bluuebunny/crossref_metadata_2025_split huggingface dataset:
Suppressor of cytokine signaling 1 attenuates IL-15 receptor signaling in CD8+ thymocytes
Authors: Ilangumaran Subburaj , Ramanathan Sheela , Ning Terry , La Rose Jose , Reinhart Brandon , Poussier Philippe , Rottapel Robert 
Published: August 2003

Abstract
SOCS1-/- mice die prematurely of increased interferon-γ (IFNγ) signaling with severe thymic atrophy and accelerated maturation of T cells. However, it was unclear whether the thymic defects were caused by SOCS1 deficiency or by increased IFNγ signaling. Using SOCS1-/-IFNγ-/- mice, we show in this study that SOCS1 deficiency skews thymocyte development toward CD8 lineage independently of IFNγ. Fetal thymic organ cultures and intrathymic transfer of CD4-CD8- precursors into Rag1-/- mice show that the lineage skewing in SOCS1-/- mice is a T-cell autonomous defect. Interestingly, SOCS1 is not required for attenuating interleukin-7 (IL-7) signaling at the CD4-CD8- stage but is essential for regulating IL-15 and IL-2 signaling in CD8+ thymocytes. IL-15 selectively stimulates SOCS1-/- CD8+ thymocytes, inducing sustained signal transducer and activator of transcription 5 (STAT5) phosphorylation and massive proliferation. IL-15 also strongly up-regulates Bcl-xL and CD44 in CD8+ thymocytes lacking SOCS1. The SOCS1 gene is induced in CD4+ thymocytes by γc cytokines, whereas CD8+ thymocytes constitutively express SOCS1 mRNA even in the absence of cytokine stimulation. Because many different cell types express IL-15, our results strongly suggest that SOCS1 functions as an indispensable attenuator of IL-15 receptor signaling in developing CD8+ thymocytes. (Blood. 2003;102:4115-4122)
What has been learnt fromP/Vcurves in patients with acute lung injury/acute respiratory distress syndrome
Authors: Maggiore S.M. , Richard J‐C. , Brochard L. 
Published: August 2003

Mechanical impairment of the respiratory system was recognised soon after the description of acute respiratory distress syndrome. The analysis of the pressure/volume (P/V) curve of the respiratory system contributed a lot to the understanding of the pathophysiology of acute lung injury and formed the basis for lung protection. The lower and upper inflection points were regarded as points of interest to avoid cyclic derecruitment and overdistension and to optimise ventilatory settings. However, because of the heterogeneity of lung injury, reducing the mechanical properties of the whole respiratory system to a single curve is a schematic approach, which makes interpretation difficult.New data suggest that alveolar re-inflation occurs along the wholeP/Vcurve that can, therefore, be considered as a recruitment curve. The lower inflection point has no relationship with alveolar opening and closure and does not indicate the positive end-expiratory pressure needed to prevent alveolar collapse. The shape of theP/Vcurve gives information about the extension and the homogeneity of lung injury, indicating the possibility of lung recruitment. The upper inflection point, classically seen as the beginning of overdistension, may also indicate the end of recruitment.The pressure/volume curve offers the unique opportunity of evaluating alveolar recruitment/derecruitment at the bedside that can be helpful for the identification of optimal ventilatory settings and makes the curve a valuable tool for the ventilatory management of acute lung injury.
Ventilator-induced lung injury
Authors: Ricard J‐D. , Dreyfuss D. , Saumon G. 
Published: August 2003

