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Secondary lymphedema (LD) corresponds to a severe lymphatic dysfunction leading to the accumulation of fluid and fibrotic adipose tissue in a limb. Here, we identified apelin (APLN) as a powerful molecule for regenerating lymphatic function in LD. We identified the loss of APLN expression in the lymphedematous arm compared to the normal arm in patients. The role of APLN in LD was confirmed in APLN knockout mice, in which LD is increased and associated with fibrosis and dermal backflow. This was reversed by intradermal injection of APLN-lentivectors. Mechanistically, APLN stimulates lymphatic endothelial cell gene expression and induces the binding of E2F8 transcription factor to the promoter of CCBE1 that controls VEGF-C processing. In addition, APLN induces Akt and eNOS pathways to stimulate lymphatic collector pumping. Our results show that APLN represents a novel partner for VEGF-C to restore lymphatic function in both initial and collecting vessels. As LD appears after cancer treatment, we validated the APLN-VEGF-C combination using a novel class of nonintegrative RNA delivery LentiFlash® vector that will be evaluated for phase I/IIa clinical trial., (© 2024. The Author(s).)

Background: The application of CRISPR/Cas9 technology in human induced pluripotent stem cells (hiPSC) holds tremendous potential for basic research and cell-based gene therapy. However, the fulfillment of these promises relies on the capacity to efficiently deliver exogenous nucleic acids and harness the repair mechanisms induced by the nuclease activity in order to knock-out or repair targeted genes. Moreover, transient delivery should be preferred to avoid persistent nuclease activity and to decrease the risk of off-target events. We recently developed bacteriophage-chimeric retrovirus-like particles that exploit the properties of bacteriophage coat proteins to package exogenous RNA, and the benefits of lentiviral transduction to achieve highly efficient, non-integrative RNA delivery in human cells. Here, we investigated the potential of bacteriophage-chimeric retrovirus-like particles for the non-integrative delivery of RNA molecules in hiPSC for CRISPR/Cas9 applications., Results: We found that these particles efficiently convey RNA molecules for transient expression in hiPSC, with minimal toxicity and without affecting the cell pluripotency and subsequent differentiation. We then used this system to transiently deliver in a single step the CRISPR-Cas9 components (Cas9 mRNA and sgRNA) to generate gene knockout with high indel rate (up to 85%) at multiple loci. Strikingly, when using an allele-specific sgRNA at a locus harboring compound heterozygous mutations, the targeted allele was not altered by NHEJ/MMEJ, but was repaired at high frequency using the homologous wild type allele, i.e., by interallelic gene conversion., Conclusions: Our results highlight the potential of bacteriophage-chimeric retrovirus-like particles to efficiently and safely deliver RNA molecules in hiPSC, and describe for the first time genome engineering by gene conversion in hiPSC. Harnessing this DNA repair mechanism could facilitate the therapeutic correction of human genetic disorders in hiPSC., (© 2021. The Author(s).)

The balance between detoxification and toxicity is linked to enzymes of the drug metabolism Phase I (cytochrome P450 or oxidoreductases) and phase II conjugating enzymes (such as the UGTs). After the reduction of quinones, the product of the reaction, the quinols-if not conjugated-re-oxidizes spontaneously to form the substrate quinone with the concomitant production of the toxic reactive oxygen species (ROS). Herein, we documented the modulation of the toxicity of the quinone menadione on a genetically modified neuroblastoma model cell line that expresses both the quinone oxidoreductase 2 (NQO2, E.C. 1.10.5.1) alone or together with the conjugation enzyme UDP-glucuronosyltransferase (UGT1A6, E.C. 2.4.1.17), one of the two UGT isoenzymes capable to conjugate menadione. As previously shown, NQO2 enzymatic activity is concomitant to massive ROS production, as previously shown. The quantification of ROS produced by the menadione metabolism was probed by electron-paramagnetic resonance (EPR) on cell homogenates, while the production of superoxide was measured by liquid chromatography coupled to mass spectrometry (LC-MS) on intact cells. In addition, the dysregulation of the redox homeostasis upon the cell exposure to menadione was studied by fluorescence measurements. Both EPR and LCMS studies confirmed a significant increase in the ROS production in the NQO2 overexpressing cells due to the fast reduction of quinone into quinol that can re-oxidize to form superoxide radicals. However, the effect of NQO2 inhibition was drastically different between cells overexpressing only NQO2 vs. both NQO2 and UGT. Whereas NQO2 inhibition decreases the amount of superoxide in the first case by decreasing the amount of quinol formed, it increased the toxicity of menadione in the cells co-expressing both enzymes. Moreover, for the cells co-expressing QR2 and UGT the homeostasis dysregulation was lower in presence of menadione than for the its counterpart expressing only QR2. Those results confirmed that the cooperation of the two enzymes plays a fundamental role during the cells' detoxification process. The fluorescence measurements of the variation of redox homeostasis of each cell line and the detection of a glucuronide form of menadiol in the cells co-expressing NQO2 and UGT1A6 enzymes further confirmed our findings., Competing Interests: Author RG was employed by company Flash Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chhour, Perio, Gayon, Ternet-Fontebasso, Ferry, Nepveu, Boutin, Sudor and Reybier.)

