[Loco-regional complications of pharyngitis: the example of Lemierre's syndrome]. / Complications locorégionales des pharyngites: 1'exemple du syndrome de Lemierre.

Pharyngitis is a common cause of consultation in ambulatory medicine. Although it is benign in most cases, serious complications may happen and must be recognized quickly. Lemierre's syndrome is one of them. It consists in the association of thrombosis of the internal jugular vein and septic emboli that generally involve the lungs and is classically associated with Fusobacterium necrophorum. It is usually found in young and healthy adults and has an estimated mortality of 5%. Diagnosis relies essentially on the characteristic presentation of the disease. Therapy consists of surgical drainage of purulent collections and necrotic tissues associated with a prolonged course of antibiotics. Some authors also recommend a anticoagulation.

Metabolic gene expression changes in astrocytes in Multiple Sclerosis cerebral cortex are indicative of immune-mediated signaling.

Emerging as an important correlate of neurological dysfunction in Multiple Sclerosis (MS), extended focal and diffuse gray matter abnormalities have been found and linked to clinical manifestations such as seizures, fatigue and cognitive dysfunction. To investigate possible underlying mechanisms we analyzed the molecular alterations in histopathological normal appearing cortical gray matter (NAGM) in MS. By performing a differential gene expression analysis of NAGM of control and MS cases we identified reduced transcription of astrocyte specific genes involved in the astrocyte-neuron lactate shuttle (ANLS) and the glutamate-glutamine cycle (GGC). Additional quantitative immunohistochemical analysis demonstrating a CX43 loss in MS NAGM confirmed a crucial involvement of astrocytes and emphasizes their importance in MS pathogenesis. Concurrently, a Toll-like/IL-1ß signaling expression signature was detected in MS NAGM, indicating that immune-related signaling might be responsible for the downregulation of ANLS and GGC gene expression in MS NAGM. Indeed, challenging astrocytes with immune stimuli such as IL-1ß and LPS reduced their ANLS and GGC gene expression in vitro. The detected upregulation of IL1B in MS NAGM suggests inflammasome priming. For this reason, astrocyte cultures were treated with ATP and ATP/LPS as for inflammasome activation. This treatment led to a reduction of ANLS and GGC gene expression in a comparable manner. To investigate potential sources for ANLS and GGC downregulation in MS NAGM, we first performed an adjuvant-driven stimulation of the peripheral immune system in C57Bl/6 mice in vivo. This led to similar gene expression changes in spinal cord demonstrating that peripheral immune signals might be one source for astrocytic gene expression changes in the brain. IL1B upregulation in MS NAGM itself points to a possible endogenous signaling process leading to ANLS and GGC downregulation. This is supported by our findings that, among others, MS NAGM astrocytes express inflammasome components and that astrocytes are capable to release Il-1ß in-vitro. Altogether, our data suggests that immune signaling of immune- and/or central nervous system origin drives alterations in astrocytic ANLS and GGC gene regulation in the MS NAGM. Such a mechanism might underlie cortical brain dysfunctions frequently encountered in MS patients.

Sleep fragmentation and sleep-disordered breathing in individuals living close to main roads: results from a population-based study.

BACKGROUND: Nighttime traffic noise is associated with sleep disturbances, but sleep fragmentation and sleep-disordered breathing (SDB) have not been demonstrated in individuals living near busy roads. METHODS: We asked 1383 participants to answer a health questionnaire and to undergo 24-h electrocardiogram (ECG). Nocturnal ECG records were used to calculate the very low frequency index (VLFI) interval, a surrogate marker of sleep fragmentation. Distances of participants' addresses to roadways were calculated using the VECTOR25© Swisstopo roads classification, a traffic noise proxy. Distances of homes within 100 or 50 m of major roads defined proximity to busy roads. Adjusted multivariate logistic regressions analyzed associations between the distance of home to main roads and VLFI or self-reported SDB. RESULTS: Distance of participants' homes to main roads was significantly associated with the VLFI in women (odds ratio [OR], 1.58 [confidence interval {CI}, 1.03-2.42]; P = .038) but not in men (OR, 1.35 [CI, 0.77-2.35]; P = .295). Women under hormonal replacement therapy (HRT) were at higher risk for increased VLFI when living close to main roads (OR, 2.10 [CI, 1.20-3.68]; P = .01) than untreated women (P = .584). Associations with self-reported SDB were not statistically relevant. CONCLUSIONS: In our large population, women living close to main roads were at significantly higher risk for sleep fragmentation than men. The 2-fold higher risk for menopausal women under HRT underscores the vulnerability of this group.

