancer with a poor prognosis due to its aggressive nature and late detection.Recently,new discoveries in PDAC demons...1 MHC-I Loss in the Immune Evasion of Cancer Cells Pancreatic ductal adenocarcinoma(PDAC)is a lethal cancer with a poor prognosis due to its aggressive nature and late detection.Recently,new discoveries in PDAC demonstrated receptor-interacting protein kinase 2(RIPK2)triggering immune evasion.Mechanistically,RIPK2 drives the desmoplastic tumor microenvironment(TME)and restricts the activation and density of tumor-infiltrating effector T cells by impairing the expression of major histocompatibility complex class I(MHC-I)[1].This process might be relevant in different solid cancer entities as illustrated by analyzing publicly available databases.展开更多
Post-traumatic stress disorder(PTSD)is a severe neuropsychiatric disorder characterised by reexperiencing,avoidance and hyperarousal.Memory abnormalities manifested as intrusive thoughts and prolonged distressful emot...Post-traumatic stress disorder(PTSD)is a severe neuropsychiatric disorder characterised by reexperiencing,avoidance and hyperarousal.Memory abnormalities manifested as intrusive thoughts and prolonged distressful emotions are postulated as key roles in PTSD development and persistence.Over the past decades,convergent results from human and animal studies have systematically investigated contributions of the amygdala,hippocampus and medial prefrontal cortex(mPFC)in fear memory processes,including fear acquisition,storage,reconsolidation and extinction.These findings provide mechanistic insights for cognitive-behavioural therapy and aid in developing pathological region-targeted neuromodulation treatment for PTSD.Taking advantage of advances in cell-type selective labelling and manipulation technologies,recent studies have focused on the spatiotemporal regulation of neural circuits underlying distinct phases of fear memory processes.These findings have revealed that multiple distributed brain areas participate in the fear memory encoding network.Moreover,the functional role of distinct neuronal ensembles within the amygdala-hippocampus-mPFC pathway,identified by genetic markers and projection profiles,has been assigned to temporally separate features of fear processing,demonstrating the sophistication of the fear encoding circuit.These results provide mechanistic insights into PTSD pathology and might shed light on aetiology-based clinical interventions for PTSD.Therefore,the present review will mainly focus on the recent progress in elucidating neural circuit mechanisms underlying the dynamic regulation of fear memory,with an emphasis on the spatial distribution of fear memory encoding neural networks and the temporal coherence between neuronal ensemble activity and fear expression.展开更多
BACKGROUND Colorectal cancer(CRC)is a prevalent gastrointestinal malignancy with a typi-cally unfavorable prognosis following the onset of liver metastases.AIM To develop and validate a new clinical prediction model t...BACKGROUND Colorectal cancer(CRC)is a prevalent gastrointestinal malignancy with a typi-cally unfavorable prognosis following the onset of liver metastases.AIM To develop and validate a new clinical prediction model to accurately forecast overall survival(OS)in CRC patients following surgical treatment for liver metastasis.METHODS This study included 1059 patients diagnosed with CRC liver metastases(CRLM)at the Xijing Hospital between 2010 and 2022.The patients were randomly divided into training and validation cohorts at a 7:3 ratio.Key clinical predictors were identified using least absolute shrinkage and selection operator(LASSO)regression combined with a Cox proportional hazards model,leading to the establishment of a prediction model and preparation of a nomogram to enhance its clinical utility.Decision curve analysis(DCA)and Kaplan-Meier survival analysis were employed to evaluate the precision and predictive performance of the model.RESULTS The LASSO-Cox regression analysis revealed multiple pivotal clinical biomarkers significantly linked to CRLM,including gamma-glutamyl transferase levels,blood chloride concentration,activated partial thromboplastin time,N stage,and vascular invasion.The model's receiver operating characteristic curve area under the curve exceeded 0.7 for both the training and validation groups with moderate-to-good predictive accuracy.Furthermore,DCA validated the nomogram's effectiveness for OS prediction.Kaplan-Meier risk stratification demonstrated markedly improved OS among patients classified as low-risk compared to those categorized as high-risk(P<0.001),highlighting its clinical utility for risk assessment and treatment guidance.CONCLUSION The nomogram prediction model constructed in this study has good predictive value and can effectively assess the survival rate of patients with CRLM.展开更多
Esophageal cancer is an aggressive malignancy often diagnosed at advanced stages,with esophageal squamous cell carcinoma being the predominant subtype worldwide.Standard first-line chemotherapy provides limited surviv...Esophageal cancer is an aggressive malignancy often diagnosed at advanced stages,with esophageal squamous cell carcinoma being the predominant subtype worldwide.Standard first-line chemotherapy provides limited survival benefits,with a median overall survival of less than 1 year.Recent advancements in immunotherapy,particularly immune checkpoint inhibitors(ICIs),have trans-formed the treatment landscape,improving overall survival and progression-free survival.However,response rates remain variable,with programmed death ligand 1(PD-L1)expression being the primary predictive biomarker.The variability in PD-L1 testing methods and immune microenvironment alterations after prior treatments complicate patient selection for ICIs.Several phase 3 trials,including KEYNOTE-590 and CheckMate 648,have demonstrated the efficacy of ICIs combined with chemotherapy,particularly in patients positive for PD-L1.Despite these advances,long-term survival remains low,emphasizing the need for better biomarkers and novel therapeutic strategies.This review explored current first-line treatment options for esophageal squamous cell carcinoma,challenges in biomarker-based patient selection,and emerging therapeutic approaches.展开更多
