Masa pulmonar en una paciente diagnosticada de lupus eritematoso sistémico / No disponible

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Structural and functional analysis of the interaction between the agonistic monoclonal antibody Apomab and the proapoptotic receptor DR5.

Activation of the proapoptotic receptor death receptor5 (DR5) in various cancer cells triggers programmed cell death through the extrinsic pathway. We have generated a fully human monoclonal antibody (Apomab) that induces tumor cell apoptosis through DR5 and investigated the structural features of its interaction with DR5. Biochemical studies showed that Apomab binds DR5 tightly and selectively. X-ray crystallographic analysis of the complex between the Apomab Fab fragment and the DR5 ectodomain revealed an interaction epitope that partially overlaps with both regions of the Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand binding site. Apomab induced DR5 clustering at the cell surface and stimulated a death-inducing signaling complex containing the adaptor molecule Fas-associated death domain and the apoptosis-initiating protease caspase-8. Fc crosslinking further augmented Apomab's proapoptotic activity. In vitro, Apomab triggered apoptosis in cancer cells, while sparing normal hepatocytes even upon anti-Fc crosslinking. In vivo, Apomab exerted potent antitumor activity as a single agent or in combination with chemotherapy in xenograft models, including those based on colorectal, non-small cell lung and pancreatic cancer cell lines. These results provide structural and functional insight into the interaction of Apomab with DR5 and support further investigation of this antibody for cancer therapy.

[Fat pulmonary embolism after liposuction]. / Embolie graisseuse pulmonaire après liposuccion.

A 24-year-old woman undergoes buttock's liposuction as an outpatient procedure. As she went back home, progressive dyspnea, respiratory distress and collapse developed. At hospital admission, she was dyspneic with thoracic oppression, tachycardia and anguish. Chest X-ray and thoracic CT scan suggested a pulmonary localisation of fat emboli. Symptomatic treatment allowed complete recovery. This report discusses diagnosis of fat emboli after liposuction as well as epidemiology and physiopathology.

[Fiberoptic intubation in adult patients with predictive signs of difficult intubation: inhalational induction using sevoflurane and an endoscopic facial mask]. / Intubation fibroscopique sous sévoflurane chez l'adulte avec un masque facial endoscopique en cas d'intubation difficile.

OBJECTIVE: To evaluate the combination of inhalational induction with sevoflurane and fiberoptic intubation through a specific facial mask for anticipated difficult tracheal intubation (DI) in adults. STUDY DESIGN: Prospective study. PATIENTS AND METHODS: Eighteen consecutive patients at risk of DI. After premedication made of hydroxyzine 2 mg x kg(-1), preoxygenation, 0.1 microg x kg(-1) sufentanil was administered (T0), then, inhalational induction was started: sevoflurane 8% in 100% O2 l x min(-1). After 1 min, sevoflurane was decreased to 5% and, if necessary, adapted to obtain an adequate depth of anaesthesia (Ramsay score > 3). Fiberoptic bronchoscopy was performed through a Fibroxy mask. BP was measured every 2.5 min, HR, SpO2, RR were recorded. The results were analyzed by Newman-Keuls test. RESULTS: Intubation was easily realized but it was necessary to assist ventilation in patients presenting prolonged apnea lasting more than 30 s (5 out of 9 patients who presented apnea during procedure). Intubation was quickly realized (T+ 4 +/- 3 min). Haemodynamics and saturation were not altered during procedure. Inhalatory induction using sevoflurane costs 6 10 versus 16 80 for intravenous target controlled propofol anesthesia (using only one preconditionned syringe). CONCLUSION: Inhalational induction with sevoflurane and fiberoptic intubation appeared easy, fast and cheap.

[Fiber-optic intubation with non-invasive ventilation with an endoscopic facial mask]. / Intubation fibroscopique sous ventilation non invasive avec un masque facial endoscopique.