During mechanical ventilation, high end-inspiratory lung volume (whether it be because of large tidal volume (VT) and/or high levels of positive end-expiratory pressure) results in a permeability type pulmonary oedema, called ventilator-induced lung injury (VILI). Previous injury sensitises lung to mechanical ventilation.This experimental concept has recently received a resounding clinical illustration after a 22% reduction of mortality was observed in acute respiratory distress syndrome patients whoseVThad been reduced. In addition, it has been suggested that repetitive opening and closing of distal units at low lung volume could induce lung injury but this notion has been challenged both conceptually and clinically after the negative results of the Acute Respiratory Distress Syndrome clinical Network Assessment of Low tidal Volume and Elevated end-expiratory volume to Obviate Lung Injury (ARDSNet ALVEOLI) study.Experimentally and clinically, involvement of inflammatory cytokines in VILI has not been unequivocally demonstrated. Cellular response to mechanical stretch has been increasingly investigated, both on the epithelial and the endothelial side. Lipid membrane trafficking has been thought to be a means by which cells respond to stress failure.Alterations in the respiratory system pressure/volume curve during ventilator-induced lung injury that include decrease in compliance and position of the upper inflection point are due to distal obstruction of airways that reduce aerated lung volume. Information from this curve could help avoid potentially harmful excessive tidal volumereduction.
Inflammatory response to infectious pulmonary injury
Authors: Delclaux C. , Azoulay E. 
Published: August 2003

This review describing the inflammatory response to infectious pulmonary injury is focused on the innate immunity of the distal lung to bacterial pneumonia. The fact that the inflammatory response varies to some extent with the bacterial strain responsible for the infection is emphasised. The key cellular components present in the distal lung are described. The major role of alveolar macrophage is described, inasmuch as it responds to the usual daily challenges of bacteria entering the terminal airways and is capable of initiating an inflammatory reaction if the microbial challenge is either too large or too virulent. Under these conditions, the alveolar macrophages initiate an inflammatory response that recruits large numbers of neutrophils into the alveolar spaces.The strategy of the innate immune response may not be to recognise every possible antigen, but rather to focus on a few, highly conserved structures present in large groups of microorganisms. These structures are referred to as pathogen-associated molecular patterns and the receptors of the innate immune system that evolved to recognise them are called pattern-recognition receptors.The soluble factors in innate defence, such as cytokines, are described, and a last paragraph discusses whether a specific inflammatory response could characterise nosocomial pneumonia.
How respiratory system mechanics may help in minimising ventilator-induced lung injury in ARDS patients
Authors: Terragni P.P. , Rosboch G.L. , Lisi A. , Viale A.G. , Ranieri V.M. 
Published: August 2003

The main supportive therapy in acute respiratory distress syndrome patients is mechanical ventilation. As with any therapy, mechanical ventilation has side-effects, and may induce lung injury (ventilator-induced lung injury (VILI)/ventilator-associated lung injury). The mechanical factors responsible for VILI are thought to be related to tidal recruitment/derecruitment of previously collapsed alveoli and/or pulmonary overdistension.The volume/pressure (V/P) curve of the respiratory system in patients as well as in animal models of acute lung injury (ALI) has a characteristic sigmoid shape, with a lower inflection point (LIP) corresponding to the pressure/end-expiratory volume required to initiate recruitment of collapsed alveoli, and an upper inflection point (UIP) corresponding to the pressure/end inspiratory volume at which alveolar overdistension occurs. “Protective” ventilatory approaches have therefore set out to minimise mechanical injury by using theV/Pcurve to individualise positive end-expiratory pressure (PEEP) (PEEP above the LIP) and tidal volume (by setting end-inspiratoryV/Pbelow the UIP) since a large number of experimental studies correlateP/Vcurves to histological and biological manifestations of VILI and two randomised trials showed that protective ventilatory strategy individually tailored to theP/Vcurve minimised pulmonary and systemic inflammation and decreased mortality in patients with ALI.However, despite the fact that several studies have: 1) proposed new techniques to perform pressure/volume curves at the bedside, 2) confirmed that the lower inflection point and upper inflection point correspond to computed tomography scan evidence of atelectasis and overdistension, and 3) demonstrated the ability of the pressure/volume curve to estimate alveolar recruitment with positive end-expiratory pressure, no large studies have assessed whether such measurement can be performed in all intensive care units as a monitoring tool to orient ventilator therapy. Preliminary experimental and clinical studies show that the shape of the dynamic inspiratory pressure/time profile during constant flow inflation (stress index), allows prediction of a ventilatory strategy that minimises the occurrence of ventilator-induced lung injury.
Pressure/volume curves and lung computed tomography in acute respiratory distress syndrome
Authors: Rouby J‐J. , Lu Q. , Vieira S. 
Published: August 2003