Background:Developing a granulomatous liver injury preclinical model may pave the way to understanding hepatic-TB(tuberculosis)and autoimmune granulomatous liver diseases.Antitubercular(ATT)and other drugs'metabol...Background:Developing a granulomatous liver injury preclinical model may pave the way to understanding hepatic-TB(tuberculosis)and autoimmune granulomatous liver diseases.Antitubercular(ATT)and other drugs'metabolism in the presence of a specific type of liver injury is not well understood.The present study aimed to establish a preclinical model of granulomatous hepatitis by using the BCG(Bacillus CalmetteGuérin)vaccine,further studying it in the presence of ATT dosing,and analyze the pharmacokinetics of isoniazid,rifampicin,and their respective primary metabolites.Methods:We used 56 rats in seven equal groups.Group I functioned as a normal control(NC)receiving normal saline only.Groups II-IV received intravenous injections of low-,medium-,and high-dose BCG vaccine daily for 21 days.Groups V,VI,and VII received isoniazid(H)alone,rifampicin(R)alone,and isoniazid+rifampicin(HR)for a subsequent 15 days in addition to high dose BCG for the first 21 days,respectively.Liver function tests(LFT)were monitored on days 0,21,28,and 36.Rats were sacrificed later for oxidative stress and histopathological examination.Results:The study observed BCG dose-specific LFT derangements in groups II-IV compared to group I on day 21(p<0.05).Isoniazid,rifampicin,and combination intervention groups demonstrated normalization of the BCG-led LFT changes.Histology and oxidative stress parameters confirmed model development and biochemical changes.Isoniazid area under the curve(AUC)showed a reduction of 16.9%in BCG+HR group in comparison to the BCG+H group(p=0.01).Des-acetyl-rifampicin AUC and maximum-concentration value demonstrated a significant rise in BCG+HR group in comparison to the BCG+R group(p=0.001).Conclusion:A novel preclinical model of granulomatous liver injury was developed using the BCG vaccine strain and validated with ATT response.展开更多
Cancer is a global health problem and one of the leading causes of mortality.Immune checkpoint inhibitors have revolutionized the field of oncology,emerging as a powerful treatment strategy.A key pathway that has garn...Cancer is a global health problem and one of the leading causes of mortality.Immune checkpoint inhibitors have revolutionized the field of oncology,emerging as a powerful treatment strategy.A key pathway that has garnered considerable attention is programmed cell death-1(PD-1)/programmed cell death-ligand 1(PD-L1).The interaction between PD-L1 expressed on tumor cells and PD-1 reduces the innate immune response and thus compromises the capability of the body’s immune system.Furthermore,it controls the phenotype and functionality of innate and adaptive immune components.A range of monoclonal antibodies,including avelumab,atezolizumab,camrelizumab,dostarlimab,durvalumab,sinitilimab,toripalimab,and zimberelimab,have been developed for targeting the interaction between PD-1 and PD-L1.These agents can induce a broad spectrum of autoimmune-like complications that may affect any organ system.Recent studies have focused on the effect of various natural compounds that inhibit immune checkpoints.This could contribute to the existing arsenal of anticancer drugs.Several bioactive natural agents have been shown to affect the PD-1/PD-L1 signaling axis,promoting tumor cell apoptosis,influencing cell proliferation,and eventually leading to tumor cell death and inhibiting cancer progression.However,there is a substantial knowledge gap regarding the role of different natural compounds targeting PD-1 in the context of cancer.Hence,this review aims to provide a common connection between PD-1/PD-L1 blockade and the anticancer effects of distinct natural molecules.Moreover,the primary focus will be on the underlying mechanism of action as well as the clinical efficacy of bioactive molecules.Current challenges along with the scope of future research directions targeting PD-1/PD-L1 interactions through natural substances are also discussed.展开更多
Sequencing of environmental samples has great potential for biodiversity research,but its application is limited by the lack of reliable DNA barcode databases for species identifications.Such a database has been creat...Sequencing of environmental samples has great potential for biodiversity research,but its application is limited by the lack of reliable DNA barcode databases for species identifications.Such a database has been created for epiphytic lichens of Europe,allowing us to compare the results of environmental sequencing with standard taxonomic surveys.The species undetected by taxonomic surveys(what we term the ghost component)amount to about half of the species actually present in hectare plots of Central European forests.Some of these,which currently occur only as diaspores or weakly developed thalli,are likely to be favoured in the course of global change.The ghost component usually represents a larger fraction in managed forests than in old-growth unmanaged forests.The total species composition of different plots is much more similar than suggested by taxonomic surveys alone.On a regional scale,this supports the well-known statement that“everything is everywhere,but,the environment selects”.展开更多
Background:In view of the ever-increasing representation of Staphylococcus spp.strains resistant to various antibiotics,the development of in vivo models for evaluation of novel antimicrobials is of utmost importance....Background:In view of the ever-increasing representation of Staphylococcus spp.strains resistant to various antibiotics,the development of in vivo models for evaluation of novel antimicrobials is of utmost importance.Methods:In this article,we describe the development of a fully immunocompetent porcine model of extensive skin and soft tissue damage suitable for testing topical anti-microbial agents that matches the real clinical situation.The model was developed in three consecutive stages with protocols for each stage amended based on the results of the previous one.Results:In the final model,10 excisions of the skin and underlying soft tissue were created in each pig under general anesthesia,with additional incisions to the fascia performed at the base of the defects and immediately inoculated with Staphylococcus aureus suspension.One pig was not inoculated and used as the negative control.Subsequently,the bandages were changed on Days 4,8,11,and 15.At these time points,a filter paper imprint technique(FPIT)was made from each wound for semi-quantitative microbiological evaluation.Tissue samples from the base of the wound together with the adjacent intact tissue of three randomly selected defects of each pig were taken for microbiological,histopathological,and molecular-biological examination.The infection with the inoculated S.aureus strains was sufficient during the whole experiment as confirmed by both FPIT and from tissue samples.The dynamics of the inflammatory markers and clinical signs of infection are also described.Conclusions:A successfully developed porcine model is suitable for in vivo testing of novel short-acting topical antimicrobial agents.展开更多