OBJECTIVES: To assess the feasibility and safety of a new technique of fiberoptic bronchoscopy (FOB) tracheal intubation (TI) with noninvasive ventilation (NIV) via an endoscopic full facial mask with two openings, in case of acute respiratory failure (ARF) temporally improved by NIV, but requiring a mechanical ventilation. STUDY DESIGN: Clinical, prospective, open, noncomparative trial of feasibility with direct individual profit. PATIENTS: Sixteen patients with ARF (age: 60 +/- 17 years, PaO2 = 59 +/- 16 mmHg, PaCO2 = 64 +/- 26 mmHg, PaO2/FIO2 = 142 +/- 70 before NIV) (m +/- SD), requiring TI. Including were: TI necessity (SpO2 < 90% or hypercapnic despite NIV, dependence of NIV, exhaustion, septic syndrome), clinical and SpO2 improvement with NIV. METHODS: After i.v. injection of 5 mg midazolam and topical anesthesia (TA) of the nose, the endoscopic mask (modified Fibroxy, Péters) was applied to the face, fixed with elastic straps, then connected to the ventilatory support system with IPAP = 20 cmH2O, EPAP = 5 to 12 cmH2O, FIO2 = 1. A tube was slid on the FOB. As soon as SpO2[[[nbsp] 94%, the extremity of the FOB, was inserted through the lower opening of the mask, slid in the nostril, positioned in front of the glottis for AL, then pushed in the trachea authorizing AL and i.v. injection of 0.15 mg.kg-1 of etomidate (Ramsay[[[nbsp]3). The tube was then slid in the trachea, then, FOB was removed from trachea. RESULTS: The FOB intubation was easy at the patient's, without any failure or any complication. The procedure was 6.7 +/- 2 min. SpO2 significantly improved during TI, from 84 +/- 5% (FIO2 = 0.6 +/- 3) to 97 +/- 1 (FIO2 = 1 +/- 0), without decrease in oxygen saturation off 90%. Arterial pressure decreased only after the 5th min. The quantities of midazolam and of etomidate used were 4.6 +/- 2 mg and 12 +/- 4 mg. Three patients benefited from EPAP > 10 cmH2O. CONCLUSION: Fiberoptic tracheal intubation with NIV via an adapted endoscopic facial mask is a safe technique in patient with ARF temporally improved by NIV. This procedure requires TA and conscious sedation.

Interaction of the TNF homologues BLyS and APRIL with the TNF receptor homologues BCMA and TACI.

BLyS (also called TALL-1, THANK, or BAFF) [1] [2] [3] [4] is a member of the tumor necrosis factor (TNF) gene family that stimulates proliferation and immunoglobulin production by B cells. BLyS interacts with the TNF receptor (TNFR) homologue TACI (transmembrane activator and CAML-interactor) [5], and treatment of mice with a TACI-Fc fusion protein abolishes germinal center formation after antigenic challenge [6]. Here we report a novel interaction between BLyS and another TNFR homologue, BCMA (B cell maturation antigen) [7] [8]. Further, the TNF homologue APRIL [9], a close relative of BLyS, also bound to BCMA and TACI. BLyS or APRIL activated nuclear factor-kappaB (NF-kappaB) through TACI and BCMA, and each ligand stimulated immunoglobulin M (IgM) production by peripheral blood B cells. These results define a dual ligand-receptor system that may play an important role in humoral immunity.

[Fiberoptic bronchoscopy during noninvasive positive-pressure ventilation in patients with chronic obstructive lung disease with hypoxemia and hypercapnia]. / Fibroscopie bronchique sous ventilation non invasive chez des patients atteints de bronchopathie chronique obstructive avec hypoxémie et hypercapnie.

OBJECTIVES: To assess the feasibility and safety of non invasive positive-pressure ventilation (NIPPV) via a face mask to performing fiberoptic bronchoscopy (FOB) in patients with COPD contraindicating FOB in spontaneous ventilation. STUDY DESIGN: Clinical, prospective, open, non comparative trial of feasibility. PATIENTS: Ten consecutive COPD patients (71 +/- 5 year-old, PaO2 = 53 +/- 13 mmHg and PaCO2 = 67 +/- 11 mmHg), without any sign of acute respiratory failure, admitted to the intensive care unit for pneumonia requiring a bronchoalveolar lavage (BAL). Including were: PaO2 < 70 mmHg despite nasal O2 delivered at 3 L.min-1, PaCO2 > 50 mmHg, improvement of SpO2 with NIPPV before FOB. METHODS: Topical anaesthesia of the nose and pharynx was obtained with a 5% lidocaine spray. NIPPV was administered using a ventilatory support system Evita 4 (Dräger) applied through a full facial mask secured to the patient with elastic straps. Patients were first allowed to acclimate for 5 min with NIPPV (IPAP = 16 cmH2O, EPAP = 0 and trigger of 0.3 cm H2O while a FIO2 kept at 0.7). A T-adapter Medisize (Péters) was attached to the facial mask. The tip of the FOB was inserted through the nose. Topical anaesthesia of the vocal cords was obtained with 1% lidocaine solution (3 mL). The FOB was inserted into the trachea up to a bronchial sub-segment. BAL was performed by instillation of 100 mL of saline solution. After FOB, the NIPPV was maintained for 5 min. Heart rate, SpO2 were measured continuously and arterial pressure at 2 min intervals. Arterial blood gas values were obtained just prior NIPPV and after 15 min and 60 min NIPPV disconnection. RESULTS: FOB duration was 11 +/- 4 min. SpO2 significantly improved during FOB (from de 91 +/- 4.7% to 97% +/- 1.7) without decrease of oxygen saturation lower than 90%. There were no changes in PaCO2 and PaO2 during the hour following the end of procedure. FOB under NIPPV was performed in all patients without complications and was very well tolerated in eight patients. After NPPV disconnecting, one patient required again NIPPV for 15 min. No patient required endotracheal intubation within 24 hours. All patients survived. CONCLUSION: Application of NIPPV during FOB is a safe technic for maintaining adequate gas exchange in hypoxaemic and hypercapnic COPD patients not in acute respiratory failure. After the end of the procedure a close surveillance in the intensive care unit is essential.

