Hôpital Albert Michallon

BACKGROUND: The median survival of patients with myeloma after conventional chemotherapy is three years or less. Promising results have been reported with high-dose therapy supported by autologous bone marrow transplantation. We conducted a randomized study comparing conventional chemotherapy and high-dose therapy. METHODS: Two hundred previously untreated patients under the age of 65 years who had myeloma were randomly assigned at the time of diagnosis to receive either conventional chemotherapy or high-dose therapy and autologous bone marrow transplantation. RESULTS: The response rate among the patients who received high-dose therapy was 81 percent (including complete responses in 22 percent and very good partial responses in 16 percent), whereas it was 57 percent (complete responses in 5 percent and very good partial responses in 9 percent) in the group treated with conventional chemotherapy (P < 0.001). The probability of event-free survival for five years was 28 percent in the high-dose group and 10 percent in the conventional-dose group (P = 0.01); the overall estimated rate of survival for five years was 52 percent in the high-dose group and 12 percent in the conventional-dose group (P = 0.03). Treatment-related mortality was similar in the two groups. CONCLUSIONS: High-dose therapy combined with transplantation improves the response rate, eventfree survival, and overall survival in patients with myeloma.

BACKGROUND: The role of fibrinolytic therapy in patients with intermediate-risk pulmonary embolism is controversial. METHODS: In a randomized, double-blind trial, we compared tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk pulmonary embolism. Eligible patients had right ventricular dysfunction on echocardiography or computed tomography, as well as myocardial injury as indicated by a positive test for cardiac troponin I or troponin T. The primary outcome was death or hemodynamic decompensation (or collapse) within 7 days after randomization. The main safety outcomes were major extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization. RESULTS: Of 1006 patients who underwent randomization, 1005 were included in the intention-to-treat analysis. Death or hemodynamic decompensation occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of 499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P=0.02). Between randomization and day 7, a total of 6 patients (1.2%) in the tenecteplase group and 9 (1.8%) in the placebo group died (P=0.42). Extracranial bleeding occurred in 32 patients (6.3%) in the tenecteplase group and 6 patients (1.2%) in the placebo group (P<0.001). Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was hemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which was hemorrhagic (P=0.003). By day 30, a total of 12 patients (2.4%) in the tenecteplase group and 16 patients (3.2%) in the placebo group had died (P=0.42). CONCLUSIONS: In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke. (Funded by the Programme Hospitalier de Recherche Clinique in France and others; PEITHO EudraCT number, 2006-005328-18; ClinicalTrials.gov number, NCT00639743.).

BACKGROUND: Trials of patent foramen ovale (PFO) closure to prevent recurrent stroke have been inconclusive. We investigated whether patients with cryptogenic stroke and echocardiographic features representing risk of stroke would benefit from PFO closure or anticoagulation, as compared with antiplatelet therapy. METHODS: In a multicenter, randomized, open-label trial, we assigned, in a 1:1:1 ratio, patients 16 to 60 years of age who had had a recent stroke attributed to PFO, with an associated atrial septal aneurysm or large interatrial shunt, to transcatheter PFO closure plus long-term antiplatelet therapy (PFO closure group), antiplatelet therapy alone (antiplatelet-only group), or oral anticoagulation (anticoagulation group) (randomization group 1). Patients with contraindications to anticoagulants or to PFO closure were randomly assigned to the alternative noncontraindicated treatment or to antiplatelet therapy (randomization groups 2 and 3). The primary outcome was occurrence of stroke. The comparison of PFO closure plus antiplatelet therapy with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 2, and the comparison of oral anticoagulation with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 3. RESULTS: A total of 663 patients underwent randomization and were followed for a mean (±SD) of 5.3±2.0 years. In the analysis of randomization groups 1 and 2, no stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet-only group (hazard ratio, 0.03; 95% confidence interval, 0 to 0.26; P<0.001). Procedural complications from PFO closure occurred in 14 patients (5.9%). The rate of atrial fibrillation was higher in the PFO closure group than in the antiplatelet-only group (4.6% vs. 0.9%, P=0.02). The number of serious adverse events did not differ significantly between the treatment groups (P=0.56). In the analysis of randomization groups 1 and 3, stroke occurred in 3 of 187 patients assigned to oral anticoagulants and in 7 of 174 patients assigned to antiplatelet therapy alone. CONCLUSIONS: Among patients who had had a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt, the rate of stroke recurrence was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone. PFO closure was associated with an increased risk of atrial fibrillation. (Funded by the French Ministry of Health; CLOSE ClinicalTrials.gov number, NCT00562289 .).