BACKGROUND The World Health Organization defined long coronavirus disease 2019(COVID-19)as the continuation or development of new symptoms 3 months after the initial severe acute respiratory syndrome coronavirus 2 inf...BACKGROUND The World Health Organization defined long coronavirus disease 2019(COVID-19)as the continuation or development of new symptoms 3 months after the initial severe acute respiratory syndrome coronavirus 2 infection,with these symptoms lasting for at least 2 months with no other explanation.AIM To evaluate the potential laboratory and instrumental findings(short-term and long-term)resulting from COVID-19.METHODS This longitudinal observational COVID-19 cohort study(March 1,2020-March 1,2021)was carried out on patients≥18 years old who were admitted to the University Hospitals of Pisa,Siena and Careggi and the Azienda USL Toscana Nord Ovest,Sud Est and USL Centro Toscana and were subjected to follow-up.Follow-up was conducted between 0 day and 89 days,90 days and 179 days,180 days and 269 days,270 days and 359 days,and more than 360 days after hospitalization.RESULTS Of 2887 patients(58.5%males,average age 66.2 years)hospitalized in the study period(March 1,2020-March 1,2021)carrying out at least one follow-up examination within 12 months of discharge,a total of 1739 patients(705 males,average age 66 years)underwent laboratory tests,of whom 714 patients(470 males,average age 63 years)underwent spirometry.Some laboratory test results remained above the threshold even at follow-up beyond 360 days(C-reactive protein:36%,fibrin degradation fragment:48.8%,gamma-glutamyl transferase:16.8%),while others showed a return to normal range more quickly in almost all patients.Alterations in liver enzymes,hematocrit,hemoglobin,lymphocytes and neutrophils were associated with the risk of requiring oxygen therapy or forced expiratory volume in one second/forced vital capacity alterations at follow-up.CONCLUSION Alterations in liver enzymes,hematocrit or hemoglobin,lymphocytes and neutrophils were associated with risk outcomes(need for oxygen therapy or spirometry alterations).These imbalanced conditions may contribute to pulmonary dysfunction.展开更多
AIM: To investigate the in vivo effects of type Ⅰdiabetes on the mechanical strength of tibial bone in a rodent model.METHODS: The biomechanical effect of diabetes on the structural integrity of the tibia in streptoz...AIM: To investigate the in vivo effects of type Ⅰdiabetes on the mechanical strength of tibial bone in a rodent model.METHODS: The biomechanical effect of diabetes on the structural integrity of the tibia in streptozotocin induced diabetic Wistar rats was analysed. Induction of diabetes was achieved by an intra-peritoneal injection and confirmed by measuring serial blood glucose levels(> 150 mg/d L). After 8 wk the tibiae were harvested and compared to a control group. Biomechanical analysis of harvested tibiae was performed using a threepoint bending technique on a servo hydraulic MTS 858 MiniB ionix frame. Maximum force applied to failure(N), stiffness(N × mm) and energy absorbed(N/mm) were recorded and plotted on load displacement curves. A displacement control loading mode of 1 mm/min was selected to simulate quasi-static loading conditions. Measurements from load-displacement curves were directly compared between groups.RESULTS: Fourteen streptozotocin induced diabetic Wistar rats were compared against nineteen non-diabetic controls. An average increase of 155.2 g in body weight was observed in the control group compared with only 5 g in the diabetic group during the experimental study period. Levels of blood glucose increased to 440.25 mg/d L in the diabetic group compared to 116.62 mg/d L in the control group.The biomechanical results demonstrate a highly significant reduction in the maximum load to failure from 69.5 N to 58 N in diabetic group compared to control(P = 0.011). Energy absorption to fracture was reduced from 28.2 N in the control group to 23.5 N in the diabetic group(P = 0.082). No significant differences were observed between the groups for bending stiffness.CONCLUSION: Streptozotocin-induced diabetes in rodents reduces the maximum force and energy absorption to failure of bone, suggesting a predisposition for fracture risk.展开更多
Transferring healthy and functional mitochondria to the lateral ventricles confers neuroprotection in a rat model of ischemia-reperfusion injury.Autologous mitochondrial transplantation is also beneficial in pediatric...Transferring healthy and functional mitochondria to the lateral ventricles confers neuroprotection in a rat model of ischemia-reperfusion injury.Autologous mitochondrial transplantation is also beneficial in pediatric patients with cardiac ischemia-reperfusion injury.Thus,transplantation of functional exogenous mitochondria may be a promising therapeutic approach for ischemic disease.To explore the neuroprotective effect of mitochondria transplantation and determine the underlying mechanism in ischemic stroke,in this study we established a photo-thrombosis-induced mouse model of focal ischemia and administered freshly isolated mitochondria via the tail vein or to the injury site(in situ).Animal behavior tests,immunofluorescence staining,2,3,5-triphenyltetrazolium chloride(TTC)staining,mRNA-seq,and western blotting were used to assess mouse anxiety and memory,cortical infarct area,pyroptosis,and neurogenesis,respectively.Using bioinformatics analysis,western blotting,co-immunoprecipitation,and mass spectroscopy,we identified S100 calcium binding protein A9(S100A9)as a potential regulator of mitochondrial function and determined its possible interacting proteins.Interactions between exogenous and endogenous mitochondria,as well as the effect of exogenous mitochondria on recipient microglia,were assessed in vitro.Our data showed that:(1)mitochondrial transplantation markedly reduced mortality and improved emotional and cognitive function,as well as reducing infarct area,inhibiting pyroptosis,and promoting cortical neurogenesis;(2)microglial expression of S100A9 was markedly increased by ischemic injury and regulated mitochondrial function;(3)in vitro,exogenous mitochondria enhanced mitochondrial function,reduced redox stress,and regulated microglial polarization and pyroptosis by fusing with endogenous mitochondria;and(4)S100A9 promoted internalization of exogenous mitochondria by the microglia,thereby amplifying their pro-proliferation and anti-inflammatory effects.Taken together,our findings show that mitochondrial transplantation protects against the deleterious effects of ischemic stroke by suppressing pyroptosis and promoting neurogenesis,and that S100A9 plays a vital role in promoting internalization of exogenous mitochondria.展开更多
文摘Vulvodynia,a chronic pain disorder affecting the vulvar region,represents a significant challenge in both diagnosis and treatment within the field of women’s health.This condition is characterized by chronic pain that significantly affects the quality of life of afflicted women.The present perspective paper examines the role of spinal sensitization and microglial activation in vulvodynia.
