Epithelial NAIPs protect against colonic tumorigenesis.

NLR family apoptosis inhibitory proteins (NAIPs) belong to both the Nod-like receptor (NLR) and the inhibitor of apoptosis (IAP) families. NAIPs are known to form an inflammasome with NLRC4, but other in vivo functions remain unexplored. Using mice deficient for all NAIP paralogs (Naip1-6(Δ/Δ)), we show that NAIPs are key regulators of colorectal tumorigenesis. Naip1-6(Δ/Δ) mice developed increased colorectal tumors, in an epithelial-intrinsic manner, in a model of colitis-associated cancer. Increased tumorigenesis, however, was not driven by an exacerbated inflammatory response. Instead, Naip1-6(Δ/Δ) mice were protected from severe colitis and displayed increased antiapoptotic and proliferation-related gene expression. Naip1-6(Δ/Δ) mice also displayed increased tumorigenesis in an inflammation-independent model of colorectal cancer. Moreover, Naip1-6(Δ/Δ) mice, but not Nlrc4-null mice, displayed hyper-activation of STAT3 and failed to activate p53 18 h after carcinogen exposure. This suggests that NAIPs protect against tumor initiation in the colon by promoting the removal of carcinogen-elicited epithelium, likely in a NLRC4 inflammasome-independent manner. Collectively, we demonstrate a novel epithelial-intrinsic function of NAIPs in protecting the colonic epithelium against tumorigenesis.

Host genetics of invasive Aspergillus and Candida infections.

Invasive candidiasis and aspergillosis are major complications in surgical and onco-hematological patients, and still associated with an important morbidity and mortality. A large number of studies highlighted the potential role of host genetic polymorphisms that may influence susceptibility to fungal pathogens, but many were limited by insufficient statistical power, problematic design, and/or lack of replication. However, some relevant polymorphisms are now emerging from well-conducted studies whose associations have been replicated and/or are supported by strong biological evidence. Such polymorphisms together with other biomarkers may play a role in the prediction, diagnosis, and management of severe fungal infections in high-risk patients in the coming years.

ENaC-mediated alveolar fluid clearance and lung fluid balance depend on the channel-activating protease 1.

Sodium transport via epithelial sodium channels (ENaC) expressed in alveolar epithelial cells (AEC) provides the driving force for removal of fluid from the alveolar space. The membrane-bound channel-activating protease 1 (CAP1/Prss8) activates ENaC in vitro in various expression systems. To study the role of CAP1/Prss8 in alveolar sodium transport and lung fluid balance in vivo, we generated mice lacking CAP1/Prss8 in the alveolar epithelium using conditional Cre-loxP-mediated recombination. Deficiency of CAP1/Prss8 in AEC induced in vitro a 40% decrease in ENaC-mediated sodium currents. Sodium-driven alveolar fluid clearance (AFC) was reduced in CAP1/Prss8-deficient mice, due to a 48% decrease in amiloride-sensitive clearance, and was less sensitive to beta(2)-agonist treatment. Intra-alveolar treatment with neutrophil elastase, a soluble serine protease activating ENaC at the cell surface, fully restored basal AFC and the stimulation by beta(2)-agonists. Finally, acute volume-overload increased alveolar lining fluid volume in CAP1/Prss8-deficient mice. This study reveals that CAP1 plays a crucial role in the regulation of ENaC-mediated alveolar sodium and water transport and in mouse lung fluid balance.

Importance of a three-dimensional measure of humeral head subluxation in osteoarthritic shoulders.

HYPOTHESIS: During total shoulder arthroplasty (TSA), humeral head subluxation may be difficult to manage. Furthermore, there is a risk for postoperative recurrence of subluxation, affecting the outcome of TSA. An accurate evaluation of the subluxation is necessary to evaluate this risk. Currently, subluxation is measured in 2 dimensions (2D), usually relative to the glenoid face. The goal of this study was to extend this measure to 3 dimensions (3D) to compare glenohumeral and scapulohumeral subluxation and to evaluate the association of subluxation with the glenoid version. MATERIALS AND METHODS: The study analyzed 112 computed tomography scans of osteoarthritic shoulders. We extended the usual 2D definition of glenohumeral subluxation, scapulohumeral subluxation, and glenoid version by measuring their orientation in 3D relative to the scapular plane and the scapular axis. We evaluated statistical associations between subluxation and version in 2D and 3D. RESULTS: Orientation of subluxation and version covered all sectors of the glenoid surface. Scapulohumeral subluxation and glenoid version were highly correlated in amplitude (R(2) = 0.71; P < .01) and in orientation (R(2) = 0.86; P < .01). Approximately every degree of glenoid version induced 1% of scapulohumeral subluxation in the same orientation of the version. Conversely, glenohumeral subluxation was not correlated to glenoid version in 2D or in 3D. CONCLUSIONS: Orientation of the humeral subluxation is rarely within the arbitrary computed tomography plane and should therefore be measured in 3D to detect out-of-plane subluxation. Scapulohumeral subluxation and glenoid version measured in 3D could bring valuable information for decision making during TSA.

