Aberrant CREB1 activation in prostate cancer disrupts normal prostate luminal cell differentiation.

The molecular mechanisms of luminal cell differentiation are not understood well enough to determine how differentiation goes awry during oncogenesis. Using RNA-Seq analysis, we discovered that CREB1 plays a central role in maintaining new luminal cell survival and that oncogenesis dramatically changes the CREB1-induced transcriptome. CREB1 is active in luminal cells, but not basal cells. We identified ING4 and its E3 ligase, JFK, as CREB1 transcriptional targets in luminal cells. During luminal cell differentiation, transient induction of ING4 expression is followed by a peak in CREB1 activity, while JFK increases concomitantly with CREB1 activation. Transient expression of ING4 is required for luminal cell induction; however, failure to properly down-regulate ING4 leads to luminal cell death. Consequently, blocking CREB1 increased ING4 expression, suppressed JFK, and led to luminal cell death. Thus, CREB1 is responsible for the suppression of ING4 required for luminal cell survival and maintenance. Oncogenic transformation by suppressing PTEN resulted in constitutive activation of CREB1. However, the tumor cells could no longer fully differentiate into luminal cells, failed to express ING4, and displayed a unique CREB1 transcriptome. Blocking CREB1 in tumorigenic cells suppressed tumor growth in vivo, rescued ING4 expression, and restored luminal cell formation, but ultimately induced luminal cell death. IHC of primary prostate tumors demonstrated a strong correlation between loss of ING4 and loss of PTEN. This is the first study to define a molecular mechanism whereby oncogenic loss of PTEN, leading to aberrant CREB1 activation, suppresses ING4 expression causing disruption of luminal cell differentiation.

Editor's Choice - Nationwide Analysis of Patients Undergoing Iliac Artery Aneurysm Repair in the Netherlands.

OBJECTIVE: The new 2019 guideline of the European Society for Vascular Surgery (ESVS) recommends consideration for elective iliac artery aneurysm (eIAA) repair when the iliac diameter exceeds 3.5 cm, as opposed to 3.0 cm previously. The current study assessed diameters at time of eIAA repair and ruptured IAA (rIAA) repair and compared clinical outcomes after open surgical repair (OSR) and endovascular aneurysm repair (EVAR). METHODS: This retrospective observational study used the nationwide Dutch Surgical Aneurysm Audit (DSAA) registry that includes all patients who undergo aorto-iliac aneurysm repair in the Netherlands. All patients who underwent primary IAA repair between 1 January 2014 and 1 January 2018 were included. Diameters at time of eIAA and rIAA repair were compared in a descriptive fashion. The anatomical location of the IAA was not registered in the registry. Patient characteristics and outcomes of OSR and EVAR were compared with appropriate statistical tests. RESULTS: The DSAA registry comprised 974 patients who underwent IAA repair. A total of 851 patients were included after exclusion of patients undergoing revision surgery and patients with missing essential variables. eIAA repair was carried out in 713 patients, rIAA repair in 102, and symptomatic IAA repair in 36. OSR was performed in 205, EVAR in 618, and hybrid repairs and conversions in 28. The median maximum IAA diameter at the time of eIAA and rIAA repair was 43 (IQR 38-50) mm and 68 (IQR 58-85) mm, respectively. Mortality was 1.3% (95% CI 0.7-2.4) after eIAA repair and 25.5% (95% CI 18.0-34.7) after rIAA repair. Mortality was not significantly different between the OSR and EVAR subgroups. Elective OSR was associated with significantly more complications than EVAR (intra-operative: 9.8% vs. 3.6%, post-operative: 34.0% vs. 13.8%, respectively). CONCLUSION: In the Netherlands, most eIAA repairs are performed at diameters larger than recommended by the ESVS guideline. These findings appear to support the recent increase in the threshold diameter for eIAA repair.

Diagnosis of prosthetic joint infection with alpha-defensin using a lateral flow device: a multicentre study.