Control of apoptosis signaling by Apo2 ligand.

Apo2 ligand (Apo2L, also called TRAIL) is a member of the tumor necrosis factor (TNF) cytokine family. The closest homolog of Apo2L is CD95 (Fas/Apo1) ligand, to which it has 24% amino acid sequence identity. Similar to CD95L, Apo2L activates rapid apoptosis in many types of cancer cells; however, whereas CD95L mRNA expression is restricted mainly to activated T cells, natural killer cells, and immune-privileged sites, Apo2L mRNA occurs in a wide variety of tissues. Most normal cells appear to be resistant to Apo2L's cytotoxic action, suggesting the existence of mechanisms that can protect against apoptosis induction by Apo2L. The first receptor described for Apo2L, called death receptor 4 (DR4), contains a cytoplasmic "death domain"; DR4 transmits the apoptosis signal carried by Apo2L. We have identified three additional receptors that bind to Apo2L. One receptor, called DR5, contains a cytoplasmic death domain and signals apoptosis much like DR4. The DR4 and DR5 mRNAs are expressed in many normal tissues and tumor cell lines. The second receptor, designated decoy receptor 1 (DcR1), is a phospholipid-anchored cell-surface protein that lacks a cytoplasmic tail. The third receptor, called DcR2, is structurally similar to DR4 and DR5 but has a truncated cytoplasmic death domain and does not transmit a death signal. The mRNAs for DcR1 and DcR2 are expressed in multiple normal tissues but in few tumor cell lines. Transfection experiments indicate that DcR1 and DcR2 act as decoys that prevent Apo2L from inducing apoptosis through DR4 and DR5. These decoy receptors thus represent a novel mechanism for regulating sensitivity to a pro-apoptotic cytokine directly at the cell's surface. The preferential expression of these inhibitory receptors in normal tissues suggests that Apo2L may be useful as an anticancer agent that induces apoptosis in cancer cells while sparing normal cells.

Identification of a new member of the tumor necrosis factor family and its receptor, a human ortholog of mouse GITR.

The tumor necrosis factor (TNF) and TNF receptor (TNFR) gene superfamilies regulate diverse biological functions, including cell proliferation, differentiation, and survival [1] [2] [3]. We have identified a new TNF-related ligand, designated human GITR ligand (hGITRL), and its human receptor (hGITR), an ortholog of the recently discovered murine glucocorticoid-induced TNFR-related (mGITR) protein [4]. The hGITRL gene mapped to chromosome 1q23, near the gene for the TNF homolog Fas/CD95 ligand [5]. The hGITR gene mapped to chromosome 1p36, near a cluster of five genes encoding TNFR homologs [1] [6]. We found hGITRL mRNA in several peripheral tissues, and detected hGITRL protein on cultured vascular endothelial cells. The levels of hGITR mRNA in tissues were generally low; in peripheral blood T cells, however, antigen-receptor stimulation led to a substantial induction of hGITR transcripts. Cotransfection of hGITRL and hGITR in embryonic kidney 293 cells activated the anti-apoptotic transcription factor NF-kappaB, via a pathway that appeared to involve TNFR-associated factor 2 (TRAF2) [7] and NF-kappaB-inducing kinase (NIK) [8]. Cotransfection of hGITRL and hGITR in Jurkat T leukemia cells inhibited antigen-receptor-induced cell death. Thus, hGITRL and hGITR may modulate T lymphocyte survival in peripheral tissues.

[Cerebral and renal toxicity of acyclovir in a patient treated for meningoencephalitis]. / Toxicité cérébrale et rénale de l'aciclovir chez un patient traité pour méningo-encéphalite.