Introduction: Recent research suggests that up to 20% of minor trauma patients admitted to the emergency department (ED) will suffer from non-specific chronic conditions over the subsequent several months. Thus, the present study assessed the correlates of symptoms that persisted at 4 months after an ED visit and, in particular, evaluated the associations between these symptoms and self-reported stress levels at ED admission and discharge., Method: This study was a prospective observational investigation conducted in the ED of Bordeaux University Hospital that included patients admitted for minor trauma. All participants were contacted by phone 4 months after presentation at the ED to assess the occurrence of post-concussion-like symptoms (PCLS)., Results: A total of 193 patients completed the follow-up assessment at 4 months; 5.2% of the participants suffered from post-traumatic stress disorder (PTSD) and 24.5% suffered from PCLS. A multivariate analysis revealed an association between PCLS and stress level at discharge from the ED (odds ratios [OR]: 2.85, 95% confidence interval [CI]: 1.10-7.40)., Conclusions: The risk of PCLS at 4 months after an ED visit for a minor injury increased in association with the level of stress at discharge from the ED. These results may improve the quality of life for the millions of patients who experience a stressful injury event every year., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Recent data suggest that 10-20% of injury patients will suffer for several months after the event from diverse symptoms, generally referred to as post-concussion-like symptoms (PCLS), which will lead to a decline in quality of life. A preliminary randomized control trial suggested that this condition may be induced by the stress experienced during the event or emergency room (ER) stay and can be prevented in up to 75% of patients with a single, early, short eye movement desensitization and reprocessing (EMDR) psychotherapeutic session delivered in the ER. The protocol of the SOFTER 3 study was designed to compare the impact on 3-month PCLS of early EMDR intervention and usual care in patients presenting at the ER. Secondary outcomes included 3-month post-traumatic stress disorder, 12-month PCLS, self-reported stress at the ER, self-assessed recovery expectation at discharge and 3 months, and self-reported chronic pain at discharge and 3 months., Methods: This is a two-group, open-label, multicenter, comparative, randomized controlled trial with 3- and 12-month phone follow-up for reports of persisting symptoms (PCLS and post-traumatic stress disorder). Those eligible for inclusion were adults (≥18 years old) presenting at the ER departments of the University Hospital of Bordeaux and University Hospital of Lyon, assessed as being at high risk of PCLS using a three-item scoring rule. The intervention groups were a (1) EMDR Recent Traumatic Episode Protocol intervention performed by a trained psychologist during ER stay or (2) usual care. The number of patients to be enrolled in each group was 223 to evidence a 15% decrease in PCLS prevalence in the EMDR group., Discussion: In 2012, the year of the last national survey in France, 10.6 million people attended the ER, some of whom did so several times since 18 million visits were recorded in the same year. The SOFTER 3 study therefore addresses a major public health challenge., Trial Registration: Clinical Trials. NCT03400813 . Registered 17 January 2018 - retrospectively registered.

