[Management of massive hemoptysis]. / Prise en charge de l'hémoptysie massive.

Less than 5% of all cases of haemoptysis are considered to be massive, representing a life-threatening condition that warrants urgent investigations and treatment. Efforts should be concentrated on determining the origin of the haemoptysis and the presence of an underlying respiratory pathology, in order to ensure supportive measures and a rapid control of the bleeding. Bronchial artery embolization is considered to be the treatment of choice and thoracic surgery should only be considered in cases of localized lesions with a high risk of re-bleeding, pulmonary artery hemorrhage and failure or contraindications to embolization.

Inclusion of shear rate effects in the kinetics of a discretized population balance model: Application to struvite precipitation.

The effect of mixing in the modelling of processes based on mass transfer phenomena is commonly ignored in wastewater treatment industry. In this contribution, the effect of the average shear rate in the nucleation and growth rates of struvite is analyzed by combining experimental data with simulation results obtained with a previously presented mass-based discretized population balance model. According to the obtained results, the effect of the average shear rate is identifiable for the selected data and mechanisms. Therefore, it should be considered when a detailed modelling of the process is needed. Consequently, in this contribution, the average shear rate has been decoupled from the kinetic constants. In addition, kinetic rates where it is explicitly included as a power law function have been proposed. The exponents in these power law functions for the primary homogeneous nucleation and growth are 1.3 and 0.3, respectively. Considering shear rate effects allowed to see in the simulation outputs experimentally observed effects: a faster pH decay and smaller particle distribution for increasing mixing intensities.

Design and simulation of an imaging neutral particle analyzer for the ASDEX Upgrade tokamak.

An Imaging Neutral Particle Analyzer (INPA) diagnostic has been designed for the ASDEX Upgrade (AUG) tokamak. The AUG INPA diagnostic will measure fast neutrals escaping the plasma after charge exchange reactions. The neutrals will be ionized by a 20 nm carbon foil and deflected toward a scintillator by the local magnetic field. The use of a neutral beam injector (NBI) as an active source of neutrals will provide radially resolved measurements, while the use of a scintillator as an active component will allow us to cover the whole plasma along the NBI line with unprecedented phase-space resolution (<12 keV and 8 cm) and a fast temporal response (up to 1 kHz with the high resolution acquisition system and above 100 kHz with the low resolution one), making it suitable to study localized fast-ion redistributions in phase space.

Endovascular management of critical limb ischemia.

Endovascular management of critical limb ischemia has advanced significantly in the recent past, especially the ability to treat tibial artery lesions with reasonable results. The indications, results, and technical aspects or endovascular management of CLI is reviewed herein. An algorithm for clinical management of CLI in patients with tibial occlusive disease is also presented.

How do I select cerebral protection devices today?

The establishment of cerebral protection has matured conceptually and clinically in recent years. We have accepted that some type of cerebral protection is desirable. We have some choices in whether to use filters, proximal occlusion, or proximal occlusion with reversed flow. There are anatomical and clinical factors that drive the choice of cerebral protection devices. Certain practical applications of cerebral protection technologies can be made based upon clinical experience. Making carotid artery stenting (CAS) safer is the key to a broader application of CAS as a treatment method and optimal selection of atherosclerosis new cerebral protection devices helps to achieve that goal.

Histone deacetylase inhibitors interrupt HSP90•RASGRP1 and HSP90•CRAF interactions to upregulate BIM and circumvent drug resistance in lymphoma cells.

Histone deacetylase (HDAC) inhibitors, which are approved for the treatment of cutaneous T-cell lymphoma and multiple myeloma, are undergoing evaluation in other lymphoid neoplasms. How they kill susceptible cells is incompletely understood. Here, we show that trichostatin A, romidepsin and panobinostat induce apoptosis across a panel of malignant B cell lines, including lines that are intrinsically resistant to bortezomib, etoposide, cytarabine and BH3 mimetics. Further analysis traces the pro-apoptotic effects of HDAC inhibitors to increased acetylation of the chaperone heat shock protein 90 (HSP90), causing release and degradation of the HSP90 client proteins RASGRP1 and CRAF, which in turn leads to downregulation of mitogen-activated protein kinase pathway signaling and upregulation of the pro-apoptotic BCL2 family member BIM in vitro and in vivo. Importantly, these pro-apoptotic effects are mimicked by RASGRP1 small interfering RNA (siRNA) or HSP90 inhibition and reversed by overexpression of constitutively active MEK1 or siRNA-mediated downregulation of BIM. Collectively, these observations not only identify a new HSP90 client protein, RASGRP1, but also delineate a complete signaling pathway from HSP90 acetylation through RASGRP1 and CRAF degradation to BIM upregulation that contributes to selective cytotoxicity of HDAC inhibitors in lymphoid malignancies.