Acute respiratory health effects of urban air pollutants in adults with different patterns of underlying respiratory disease.

OBJECTIVE: Whether underlying chronic respiratory diseases are susceptible factors for symptomatic episodes, which lead to primary-level care, in association with air pollutant exposures is unknown. We evaluated and compared association lag structures between daily ambient levels of nitrogen dioxide (NO(2)) and total suspended particulates (TSP) and respiratory symptom-related doctor visits in adults with different patterns of underlying chronic respiratory disease. METHODS: In a time-stratified case-crossover analysis nested within a diary panel study, 459 Swiss adult participants with asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD) and healthy participants recorded occurrence of respiratory-symptom related doctor visits (n = 1,048) in one to six four-week intervals over two years. For each disease subgroup, odds ratios (ORs) for doctor visit were estimated as a function of NO(2) or TSP concentrations (per 10 micrograms per cubic meter [µg/m(3)]) lagged between 0-13 days in a polynomial distributed lag model. RESULTS: Higher ORs for NO(2) in participants with COPD (OR: 1.17, 95%CI: 1.02-1.35) and asthma (OR: 1.15, 95%CI: 1.02-1.30) occurred at exposure lags of two and five days, respectively. Doctor visits increased by 9.1% (95%CI: 3.2-15.4%) and 4.2% (95%CI: 1.2-7.2%) over the first week following a 10 µg/m(3) increase in NO(2) concentration in the COPD and chronic bronchitis subgroups, respectively. The percent increase in the COPD subgroup was significantly greater (p <0.05) when compared with the healthy subgroup. Observed findings were similar for TSP. CONCLUSIONS: Respiratory problems leading to a doctor visit, associated with an increase in exposure to NO(2) and TSP, may have a faster dynamic in individuals with COPD.

ER stress activates the NLRP3 inflammasome via an UPR-independent pathway.

Uncontrolled endoplasmic reticulum (ER) stress responses are proposed to contribute to the pathology of chronic inflammatory diseases such as type 2 diabetes or atherosclerosis. However, the connection between ER stress and inflammation remains largely unexplored. Here, we show that ER stress causes activation of the NLRP3 inflammasome, with subsequent release of the pro-inflammatory cytokine interleukin-1ß. This ER-triggered proinflammatory signal shares the same requirement for reactive oxygen species production and potassium efflux compared with other known NLRP3 inflammasome activators, but is independent of the classical unfolded protein response (UPR). We thus propose that the NLRP3 inflammasome senses and responds to ER stress downstream of a previously uncharacterized ER stress response signaling pathway distinct from the UPR, thus providing mechanistic insight to the link between ER stress and chronic inflammatory diseases.

The death domain-containing protein Unc5CL is a novel MyD88-independent activator of the pro-inflammatory IRAK signaling cascade.

The family of death domain (DD)-containing proteins are involved in many cellular processes, including apoptosis, inflammation and development. One of these molecules, the adapter protein MyD88, is a key factor in innate and adaptive immunity that integrates signals from the Toll-like receptor/interleukin (IL)-1 receptor (TLR/IL-1R) superfamily by providing an activation platform for IL-1R-associated kinases (IRAKs). Here we show that the DD-containing protein Unc5CL (also known as ZUD) is involved in a novel MyD88-independent mode of IRAK signaling that culminates in the activation of the transcription factor nuclear factor kappa B (NF-κB) and c-Jun N-terminal kinase. Unc5CL required IRAK1, IRAK4 and TNF receptor-associated factor 6 but not MyD88 for its ability to activate these pathways. Interestingly, the protein is constitutively autoproteolytically processed, and is anchored by its N-terminus specifically to the apical face of mucosal epithelial cells. Transcriptional profiling identified mainly chemokines, including IL-8, CXCL1 and CCL20 as Unc5CL target genes. Its prominent expression in mucosal tissues, as well as its ability to induce a pro-inflammatory program in cells, suggests that Unc5CL is a factor in epithelial inflammation and immunity as well as a candidate gene involved in mucosal diseases such as inflammatory bowel disease.

