Acute respiratory failure in the elderly: etiology, emergency diagnosis and prognosis

INTRODUCTION: Our objectives were to determine the causes of acute respiratory failure (ARF) in elderly patients and to assess the accuracy of the initial diagnosis by the emergency physician, and that of the prognosis. METHOD: In this prospective observational study, patients were included if they were admitted to our emergency department, aged 65 years or more with dyspnea, and fulfilled at least one of the following criteria of ARF: respiratory rate at least 25 minute(-1); arterial partial pressure of oxygen (PaO(2)) 70 mmHg or less, or peripheral oxygen saturation 92% or less in breathing room air; arterial partial pressure of CO(2 )(PaCO(2)) ≥ 45 mmHg, with pH ≤ 7.35. The final diagnoses were determined by an expert panel from the completed medical chart. RESULTS: A total of 514 patients (aged (mean ± standard deviation) 80 ± 9 years) were included. The main causes of ARF were cardiogenic pulmonary edema (43%), community-acquired pneumonia (35%), acute exacerbation of chronic respiratory disease (32%), pulmonary embolism (18%), and acute asthma (3%); 47% had more than two diagnoses. In-hospital mortality was 16%. A missed diagnosis in the emergency department was noted in 101 (20%) patients. The accuracy of the diagnosis of the emergency physician ranged from 0.76 for cardiogenic pulmonary edema to 0.96 for asthma. An inappropriate treatment occurred in 162 (32%) patients, and lead to a higher mortality (25% versus 11%; p < 0.001). In a multivariate analysis, inappropriate initial treatment (odds ratio 2.83, p < 0.002), hypercapnia > 45 mmHg (odds ratio 2.79, p < 0.004), clearance of creatinine < 50 ml minute(-1 )(odds ratio 2.37, p < 0.013), elevated NT-pro-B-type natriuretic peptide or B-type natriuretic peptide (odds ratio 2.06, p < 0.046), and clinical signs of acute ventilatory failure (odds ratio 1.98, p < 0.047) were predictive of death. CONCLUSION: Inappropriate initial treatment in the emergency room was associated with increased mortality in elderly patients with ARF

Clinical, radiologic, pathologic, and molecular characteristics of long-term survivors of diffuse intrinsic pontine glioma (DIPG): a collaborative report from the International and European Society for Pediatric Oncology DIPG registries

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of &lt; 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age &lt; 3 or &gt; 10 years (11% v 3% and 33% v 23%, respectively; P &lt; .001) and with longer symptom duration ( P &lt; .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials

Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis

Atherosclerosis is an inflammatory vascular disease responsible for the first cause of mortality worldwide. Recent studies have clearly highlighted the critical role of the immunoinflammatory balance in the modulation of disease development and progression. However, the immunoregulatory pathways that control atherosclerosis remain largely unknown. We show that loss of suppressor of cytokine signaling (SOCS) 3 in T cells increases both interleukin (IL)-17 and IL-10 production, induces an antiinflammatory macrophage phenotype, and leads to unexpected IL-17–dependent reduction in lesion development and vascular inflammation. In vivo administration of IL-17 reduces endothelial vascular cell adhesion molecule–1 expression and vascular T cell infiltration, and significantly limits atherosclerotic lesion development. In contrast, overexpression of SOCS3 in T cells reduces IL-17 and accelerates atherosclerosis. We also show that in human lesions, increased levels of signal transducer and activator of transcription (STAT) 3 phosphorylation and IL-17 are associated with a stable plaque phenotype. These results identify novel SOCS3-controlled IL-17 regulatory pathways in atherosclerosis and may have important implications for the understanding of the increased susceptibility to vascular inflammation in patients with dominant-negative STAT3 mutations and defective Th17 cell differentiation

Limitations in a frataxin knockdown cell model for Friedreich ataxia in a high-throughput drug screen

<p>Abstract</p> <p>Background</p> <p>Pharmacological high-throughput screening (HTS) represents a powerful strategy for drug discovery in genetic diseases, particularly when the full spectrum of pathological dysfunctions remains unclear, such as in Friedreich ataxia (FRDA). FRDA, the most common recessive ataxia, results from a generalized deficiency of mitochondrial and cytosolic iron-sulfur cluster (ISC) proteins activity, due to a partial loss of frataxin function, a mitochondrial protein proposed to function as an iron-chaperone for ISC biosynthesis. In the absence of measurable catalytic function for frataxin, a cell-based assay is required for HTS assay.</p> <p>Methods</p> <p>Using a targeted ribozyme strategy in murine fibroblasts, we have developed a cellular model with strongly reduced levels of frataxin. We have used this model to screen the Prestwick Chemical Library, a collection of one thousand off-patent drugs, for potential molecules for FRDA.</p> <p>Results</p> <p>The frataxin deficient cell lines exhibit a proliferation defect, associated with an ISC enzyme deficit. Using the growth defect as end-point criteria, we screened the Prestwick Chemical Library. However no molecule presented a significant and reproducible effect on the proliferation rate of frataxin deficient cells. Moreover over numerous passages, the antisense ribozyme fibroblast cell lines revealed an increase in frataxin residual level associated with the normalization of ISC enzyme activities. However, the ribozyme cell lines and FRDA patient cells presented an increase in Mthfd2 transcript, a mitochondrial enzyme that was previously shown to be upregulated at very early stages of the pathogenesis in the cardiac mouse model.</p> <p>Conclusion</p> <p>Although no active hit has been identified, the present study demonstrates the feasibility of using a cell-based approach to HTS for FRDA. Furthermore, it highlights the difficulty in the development of a stable frataxin-deficient cell model, an essential condition for productive HTS in the future.</p