Pressure/volume (P/V) curves can be measured by static methods, constant or sinusoidal flow methods and the dynostatic method that allows a breath-to-breath determination ofP/Vcurves. Recent ventilators are equipped with specific flow generators and software aimed at obtainingP/Vcurves without disconnecting the patient from the ventilator.The most recent generation of computed tomography scanners allows the quantitative determination of lung aeration, lung volumes (gas and tissue), alveolar recruitment and lung overinflation of the whole lung. In the supine position, the acute respiratory distress syndrome (ARDS) lung is characterised by an increase in lung tissue that predominates in upper lobes and a massive loss of aeration that predominates in lower lobes.In a minority of ARDS patients, the loss of aeration is homogeneously distributed. The overall lung volume of upper lobes is preserved suggesting an alveolar flooding-induced loss of aeration. In contrast, the overall lung volume of lower lobes is reduced because the heart and the abdomen exert an external compression that contributes to the loss of aeration. TheP/Vcurve is a lung recruitment curve and the chord compliance indicates the potential for recruitment. In such patients, alveolar recruitment resulting from positive end-expiratory pressure is not accompanied by lung overinflation.In a majority of acute respiratory distress syndrome patients, upper lobes remain partially or totally aerated despite a marked regional increase in lung tissue. The upper lobes' overall lung volume is either normal or increased, suggesting that the lung does not collapse under its own weight as generally believed. In lower lobes, the overall lung volume is reduced because the heart and the abdomen exert an external compression that contributes to the loss of aeration. The pressure/volume curve is influenced by the recruitment of poorly and nonaerated lung regions and by the mechanical properties of the part of the lung remaining aerated. In such patients, alveolar recruitment resulting from positive end-expiratory pressure >10 cmH2O is preceded and accompanied by lung overinflation.
Recruitment manoeuvres in acute lung injury/acute respiratory distress syndrome
Authors: Morán I. , Zavala E. , Fernández R. , Blanch L. , Mancebo J. 
Published: August 2003

Acute respiratory distress syndrome/acute lung injury is characterised by profound hypoxaemia due to a permeability pulmonary oedema.In this setting, recruitment manoeuvres (RMs) can be a useful tool as adjuncts to lung protective ventilatory strategies to prevent cyclic alveolar stress and avoid alveolar collapse.Many experimental and physiological studies have discussed the use of RMs but only a few heterogeneous clinical experiences have demonstrated the beneficial and deleterious effects that can occur using these manoeuvres. Besides, a lot of questions remain to be answered to find the best way to perform optimal RMs.Further experimental and clinical trials are needed to understand the potential beneficial effects of recruitment manoeuvres when using a protective mechanical ventilation strategy. This paper is a general review of experimental works that support application of recruitment manoeuvres emphasising the clinical studies that have been published to date in acute respiratory distress syndrome patients.
The issue of dynamic hyperinflation in acute respiratory distress syndrome patients
Authors: Vieillard-Baron A. , Jardin F. 
Published: August 2003

Dynamic hyperinflation is produced by a diffuse expiratory flow limitation impairing exhalation under mechanical ventilation. It constitutes a serious clinical problem in patients exhibiting bronchial asthma or chronic obstructive pulmonary disease, when mechanical ventilation is required. But this phenomenon may also complicate respiratory support in acute respiratory distress syndrome (ARDS) patients.The presence of diffuse airflow limitation in ARDS patients has sometimes been noticed in the past, but its consequences have only recently been emphasised in a dynamic study, using bedside recording of flow/volume loops during respiratory support.More recently, by recording systematically a prolonged expiration, the current authors have observed a localised airflow limitation in a majority of ARDS patients, constituting another potential factor of dynamic hyperinflation under respiratory support. In the same report, the current authors' have emphasised the impact of this limitation on the shape of the pressure/volume loop.At a time when increasing respiratory support is proposed to improve carbon dioxide clearance in acute respiratory distress syndrome submitted to protective ventilation, dynamic hyperinflation may become a major clinical problem in this setting.
Pulmonary and extrapulmonary acute respiratory distress syndrome are different
Authors: Pelosi P. , D'Onofrio D. , Chiumello D. , Paolo S. , Chiara G. , Capelozzi V.L. , Barbas C.S.V. , Chiaranda M. , Gattinoni L. 
Published: August 2003