BACKGROUND: High-dose chemotherapy with autologous stem-cell transplantation is a standard treatment for young patients with multiple myeloma. Residual disease is almost always present after transplantation and is responsible for relapse. This phase 3, placebo-controlled trial investigated the efficacy of lenalidomide maintenance therapy after transplantation. METHODS: We randomly assigned 614 patients younger than 65 years of age who had nonprogressive disease after first-line transplantation to maintenance treatment with either lenalidomide (10 mg per day for the first 3 months, increased to 15 mg if tolerated) or placebo until relapse. The primary end point was progression-free survival. RESULTS: Lenalidomide maintenance therapy improved median progression-free survival (41 months, vs. 23 months with placebo; hazard ratio, 0.50; P<0.001). This benefit was observed across all patient subgroups, including those based on the β(2)-microglobulin level, cytogenetic profile, and response after transplantation. With a median follow-up period of 45 months, more than 70% of patients in both groups were alive at 4 years. The rates of grade 3 or 4 peripheral neuropathy were similar in the two groups. The incidence of second primary cancers was 3.1 per 100 patient-years in the lenalidomide group versus 1.2 per 100 patient-years in the placebo group (P=0.002). Median event-free survival (with events that included second primary cancers) was significantly improved with lenalidomide (40 months, vs. 23 months with placebo; P<0.001). CONCLUSIONS: Lenalidomide maintenance after transplantation significantly prolonged progression-free and event-free survival among patients with multiple myeloma. Four years after randomization, overall survival was similar in the two study groups. (Funded by the Programme Hospitalier de Recherche Clinique and others; ClinicalTrials.gov number, NCT00430365.).

Tremor was suppressed by test stimulation of the thalamic ventralis intermedius (VIM) nucleus at high frequency (130 Hz) during stereotaxy in nonanesthetized patients suffering from Parkinson's disease or essential tremor. Ventralis intermedius stimulation has since been used by the authors over the last 8 years as a treatment in 117 patients with movement disorders (80 cases of Parkinson's disease, 20 cases of essential tremor, and 17 cases of various dyskinesias and dystonias including four multiple sclerosis). Chronic electrodes were stereotactically implanted in the VIM and connected to a programmable stimulator. Results depend on the indication. In Parkinson's disease patients, tremor, but not bradykinesia and rigidity, was selectively suppressed for as long as 8 years. Administration of L-Dopa was decreased by more than 30% in 40 Parkinson's disease patients. In essential tremor patients, results were satisfactory but deteriorated with time in 18.5% of cases, mainly for patients who presented an action component of their but deteriorated with time in 18.5% of cases, mainly for patients who presented an action component of their tremor. In other types of dyskinesias (except multiple sclerosis), results were much less favorable. Fifty-nine patients underwent bilateral implantation and 14 other patients received implantation contralateral to a previous thalamotomy. Thirty-seven patients (31.6%) experienced minor side effects, which were always well tolerated and immediately reversible. Three secondary scalp infections led to temporary removal of the implanted material. There was no permanent morbidity. This tremor suppression effect could be due to the inhibition or jamming of a retroactive loop. Chronic VIM stimulation, which is reversible, adaptable, and well tolerated even by patients undergoing bilateral surgery (74 of 117 patients) and by elderly patients, should replace thalamotomy in the regular surgical treatment of parkinsonian and essential tremors.

OBJECTIVE: To establish the validity and reliability of a new behavioral pain scale (BPS) for critically ill sedated adult patients. DESIGN: Prospective evaluation. SETTING: Ten-bed trauma and surgical intensive care unit in a university teaching hospital. PATIENTS: Thirty mechanically ventilated patients who were receiving analgesia and sedation. INTERVENTION: Assessments with the BPS were completed consecutively at standardized times (morning, afternoon, night) by pairs of evaluators (nurse and nurse's aide). They collected physiologic parameters and BPS results before and during care procedures: non-nociceptive (group 1, compression stockings application and central venous catheter dressing change), nociceptive (group 2, endotracheal suctioning and mobilization), and retested nociceptive (group 3). The BPS score was the sum of three items that had a range score of 1-4: facial expression, movements of upper limbs, and compliance with mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Two hundred and sixty nine assessments were completed, including 104, 134, and 31 measurements in groups 1, 2 and 3, respectively. There was no difference in Ramsay scale scores between the three groups (Ramsay 4-6). Nociceptive stimulations (group 2) resulted in significantly higher BPS values than non-nociceptive ones (group 1, 4.9 vs. 3.5, p <.01), whereas the two groups had comparable BPS values before stimulation (3.1 vs. 3.0). A trend was found in group 2 between the dosage of sedation/analgesia and BPS: the higher the dosage, the lower BPS values and BPS changes to nociceptive stimulation. Group 3 had BPS values similar to group 2 at rest (3.2 vs. 3.2) and during the procedure (4.4 vs. 4.5), with good interrater correlations (r(2) =.71 and.50, respectively). CONCLUSIONS: These results indicate that the expression of pain can be scored validly and reliably by using the BPS in sedated, mechanically ventilated patients. Further studies are warranted regarding the utility of the BPS in making clinical decisions about the use of analgesic drugs in the intensive care unit.