MLN4924 induces Noxa upregulation in acute myelogenous leukemia and synergizes with Bcl-2 inhibitors.

MLN4924 (pevonedistat), an inhibitor of the Nedd8 activating enzyme (NAE), has exhibited promising clinical activity in acute myelogenous leukemia (AML). Here we demonstrate that MLN4924 induces apoptosis in AML cell lines and clinical samples via a mechanism distinct from those observed in other malignancies. Inactivation of E3 cullin ring ligases (CRLs) through NAE inhibition causes accumulation of the CRL substrate c-Myc, which transactivates the PMAIP1 gene encoding Noxa, leading to increased Noxa protein, Bax and Bak activation, and subsequent apoptotic changes. Importantly, c-Myc knockdown diminishes Noxa induction; and Noxa siRNA diminishes MLN4924-induced killing. Because Noxa also neutralizes Mcl-1, an anti-apoptotic Bcl-2 paralog often upregulated in resistant AML, further experiments have examined the effect of combining MLN4924 with BH3 mimetics that target other anti-apoptotic proteins. In combination with ABT-199 or ABT-263 (navitoclax), MLN4924 exerts a synergistic cytotoxic effect. Collectively, these results provide new insight into MLN4924-induced engagement of the apoptotic machinery that could help guide further exploration of MLN4924 for AML.

A new compact solid-state neutral particle analyser at ASDEX Upgrade: Setup and physics modeling.

At ASDEX Upgrade (AUG), a new compact solid-state detector has been installed to measure the energy spectrum of fast neutrals based on the principle described by Shinohara et al. [Rev. Sci. Instrum. 75, 3640 (2004)]. The diagnostic relies on the usual charge exchange of supra-thermal fast-ions with neutrals in the plasma. Therefore, the measured energy spectra directly correspond to those of confined fast-ions with a pitch angle defined by the line of sight of the detector. Experiments in AUG showed the good signal to noise characteristics of the detector. It is energy calibrated and can measure energies of 40-200 keV with count rates of up to 140 kcps. The detector has an active view on one of the heating beams. The heating beam increases the neutral density locally; thereby, information about the central fast-ion velocity distribution is obtained. The measured fluxes are modeled with a newly developed module for the 3D Monte Carlo code F90FIDASIM [Geiger et al., Plasma Phys. Controlled Fusion 53, 65010 (2011)]. The modeling allows to distinguish between the active (beam) and passive contributions to the signal. Thereby, the birth profile of the measured fast neutrals can be reconstructed. This model reproduces the measured energy spectra with good accuracy when the passive contribution is taken into account.

Long-term results of a pilot study of low dose cranial-spinal irradiation for cerebellar medulloblastoma.

Between May 1974 and March 1983, 44 children with histologically verified cerebellar medulloblastoma were seen for post-operative cranial-spinal irradiation following attempted total tumor removal. Six patients were excluded from review because they received all or part of their treatment at another institution (3 patients) or did not complete the planned course of irradiation (3 patients). All of the 38 remaining patients were treated by a previously described technique on a 4 MeV Linear Accelerator with 55 Gy delivered to the primary tumor site. Prior to December 1978, 19 consecutive children (Group A) had spinal prophylactic doses of 30-40 Gy and brain prophylactic doses of 40-50 Gy. After the date, 25 Gy was given to the cranial-spinal axis of 19 consecutive children (Group B). This lower dose was arbitrarily selected with the hope of reducing morbidity in treated survivors and achieving the same tumor control. Risk factors that define good and poor prognosis were evaluated for each group, and there were no differences noted. Myelography and CSF cytology were not routinely performed. Follow-up for the 38 patients ranges from 20 months to 124 months. For the low risk patients, survival (12/15 or 80%) was independent of cranial-spinal radiation dose (Group A 6/8, Group B 6/7). For the high risk patients survival was poor (9/23 or 39%), not dependent on cranial-spinal radiation dose (Group A 5/11, Group B 4/12), and associated with failure at the primary site (10/14), often with CSF seeding (8/10). The other 4 failures include 2 who had moved outside the United States (details of failure are unknown), 1 with supratentorial, CSF seeding and distant metastases, and 1 with distant metastasis only. There were no isolated spinal failures. This pilot study shows that the prophylactic radiation dose to the cranial-spinal axis can be decreased to 25 Gy without jeopardizing control rate and survival in patients with medulloblastoma.