Acute respiratory distress syndrome (ARDS) can be derived from two pathogenetic pathways: a direct insult on lung cells (pulmonary ARDS (ARDSp)) or indirectly (extrapulmonary ARDS (ARDSexp)). This review reports and discusses differences in biochemical activation, histology, morphological aspects, respiratory mechanics and response to different ventilatory strategies between ARDSp and ARDSexp. In ARDSp the direct insult primarily affects the alveolar epithelium with a local alveolar inflammatory response while in ARDSexp the indirect insult affects the vascular endothelium by inflammatory mediators through the bloodstream.Radiological pattern in ARDSp is characterised by a prevalent alveolar consolidation while the ARDSexp by a prevalent ground-glass opacification. In ARDSp the lung elastance, while in ARDSexp the chest wall and intra-abdominal chest elastance are increased. The effects of positive end-expiratory pressure, recruitment manoeuvres and prone position are clearly greater in ARDSexp.Although these two types of acute respiratory distress syndrome have different pathogenic pathways, morphological aspects, respiratory mechanics, and different response to ventilatory strategies, at the present, is still not clear, if this distinction can really ameliorate the outcome.
Evidence of biological efficacy for prolonged glucocorticoid treatment in patients with unresolving ARDS
Authors: Meduri G.U. , Carratu P. , Freire A.X. 
Published: August 2003

Acute respiratory distress syndrome (ARDS) is a disease of multifactorial etiology characterised by rapid development of severe diffuse and nonhomogenous inflammation of the pulmonary lobules causing life-threatening hypoxaemic respiratory failure. The current authors tested a therapeutic intervention on a previously defined pathophysiological model of ARDS. The model was defined by investigating, during the natural history of ARDS, the relationship among the three fundamental elements of a disease process pathogenesis, structural alterations, and functional consequences. In these studies, the present authors provided biological and morphological evidence indicating that ARDS patients failing to improve after 1 week of mechanical ventilation (unresolving ARDS) have intense and protracted (dysregulated) pulmonary and systemic inflammatory and neo-fibrogenetic activity.Nuclear factor-κB and the glucocorticoid receptor have diametrically opposed functions in regulating inflammation. This chapter will review recent data indicating that poor outcome in acute respiratory distress syndrome might be related in part to failure of the activated glucocorticoid receptors to downregulate the transcription of inflammatory cytokines despite elevated levels of circulating cortisol. In a small randomised study of patients with unresolving acute respiratory distress syndrome, the current authors have shown that prolonged glucocorticoid supplementation improved all aspects of glucocorticoid receptors function and enhanced glucocorticoid-mediated anti-inflammatory action by interfering with nuclear factor-κB activation.
New advances in the use of noninvasive ventilation for acute hypoxaemic respiratory failure
Authors: Antonelli M. , Pennisi M.A. , Conti G. 
Published: August 2003

Noninvasive ventilation (NIV) includes various techniques for augmenting alveolar ventilation without an endotracheal airway. The theoretical advantages of this approach include avoiding the complications associated with endotracheal intubation, improving patient comfort, preserving airway defence mechanisms, speech and swallowing.The successful application of NIV in hypoxaemic acute respiratory failure (ARF) of varied etiologies has been extensively described but success rate is strictly dependent on ARF etiology and until today the application of NIV strategies in the setting of hypoxaemic ARF is controversial. Larger, controlled studies are required to clarify the role of NIV in the setting of hypoxaemic ARF.The correct choice of the patient ventilator interface is a crucial issue in noninvasive ventilation. The study of new interfaces could improve tolerability reducing the noninvasive ventilation failure rate.
Diagnosis and treatment of nosocomial pneumonia in ALI/ARDS patients
Authors: Fagon J‐Y. , Chastre J. 
Published: August 2003