文摘Background:Platinum chemotherapy(CT)remains the backbone of systemic therapy for patients with smallcell lung cancer(SCLC).The nucleotide excision repair(NER)pathway plays a central role in the repair of the DNA damage exerted by platinum agents.Alteration in this repair mechanism may affect patients’survival.Materials and Methods:We conducted a retrospective analysis of data from 38 patients with extensive disease(ED)-SCLC who underwent platinum-CT at the Clinical Oncology Unit,Careggi University Hospital,Florence(Italy),from 2015 to 2020.mRNA expression analysis and single nucleotide polymorphism(SNP)characterization of three NER pathway genes—namely ERCC1,ERCC2,and ERCC5—were performed on patient tumor samples.Results:Overall,elevated expression of ERCC genes was observed in SCLC patients compared to healthy controls.Patients with low ERCC1 and ERCC5 expression levels exhibited a better median progression-free survival(mPFS=7.1 vs.4.9 months,p=0.39 for ERCC1 and mPFS=6.9 vs.4.8 months,p=0.093 for ERCC5)and overall survival(mOS=8.7 vs.6.0 months,p=0.4 for ERCC1 and mOS=7.2 vs.6.2 months,p=0.13 for ERCC5).Genotyping analysis of five SNPs of ERCC genes showed a longer survival in patients harboring the wild-type genotype or the heterozygous variant of the ERCC1 rs11615 SNP(p=0.24 for PFS and p=0.14 for OS)and of the rs13181 and rs1799793 ERCC2 SNPs(p=0.43 and p=0.26 for PFS and p=0.21 and p=0.16 for OS,respectively)compared to patients with homozygous mutant genotypes.Conclusions:The comprehensive analysis of ERCC gene expression and SNP variants appears to identify patients who derive greater survival benefits from platinum-CT.
基金supported by an under-40 grant from the Italian Association for Alzheimer’s Research [AIRALZH AGYR2021]the Strategic University Projects–Young Researcher Independence grant [YRG2021] from the Università Campus Bio-Medico di Roma (Rome, Italy)(to LLB)+1 种基金Italian Ministry of Health [Research Grant:GR-2019-12370446]the American Alzheimer’s Association [AARG-22-922961](to PK)。
文摘Despite decades of dedicated resea rch,Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disorder for which the mechanisms of onset are sti unc ear.AD is cha racterized by featured histological alterations including amyloid-beta (AB) plaque deposition,accumulation of neurofibrillary to ngles of hyperphosphorylated-tau,and neuronal loss,accompanied by progressive cognitive decline and behavioral changes.
文摘Primary biliary cholangitis is a chronic cholestatic autoimmune liver disease that progressively damages the bile ducts,leading to cholestasis and,in advanced stages,cirrhosis.While it primarily affects middle-aged women,recent data indicate a rising incidence in men.The interplay between genetic susceptibility,environmental exposures,and gut microbiome alterations is thought to drive disease onset.Diagnosis relies on persistent cholestatic enzyme elevation,diseasespecific autoantibodies,and,in select cases,liver biopsy.Ursodeoxycholic acid remains the cornerstone of treatment,but many patients show an incomplete response.The recent withdrawal of obeticholic acid from the market,due to insufficient evidence of long-term benefit,has highlighted the urgent need for effective second-line therapies.Agonists of peroxisome proliferator-activated receptors,such as elafibranor and seladelpar,have demonstrated promising biochemical improvements and may reshape the therapeutic landscape.Future research is focused on refining risk assessment,optimizing treatment combinations,and addressing symptoms such as fatigue and pruritus to enhance patient well-being.A shift toward early intervention and personalized treatment strategies may further improve long-term outcomes in primary biliary cholangitis.
文摘Objective:Nowadays robot-assisted partial nephrectomy(RAPN)represents the standard of care for clinical T1(cT1)renal masses,providing similar oncological outcomes when compared to open or laparoscopic PN with advantages in terms of functional outcomes and lower perioperative comorbidity,when compared to radical nephrectomy.Methods:We performed an extensive literature review of studies regarding RAPN,its evolution,technical aspects and applications,and new technological tools using different combinations of Medical Subject Headings terms“RAPN”,“partial nephrectomy”,“robot-assisted”,“nephron-sparing surgery”,“renal cell carcinoma”,“complex renal masses”,“endophytic renal masses”,and“bilateral renal tumors”.Results:A consistent body of evidence was selected,including original articles,systematic reviews,meta-analyses,and clinical trials having RAPN as the central focus in adult patients,with all its technical nuances.We started our narrative review with a background on PN and its evolution toward the robotic era with a special spotlight on the extending indications for PN in large and highly complex renal masses.Our review continued with an overview of nephron-sparing surgery in bilateral and recurrent masses.RAPN for bilateral synchronous renal masses represents a challenging scenario with no formal recommendations provided by international guidelines and controversial management and decision-making.Additionally,we reported evidence on redo RAPN which seems to be safe and effective.A final overview of the available technological tools,and in particular on three-dimensional reconstruction was provided.Conclusion:RAPN has been established as the standard of care for cT1 renal masses with an expanding spectrum of applications in different scenarios,including large(cT2),highly complex,and bilateral renal masses,as well as the surgical treatment of local recurrences after nephron-sparing surgery with acknowledged advantages in terms of functional outcomes and perioperative risk profiles while maintaining similar oncological outcomes when compared to open or laparoscopic PN and radical treatment.