Chest pain in daily practice: occurrence, causes and management

QUESTIONS UNDER STUDY: We assessed the occurrence and aetiology of chest pain in primary care practice. These features differ between primary and emergency care settings, where most previous studies have been performed. METHODS: 59 GPs in western Switzerland recorded all consecutive cases presenting with chest pain. Clinical characteristics, laboratory tests and other investigations as well as the diagnoses remaining after 12 months of follow-up were systematically registered. RESULTS: Among 24,620 patients examined during a total duration of 300 weeks of observation, 672 (2.7%) presented with chest pain (52% female, mean age 55 +/- 19(SD)). Most cases, 442 (1.8%), presented new symptoms and in 356 (1.4%) it was the reason for consulting. Over 40 ailments were diagnosed: musculoskeletal chest pain (including chest wall syndrome) (49%), cardiovascular (16%), psychogenic (11%), respiratory (10%), digestive (8%), miscellaneous (2%) and without diagnosis (3%). The three most prevalent diseases were: chest wall syndrome (43%), coronary artery disease (12%) and anxiety (7%). Unstable angina (6), myocardial infarction (4) and pulmonary embolism (2) were uncommon (1.8%). Potentially serious conditions including cardiac, respiratory and neoplasic diseases accounted for 20% of cases. A large number of laboratory tests (42%), referral to a specialist (16%) or hospitalisation (5%) were performed. Twentyfive patients died during follow-up, of which twelve were for a reason directly associated with thoracic pain [cancer (7) and cardiac causes (5)]. CONCLUSIONS: Thoracic pain was present in 2.7% of primary care consultations. Chest wall syndrome pain was the main aetiology. Cardio - vascular emergencies were uncommon. However chest pain deserves full consideration because of the occurrence of potentially serious conditions.

Disrupting the EMMPRIN (CD147)-cyclophilin A interaction reduces infarct size and preserves systolic function after myocardial ischemia and reperfusion.

Objective-Inflammation and proteolysis crucially contribute to myocardial ischemia and reperfusion injury. The extracellular matrix metalloproteinase inducer EMMPRIN (CD147) and its ligand cyclophilin A (CyPA) may be involved in both processes. The aim of the study was to characterize the role of the CD147 and CyPA interplay in myocardial ischemia/reperfusion (I/R) injury.Methods and Results-Immunohistochemistry showed enhanced expression of CD147 and CyPA in myocardial sections from human autopsies of patients who had died from acute myocardial infarction and from mice at 24 hours after I/R. At 24 hours and 7 days after I/R, the infarct size was reduced in CD147(+/-) mice vs CD147(+/+) mice (C57Bl/6), in mice (C57Bl/6) treated with monoclonal antibody anti-CD147 vs control monoclonal antibody, and in CyPA(-/-) mice vs CyPA(+/+) mice (129S6/SvEv), all of which are associated with reduced monocyte and neutrophil recruitment at 24 hours and with a preserved systolic function at 7 days. The combination of CyPA(-/-) mice with anti-CD147 treatment did not yield further protection compared with either inhibition strategy alone. In vitro, treatment with CyPA induced monocyte chemotaxis in a CD147-and phosphatidylinositol 3-kinase-dependent manner and induced monocyte rolling and adhesion to endothelium (human umbilical vein endothelial cells) under flow in a CD147-dependent manner.Conclusion-CD147 and its ligand CyPA are inflammatory mediators after myocardial ischemia and reperfusion and represent potential targets to prevent myocardial I/R injury.

Endogenous cannabinoid receptor CB1 activation promotes vascular smooth-muscle cell proliferation and neointima formation.

Percutaneous transluminal angioplasty is frequently used in patients with severe arterial narrowing due to atherosclerosis. However, it induces severe arterial injury and an inflammatory response leading to restenosis. Here, we studied a potential activation of the endocannabinoid system and the effect of FA amide hydrolase (FAAH) deficiency, the major enzyme responsible for endocannabinoid anandamide degradation, in arterial injury. We performed carotid balloon injury in atherosclerosis-prone apoE knockout (apoE(-/-)) and apoE(-/-)FAAH(-/-) mice. Anandamide levels were systemically elevated in apoE(-/-) mice after balloon injury. ApoE(-/-)FAAH(-/-) mice had significantly higher baseline anandamide levels and enhanced neointima formation compared with apoE(-/-) controls. The latter effect was inhibited by treatment with CB1 antagonist AM281. Similarly, apoE(-/-) mice treated with AM281 had reduced neointimal areas, reduced lesional vascular smooth-muscle cell (SMC) content, and proliferating cell counts. The lesional macrophage content was unchanged. In vitro proliferation rates were significantly reduced in CB1(-/-) SMCs or when treating apoE(-/-) or apoE(-/-)FAAH(-/-) SMCs with AM281. Macrophage in vitro adhesion and migration were marginally affected by CB1 deficiency. Reendothelialization was not inhibited by treatment with AM281. In conclusion, endogenous CB1 activation contributes to vascular SMC proliferation and neointima formation in response to arterial injury.