Up to 20% of patients presenting at an emergency room (ER) after a stressful event will for several months suffer from very diverse long-lasting symptoms and a potentially significant decline in quality of life, often described as post concussion-like symptoms (PCLS). The objectives of our randomized open-label single-center study were to assess the feasibility of psychologist-led interventions in the context of the ER and to compare the effect of eye movement desensitization and reprocessing (EMDR) with reassurance and usual care. Conducted in the ER of Bordeaux University Hospital, the study included patients with a high risk of PCLS randomized in three groups: a 15-min reassurance session, a 60-min session of EMDR, and usual care. Main outcomes were the proportion of interventions that could be carried out and the prevalence of PCSL and post-traumatic stress disorder (PTSD) three months after the ER visit. One hundred and thirty patients with a high risk of PCLS were randomized. No logistic problem or patient refusal was observed. In the EMDR, reassurance and control groups, proportions of patients with PCLS at three months were 18%, 37% and 65% and those with PTSD were 3%, 16% and 19% respectively. The risk ratio for PCLS adjusted for the type of event (injury, non-injury) for the comparison between EMDR and control was 0.36 [95% CI 0.20-0.66]. This is the first randomized controlled trial that shows that a short EMDR intervention is feasible and potentially effective in the context of the ER. The study was registered at ClinicalTrials.gov (NCT03194386)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

There is increasing evidence that oxidative stress is involved in the etiology and pathogenesis of neurodegenerative disorders. Overproduction of reactive oxygen species (ROS) is due in part to the reactivity of catecholamines, such as dopamine, adrenaline, and noradrenaline. These molecules are rapidly converted, chemically or enzymatically, into catechol-quinone and then into highly deleterious semiquinone radicals after 1-electron reduction in cells. Notably, the overexpression of dihydronicotinamide riboside:quinone oxidoreductase (QR2) in Chinese hamster ovary (CHO) cells increases the production of ROS, mainly superoxide radicals, when it is exposed to exogenous catechol-quinones (e.g. dopachrome, aminochrome, and adrenochrome). Here we used electron paramagnetic resonance analysis to demonstrate that the phenomenon observed in CHO cells is also seen in human leukemic cells (K562 cells) that naturally express QR2. Moreover, by manipulating the level of QR2 in neuronal cells, including immortalized neuroblast cells and ex vivo neurons isolated from QR2 knockout animals, we showed that there is a direct relationship between QR2-mediated quinone reduction and ROS overproduction. Supporting this result, the withdraw of the QR2 co-factor (BNAH) or the addition of the specific QR2 inhibitor S29434 suppressed oxidative stress. Taken together, these data suggest that the overexpression of QR2 in brain cells in the presence of catechol quinones might lead to ROS-induced cell death via the rapid conversion of superoxide radicals into hydrogen peroxide and then into highly reactive hydroxyl radicals. Thus, QR2 may be implicated in the early stages of neurodegenerative disorders., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Indolone-N-oxides have antiplasmodial properties against Plasmodium falciparum at the erythrocytic stage, with IC50 values in the nanomolar range. The mechanism of action of indolone derivatives involves the production of free radicals, which follows their bioreduction by an unknown mechanism. In this study, we hypothesized that human quinone reductase 2 (hQR2), known to act as a flavin redox switch upon binding to the broadly used antimalarial chloroquine, could be involved in the activity of the redox-active indolone derivatives. Therefore, we investigated the role of hQR2 in the reduction of indolone derivatives. We analyzed the interaction between hQR2 and several indolone-type derivatives by examining enzymatic kinetics, the substrate/protein complex structure with X-ray diffraction analysis, and the production of free radicals with electron paramagnetic resonance. The reduction of each compound in cells overexpressing hQR2 was compared to its reduction in naïve cells. This process could be inhibited by the specific hQR2 inhibitor, S29434. These results confirmed that the anti-malarial activity of indolone-type derivatives was linked to their ability to serve as hQR2 substrates and not as hQR2 inhibitors as reported for chloroquine, leading to the possibility that substrate of hQR2 could be considered as a new avenue for the design of new antimalarial compounds.

Quinones are highly reactive molecules that readily undergo either one- or two-electron reduction. One-electron reduction of quinones or their derivatives by enzymes such as cytochrome P450 reductase or other flavoproteins generates unstable semiquinones, which undergo redox cycling in the presence of molecular oxygen leading to the formation of highly reactive oxygen species. Quinone reductases 1 and 2 (QR1 and QR2) catalyze the two-electron reduction of quinones to form hydroquinones, which can be removed from the cell by conjugation of the hydroxyl with glucuronide or sulfate thus avoiding its autoxidation and the formation of free radicals and highly reactive oxygen species. This characteristic confers a detoxifying enzyme role to QR1 and QR2, even if this character is strongly linked to the excretion capacity of the cell. Using EPR spectroscopy and confocal microscopy we demonstrated that the amount of reactive oxygen species (ROS) produced by Chinese hamster ovary (CHO) cells overexpressing QR1 or QR2 compared to naive CHO cells was determined by the quinone structural type. Indeed, whereas the amount of ROS produced in the cell was strongly decreased with para-quinones such as menadione in the presence of quinone reductase 1 or 2, a strong increase in ROS was recorded with ortho-quinones such as adrenochrome, aminochrome, dopachrome, or 3,5-di-tert-butyl-o-benzoquinone in cells overexpressing QR, especially QR2. These differences could originate from the excretion process, which is different for para- and ortho-quinones. These results are of particular interest in the case of dopamine considering the association of QR2 with various neurological disorders such as Parkinson disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