Multiple site estimates of erythropoietin and renin in polycythemic kidney transplant patients.

The development of polycythemia after renal transplantation is a well known phenomenon and its etiology remains controversial. In particular, it is unknown whether inappropriate erythropoietin (EPO) production could be a reason. Utilizing a sensitive radioimmunoassay for EPO we have measured EPO concentrations in venous blood from native and grafted kidneys in three normocythemic and seven polycythemic patients. We found that (1) in our posttransplantation polycythemic patients there are inappropriately high systemic EPO levels, hence that posttransplantation polycythemia is related to EPO overproduction. (2) This high EPO production comes from the native kidneys. (3) There is a correlation between EPO and renin levels in the peripheral as well as in native and transplanted kidneys' venous samples.

Value of liquid crystal contact thermography and plasma level of D-dimer for screening of deep venous thrombosis following general abdominal surgery.

Because the use of radioactive fibrinogen uptake test (FUT) has become questionable both for ethical (risk of virus transmission) and technical (lack of sensitivity) reasons, we investigated the potential value of two alternative methods for screening of asymptomatic deep venous thrombosis following elective digestive surgery: liquid crystal contact thermography (LCCT) and measurement of plasma concentration of D-dimer (DD), as compared with bilateral ascending phlebography. Out of 194 patients, 185 underwent phlebography on the 8th (0-19, median and range) postoperative day. Despite prophylaxis with low-molecular-weight heparin and elastic stockings, DVT was detected on phlebography in 58 legs of 45 patients. Sensitivity of LCCT with respect to the presence of DVT was 55% (n = 184 patients) or 28% (n = 368 legs) with a specificity of 67% and 82%, respectively. These poor performances were obtained despite a good interobserver agreement for the LCCT assessments (overall kappa coefficient of 0.66 between three experts). The most accurate cut-off of DD for discriminating patients with or without DVT was 3,000 micrograms/l, as determined by ROC curve analysis. Sensitivity of a DD level of more than 3,000 micrograms/l for the presence of phlebographically documented DVT on the 8th postoperative day was 89% for a specificity of 48%. Thus, LCCT cannot be used for screening of postoperative, mainly asymptomatic DVT following general surgery. On the other hand, measurement of plasma DD may be useful for initial screening, a negative result (level less than 3,000 micrograms/l) allowing to exclude DVT (negative predictive value of 93%) and a positive result (positive predictive value of 35%) requiring confirmation by phlebography.(ABSTRACT TRUNCATED AT 250 WORDS)

Double-blind, randomized comparison of systemic continuous infusion of 0.25 versus 0.50 mg/kg/24 h of alteplase over 3 to 7 days for treatment of deep venous thrombosis in heparinized patients: results of the European Thrombolysis with rt-PA in Venous Thrombosis (ETTT) trial.

Thirty-two patients with acute, proximal-vein thrombosis were treated with heparin and alteplase (0.25 versus 0.5 mg/kg/24 h during 3-7 days) in a randomized, double-blind, multicenter, European (ETTT) trial. The treatment resulted in a decrease of the venographic Marder's score from 18 (6-25) to 13 (2-24) units (median, range) in Group I (0.25 mg/kg/24 h, n = 15, median decrease 3.0, p = 0.32) and from 17.5 (3-33) to 15.5 (0-27) in Group II (0.5 mg/kg/24 h, n = 16, median decrease 4.0, p = 0.23). Comparison of the sequential venograms could be performed in 14 cases of Group I and in 15 cases in Group II. A minority of patients showed substantial partial recanalization of the initially obstructed veins on the control venogram (one in each treatment group) and most of the control venograms showed either thrombus size reductions (5 in Group I, 7 in Group II) or no change or even deterioration (8 in Group I, 7 in Group II). Major bleedings were observed in 7 patients (7/32, 22%), 5 of them occurring in Group II (5/17, 29%). Thus, the results of the ETTT trial show that the used low dosages of alteplase administered intravenously over 3-7 days in heparinized patients cannot be recommended as a treatment for patients with deep venous thrombosis of lower limbs and/or pelvis. Further studies are needed to define a more suitable dosage regimen of alteplase in this indication.