Atherosclerosis in ApoE-deficient mice progresses independently of the NLRP3 inflammasome.

The interleukin-1 (IL-1) family of cytokines has been implicated in the pathogenesis of atherosclerosis in previous studies. The NLRP3 inflammasome has recently emerged as a pivotal regulator of IL-1ß maturation and secretion by macrophages. Little is currently known about a possible role for the NLRP3 inflammasome in atherosclerosis progression in vivo. We generated ApoE-/- Nlrp3-/-, ApoE-/- Asc-/- and ApoE-/- caspase-1-/- double-deficient mice, fed them a high-fat diet for 11 weeks and subsequently assessed atherosclerosis progression and plaque phenotype. No differences in atherosclerosis progression, infiltration of plaques by macrophages, nor plaque stability and phenotype across the genotypes studied were found. Our results demonstrate that the NLRP3 inflammasome is not critically implicated in atherosclerosis progression in the ApoE mouse model.

Short-term safety of thoracoscopic talc pleurodesis for recurrent primary spontaneous pneumothorax: a prospective European multicentre study.

The safety of talc pleurodesis is under dispute following reports of talc-induced acute respiratory distress syndrome (ARDS) and death. We investigated the safety of large-particle talc for thoracoscopic pleurodesis to prevent recurrence of primary spontaneous pneumothorax (PSP). 418 patients with recurrent PSP were enrolled between 2002 and 2008 in nine centres in Europe and South Africa. The main exclusion criteria were infection, heart disease and coagulation disorders. Serious adverse events (ARDS, death or other) were recorded up to 30 days after the procedure. Oxygen saturation, supplemental oxygen use and temperature were recorded daily at baseline and after thoracoscopic pleurodesis (2 g graded talc). During the 30-day observation period following talc poudrage, no ARDS (95% CI 0.0-0.9%), intensive care unit admission or death were recorded. Seven patients presented with minor complications (1.7%, 95% CI 0.7-3.4%). After pleurodesis, mean body temperature increased by 0.41°C (95% CI 0.33-0.48°C; p<0.001) at day 1 and returned to baseline value at day 5. Pleural drains were removed after day 4 in 80% of patients. Serious adverse events, including ARDS or death, did not occur in this large, multicentre cohort. Thoracoscopic talc poudrage using larger particle talc to prevent recurrence of PSPS can be considered safe.

PIDD orchestrates translesion DNA synthesis in response to UV irradiation.

PIDD has been implicated in survival and apoptotic pathways in response to DNA damage, and a role for PIDD was recently identified in non-homologous end-joining (NHEJ) repair induced by γ-irradiation. Here, we present an interaction of PIDD with PCNA, first identified in a proteomics screen. PCNA has essential functions in DNA replication and repair following UV irradiation. Translesion synthesis (TLS) is a process that prevents UV irradiation-induced replication blockage and is characterized by PCNA monoubiquitination and interaction with the TLS polymerase eta (polη). Both of these processes are inhibited by p21. We report that PIDD modulates p21-PCNA dissociation, and promotes PCNA monoubiquitination and interaction with polη in response to UV irradiation. Furthermore, PIDD deficiency leads to a defect in TLS that is associated, both in vitro and in vivo, with cellular sensitization to UV-induced apoptosis. Thus, PIDD performs key functions upon UV irradiation, including TLS, NHEJ, NF-κB activation and cell death.

NLRP3 inflammasome is required in murine asthma in the absence of aluminum adjuvant.

BACKGROUND: Inflammasome activation with the production of IL-1ß received substantial attention recently in inflammatory diseases. However, the role of inflammasome in the pathogenesis of asthma is not clear. Using an adjuvant-free model of allergic lung inflammation induced by ovalbumin (OVA), we investigated the role of NLRP3 inflammasome and related it to IL-1R1 signaling pathway. METHODS: Allergic lung inflammation induced by OVA was evaluated in vivo in mice deficient in NLRP3 inflammasome, IL-1R1, IL-1ß or IL-1α. Eosinophil recruitment, Th2 cytokine, and chemokine levels were determined in bronchoalveolar lavage fluid, lung homogenates, and mediastinal lymph node cells ex vivo. RESULTS: Allergic airway inflammation depends on NLRP3 inflammasome activation. Dendritic cell recruitment into lymph nodes, Th2 lymphocyte activation in the lung and secretion of Th2 cytokines and chemokines are reduced in the absence of NLRP3. Absence of NLRP3 and IL-1ß is associated with reduced expression of other proinflammatory cytokines such as IL-5, IL-13, IL-33, and thymic stromal lymphopoietin. Furthermore, the critical role of IL-1R1 signaling in allergic inflammation is confirmed in IL-1R1-, IL-1ß-, and IL-1α-deficient mice. CONCLUSION: NLRP3 inflammasome activation leading to IL-1 production is critical for the induction of a Th2 inflammatory allergic response.