BACKGROUND: We conducted a randomized trial of the treatment of multiple myeloma with high-dose chemotherapy followed by either one or two successive autologous stem-cell transplantations. METHODS: At the time of diagnosis, 399 previously untreated patients under the age of 60 years were randomly assigned to receive a single or double transplant. RESULTS: A complete or a very good partial response was achieved by 42 percent of patients in the single-transplant group and 50 percent of patients in the double-transplant group (P=0.10). The probability of surviving event-free for seven years after the diagnosis was 10 percent in the single-transplant group and 20 percent in the double-transplant group (P=0.03). The estimated overall seven-year survival rate was 21 percent in the single-transplant group and 42 percent in the double-transplant group (P=0.01). Among patients who did not have a very good partial response within three months after one transplantation, the probability of surviving seven years was 11 percent in the single-transplant group and 43 percent in the double-transplant group (P<0.001). Four factors were significantly related to survival: base-line serum levels of beta2-microglobulin (P<0.01) and lactate dehydrogenase (P<0.01), age (P<0.05), and treatment group (P<0.01). CONCLUSIONS: As compared with a single autologous stem-cell transplantation after high-dose chemotherapy, double transplantation improves overall survival among patients with myeloma, especially those who do not have a very good partial response after undergoing one transplantation.

BACKGROUND: Recombinant human interleukin-2 (aldesleukin) and recombinant human interferon alfa can induce notable tumor regression in a limited number of patients with metastatic renal-cell carcinoma. We conducted a multicenter, randomized trial to determine the effect of each cytokine independently and in combination, and to identify patients who are best suited for this treatment. METHODS: Four hundred twenty-five patients with metastatic renal-cell carcinoma were randomly assigned to receive either a continuous intravenous infusion of interleukin-2, subcutaneous injections of interferon alfa-2a, or both. The main outcome measure was the response rate; secondary outcomes were the rates of event-free and overall survival. Predictive factors for response and rapid progression were identified by multivariate analysis. RESULTS: Response rates were 6.5 percent, 7.5 percent, and 18.6 percent (P<0.01) for the groups receiving interleukin-2, interferon alfa-2a, and interleukin-2 plus interferon alfa-2a, respectively. At one year, the event-free survival rates were 15 percent, 12 percent, and 20 percent, respectively (P=0.01). There was no significant difference in overall survival among the three groups. Toxic effects of therapy were more common in patients receiving interleukin-2 than in those receiving interferon alfa-2a. Response to treatment was associated with having metastasis to a single organ and with receiving the combined treatment. The probability of rapid progression of disease was at least 70 percent for patients with at least two metastatic sites, liver metastases, and a period of less than one year between the diagnosis of the primary tumor and the appearance of metastases. CONCLUSIONS: Cytokines are active in a few patients with metastatic renal-cell carcinoma. The higher response rate and longer event-free survival obtained with a combination of cytokines must be balanced against the toxicity of such treatment.