Influence of variability of interpretation of contrast venography for screening of postoperative deep venous thrombosis on the results of a thromboprophylactic study.

To assess interobserver variability of venography for screening for postoperative deep venous thrombosis (DVT), we used 185 bilateral ascending contrast venograms (366 lower limbs) which were performed using the long-leg film technique, in the frame of a trial of the efficacy of two low-molecular-weight-heparin fractions (initial evaluation). These venograms were submitted in a multicenter setting to three further readers who performed a serial scoring as DVT, no DVT or non-evaluable. DVTs were diagnosed in 78, 55 and 59/366 limbs (initial evaluation: 58). The proximal locations of DVTs were 16, 9 and 16 (initial evaluation: 15) and the non evaluable limbs 3, 5 and 18 (initial evaluation: 0). Apparent pairwise agreement between the three readers ranged from 87 to 90% (true coefficient of agreement Kappa 0.63-0.70). It ranged from 89 to 93% (Kappa 0.63-0.74) for the comparison between the readers and the initial evaluation. This considerable degree of disagreement among experienced readers should be taken into account in calculating sample sizes in prospective thromboprophylactic studies. Indeed, one of the two prophylactic regimens proved to be significantly (p = 0.012, p = 0.031, p = 0.049) or non-significantly (p = 0.073) superior to the other one depending upon the reading of venograms.

Venography of the lower limbs. Pitfalls of the diagnostic standard. The ETTT Trial Investigators.

RATIONALE AND OBJECTIVES: Phlebography is considered the diagnostic standard for suspected deep venous thrombosis. The authors studied the inter-observer variability of phlebogram interpretation in the setting of a multicenter therapeutic trial of the thrombolytic agent alteplase. METHODS: The interpretation of 31 pairs of venograms (before and after thrombolytic therapy) was studied by comparing the quantitative Marder's scores which were computed by three experts and the qualitative assessment of phlebographic changes induced by thrombolysis by the panel of experts and by the investigators. RESULTS: Although the scores of the three experts correlated fairly well (r = .67-.82; P < .001), they differed significantly from each other (P < .0001). Substantial differences also were found between local (by investigators) qualitative evaluation of the venographic changes induced by the treatment and central evaluation by the panel of experts (coefficient of agreement kappa = 0.19), local assessment being significantly more optimistic (P = .002) than central judgment. CONCLUSION: Significant differences were observed between assessment of changes in venographic scores after thrombolytic treatment both among three expert radiologists, and between the panel of experts and the local investigators of the multicenter trial. This observation points to the need for an a priori definition of well-characterized decision criteria to allow a valid interpretation of the effects of the therapeutic intervention.

Measurement of plasma D-dimer for diagnosis of deep venous thrombosis.

Venography was performed on fifty-six patients suspected of having deep venous thrombosis (DVT) of the legs. The accuracy of the D-dimer measurement in plasma using two latex tests and an enzyme-linked immunosorbent assay (ELISA) was compared with that of usual determination of total fibrin(ogen) degradation products (FDPs) in serum with respect to the presence of DVT. The three D-dimer tests were clearly superior to the FDP assay, but only the ELISA could accurately rule out the diagnosis of DVT with a predictive value of 100% when plasma D-dimer level was less than 200 micrograms/L. However, this test cannot be used for positive diagnosis (false positive rate of 69%). Thus, plasma D-dimer measurement with ELISA allows identification of patients in whom further investigation by means of more specific tests (venography or plethysmography) is indicated in order to establish the diagnosis of DVT. In contrast to this, sensitivity of the two latex tests studied was low (60 and 76%, respectively), which makes them unsuitable for emergency screening. In addition, the potential of D-dimer dosage for diagnosis of DVT in hospitalized patients is hampered by the presence of associated conditions that are responsible for elevated plasma levels in most cases.

Durability of confluent endothelial cell monolayers on small-caliber vascular prostheses in vitro.