Perceived discrimination against diabetics in the workplace and in work-related insurances in Switzerland.

To investigate the prevalence and risk factors of perceived diabetes-related discrimination in the workplace and in work-related insurances in persons with diabetes mellitus in Switzerland. 509 insulin-treated diabetic subjects representative of the northwestern Swiss population responded to a self-report questionnaire on perceived diabetes-related discrimination in the workplace and in work-related insurances (salary loss insurance, supplementary occupational plan). Discrimination was defined as being treated differently at least once in relation to diabetes. The reported rates of different aspects of discrimination in the workplace and in work-related insurances ranged between 5-11% and 4-15% respectively. Risk factors that independently increased the risk of not being hired due to diabetes were the presence of at least two severe hypoglycaemic events/year and relevant diabetic complications (OR 5.6 and OR 2.6 respectively; both<0.05). The presence of at least two severe hypoglycaemic events/year was also associated with an increased risk of losing one's job (OR 6.5, <0.01). Overweight or obesity were related to increased discrimination in work-related insurances (OR for denial 2.1-2.4; OR for reserve 3.9-4.4; all<0.05). Perceived diabetes-related discrimination in the workplace and by work-related insurances is a common problem. In the light of our findings the introduction of effective non-discrimination legislation for patients with chronic illnesses appears to be desirable.

How critical is timing for the diagnosis of influenza in general practice?

QUESTIONS UNDER STUDY: The diagnostic significance of clinical symptoms/signs of influenza has mainly been assessed in the context of controlled studies with stringent inclusion criteria. There was a need to extend the evaluation of these predictors not only in the context of general practice but also according to the duration of symptoms and to the dynamics of the epidemic. PRINCIPLES: A prospective study conducted in the Medical Outpatient Clinic in the winter season 1999-2000. Patients with influenza-like syndrome were included, as long as the primary care physician envisaged the diagnosis of influenza. The physician administered a questionnaire, a throat swab was performed and a culture acquired to document the diagnosis of influenza. RESULTS: 201 patients were included in the study. 52% were culture positive for influenza. By univariate analysis, temperature >37.8 degrees C (OR 4.2; 95% CI 2.3-7.7), duration of symptoms <48 hours (OR 3.2; 1.8-5.7), cough (OR 3.2; 1-10.4) and myalgia (OR 2.8; 1.0-7.5) were associated with a diagnosis of influenza. In a multivariable logistic analysis, the best model predicting influenza was the association of a duration of symptom <48 hours, medical attendance at the beginning of the epidemic (weeks 49-50), fever >37.8 and cough, with a sensitivity of 79%, specificity of 69%, positive predictive value of 67%, negative predictive value of 73% and an area under the ROC curve of 0.74. CONCLUSIONS: Besides relevant symptoms and signs, the physician should also consider the duration of symptoms and the epidemiological context (start, peak or end of the epidemic) in his appraisal, since both parameters considerably modify the value of the clinical predictors when assessing the probability of a patient having influenza.

A simple, robust and rapid approach to detect carbapenemases in Gram-negative isolates by MALDI-TOF mass spectrometry: validation with triple quadripole tandem mass spectrometry, microarray and PCR.

Carbapenemases should be accurately and rapidly detected, given their possible epidemiological spread and their impact on treatment options. Here, we developed a simple, easy and rapid matrix-assisted laser desorption ionization-time of flight (MALDI-TOF)-based assay to detect carbapenemases and compared this innovative test with four other diagnostic approaches on 47 clinical isolates. Tandem mass spectrometry (MS-MS) was also used to determine accurately the amount of antibiotic present in the supernatant after 1 h of incubation and both MALDI-TOF and MS-MS approaches exhibited a 100% sensitivity and a 100% specificity. By comparison, molecular genetic techniques (Check-MDR Carba PCR and Check-MDR CT103 microarray) showed a 90.5% sensitivity and a 100% specificity, as two strains of Aeromonas were not detected because their chromosomal carbapenemase is not targeted by probes used in both kits. Altogether, this innovative MALDI-TOF-based approach that uses a stable 10-μg disk of ertapenem was highly efficient in detecting carbapenemase, with a sensitivity higher than that of PCR and microarray.