AIMS: The purpose of this current multicentre study is to analyse the presence of alpha-defensin proteins in synovial fluid using the Synovasure lateral flow device and to determine its diagnostic reliability and accuracy compared with the prosthetic joint infection (PJI) criteria produced by the Musculoskeletal Infection Society (MSIS). PATIENTS AND METHODS: A cohort of 121 patients comprising 85 total knee arthroplasties and 36 total hip arthroplasties was prospectively evaluated between May 2015 and June 2016 in three different orthopaedic centres. The tests were performed on patients with a chronically painful prosthesis undergoing a joint aspiration in a diagnostic pathway or during revision surgery. RESULTS: Based on the MSIS criteria, 34 patients (28%) would have had a PJI, and 87 patients had no PJI. Testing with the lateral flow device had a sensitivity of 97.1% (95% confidence intervals (CI) 84.5 to 99.9) and a specificity of 96.6% (95% CI 90.3 to 99.2). The positive predictive value was 91.7% (95% CI 77.7% to 98.3), and the negative predictive value was 98.8% (95% CI 93.6 to 99.9). Receiver operator characteristics analysis demonstrated an area under the curve for the Synovasure test of 0.97 (95% CI 0.93 to 1.00). CONCLUSION: Our findings suggest that the Synovasure test has an excellent diagnostic performance to confirm or reject the diagnosis of a PJI. The results are promising for the care of the painful or problematic knee and hip joint arthroplasty and the test should be considered as part of the diagnostic toolbox for PJIs. Cite this article: Bone Joint J 2017;99-B:1176-82.

[MRI of the pulmonary parenchyma: Towards clinical applicability?] / IRM du parenchyme pulmonaire : vers une application clinique ?

Lung parenchyma has long been considered out of the scope of magnetic resonance imaging (MRI) clinical applicability. However, technological advances have emerged to soluce the technical difficulties and thus, applications in clinical practice have become realistic. Nevertheless, various approaches have been proposed and there is a need to synthetize the most recent literature data in order to envision a rationale to build lung MR protocols for clinical use. In addition, these technological innovations may modify the usual paradigms of lung MRI, which are still not consensual. Thus, lung MR protocols appear to be heterogeneous across expert centers in the current context. In this literature review, we ought to describe a rationale on the need to get an alternative to ionizing imaging modalities, in particular in the follow-up of patients with chronic lung diseases. We will describe the most recent technical advances regarding both morphological and functional MRI. Finally, we will conclude on the clinical applicability of MRI of the pulmonary parenchyma, as a routine or research tool.

Differential FDG-PET Uptake Patterns in Uninfected and Infected Central Prosthetic Vascular Grafts.

OBJECTIVE: (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scanning has been suggested as a means to detect vascular graft infections. However, little is known about the typical FDG uptake patterns associated with synthetic vascular graft implantation. The aim of the present study was to compare uninfected and infected central vascular grafts in terms of various parameters used to interpret PET images. METHODS: From 2007 through 2013, patients in whom a FDG-PET scan was performed for any indication after open or endovascular central arterial prosthetic reconstruction were identified. Graft infection was defined as the presence of clinical or biochemical signs of graft infection with positive cultures or based on a combination of clinical, biochemical, and imaging parameters (other than PET scan data). All other grafts were deemed uninfected. PET images were analyzed using maximum systemic uptake value (SUVmax), tissue to background ratio (TBR), visual grading scale (VGS), and focality of FDG uptake (focal or homogenous). RESULTS: Twenty-seven uninfected and 32 infected grafts were identified. Median SUVmax was 3.3 (interquartile range [IQR] 2.0-4.2) for the uninfected grafts and 5.7 for the infected grafts (IQR 2.2-7.8). Mean TBR was 2.0 (IQR 1.4-2.5) and 3.2 (IQR 1.5-3.5), respectively. On VGS, 44% of the uninfected and 72% of the infected grafts were judged as a high probability for infection. Homogenous FDG uptake was noted in 74% of the uninfected and 31% of the infected grafts. Uptake patterns of uninfected and infected grafts showed a large overlap for all parameters. CONCLUSION: The patterns of FDG uptake for uninfected vascular grafts largely overlap with those of infected vascular grafts. This questions the value of these individual FDG-PET-CT parameters in identifying infected grafts.

Cumulative incidence of graft infection after primary prosthetic aortic reconstruction in the endovascular era.