Since implantation of small-caliber vascular grafts with preformed confluent endothelial cell monolayers (ECMs) may prevent acute platelet deposition and thrombus formation, we have evaluated the conditions necessary to produce durable ECMs. Cultured human umbilical-vein ECs in buffer were attached to vascular grafts--either expanded polytetrafluoroethylene (ePTFE) or knitted Dacron, both with inside diameters of 4 mm--precoated with collaten type I and perfused in vitro with serum-containing culture medium to achieve cell spreading into confluent monolayers. The number of cells attached was quantified by DNA measurements and indium-111 labeling. Morphology was evaluated by scanning electron microscopy. The maximum number of cells that attached acutely was 3.6 X 10(5) cells/cm2 graft, and the minimum number needed for confluence was 1.4 X 10(5) cells/cm2 graft. Confluence was morphologically complete after 2 hours of in vitro perfusion at 15 ml/min. When ECMs were exposed to varying flow rates, cell retention after 1 hour was 96.1% +/- 5.6% at 50 ml/min, 94.6% +/- 6.1% at 100 ml/min, 77.6% +/- 10.8% at 200 ml/min (p less than 0.001), and 40.1% +/- 10.4% at 400 ml/min (p less than 0.0001). Confluence was maintained for all grafts exposed to flows of 100 ml/min or less. Fewer cells were retained when acutely attached, unspread cells (71.5% +/- 11.5%) were compared with established ECMs (89.9% +/- 6.7%) at a flow rate of 100 ml/min (p less than 0.0001). ECMs on knitted Dacron were more durable than on ePTFE (82.7% +/- 5.3% versus 75.5% +/- 4.8% remained attached at 200 ml/min, P less than 0.05). 111Indium-labeled and unlabeled cells were equivalent with respect to saturation level attachment, spreading time to confluence, and durability under flow at 100 ml/min. We conclude that confluent and durable endothelial cell monolayers can be established on small-caliber vascular grafts within 2 hours.

Unexpectedly high rate of phlebographic deep venous thrombosis following elective general abdominal surgery among patients given prophylaxis with low-molecular-weight heparin.

One hundred ninety-four patients undergoing elective general abdominal surgery were randomized in a single-blind study to receive one daily subcutaneous injection of a low-molecular-weight heparin, dalteparin sodium (2500 IU, n = 97) or nadroparin calcium (3075 IU, n = 97), two regimens that are approved in Europe to prevent deep venous thrombosis. On the eight postoperative day, bilateral ascending leg phlebography (n = 185) showed the presence of deep venous thrombosis in 45 cases (24.3%; 95% confidence interval, 18% to 31%), with a significantly higher rate (on intention-to-treat) among the patients who received the lower dosage (30 vs 15 deep venous thromboses). We conclude that the two regimens of low-molecular-weight heparin that were used in this study failed to prevent postoperative phlebographically proved deep venous thrombosis in one of four patients.

Immunodeficiency-associated thrombocytopenic purpura (IDTP). Response to splenectomy.

Immunodeficiency-associated thrombocytopenic purpura (IDTP) is a feature of the acquired immunodeficiency syndrome--related complex. Current therapeutic modalities for IDTP include splenectomy and the administration of corticosteroids or other agents. Empiric treatment of IDTP has been analogous to that for immunologic thrombocytopenic purpura (ITP). The present report reviews 15 patients who underwent splenectomy for IDTP, demonstrates the successful use of surgical therapy, and defines our indications for splenectomy in the treatment of this disorder. Thirteen of 15 patients had initially failed to respond to steroid therapy. Fourteen patients (93%) initially responded to splenectomy, with platelet counts increasing to 150 X 10(9)/L (150,000/mm3) or greater. A continuing complete response was achieved in nine patients (60%) following splenectomy. After postsurgical adjunctive therapy, durable remission was achieved in 73% (11/15) of the patients. Complications occurred in three patients, and there were no deaths. The mean follow-up was 12.4 months. Splenectomy may be performed in the treatment of IDTP with acceptable morbidity and likelihood of response.

Plasma D-dimer in suspected pulmonary embolism: a comparison with pulmonary angiography and ventilation--perfusion scintigraphy.

The diagnosis of pulmonary embolism remains a difficult issue. In a previous study of patients submitted to ventilation--perfusion (V-P) scintigraphy we suggested that measurement of D-dimer might be of value for ruling out the diagnosis of pulmonary embolism if the plasma level was less than 500 micrograms/l (ELISA). In the present paper, this cut-off was validated in a consecutive series of 21 patients who were submitted to pulmonary angiography. Sensitivity and specificity were 100% and 36%, respectively. When these data were pooled with the results obtained following V-P scintigraphy (total number of patients = 67), sensitivity, specificity, and positive and negative predictive values were 100%, 70%, 59% and 100%, respectively. It is therefore worthwhile to further evaluate the value of the plasma measurement of D-dimers, especially in patients with inconclusive lung scintigraphy.