文摘Background:The surgical management of patients with benign prostatic hyperplasia(BPH)has considerably evolved through recent years.Nonetheless,benefits and harms of several laser procedures are still to be determined.The study aimed to report perioperative and early functional results of patients treated with anatomical photo vaporization of the prostate(aPVP).Methods:Data from consecutive patients treated with aPVP by using a 180-W XPS GreenLight laser were prospectively collected in a single tertiary center between 2020 and 2023.The surgical procedure was divided into a modular step-by-step fashion.Patients were asked to complete self-administered questionnaires at baseline and during follow-up visits.Results:Overall,176 consecutive patients were enrolled.Median age was 65[interquartile range(IQR)63–72]years.The baseline median prostate volume was 61.2(IQR 52.5–71.0)mL,and the median max flow rate(Qmax)was 9.3(IQR 7.8–11.5)mL/s.Median preoperative International Prostate Symptom Score(IPSS)was 25(IQR 22–29).Overall,the median operative time was 42(IQR 31–47)minutes with a median energy/mL of tissue delivered of 2447 kJ/mL.At 3 month-evaluation,significant improvements were observed,with a median Qmax of 28(IQR:24–32)mL/s and a median IPSS reduction of 15(IQR:11–18)points.A strong inverse correlation was identified between energy delivery during initial procedural steps and the severity of postoperative storage symptoms(all p<0.05),underscoring the importance of precise energy modulation.Multivariate analysis identified increased prostate volume(odds ratio[OR]:1.02;95%confidence interval[CI]1.01–1.11;p=0.001)and higher prostate width-to-length ratio(OR:1.28;95%CI 1.04–1.78;p=0.03)as independent predictors of increased energy requirements.Conclusions:aPVP with 180-W XPS GreenLight laser is a safe and effective technique showing worthy early functional results.The limitation of the energy delivered in some key phases of the procedure may be associated with a significant reduction in postoperative irritative symptoms.The shape and dimensions of the prostate also play a critical role in determining the total energy required for complete adenoma removal.
文摘BACKGROUND Barrett esophagus(BE),a metaplastic adaptive process to gastrointestinal reflux,is associated with a higher risk of developing esophageal adenocarcinoma.However,the factors and mechanism that drive the malignant progression of BE is not well understood.AIM To investigate the role of bile acids,a component of the reflux fluid,in the malignant progression of BE.METHODS Using engineered green fluorescent protein-labeled adult tissue-resident stem cells isolated from BE clinical biopsies(BE-ASCs)as the target,we studied the effect of hydrophobic deoxycholic acid(DCA)and hydrophilic tetrahydroxylated bile acids(THBA)on cell viability by fluorescence intensity analysis,mucin production by dark density measurement,tissue structure by pathology analysis,expression of different pro-inflammatory factors gene by quantitative polymerase chain reaction and proteins by Western blot.RESULTS We found that hydrophobic DCA has cytotoxic and proinflammatory effects through activation of interleukin-1β(IL-1β)-nuclear factor kappa-B(NF-κB)inflammatory pathway on BE-ASCs.This action results in impaired cell viability,tissue intactness,reduced mucin production,and increased transition to disorganized atypical cells without intestinal features.In contrast,co-culture with hydrophilic THBA inhibited the IL-1β-NF-κB inflammatory pathway with maintenance of mature intestinal type cellular and histomorphology.CONCLUSION Our data indicates that the hydrophilic bile acid THBA can counteract the cytotoxic and proinflammatory effect of hydrophobic DCA and prevent the malignant progression of BE by inhibiting the IL-1β-NF-κB pathway.
基金supported by #NEXTGENERATIONEU(NGEU)and funded by the Ministry of University and Research(MUR),National Recovery and Resilience Plan(NRRP),project MNESYS(PE0000006)-(DN.155311.10.2022)supported by Sapienza Grant 2021(RM12117A60BDF685).
文摘Background Non-suicidal self-injury(NSSI)is a significant health concern among adolescents and young adults,often resulting from adverse childhood experiences(ACEs).Dissociation,post-traumatic symptoms and attachment style may have a role in shaping such associations.Aims This study aims to provide a unified model of the impact of ACEs on NSSI,exploring complex post-traumatic stress disorder(cPTSD)symptoms and dissociation as potential mediators and the role of the predominant attachment style in affecting such associations.Methods 1010 young individuals attending the last year of high school participated in this cross-sectional study.ACEs,cPTSD,dissociation and NSSI were evaluated using self-report questionnaires.We fitted a path model of NSSI,with ACEs as exogenous variables and cPTSD and dissociation as sequential mediators.Secure,fearful and preoccupied attachment styles were modelled as grouping variables.Results Our findings showed that dissociation mediated the impact of ACEs on NSSI in subjects with a fearful attachment style,as opposed to those with a preoccupied attachment for whom cPTSD symptoms mediated the ACEs-NSSI association.Conclusions Attachment styles moderate the relationship between ACEs and NSSI,with either dissociation or post-traumatic symptomatology mediating the impact of ACEs on NSSI,depending on the predominant attachment style.Our results highlight the importance of attachment as a pathway modifier in the relationships between different psychopathology dimensions,providing a useful framework to better conceptualise the ACEs-NSSI association.
基金supported by the Spanish Ministerio de Ciencia e Innovación/Agencia Española de Investigación(PID2021-124096OB-I00)(to JLV)JGR was granted by Demensfonden,The Royal Physiografic Society of Lund,Neurofonden,The Greta och Johan Kocks stiftelser,and Bertil och Ebon Norlins stiftelse.