OBJECTIVE: The introduction of endovascular techniques has had a major impact on the case mix of patients that undergo open aortic reconstruction. Hypothetically, this may also have increased the incidence of aortic graft infection (AGI). The aim of this study was to report on the short and mid-term incidence of AGI after primary open prosthetic aortic reconstruction in the endovascular era. METHODS: From 2000 to 2010, all 514 patients in a tertiary referral university hospital, undergoing primary open prosthetic aortic reconstruction for aneurysmal or occlusive aortic disease with at least one aortic anastomosis were included. Data were obtained by retrospectively analyzing the medical records, by contacting patients or their general practitioner by telephone, and by merging the dataset with the national Cause of Death Register. AGI was defined as proven by cultures or clinically in combination with positive imaging results. The 30 day, 1 year, and 2 year incidence rates were computed using life table analysis and expressed as percentages with 95% confidence intervals (CI). RESULTS: AGI was diagnosed in 23 of the 514 included patients. 56% of the patients underwent elective surgery and 86% underwent surgery for an abdominal aortic aneurysm. The 30 day incidence was 1.6% (95% CI 0.4-2.8%), 1 year incidence was 3.6% (95% CI 1.7-5.5%), and 2 year incidence for AGI was 4.5% (95% CI 2.4-6.6%). The total number of person years (1058) yielded an AGI rate of 2.2 per 100 person years. CONCLUSION: The 2 year cumulative incidence of AGI following primary, open aortic procedures with at least one aortic anastomosis is considerable, at around 1 in 20.

Current opinions about diagnosis and treatment strategy for aortic graft infections in The Netherlands.

AIM: Aortic graft infection (AGI) is a dreaded complication in vascular surgery. Research on AGI is hampered by its rarity combined with a broad range of clinical presentation in critically ill patients. This report aims to explore the various current opinions on the diagnosis and treatment of AGI. METHODS: A questionnaire was sent to all members of the Dutch Society of Vascular Surgery. Six weeks after the initial questionnaire a reminder was sent. A total of 306 questionnaires were sent. Data were analyzed for 124 vascular surgeons (VS) and 19 vascular surgeons in training (VT). Data analysis was performed in a descriptive manner. RESULTS: Total response rate was 51.3%, Response rate of the VS and VT combined was 47%. 85% of the VS versus 58% of VT rely on computed tomography scanning (CT) scanning for diagnosing AGI. Positron emission tomography scanning with CT fusion was used by 40% of VS versus 58% of VT. Antibiotic treatment was started at the first suspicion of AGI by 52% of VS and 58% of VT. 13 different opinions were noted on total antibiotic duration. Extra-anatomic bypass (EAB) was used by and 42% of VT. In-situ reconstructions were used by 59% of VS versus % of VT. Venous reconstructions were the first reconstruction choice in 63% VS and 52% of VT. Antibiotic-bonded grafts were used by 17% of VS and 16% of VT. CONCLUSION: This survey shows highly mixed opinions about clinical diagnosis, diagnostic imaging, and treatment of AGI, reflecting available literature. Further research is therefore desperately needed. More research and development of treatment guidelines is needed to reach uniformity and consensus for patients with infected vascular grafts.

Association of adenovirus 36 infection with adiposity and inflammatory-related markers in children.

CONTEXT: Although animal studies suggest that adenovirus 36 (Ad36) infection is linked to obesity and systemic inflammation, human data are scant and equivocal. OBJECTIVE: Associations of Ad36 infection with total body adiposity and inflammatory-related markers were determined in 291 children aged 9-13 years (50% female, 49% black). DESIGN: Fasting blood samples were measured for presence of Ad36-specific antibodies and TNF-α, IL-6, vascular endothelial growth factor (VEGF), and monocyte chemoattractant protein-1 (MCP-1). Fat mass and fat-free soft tissue mass were measured by dual-energy X-ray absorptiometry. RESULTS: The overall prevalence of Ad36 seropositivity [Ad36(+)] was 42%. There was a higher percentage of Ad36(+) children in the highest tertiles of TNF-α and IL-6 compared with their respective middle and lowest tertiles (both P < .03). There was also a trend toward a higher prevalence of Ad36(+) children in the highest tertile of VEGF compared with tertiles 1 and 2 (P = .05). Multinomial logistic regression, adjusting for age, race, sex, and fat-free soft tissue mass, revealed that compared with children with the lowest TNF-α, IL-6, and VEGF levels (tertile 1), the adjusted odds ratios for Ad36(+) were 2.2 [95% confidence interval (CI) 1.2-4.0], 2.4 (95% CI 1.4-4.0), and 1.8 (95% CI 1.0-3.3), respectively, for those in the highest TNF-α, IL-6, and VEGF levels (tertile 3). No association was observed between Ad36(+) and greater levels of fat mass or MCP-1 (all P > .05). CONCLUSIONS: In children, our data suggest that Ad36(+) may be associated with biomarkers implicated in inflammation but not with greater levels of fat mass.