Arch Cardiovasc Dis

International audienc

Type I interferon-mediated autoinflammation due to DNase II deficiency

Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2, associated with a loss of DNase II endonuclease activity. We record increased interferon alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans

Apport de la procalcitonine comme marqueur d' infection bactérienne chez les patients de plus de 75 ans

Le diagnostic d infection bactérienne en médecine représente un enjeu de Santé Publique majeur, et est une difficulté quotidienne. En améliorer le diagnostic permet d améliorer le pronostic de l infection, en mettant en route dans des délais les plus brefs un traitement adapté et de limiter les traitements donnés par excès, source de surcoût et de résistance aux antibiotiques. Les personnes âgées représentent une population particulière en médecine. Elles ont des réserves fonctionnelles diminuées du fait du vieillissement. Elles présentent des modifications anatomiques et physiologiques, des co- morbidités, une poly-médication souvent source de iatrogénie ainsi qu une fragilité immunitaire les rendant plus sensibles aux infections. Les infections sont plus sévères, plus fréquentes et les germes en cause sont différents dans ce groupe. Le diagnostic d infection bactérienne est d autant plus difficile et souvent retardé que les symptômes et manifestations sont modifiés et les prélèvements microbiologiques compliqués à obtenir. En l absence de gold standard pour le diagnostic d infection bactérienne, le praticien doit s appuyer sur un faisceau d arguments, comprenant des paramètres cliniques, biologiques, et d imagerie. Mais les marqueurs biologiques d infection bactérienne habituellement utilisées (C Reactive protein, hyperleucocytose) manquent de sensibilité chez le sujet âgé. Or dans cette population prédisposée aux infections avec un pronostic beaucoup plus défavorable, un outil sensible et/ou spécifique, conduisant à un diagnostic d infection bactérienne et une prise en charge thérapeutique rapide serait particulièrement utile. Très étudiée en pédiatrie et services de réanimation ou d urgences depuis les années 1990, la procalcitoine (PCT) semble être un marqueur d infection bactérienne spécifique. Sa valeur pronostic dans certaines infections bactériennes est aussi bien documentée. Cependant à notre connaissance, les données sur la valeur de la PCT dans le diagnostic d infection bactérienne chez le patient âgé sont rares, et la méthode de dosage varie selon les études. Nous avons donc voulu étudier l intérêt de la PCT dans cette population comme marqueur diagnostic d infection bactérienne, en utilisant la méthode de dosage la plus sensible.Notre étude montre que dans une population gériatrique, en service de médecine, avec la méthode de dosage TRACE à un seuil de 0,3 ng/ml, la procalcitonine présente des valeurs intéressantes pour le diagnostic d infection bactérienne avec une sensibilité de 76%, une spécificité de 82%, une VPP de 74%, une VPN de 80% et une aire sous la courbe de 0,788. Bien que ces paramètres soient meilleurs que dans de nombreuses études et notamment celles portant sur le sujet âgé, la PCT présente une zone d incertitude diagnostic très large et ne permet, en pratique, de faire le diagnostic d infection que dans 54% des cas dans notre étude. La PCT apparait donc comme un outil intéressant dans l arsenal du médecin dans un contexte de suspicion d infection bactérienne, mais toujours associé à l évaluation complète du patient comportant l anamnèse, l examen clinique et notamment les signes généraux qui restent significatifs (température, fréquence cardiaque, SIRS), ainsi que les autres marqueurs biologiques tels que la CRP et l hyperleucocytose. Le nombre de patients dans notre étude limite la puissance statistique, et on ne peut exclure qu avec un effectif plus conséquent, la valeur de la PCT autant diagnostic que pronostic ait été améliorée, ainsi que l étude du lien PCT et fonction rénale dans cette population souvent touchée par l insuffisance rénale. Des études portant sur un nombre de patients âgés plus important, dès l arrivée aux urgences, vierges de toute antibiothérapie préalable mais aussi évaluant des facteurs interférant possiblement avec le taux de procalcitonine comme l insuffisance hépato-cellulaire ou les chutes seraient intéressantes. En effet il est essentiel de mieux étudier cette population gériatrique grandissante, et de trouver des marqueurs aidant au diagnostic d infection souvent complexe et au pronostic sévère, tout en en connaissant les limites pour améliorer la prise en charge de ces patients.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Pronostic de l'hypotension orthostatique chez les sujets âgés aux urgences (efficacité et observance de la contention veineuse)

PARIS6-Bibl. St Antoine CHU (751122104) / SudocSudocFranceF