RNA delivery is an attractive strategy to achieve transient gene expression in research projects and in cell- or gene-based therapies. Despite significant efforts investigating vector-directed RNA transfer, there is still a requirement for better efficiency of delivery to primary cells and in vivo. Retroviral platforms drive RNA delivery, yet retrovirus RNA-packaging constraints limit gene transfer to two genome-molecules per viral particle. To improve retroviral transfer, we designed a dimerization-independent MS2-driven RNA packaging system using MS2-Coat-retrovirus chimeras. The engineered chimeric particles promoted effective packaging of several types of RNAs and enabled efficient transfer of biologically active RNAs in various cell types, including human CD34(+) and iPS cells. Systemic injection of high-titer particles led to gene expression in mouse liver and transferring Cre-recombinase mRNA in muscle permitted widespread editing at the ROSA26 locus. We could further show that the VLPs were able to activate an osteoblast differentiation pathway by delivering RUNX2- or DLX5-mRNA into primary human bone-marrow mesenchymal-stem cells. Thus, the novel chimeric MS2-lentiviral particles are a versatile tool for a wide range of applications including cellular-programming or genome-editing.

Importance: A proportion of patients experience long-lasting symptoms following mild traumatic brain injury (MTBI). The postconcussion syndrome (PCS), included in the DSM-IV, has been proposed to describe this condition. Because these symptoms are subjective and common to other conditions, there is controversy whether PCS deserves to be identified as a diagnostic syndrome., Objective: To assess whether persistent symptoms 3 months following head injury are specific to MTBI or whether they are better described as part of posttraumatic stress disorder (PTSD)., Design, Setting, and Participants: We conducted a prospective cohort study of injured patients recruited at the adult emergency department of the University Hospital of Bordeaux from December 4, 2007, to February 25, 2009., Main Outcomes and Measures: At 3-month follow-up, we compared the prevalence and risk factors for PCS and PTSD. Multiple correspondence analyses were used to assess clustering of symptoms and their associations with the type of injury., Results: We included 534 patients with head injury and 827 control patients with other nonhead injuries. Three months following the trauma, 21.2% of head-injured and 16.3% of nonhead-injured patients fulfilled the DSM-IV diagnosis of PCS; 8.8% of head-injured patients fulfilled the diagnostic criteria for PTSD compared with 2.2% of control patients. In multivariate analysis, MTBI was a predictor of PTSD (odds ratio, 4.47; 95% CI, 2.38-8.40) but not of PCS (odds ratio, 1.13; 95% CI, 0.82-1.55). Correspondence analysis suggested that symptoms considered part of PCS behave similarly to PTSD symptoms in the hyperarousal dimension. None of these 22 symptoms showed any pattern of clustering, and no clear proximity with head or nonhead injury status could be found., Conclusions and Relevance: Persistent subjective symptoms frequently reported 3 months after MTBI are not specific enough to be identified as a unique PCS and should be considered part of the hyperarousal dimension of PTSD.

Objective: To assess the specificity of symptoms included in various symptom lists used to identify postconcussion syndrome (PCS), by using follow-up data comparing patients with mild traumatic brain injury (MTBI) and control patients during the month prior to injury and 3 months later., Setting: The adult emergency department of a teaching hospital in Bordeaux, France., Participants: A cohort of patients with MTBI (n = 536) and a comparison group with nonhead injuries (n = 946)., Main Measures: Postconcussion symptoms listed in the Rivermead Postconcussion Symptoms Questionnaire (RPQ), the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), and the 10th International Classification of Diseases (ICD-10)., Results: Analyses were performed comparing symptom occurrence in patients with MTBI and controls, before and 3 months after injury. Eight symptoms were identified as being specific to MTBI: headache, dizziness, intolerance of stress, forgetfulness, poor concentration, taking longer to think, blurred vision, and personality change., Conclusion: The relevance of symptoms proposed to constitute PCS should be reviewed. A more specific definition of PCS would make diagnosis easier and facilitate prevention as well as treatment of patients with MTBI.