Risk factors of Ganciclovir-related neutropenia after allogeneic stem cell transplantation: a retrospective monocentre study on 547 patients.

Cytomegalovirus (CMV) infection is a serious complication that may occur in the weeks or months following bone marrow transplantation. However, both Ganciclovir and the CMV infection itself can cause marrow toxicity, notably neutropenia, that may consequently expose these immunosuppressed patients to life-threatening bacterial and/or fungal infections. The aim of this retrospective study was to identify factors associated with the occurrence of grade III-IV neutropenia among patients receiving pre-emptive Ganciclovir therapy after allogeneic stem cell transplantation at our Institution. We identified 547 consecutive patients transplanted from January 2005 to June 2011 at our Institution. In all, 190 patients (35%) presented with CMV reactivation of whom 30 patients (5%) were excluded from the analysis because they already had neutropenia at the time of reactivation. Finally, 160 (29%) patients were analysed. According to multivariate analysis, at the time of treatment initiation, the risk factors significantly associated with a grade III-IV Ganciclovir-related neutropenia included a high viral load (hazard ratio (HR) = 2.68, 95% CI 1.25-5.737, p 0.01); an absolute neutrophil count >3000 was a protective factor (HR = 0.26, 95% CI 0.125-0.545, p <0001) whereas serum creatinine >2 mg/dL was associated with higher Ganciclovir-related neutropenia (HR = 2.4, 95% CI 1.11-5.17, p 0.002). This large analysis revealed three risk factors for Ganciclovir-related neutropenia among patients with CMV reactivation after allogeneic stem cell transplantation; prompt identification of patients at risk when antiviral therapy is started may allow clinicians to adopt adequate preventive measures, so reducing the morbidity and mortality associated with CMV reactivation.

Alveolar echinococcosis in a Belgian urban dweller.

Human alveolar echinococcosis is a rare parasitic disease caused by larvae of the tapeworm E. multilocularis that colonizes the intestines of foxes. The disease predominantly affects the liver and mimics slow growing liver cancer. With a mere 13 reports coming mostly from southern rural regions Belgium has so far been spared from the disease. However alveolar echinococcosis appears to be slowly spreading to non-endemic European countries like Belgium and to urban centres. We report the first autochthonous case involving a patient having lived exclusively in downtown Brussels. Heightened awareness by the medical community is necessary to detect this lethal disease at an early curable stage. In patients with an undetermined focal liver lesion--especially if calcified--and no firm evidence of malignancy, serological screening should be performed to exclude alveolar echinococcosis.

Localized argyria caused by metallic silver aortic grafts: a unique adverse effect.

INTRODUCTION: Silver-coated grafts are designed to prevent vascular graft infections. Silver is a safe element but toxic effects have been reported. We describe two cases of possible localized argyria after silver graft implantation. REPORT: Two patients presented with perigraft groin collections after implantation of silver grafts. During reoperation, an ashen-grey necrotic substance was seen surrounding the grafts. The grafts were explanted and lower limb perfusion restored. Cultures were negative and both patients had uneventful recoveries. DISCUSSION: Our cases are highly suggestive of a possible unique adverse effect: a combination of localized silver toxicity and neutrophilic mediated tissue destruction.

Candidate epitopes for measurement of hCG and related molecules: the second ISOBM TD-7 workshop.