文摘Different forms of programmed cell death have been described to participate in the degeneration of dopaminergic neurons in Parkinson’s disease(PD).Given the critical role that disturbance of mitochondrial homeostasis plays in the pathogenesis of PD,apoptosis can be reasonably considered as one of the cell death pathways involved in neuronal loss(Schon and Przedborski,2011).Multiple lines of evidence support that proposal such as the observations in postmortem human brain samples of PD patients including mitochondrial complex I deficiency,reactive oxygen species generation,and oxidative damage to lipids,proteins,and DNA,among others.
文摘1 MHC-I Loss in the Immune Evasion of Cancer Cells Pancreatic ductal adenocarcinoma(PDAC)is a lethal cancer with a poor prognosis due to its aggressive nature and late detection.Recently,new discoveries in PDAC demonstrated receptor-interacting protein kinase 2(RIPK2)triggering immune evasion.Mechanistically,RIPK2 drives the desmoplastic tumor microenvironment(TME)and restricts the activation and density of tumor-infiltrating effector T cells by impairing the expression of major histocompatibility complex class I(MHC-I)[1].This process might be relevant in different solid cancer entities as illustrated by analyzing publicly available databases.
基金supported by the National Natural Science Foundation of China(82401772)the Shanghai Municipal Education Commission(2021-01-07-00-02-E0086).
文摘Post-traumatic stress disorder(PTSD)is a severe neuropsychiatric disorder characterised by reexperiencing,avoidance and hyperarousal.Memory abnormalities manifested as intrusive thoughts and prolonged distressful emotions are postulated as key roles in PTSD development and persistence.Over the past decades,convergent results from human and animal studies have systematically investigated contributions of the amygdala,hippocampus and medial prefrontal cortex(mPFC)in fear memory processes,including fear acquisition,storage,reconsolidation and extinction.These findings provide mechanistic insights for cognitive-behavioural therapy and aid in developing pathological region-targeted neuromodulation treatment for PTSD.Taking advantage of advances in cell-type selective labelling and manipulation technologies,recent studies have focused on the spatiotemporal regulation of neural circuits underlying distinct phases of fear memory processes.These findings have revealed that multiple distributed brain areas participate in the fear memory encoding network.Moreover,the functional role of distinct neuronal ensembles within the amygdala-hippocampus-mPFC pathway,identified by genetic markers and projection profiles,has been assigned to temporally separate features of fear processing,demonstrating the sophistication of the fear encoding circuit.These results provide mechanistic insights into PTSD pathology and might shed light on aetiology-based clinical interventions for PTSD.Therefore,the present review will mainly focus on the recent progress in elucidating neural circuit mechanisms underlying the dynamic regulation of fear memory,with an emphasis on the spatial distribution of fear memory encoding neural networks and the temporal coherence between neuronal ensemble activity and fear expression.
文摘BACKGROUND Colorectal cancer(CRC)is a prevalent gastrointestinal malignancy with a typi-cally unfavorable prognosis following the onset of liver metastases.AIM To develop and validate a new clinical prediction model to accurately forecast overall survival(OS)in CRC patients following surgical treatment for liver metastasis.METHODS This study included 1059 patients diagnosed with CRC liver metastases(CRLM)at the Xijing Hospital between 2010 and 2022.The patients were randomly divided into training and validation cohorts at a 7:3 ratio.Key clinical predictors were identified using least absolute shrinkage and selection operator(LASSO)regression combined with a Cox proportional hazards model,leading to the establishment of a prediction model and preparation of a nomogram to enhance its clinical utility.Decision curve analysis(DCA)and Kaplan-Meier survival analysis were employed to evaluate the precision and predictive performance of the model.RESULTS The LASSO-Cox regression analysis revealed multiple pivotal clinical biomarkers significantly linked to CRLM,including gamma-glutamyl transferase levels,blood chloride concentration,activated partial thromboplastin time,N stage,and vascular invasion.The model's receiver operating characteristic curve area under the curve exceeded 0.7 for both the training and validation groups with moderate-to-good predictive accuracy.Furthermore,DCA validated the nomogram's effectiveness for OS prediction.Kaplan-Meier risk stratification demonstrated markedly improved OS among patients classified as low-risk compared to those categorized as high-risk(P<0.001),highlighting its clinical utility for risk assessment and treatment guidance.CONCLUSION The nomogram prediction model constructed in this study has good predictive value and can effectively assess the survival rate of patients with CRLM.
文摘Esophageal cancer is an aggressive malignancy often diagnosed at advanced stages,with esophageal squamous cell carcinoma being the predominant subtype worldwide.Standard first-line chemotherapy provides limited survival benefits,with a median overall survival of less than 1 year.Recent advancements in immunotherapy,particularly immune checkpoint inhibitors(ICIs),have trans-formed the treatment landscape,improving overall survival and progression-free survival.However,response rates remain variable,with programmed death ligand 1(PD-L1)expression being the primary predictive biomarker.The variability in PD-L1 testing methods and immune microenvironment alterations after prior treatments complicate patient selection for ICIs.Several phase 3 trials,including KEYNOTE-590 and CheckMate 648,have demonstrated the efficacy of ICIs combined with chemotherapy,particularly in patients positive for PD-L1.Despite these advances,long-term survival remains low,emphasizing the need for better biomarkers and novel therapeutic strategies.This review explored current first-line treatment options for esophageal squamous cell carcinoma,challenges in biomarker-based patient selection,and emerging therapeutic approaches.