Background: Use of cellular phones has been shown to be associated with crashes but many external distractions remain to be studied., Objective: To assess the risk associated with diversion of attention due to unexpected events or secondary tasks at the wheel., Design: Responsibility case-control study., Setting: Adult emergency department of the Bordeaux University Hospital (France) from April 2010 to August 2011., Participants: 955 injured drivers presenting as a result of motor vehicle crash., Main Outcome Measures: The main outcome variable was responsibility for the crash. Exposures were external distraction, alcohol use, psychotropic medicine use, and sleep deprivation. Potential confounders were sociodemographic and crash characteristics., Results: Beyond classical risk factor found to be associated with responsibility, results showed that distracting events inside the vehicle (picking up an object), distraction due to driver activity (smoking) and distracting events occurring outside were associated with an increased probability of being at fault. These distraction-related factors accounted for 8% of injurious road crashes., Limitations: Retrospective responsibility self-assessment., Conclusions: Diverted attention may carry more risk than expected. Our results are supporting recent research efforts to detect periods of driving vulnerability related to inattention., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Human pluripotent stem cells (hPSCs) hold great promise for applications in regenerative medicine. However, the safety of cell therapy using differentiated hPSC derivatives must be improved through methods that will permit the transplantation of homogenous populations of a specific cell type. To date, purification of progenitors and mature cells generated from either embryonic or induced pluripotent stem cells remains challenging with use of conventional methods., Results: We used lentivectors encoding green fluorescent protein (GFP) driven by the liver-specific apoliprotein A-II (APOA-II) promoter to purify human hepatic progenitors. We evaluated both integrating and integration-defective lentivectors in combination with an HIV integrase inhibitor. A human embryonic stem cell line was differentiated into hepatic progenitors using a chemically defined protocol. Subsequently, cells were transduced and sorted at day 16 of differentiation to obtain a cell population enriched in hepatic progenitor cells. After sorting, more than 99% of these APOA-II-GFP-positive cells expressed hepatoblast markers such as α-fetoprotein and cytokeratin 19. When further cultured for 16 days, these cells underwent differentiation into more mature cells and exhibited hepatocyte properties such as albumin secretion. Moreover, they were devoid of vector DNA integration., Conclusions: We have developed an effective strategy to purify human hepatic cells from cultures of differentiating hPSCs, producing a novel tool that could be used not only for cell therapy but also for in vitro applications such as drug screening. The present strategy should also be suitable for the purification of a broad range of cell types derived from either pluripotent or adult stem cells.

Background: Post-traumatic stress disorder (PTSD) is a severe anxiety disorder whose symptoms include re-experiencing, avoidance, and hyperarousal after a particularly intense event. In view of the aging of the population, increased clinical knowledge is required for better understanding of PTSD in the elderly. Extending previous research in this field in adults and children, the aim of our study was to assess the utility of peri-traumatic dissociation and distress as a predictor of PTSD in the elderly., Methods: A prospective longitudinal study was conducted in a consecutive cohort of subjects aged 65 years and over admitted to emergency departments after a physical assault or a road traffic accident. Peri-traumatic responses of distress and of dissociation were measured. One, 6, and 12 months after trauma exposure, PTSD symptoms and diagnosis were assessed using both a dimensional and a semistructured interview., Results: Thirty-nine male and female participants with an average age of 72.4 years were recruited. Mixed model regression analyses did not detect a significant effect of age, sex, nor time. Significant associations were detected between peri-traumatic distress and the self-report PTSD Checklist (p = 0.008), as well as the Clinician-administered PTSD scale (p = 0.03). No association was detected between peri-traumatic dissociation and PTSD., Conclusions: Peri-traumatic distress predicts PTSD symptoms and diagnosis in the elderly, thereby suggesting its systematic evaluation at the emergency department would be a worthwhile thing to do.