Participants of the Second International Workshop (WS) on human chorionic gonadotropin (hCG) of the International Society of Oncology and Biomarkers Tissue Differentiation 7 (ISOBM TD-7) have characterized in detail a panel of 69 antibodies (Abs) directed against hCG and hCG-related variants that were submitted by eight companies and research groups. Specificities of the Abs were determined using the First WHO International Reference Reagents for six hCG variants, i.e., hCG, hCGn, hCGß, hCGßn, hCGßcf, and hCGα, which are calibrated in SI units, and hLH. Molecular epitope localizations were assigned to the ISOBM-mAbs by comparing ISOBM-Ab specificity, sandwich compatibility, and mutual inhibition profiles, to those of 17 reference monoclonal (m)Abs of known molecular epitope specificities. It appeared that 48 Abs recognized hCGß-, 8 hCGα-, and 13 αß-heterodimer-specific epitopes. Twenty-seven mAbs were of pan hCG specificity, two thereof with no (<0.1%; epitope ß1), 12 with low (<1.0%; epitopes ß2/4), and 13 with high (>>1%; epitopes ß3/5) hLH cross-reactivity. The majority of hCGß epitopes recognized were located in two major antigenic domains, one on the peptide chain of the tips of ß-sheet loops 1 and 3 (epitopes ß2-6; 27 mAbs) and the second around the cystine knot (e.g., epitopes ß1, ß7, and ß10; 9 mAbs). Four mAbs recognized epitopes on hCGßcf-only (e.g., epitopes ß11 and ß13) and six mAbs epitopes on the remote hCGß-carboxyl-terminal peptide (epitopes ß8 and ß9 corresponding to amino acids 135-144 and 111-116, respectively). For routine diagnostic measurements, methods are used that either detect hCG-only, hCGß-only, or hCG together with hCGß or hCG together with hCGß and hCGßcf. Sandwich assays that measure hCG plus hCGß and eventually hCGßcf should recognize the protein backbone of the analytes preferably on an equimolar basis, should not cross-react with hLH and not be susceptible to blunting of signal by nonmeasured variants like hCGßcf. Such assays can be constructed using pairs of mAbs directed against the cystine knot-associated epitope ß1 (Asp10, Asp60, and Gln89) in combination with epitopes ß2 or ß4 located at the top of ß-sheet loops 1 + 3 of hCGß involving aa hCGß20-25 + 68-77. In summary, the results of the First and Second ISOBM TD-7 WSs on hCG provide the basis for harmonization of specificities and epitopes of mAbs to be used in multifunctional and selective diagnostic hCG methods for different clinical purposes.

Efficacy and safety of micafungin for prophylaxis of invasive fungal infections in patients undergoing haplo-identical hematopoietic SCT.

Invasive fungal infections (IFIs) such as candidiasis and mold infections have caused significant morbidity and mortality among immunocompromised patients in recent years. Micafungin, a new echinocandin, inhibits fungal cell wall ß-glucan synthesis, with potent activity against most species of Candida and Aspergillus. The aim of this observational study was to investigate the efficacy and safety of micafungin in prophylaxis of IFIs in 26 high-risk adult patients with various hematological diseases receiving haplo-identical Allo-SCT. Only two patients had a history of possible aspergillosis before transplant treated by voriconazole. The patients received a median of four lines (2-7) of treatment before Allo-SCT. Thirteen patients (50%) received at least one prior Auto-SCT; and eight patients (31%) received a previous Allo-SCT. Patients received a median of 29 infusions (range, 15-85) of micafungin (50 mg/day i.v. as a 1-h infusion). The treatment was initiated at the beginning of the transplant conditioning regimen until the hospital discharge. None of our patients discontinued the treatment for drug-related adverse events. Micafungin was not associated with any hepatotoxicity. Only one patient (4%) discontinued the treatment because of early disease progression. In all patients no Candida and/or Aspergillus species was documented after 3 and 6 months from transplant. None of our patients presented a positive galactomannan antigenemia >0.5. Nine patients (35%) presented a CMV reactivation. Four patients presented an acute GVHD grade II and two patients presented a chronic GVHD. The median follow-up was 11 months (3-23). At the last follow-up, there were 20 patients (77%) who were alive; four patients (12%) died because of disease progression and two patients because of graft failure. Micafungin has a good safety and tolerability profile, with an efficacy in preventing IFI in this high-risk population. Our data provide support for an efficacy study in a prophylaxis setting, but prospective and comparative clinical trials using micafungin are urgently needed to define the role of this drug in prophylaxis after haplo-identical Allo-SCT.