Impact of aerobic exercise capacity and procedure-related factors in lung cancer surgery.

Over the past decades, major progress in patient selection, surgical techniques and anaesthetic management have largely contributed to improved outcome in lung cancer surgery. The purpose of this study was to identify predictors of post-operative cardiopulmonary morbidity in patients with a forced expiratory volume in 1 s <80% predicted, who underwent cardiopulmonary exercise testing (CPET). In this observational study, 210 consecutive patients with lung cancer underwent CPET with completed data over a 9-yr period (2001-2009). Cardiopulmonary complications occurred in 46 (22%) patients, including four (1.9%) deaths. On logistic regression analysis, peak oxygen uptake (peak V'(O2) and anaesthesia duration were independent risk factors of both cardiovascular and pulmonary complications; age and the extent of lung resection were additional predictors of cardiovascular complications, whereas tidal volume during one-lung ventilation was a predictor of pulmonary complications. Compared with patients with peak V'(O2) >17 mL·kg⁻¹·min⁻¹, those with a peak V'(O2) <10 mL·kg⁻¹·min⁻¹ had a four-fold higher incidence of cardiac and pulmonary morbidity. Our data support the use of pre-operative CPET and the application of an intra-operative protective ventilation strategy. Further studies should evaluate whether pre-operative physical training can improve post-operative outcome.

Regulation of PIDD auto-proteolysis and activity by the molecular chaperone Hsp90.

In response to DNA damage, p53-induced protein with a death domain (PIDD) forms a complex called the PIDDosome, which either consists of PIDD, RIP-associated protein with a death domain and caspase-2, forming a platform for the activation of caspase-2, or contains PIDD, RIP1 and NEMO, important for NF-κB activation. PIDDosome activation is dependent on auto-processing of PIDD at two different sites, generating the fragments PIDD-C and PIDD-CC. Despite constitutive cleavage, endogenous PIDD remains inactive. In this study, we screened for novel PIDD regulators and identified heat shock protein 90 (Hsp90) as a major effector in both PIDD protein maturation and activation. Hsp90, together with p23, binds PIDD and inhibition of Hsp90 activity with geldanamycin efficiently disrupts this association and impairs PIDD auto-processing. Consequently, both PIDD-mediated NF-κB and caspase-2 activation are abrogated. Interestingly, PIDDosome formation itself is associated with Hsp90 release. Characterisation of cytoplasmic and nuclear pools of PIDD showed that active PIDD accumulates in the nucleus and that only cytoplasmic PIDD is bound to Hsp90. Finally, heat shock induces Hsp90 release from PIDD and PIDD nuclear translocation. Thus, Hsp90 has a major role in controlling PIDD functional activity.

A novel potent Fas agonist for selective depletion of tumor cells in hematopoietic transplants.

There remains a clear need for effective tumor cell purging in autologous stem cell transplantation (ASCT) where residual malignant cells within the autograft contribute to disease relapse. Here we propose the use of a novel Fas agonist with potent pro-apoptotic activity, termed MegaFasL, as an effective ex-vivo purging agent. MegaFasL selectively kills hematological cancer cells from lymphomas and leukemias and prevents tumor development at concentrations that do not reduce the functional capacity of human hematopoietic stem/progenitor cells both in in vitro and in in vivo transplantation models. These findings highlight the potential use of MegaFasL as an ex-vivo purging agent in ASCT.

Prevalence of airflow obstruction in smokers and never-smokers in Switzerland.