We report the case of a 65-year-old man treated with intravenous acyclovir and amoxicilline for meningoencephalitis. Six days later, he suddenly developed acute renal failure, associated with central nervous system symptoms. The high acyclovir concentration in plasma and spinal fluid confirmed the hypothesis of acyclovir toxicity. Continuous haemofiltration resulted in a rapid amendment of neurologic and renal symptoms. Despite the high therapeutic index of acyclovir, manifestations of neurotoxicity and nephrotoxicity are not a rare event. The risk is increased in the elderly and in patients with renal insufficiency. Rapid intravenous injections are contraindicated. Continuous haemofiltration is rapidly efficient. The value of acyclovir concentration determination in plasma and spinal fluid are stressed.

Identification of a ligand for the death-domain-containing receptor Apo3.

The tumor necrosis factor (TNF) cytokine family regulates development and function of the immune system [1]. TNF is expressed primarily by activated lymphocytes and macrophages and induces gene transcription or apoptosis in target cells [2,3]. We have identified a novel relative of TNF that binds to the recently discovered, death-domain-containing receptor called Apo3 [4] (also known as DR3, WSL-1, TRAMP or LARD [5-9]). The Apo3 ligand (Apo3L) is a 249 amino-acid, type II transmembrane protein. The extracellular sequence of Apo3L shows highest identity to that of TNF. We detected Apo3L mRNA in many human tissues and mapped its encoding gene to chromosome 17p13, near the p53 tumor-suppressor gene. Soluble Apo3L induced apoptosis and nuclear factor kappaB (NF-kappaB) activation in human cell lines. Caspase inhibitors blocked apoptosis induction by Apo3L, as did a dominant-negative mutant of the cell death adaptor protein Fas-associated death domain protein (FADD/MORT1), which is critical for apoptosis induction by TNF [3]. Dominant-negative mutants of several factors that play a key role in NF-kappaB induction by TNF [10] inhibited NF-kappaB activation by Apo3L. Thus, Apo3L has overlapping signaling functions with TNF, but displays a much wider tissue distribution.

Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer.

Fas ligand (FasL) is produced by activated T cells and natural killer cells and it induces apoptosis (programmed cell death) in target cells through the death receptor Fas/Apol/CD95. One important role of FasL and Fas is to mediate immune-cytotoxic killing of cells that are potentially harmful to the organism, such as virus-infected or tumour cells. Here we report the discovery of a soluble decoy receptor, termed decoy receptor 3 (DcR3), that binds to FasL and inhibits FasL-induced apoptosis. The DcR3 gene was amplified in about half of 35 primary lung and colon tumours studied, and DcR3 messenger RNA was expressed in malignant tissue. Thus, certain tumours may escape FasL-dependent immune-cytotoxic attack by expressing a decoy receptor that blocks FasL.

Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors.

TRAIL (also called Apo2L) belongs to the tumor necrosis factor family, activates rapid apoptosis in tumor cells, and binds to the death-signaling receptor DR4. Two additional TRAIL receptors were identified. The receptor designated death receptor 5 (DR5) contained a cytoplasmic death domain and induced apoptosis much like DR4. The receptor designated decoy receptor 1 (DcR1) displayed properties of a glycophospholipid-anchored cell surface protein. DcR1 acted as a decoy receptor that inhibited TRAIL signaling. Thus, a cell surface mechanism exists for the regulation of cellular responsiveness to pro-apoptotic stimuli.

A novel receptor for Apo2L/TRAIL contains a truncated death domain.

Apo2 ligand (Apo2L [1], also called TRAIL for tumor necrosis factor (TNF)-related apoptosis-inducing ligand [2]) belongs to the TNF family and activates apoptosis in tumor cells. Three closely related receptors bind Apo2L: DR4 and DR5, which contain cytoplasmic death domains and signal apoptosis, and DcR1, a decoy receptor that lacks a cytoplasmic tail and inhibits Apo2L function [3-5]. By cross-hybridization with DcR1, we have identified a fourth Apo2L receptor, which contains a cytoplasmic region with a truncated death domain. We subsequently named this protein decoy receptor 2 (DcR2). The DcR2 gene mapped to human chromosome 8p21, as did the genes encoding DR4, DR5 and DcR1. A single DcR2 mRNA transcript showed a unique expression pattern in human tissues and was particularly abundant in fetal liver and adult testis. Upon overexpression, DcR2 did not activate apoptosis or nuclear factor-kappaB; however, it substantially reduced cellular sensitivity to Apo2L-induced apoptosis. These results suggest that DcR2 functions as an inhibitory Apo2L receptor.