Surgical treatment of infected aortic grafts.

An infection of an aortic prosthesis is a severe condition with high morbidity and mortality rates. Surgical treatment of an infected aortic graft or infected aortic stent-graft focuses on treatment of the infection and maintaining or restoring perfusion of the lower limbs. Over the years various reconstruction options have been introduced, each claiming to be the most successful in securing lower limb perfusion. Consensus about the optimum treatment strategy is lacking. The frail patient population and the relative rarity of the disease limits research on this topic which is an important reason for this lack of consensus. In order to determine which of the various treatment options is the most suitable to treat aortic graft infections, this systematic review was conducted of the available literature of the last 20 years. The search strategy and data collection were based on the guidelines of the Meta-analysis Of Observational Studies in Epidemiology (MOOSE). Appropriate inclusion and exclusion criteria were defined. A total of 862 possibly relevant papers were identified. After applying the in- and exclusion, data on mortality, morbidity and complications were extracted from a total of 93 papers. This review covers the various surgical treatment options available in the treatment of infected aortic (stent) grafts. Strategies concerning graft excision are discussed as are the advantages and disadvantages of the extra-anatomic reconstruction and its counterpart, the in situ reconstruction (using antibiotic-impregnated grafts, autologous vein grafts, fresh or cryopreserved allografts, and silver impregnated grafts). Available evidence was summarized and used to construct a clinical decision flowchart. All reconstruction options seem to have their pros and cons, and all have their use in specific situations. The treatment of infected aortic grafts must therefore be tailor-made.

Surgical treatment of infected aortic grafts.

An infection of an aortic prosthesis is a severe condition with high morbidity and mortality rates. Surgical treatment of an infected aortic graft or infected aortic stent-graft focuses on treatment of the infection and maintaining or restoring perfusion of the lower limbs. Over the years various reconstruction options have been introduced, each claiming to be the most successful in securing lower limb perfusion. Consensus about the optimum treatment strategy is lacking. The frail patient population and the relative rarity of the disease limits research on this topic which is an important reason for this lack of consensus. In order to determine which of the various treatment options is the most suitable to treat aortic graft infections, this systematic review was conducted of the available literature of the last 20 years. The search strategy and data collection were based on the guidelines of the Meta-analysis Of Observational Studies in Epidemiology (MOOSE). Appropriate inclusion and exclusion criteria were defined. A total of 862 possibly relevant papers were identified. After applying the in- and exclusion, data on mortality, morbidity and complications were extracted from a total of 93 papers. This review covers the various surgical treatment options available in the treatment of infected aortic (stent) grafts. Strategies concerning graft excision are discussed as are the advantages and disadvantages of the extra-anatomic reconstruction and its counterpart, the in situ reconstruction (using antibiotic-impregnated grafts, autologous vein grafts, fresh or cryopreserved allografts, and silver impregnated grafts). Available evidence was summarized and used to construct a clinical decision flowchart. All reconstruction options seem to have their pros and cons, and all have their use in specific situations. The treatment of infected aortic grafts must therefore be tailor-made.

Seminal plasma enhances and accelerates progesterone-induced decidualisation of human endometrial stromal cells.

In preparation for embryo implantation, endometrial stromal cells (ESC) undergo differentiation, termed decidualisation. Enhancing endometrial decidualisation may overcome reduced endometrial receptivity, a major limiting factor in natural and assisted reproduction. To determine whether seminal plasma (SP) influences decidualisation, primary human ESC were treated with progesterone (P4, 50 ng mL(-1)) in the presence or absence of dialysed SP (0.5%) for 24 h or for up to 27 days to investigate immediate early effects or the effects of prolonged exposure, respectively. Combined SP and P4 treatment induced ESC morphological differentiation. Relative to control, P4 alone, and SP alone combined treatment with SP and P4 for 27 days significantly upregulated mRNA levels of the decidua-specific markers prolactin (PRL) and insulin-like growth factor binding protein 1 (IGFBP1). Consistently, PRL protein secretion was significantly increased over the course of 27 days combined SP and P4 treatment relative to control, P4 alone and SP alone. Likewise, IGFBP1 secretion was significantly greater relative to control and P4 alone over the course of 27 days. Thus, SP enhances and accelerates P4-mediated decidualisation of human ESC and may enhance endometrial receptivity.