The aim of the present study was to measure age-specific prevalence of airflow obstruction in Switzerland in smokers and never-smokers using pulmonary function tests and respiratory symptoms from 6,126 subjects participating in the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults. The lower limit of normal of the forced expiratory volume in 1 s/forced vital capacity ratio was used to define airflow obstruction. Severity of airflow obstruction was graded according to the recommendations of the Global Initiative for Chronic Obstructive Lung Disease. Prevalence of airflow obstruction ranged from 2.5% in subjects aged 30-39 yrs to 8.0% in those aged ≥ 70 yrs. In multivariate analysis, age (OR 2.8, ≥ 70 yrs versus 30-39 yrs), smoking (OR 1.8) and asthma (OR 6.7) were associated with airflow obstruction. Never-smokers constituted 29.3% of subjects with airflow obstruction. Never-smokers with airflow obstruction were younger, more likely to be male and reported asthma more frequently than obstructive smokers. Obstructive smokers and never-smokers had similar level of symptoms and quality of life impairment. The prevalence of airflow obstruction in Switzerland is similar to other developed countries. Never-smokers account for a third of the prevalence, which is higher proportion than elsewhere. Airflow obstruction in never-smokers deserves attention because of its frequency and its similar health impact to that in smokers.

Altered thymic selection by overexpressing cellular FLICE inhibitory protein in T cells causes lupus-like syndrome in a BALB/c but not C57BL/6 strain.

The cellular FLICE inhibitory protein (c-FLIP) is an endogenous inhibitor of the caspase-8 proapoptotic signaling pathway downstream of death receptors. Recent evidence indicates that the long form of c-FLIP (c-FLIP(L)) is required for proliferation and effector T-cell development. However, the role of c-FLIP(L) in triggering autoimmunity has not been carefully analyzed. We now report that c-FLIP(L) transgenic (Tg) mice develop splenomegaly, lymphadenopathy, multiorgan infiltration, high titers of auto-antibodies, and proliferative glomerulonephritis with immune complex deposition in a strain-dependent manner. The development of autoimmunity requires CD4(+) T cells and may result from impaired thymic selection. At the molecular level, c-FLIP(L) overexpression inhibits the zeta chain-associated protein tyrosine kinase of 70 kDa (ZAP-70) activation, thus impairing the signaling pathway derived from ZAP-70 required for thymic selection. Therefore, we have identified c-FLIP(L) as a susceptibility factor under the influence of epistatic modifiers for the development of autoimmunity.

Longitudinal change of prebronchodilator spirometric obstruction and health outcomes: results from the SAPALDIA cohort.

BACKGROUND: Understanding the prognostic meaning of early stages of chronic obstructive pulmonary disease (COPD) in the general population is relevant for discussions about underdiagnosis. To date, COPD prevalence and incidence have often been estimated using prebrochodilation spirometry instead of postbronchodilation spirometry. In the SAPALDIA (Swiss Study on Air Pollution and Lung Disease in Adults) cohort, time course, clinical relevance and determinants of severity stages of obstruction were investigated using prebronchodilator spirometry. METHODS: Incident obstruction was defined as an FEV(1)/FVC (forced expiratory volume in 1 s/forced vital capacity) ratio >or=0.70 at baseline and <0.70 at follow-up, and non-persistence was defined inversely. Determinants were assessed in 5490 adults with spirometry and respiratory symptom data in 1991 and 2002 using Poisson regression controlling for self-declared asthma and wheezing. Change in obstruction severity (defined analogously to the GOLD (Global Initiative for Chronic Obstructive Lung Disease) classification) over 11 years was related to shortness of breath and health service utilisation for respiratory problems by logistic models. RESULTS: The incidence rate of obstruction was 14.2 cases/1000 person years. 20.9% of obstructive cases (n = 113/540) were non-persistent. Age, smoking, chronic bronchitis and non-current asthma were determinants of incidence. After adjustment for asthma, only progressive stage I or persistent stage II obstruction was associated with shortness of breath (OR 1.71, 95% CI 0.83 to 3.54; OR 3.11, 95% CI 1.50 to 6.42, respectively) and health service utilisation for respiratory problems (OR 2.49, 95% CI 1.02 to 6.10; OR 4.17 95% CI 1.91 to 9.13, respectively) at follow-up. CONCLUSIONS: The observed non-persistence of obstruction suggests that prebronchodilation spirometry, as used in epidemiological studies, might misclassify COPD. Future epidemiological studies should consider both prebronchodilation and postbronchodilation measurements and take specific clinical factors related to asthma and COPD into consideration for estimation of disease burden and prediction of health outcomes.