Ventilator-associated pneumonia (VAP) is a common complication of the acute respiratory distress syndrome (ARDS) or acute lung injury (ALI), often leading to the development of sepsis, multiple organ failure, and death. However, the diagnosis of pulmonary infection in patients with ARDS/ALI is often difficult: the systemic signs of infection, such as fever, tachycardia, leukocytosis are nonspecific findings in such patients; a variety of causes other than pneumonia can explain asymmetric consolidation in patients with ARDS and marked asymmetry of radiographic abnormalities has also been reported in patients with uncomplicated ARDS.In 2003, physicians in charge of these patients have to identify patients with true bacterial lung infection, to select appropriate initial antibiotic therapy, to adjust therapy as soon as possible, and to withhold antibiotics in patients without VAP. To do that, a bacteriological strategy based on the use of quantitative cultures of specimen obtained with fibreoptic bronchoscopy performed before initiation or modification of antibiotic treatment seems better than a strategy based on clinical evaluation alone, lowering antibiotic consumption and improving outcome. When bronchoscopy is not available or contraindicated, a nonbronchoscopic strategy or a clinical strategy with re-evaluation 3 days after initiation of treatment may be used.Antimicrobial treatment of VAP is a complex issue. Some general principles can be helpful for the selection of initial treatment: knowledge of most frequently identified responsible pathogens and their susceptibility patterns in the unit; prior duration of hospitalisation; previously prescribed antibiotics; information obtained by direct examination of pulmonary secretions; antibacterial activity and pharmacodynamic characteristics of antibiotics that could be used to treat this infection.Appropriateness of initial antimicrobial therapy is probably a major prognostic factor for patients with ventilator-associated pneumonia. Thus, before new antiboitics are administered, reliable pulmonary specimens must be obtained for direct examination and cultures.
CHOP Compared With CHOP Plus Granulocyte Colony-Stimulating Factor in Elderly Patients With Aggressive Non-Hodgkin’s Lymphoma
Authors: Doorduijn J.K. , van der Holt B. , van Imhoff G.W. , van der Hem K.G. , Kramer M.H.H. , van Oers M.H.J. , Ossenkoppele G.J. , Schaafsma M.R. , Verdonck L.F. , Verhoef G.E.G. , Steijaert M.M.C. , Buijt I. , Uyl-de Groot C.A. , van Agthoven M. , Mulder A.H. , Sonneveld P. 
Published: August 2003

Purpose: To investigate whether the relative dose-intensity of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy could be improved by prophylactic administration of granulocyte colony-stimulating factor (G-CSF) in elderly patients with aggressive non-Hodgkin’s lymphoma (NHL). Patients and Methods: Patients aged 65 to 90 years (median, 72 years) with stage II to IV aggressive NHL were randomly assigned to receive standard CHOP every 3 weeks or CHOP plus G-CSF every 3 weeks on days 2 to 11 of each cycle. Results: In 389 eligible patients, the relative dose intensities (RDIs) of cyclophosphamide (median, 96.3% v 93.9%; P = .01) and doxorubicin (median, 95.4% v 93.3%; P = .04) were higher in patients treated with CHOP plus G-CSF. The complete response rates were 55% and 52% for CHOP and CHOP plus G-CSF, respectively (P = .63). The actuarial overall survival at 5 years was 22% with CHOP alone, compared with 24% with CHOP plus G-CSF (P = .76), with a median follow-up of 33 months. Patients treated with CHOP plus G-CSF had an identical incidence of infections, with World Health Organization grade 3 to 4 (34 of 1,191 cycles v 36 of 1,195 cycles). Only the cumulative days with antibiotics were fewer with CHOP plus G-CSF (median, 0 v 6 days; P = .006) than with CHOP alone. The number of hospital admissions and the number of days in hospital were not different. Conclusion: In elderly patients, G-CSF improved the RDI of CHOP, but this did not lead to a higher complete response rate or better overall survival. G-CSF did not prevent serious infections.