Beyond corticosteroids: future prospects in the management of inflammation in COPD.

Inflammation plays a central role in the pathophysiology of chronic obstructive pulmonary disease (COPD). Exposure to cigarette smoke induces the recruitment of inflammatory cells in the airways and stimulates innate and adaptive immune mechanisms. Airway inflammation is involved in increased bronchial wall thickness, increased bronchial smooth muscle tone, mucus hypersecretion and loss of parenchymal elastic structures. Oxidative stress impairs tissue integrity, accelerates lung ageing and reduces the efficacy of corticosteroids by decreasing levels of histone deacetylase-2. Protease-antiprotease imbalance impairs tissues and is involved in inflammatory processes. Inflammation is also present in the pulmonary artery wall and at the systemic level in COPD patients, and may be involved in COPD-associated comorbidities. Proximal airways inflammation contributes to symptoms of chronic bronchitis while distal and parenchymal inflammation relates to airflow obstruction, emphysema and hyperinflation. Basal levels of airways and systemic inflammation are increased in frequent exacerbators. Inhaled corticosteroids are much less effective in COPD than in asthma, which relates to the intrinsically poor reversibility of COPD-related airflow obstruction and to molecular mechanisms of resistance relating to oxidative stress. Ongoing research aims at developing new drugs targeting more intimately COPD-specific mechanisms of inflammation, hypersecretion and tissue destruction and repair. Among new anti-inflammatory agents, phosphodiesterase-4 inhibitors have been the first to emerge.

[COPD and inflammation: Statement from a French expert group. How to treat inflammation?]. / BPCO et inflammation : mise au point d'un groupe d'experts. Comment traiter l'inflammation ?

INTRODUCTION: Management of chronic obstructive pulmonary disease (COPD) has made considerable progress over the last 15 years, with the development of pulmonary rehabilitation, new molecules to facilitate smoking cessation, and several medical treatments. Many therapeutic needs, however, remain to be met. STATE OF THE ART: Several lines of research on inflammation and COPD are promising, and some will probably result in new treatments. These may target specific populations, identified by clinical phenotype or by biomarkers. The forthcoming arrival of iPDE-4s on the market illustrates how knowledge of inflammation and remodeling and of some of the underlying mechanisms finally, after many years' development, has broadened the range of treatments available to help improve patients' daily life and outcomes. PERSPECTIVES AND CONCLUSIONS: The availability of such treatments, however, does not mean that knowledge of the disease in the general population and among healthcare workers can be neglected. Early detection (at a stage when treatment can already be effective) and patient education which promotes therapeutic compliance and lasting lifestyle change need to be developed further.

[COPD and inflammation: statement from a French expert group. Phenotypes related to inflammation]. / BPCO et inflammation: mise au point d'un groupe d'experts. Les phénotypes en lien avec l'inflammation.

INTRODUCTION: The objective of the present article is to review available data on possible links between phenotypes and inflammatory profiles in patients with chronic obstructive pulmonary disease (COPD). BACKGROUND: Chronic bronchitis is associated with proximal bronchial inflammation and small airway inflammation with remodeling at the site of obstruction. CT scanning enables patients to be phenotyped according to the predominantly bronchial or emphysematous nature of the morphological abnormality. Exacerbations, in a context of persistently elevated baseline inflammation, are associated with increased inflammation and a poor prognosis. Long-term studies have correlated inflammatory markers (and anti-inflammatory drug effects) with dynamic hyperinflation, possibly confirming that inflammation promotes hyperinflation. The inflammatory cell count in the pulmonary arterial walls correlates with the severity of endothelial dysfunction. The risk of developing pulmonary hypertension would seem to increase with low-grade systemic inflammation. The role of low-grade systemic inflammation in COPD co-morbidities, and in nutritional and muscular involvement in particular, remains a matter of debate. Regular physical exercise may help reduce this inflammation. CONCLUSIONS: In COPD, many aspects of the clinical phenotype are related to inflammation. Better knowledge of these relationships could help optimize current and future treatments.