文摘Background:Developing a granulomatous liver injury preclinical model may pave the way to understanding hepatic-TB(tuberculosis)and autoimmune granulomatous liver diseases.Antitubercular(ATT)and other drugs'metabolism in the presence of a specific type of liver injury is not well understood.The present study aimed to establish a preclinical model of granulomatous hepatitis by using the BCG(Bacillus CalmetteGuérin)vaccine,further studying it in the presence of ATT dosing,and analyze the pharmacokinetics of isoniazid,rifampicin,and their respective primary metabolites.Methods:We used 56 rats in seven equal groups.Group I functioned as a normal control(NC)receiving normal saline only.Groups II-IV received intravenous injections of low-,medium-,and high-dose BCG vaccine daily for 21 days.Groups V,VI,and VII received isoniazid(H)alone,rifampicin(R)alone,and isoniazid+rifampicin(HR)for a subsequent 15 days in addition to high dose BCG for the first 21 days,respectively.Liver function tests(LFT)were monitored on days 0,21,28,and 36.Rats were sacrificed later for oxidative stress and histopathological examination.Results:The study observed BCG dose-specific LFT derangements in groups II-IV compared to group I on day 21(p<0.05).Isoniazid,rifampicin,and combination intervention groups demonstrated normalization of the BCG-led LFT changes.Histology and oxidative stress parameters confirmed model development and biochemical changes.Isoniazid area under the curve(AUC)showed a reduction of 16.9%in BCG+HR group in comparison to the BCG+H group(p=0.01).Des-acetyl-rifampicin AUC and maximum-concentration value demonstrated a significant rise in BCG+HR group in comparison to the BCG+R group(p=0.001).Conclusion:A novel preclinical model of granulomatous liver injury was developed using the BCG vaccine strain and validated with ATT response.
基金support provided by the Department of Science and Technology,Science and Engineering Research Board(DST-SERB),the Anusandhan National Research Foundation(ANRF),State University Research Excellence(SERB-SURE),Ministry of Science and Technology,Govt.of India(SUR/2022/001353).
文摘Cancer is a global health problem and one of the leading causes of mortality.Immune checkpoint inhibitors have revolutionized the field of oncology,emerging as a powerful treatment strategy.A key pathway that has garnered considerable attention is programmed cell death-1(PD-1)/programmed cell death-ligand 1(PD-L1).The interaction between PD-L1 expressed on tumor cells and PD-1 reduces the innate immune response and thus compromises the capability of the body’s immune system.Furthermore,it controls the phenotype and functionality of innate and adaptive immune components.A range of monoclonal antibodies,including avelumab,atezolizumab,camrelizumab,dostarlimab,durvalumab,sinitilimab,toripalimab,and zimberelimab,have been developed for targeting the interaction between PD-1 and PD-L1.These agents can induce a broad spectrum of autoimmune-like complications that may affect any organ system.Recent studies have focused on the effect of various natural compounds that inhibit immune checkpoints.This could contribute to the existing arsenal of anticancer drugs.Several bioactive natural agents have been shown to affect the PD-1/PD-L1 signaling axis,promoting tumor cell apoptosis,influencing cell proliferation,and eventually leading to tumor cell death and inhibiting cancer progression.However,there is a substantial knowledge gap regarding the role of different natural compounds targeting PD-1 in the context of cancer.Hence,this review aims to provide a common connection between PD-1/PD-L1 blockade and the anticancer effects of distinct natural molecules.Moreover,the primary focus will be on the underlying mechanism of action as well as the clinical efficacy of bioactive molecules.Current challenges along with the scope of future research directions targeting PD-1/PD-L1 interactions through natural substances are also discussed.
基金supported by the Technology Agency of the Czech Republic(Grant Nos.SS01010270,SS06010420)by a long-term research development grant RVO(Grant No.67985939)。
文摘Sequencing of environmental samples has great potential for biodiversity research,but its application is limited by the lack of reliable DNA barcode databases for species identifications.Such a database has been created for epiphytic lichens of Europe,allowing us to compare the results of environmental sequencing with standard taxonomic surveys.The species undetected by taxonomic surveys(what we term the ghost component)amount to about half of the species actually present in hectare plots of Central European forests.Some of these,which currently occur only as diaspores or weakly developed thalli,are likely to be favoured in the course of global change.The ghost component usually represents a larger fraction in managed forests than in old-growth unmanaged forests.The total species composition of different plots is much more similar than suggested by taxonomic surveys alone.On a regional scale,this supports the well-known statement that“everything is everywhere,but,the environment selects”.
基金Supported by the Ministry of Health of the Czech Republic,Grant/Award Number:NU22-05-00475 and NV19-05-00214。
文摘Background:In view of the ever-increasing representation of Staphylococcus spp.strains resistant to various antibiotics,the development of in vivo models for evaluation of novel antimicrobials is of utmost importance.Methods:In this article,we describe the development of a fully immunocompetent porcine model of extensive skin and soft tissue damage suitable for testing topical anti-microbial agents that matches the real clinical situation.The model was developed in three consecutive stages with protocols for each stage amended based on the results of the previous one.Results:In the final model,10 excisions of the skin and underlying soft tissue were created in each pig under general anesthesia,with additional incisions to the fascia performed at the base of the defects and immediately inoculated with Staphylococcus aureus suspension.One pig was not inoculated and used as the negative control.Subsequently,the bandages were changed on Days 4,8,11,and 15.At these time points,a filter paper imprint technique(FPIT)was made from each wound for semi-quantitative microbiological evaluation.Tissue samples from the base of the wound together with the adjacent intact tissue of three randomly selected defects of each pig were taken for microbiological,histopathological,and molecular-biological examination.The infection with the inoculated S.aureus strains was sufficient during the whole experiment as confirmed by both FPIT and from tissue samples.The dynamics of the inflammatory markers and clinical signs of infection are also described.Conclusions:A successfully developed porcine model is suitable for in vivo testing of novel short-acting topical antimicrobial agents.
基金Supported by Regione Toscana,No.D55H20000210002.