Study Objective: A computed tomography (CT) scan has high sensitivity in detecting intracranial injury in patients with minor head injury but is costly, exposes patients to high radiation doses, and reveals clinically relevant lesions in less than 10% of cases. We evaluate S100-B protein measurement as a screening tool in a large population of patients with minor head injury., Methods: We conducted a prospective observational study in the emergency department of a teaching hospital (Bordeaux, France). Patients with minor head injury (2,128) were consecutively included from December 2007 to February 2009. CT scans and plasma S100-B levels were compared for 1,560 patients. The main outcome was to evaluate the diagnostic value of the S100-B test, focusing on the negative predictive value and the negative likelihood ratio., Results: CT scan revealed intracranial lesions in 111 (7%) participants, and their median S100-B protein plasma level was 0.46 μg/L (interquartile range [IQR] 0.27 to 0.72) versus 0.22 μg/L (IQR 0.14 to 0.36) in the other 1,449 patients. With a cutoff of 0.12 μg/L, traumatic brain injuries on CT were identified with a sensitivity of 99.1% (95% confidence interval [CI] 95.0% to 100%), a specificity of 19.7% (95% CI 17.7% to 21.9%), a negative predictive value of 99.7% (95% CI 98.1% to 100%), a positive likelihood ratio of 1.24 (95% CI 1.20 to 1.28), and a negative likelihood ratio of 0.04 (95% CI 0.006 to 0.32)., Conclusion: Measurement of plasma S100-B on admission of patients with minor head injury is a promising screening tool that may be of help to support the clinician's decision not to perform CT imaging in certain cases of low-risk head injury., (Copyright © 2011 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.)

Notch signaling participates in the development of multicellular organisms by maintaining self-renewal potential or inducing differentiation of numerous tissues. In this study, we characterized Notch4, the evolutionary most distant and least studied Notch family member. We identified a Notch4 inter-strain polymorphism with a previously undescribed mRNA variant. This longer Notch4 mRNA, which represented up to one-third of total Notch4 mRNA, resulted from intron 10 retention. Analysis of Notch4 intron 10 revealed that an 8-bp deletion, reducing its length from 68 to 60 bp, strictly correlated with its retention. Further experiments demonstrated that intron length was the only cause of the mis-splicing. Moreover, this mRNA variant resulted in a truncated protein containing half the extracellular domain of Notch4, including the ligand-binding domain.

Endothelial cells play a central role in chronic inflammation: for example, they express adhesion molecules and present chemokines leading to enhanced leukocyte recruitment into tissues. Numerous markers of endothelial cells have been reported but there has been a lack of comparative data on their specificity. The present study compared the specificity of seven endothelial cell markers in the rheumatoid synovium and the colon of patients with Crohn's disease. These markers were: the sulphated epitope MECA-79, the Duffy antigen receptor for chemokines (DARC), von Willebrand factor, CD31 (PECAM-1), CD34, CD105 (endoglin) and CD146. MECA-79, DARC and von Willebrand factor showed a specific endothelial cell distribution. MECA-79, which recognizes sulphated ligands for leukocyte adhesion receptor L-selectin (CD62L), was selective for a subset of venules in highly inflamed tissue and was present in rheumatoid but not control osteoarthritic synovia. DARC was also specific for venules but had a more widespread distribution than MECA-79, and was present in rheumatoid and control synovia. The other markers all labelled endothelial cells in venules, arterioles and capillaries. However, they also localized to other cell types. For example, CD34 stained fibroblasts, CD146 was expressed by the pericytes and smooth muscle cells of vessel walls and CD31 and CD105 labelled a broad range of cell types., (Copyright 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Endothelial cells are active participants in chronic inflammatory diseases. These cells undergo phenotypic changes that can be characterised as activated, angiogenic, apoptotic and leaky. In the present review, these phenotypes are described in the context of human rheumatoid arthritis as the disease example. Endothelial cells become activated in rheumatoid arthritis pathophysiology, expressing adhesion molecules and presenting chemokines, leading to leukocyte migration from the blood into the tissue. Endothelial cell permeability increases, leading to oedema formation and swelling of the joints. These cells proliferate as part of the angiogenic response and there is also a net increase in the turnover of endothelial cells since the number of apoptotic endothelial cells increases. The endothelium expresses various cytokines, cytokine receptors and proteases that are involved in angiogenesis, proliferation and tissue degradation. Associated with these mechanisms is a change in the spectrum of genes expressed, some of which are relatively endothelial specific and others are widely expressed by other cells in the synovium. Better knowledge of molecular and functional changes occurring in endothelial cells during chronic inflammation may lead to the development of endothelium-targeted therapies for rheumatoid arthritis and other chronic inflammatory diseases.