文摘BACKGROUND The World Health Organization defined long coronavirus disease 2019(COVID-19)as the continuation or development of new symptoms 3 months after the initial severe acute respiratory syndrome coronavirus 2 infection,with these symptoms lasting for at least 2 months with no other explanation.AIM To evaluate the potential laboratory and instrumental findings(short-term and long-term)resulting from COVID-19.METHODS This longitudinal observational COVID-19 cohort study(March 1,2020-March 1,2021)was carried out on patients≥18 years old who were admitted to the University Hospitals of Pisa,Siena and Careggi and the Azienda USL Toscana Nord Ovest,Sud Est and USL Centro Toscana and were subjected to follow-up.Follow-up was conducted between 0 day and 89 days,90 days and 179 days,180 days and 269 days,270 days and 359 days,and more than 360 days after hospitalization.RESULTS Of 2887 patients(58.5%males,average age 66.2 years)hospitalized in the study period(March 1,2020-March 1,2021)carrying out at least one follow-up examination within 12 months of discharge,a total of 1739 patients(705 males,average age 66 years)underwent laboratory tests,of whom 714 patients(470 males,average age 63 years)underwent spirometry.Some laboratory test results remained above the threshold even at follow-up beyond 360 days(C-reactive protein:36%,fibrin degradation fragment:48.8%,gamma-glutamyl transferase:16.8%),while others showed a return to normal range more quickly in almost all patients.Alterations in liver enzymes,hematocrit,hemoglobin,lymphocytes and neutrophils were associated with the risk of requiring oxygen therapy or forced expiratory volume in one second/forced vital capacity alterations at follow-up.CONCLUSION Alterations in liver enzymes,hematocrit or hemoglobin,lymphocytes and neutrophils were associated with risk outcomes(need for oxygen therapy or spirometry alterations).These imbalanced conditions may contribute to pulmonary dysfunction.
文摘AIM: To investigate the in vivo effects of type Ⅰdiabetes on the mechanical strength of tibial bone in a rodent model.METHODS: The biomechanical effect of diabetes on the structural integrity of the tibia in streptozotocin induced diabetic Wistar rats was analysed. Induction of diabetes was achieved by an intra-peritoneal injection and confirmed by measuring serial blood glucose levels(> 150 mg/d L). After 8 wk the tibiae were harvested and compared to a control group. Biomechanical analysis of harvested tibiae was performed using a threepoint bending technique on a servo hydraulic MTS 858 MiniB ionix frame. Maximum force applied to failure(N), stiffness(N × mm) and energy absorbed(N/mm) were recorded and plotted on load displacement curves. A displacement control loading mode of 1 mm/min was selected to simulate quasi-static loading conditions. Measurements from load-displacement curves were directly compared between groups.RESULTS: Fourteen streptozotocin induced diabetic Wistar rats were compared against nineteen non-diabetic controls. An average increase of 155.2 g in body weight was observed in the control group compared with only 5 g in the diabetic group during the experimental study period. Levels of blood glucose increased to 440.25 mg/d L in the diabetic group compared to 116.62 mg/d L in the control group.The biomechanical results demonstrate a highly significant reduction in the maximum load to failure from 69.5 N to 58 N in diabetic group compared to control(P = 0.011). Energy absorption to fracture was reduced from 28.2 N in the control group to 23.5 N in the diabetic group(P = 0.082). No significant differences were observed between the groups for bending stiffness.CONCLUSION: Streptozotocin-induced diabetes in rodents reduces the maximum force and energy absorption to failure of bone, suggesting a predisposition for fracture risk.
基金supported by the National Natural Science Foundation of China,Nos.82201621(to LS),31930048(to QY)and 81720108016(to QY),and 81971225(to CG)the Key Research and Development Project of Shaanxi Province,No.2022SF-189(to XS)the Tangdu Hospital Supporting Foundation,Nos.2021ZTXM-006(to LS)and 2021JSZH-006(to CG)。
文摘Transferring healthy and functional mitochondria to the lateral ventricles confers neuroprotection in a rat model of ischemia-reperfusion injury.Autologous mitochondrial transplantation is also beneficial in pediatric patients with cardiac ischemia-reperfusion injury.Thus,transplantation of functional exogenous mitochondria may be a promising therapeutic approach for ischemic disease.To explore the neuroprotective effect of mitochondria transplantation and determine the underlying mechanism in ischemic stroke,in this study we established a photo-thrombosis-induced mouse model of focal ischemia and administered freshly isolated mitochondria via the tail vein or to the injury site(in situ).Animal behavior tests,immunofluorescence staining,2,3,5-triphenyltetrazolium chloride(TTC)staining,mRNA-seq,and western blotting were used to assess mouse anxiety and memory,cortical infarct area,pyroptosis,and neurogenesis,respectively.Using bioinformatics analysis,western blotting,co-immunoprecipitation,and mass spectroscopy,we identified S100 calcium binding protein A9(S100A9)as a potential regulator of mitochondrial function and determined its possible interacting proteins.Interactions between exogenous and endogenous mitochondria,as well as the effect of exogenous mitochondria on recipient microglia,were assessed in vitro.Our data showed that:(1)mitochondrial transplantation markedly reduced mortality and improved emotional and cognitive function,as well as reducing infarct area,inhibiting pyroptosis,and promoting cortical neurogenesis;(2)microglial expression of S100A9 was markedly increased by ischemic injury and regulated mitochondrial function;(3)in vitro,exogenous mitochondria enhanced mitochondrial function,reduced redox stress,and regulated microglial polarization and pyroptosis by fusing with endogenous mitochondria;and(4)S100A9 promoted internalization of exogenous mitochondria by the microglia,thereby amplifying their pro-proliferation and anti-inflammatory effects.Taken together,our findings show that mitochondrial transplantation protects against the deleterious effects of ischemic stroke by suppressing pyroptosis and promoting neurogenesis,and that S100A9 plays a vital role in promoting internalization of exogenous mitochondria.