BACKGROUND: A 6-month abstinence from alcohol is usually required before patients with severe alcoholic hepatitis are considered for liver transplantation. Patients whose hepatitis is not responding to medical therapy have a 6-month survival rate of approximately 30%. Since most alcoholic hepatitis deaths occur within 2 months, early liver transplantation is attractive but controversial. METHODS: We selected patients from seven centers for early liver transplantation. The patients had no prior episodes of alcoholic hepatitis and had scores of 0.45 or higher according to the Lille model (which calculates scores ranging from 0 to 1, with a score ≥ 0.45 indicating nonresponse to medical therapy and an increased risk of death in the absence of transplantation) or rapid worsening of liver function despite medical therapy. Selected patients also had supportive family members, no severe coexisting conditions, and a commitment to alcohol abstinence. Survival was compared between patients who underwent early liver transplantation and matched patients who did not. RESULTS: In all, 26 patients with severe alcoholic hepatitis at high risk of death (median Lille score, 0.88) were selected and placed on the list for a liver transplant within a median of 13 days after nonresponse to medical therapy. Fewer than 2% of patients admitted for an episode of severe alcoholic hepatitis were selected. The centers used 2.9% of available grafts for this indication. The cumulative 6-month survival rate (±SE) was higher among patients who received early transplantation than among those who did not (77 ± 8% vs. 23 ± 8%, P<0.001). This benefit of early transplantation was maintained through 2 years of follow-up (hazard ratio, 6.08; P = 0.004). Three patients resumed drinking alcohol: one at 720 days, one at 740 days, and one at 1140 days after transplantation. CONCLUSIONS: Early liver transplantation can improve survival in patients with a first episode of severe alcoholic hepatitis not responding to medical therapy. (Funded by Société Nationale Française de Gastroentérologie.).

BACKGROUND: Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy. METHODS: We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%). RESULTS: The onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of the patients (88.7% of cases were in adults), tumors (mainly ganglioglioma) in 23.6%, and malformations of cortical development in 19.8% (focal cortical dysplasia was the most common type, 52.7% of cases of which were in children). No histopathological diagnosis could be established for 7.7% of the patients. CONCLUSIONS: In patients with drug-resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the most common diagnosis among children. Tumors were the second most common lesion in both groups. (Funded by the European Union and others.).

Acquired genomic aberrations have been shown to significantly impact survival in several hematologic malignancies. We analyzed the prognostic value of the most frequent chromosomal changes in a large series of patients with newly diagnosed symptomatic myeloma prospectively enrolled in homogeneous therapeutic trials. All the 1064 patients enrolled in the IFM99 trials conducted by the Intergroupe Francophone du Myélome benefited from an interphase fluorescence in situ hybridization analysis performed on purified bone marrow plasma cells. They were systematically screened for the following genomic aberrations: del(13), t(11;14), t(4;14), hyperdiploidy, MYC translocations, and del(17p). Chromosomal changes were observed in 90% of the patients. The del(13), t(11;14), t(4;14), hyperdiploidy, MYC translocations, and del(17p) were present in 48%, 21%, 14%, 39%, 13%, and 11% of the patients, respectively. After a median follow-up of 41 months, univariate statistical analyses revealed that del(13), t(4;14), nonhyperdiploidy, and del(17p) negatively impacted both the event-free survival and the overall survival, whereas t(11;14) and MYC translocations did not influence the prognosis. Multivariate analyses on 513 patients annotated for all the parameters showed that only t(4;14) and del(17p) retained prognostic value for both the event-free and overall survivals. When compared with the currently used International Staging System, this prognostic model compares favorably. In myeloma, the genomic aberrations t(4;14) and del(17p), together with beta2-microglobulin level, are important independent predictors of survival. These findings have implications for the design of risk-adapted treatment strategies.

RATIONALE: Burnout syndrome (BOS) associated with stress has been documented in health care professionals in many specialties. The intensive care unit (ICU) is a highly stressful environment. Little is known about BOS in critical care nursing staff. OBJECTIVES: To identify determinants of BOS in critical care nurses. METHODS: We conducted a questionnaire survey in France. Among 278 ICUs contacted for the study, 165 (59.4%) included 2,525 nursing staff members, of whom 2,392 returned questionnaires with complete Maslach Burnout Inventory data. MEASUREMENTS AND MAIN RESULTS: Of the 2,392 respondents (82% female), 80% were nurses, 15% nursing assistants, and 5% head nurses. Severe BOS-related symptoms were identified in 790 (33%) respondents. By multivariate analysis, four domains were associated with severe BOS: (1) personal characteristics, such as age (odds ratio [OR], 0.97/yr; confidence interval [CI], 0.96-0.99; p=0.0008); (2) organizational factors, such as ability to choose days off (OR, 0.69; CI, 0.52-0.91; p=0.009) or participation in an ICU research group (OR, 0.74; CI, 0.56-0.97; p=0.03); (3) quality of working relations (1-10 scale), such as conflicts with patients (OR, 1.96; CI, 1.16-1.30; p=0.01), relationship with head nurse (OR, 0.92/point; CI, 0.86-0.98; p=0.02) or physicians (OR, 0.81; CI, 0.74-0.87; p=0.0001); and (4) end-of-life related factors, such as caring for a dying patient (OR, 1.39; CI, 1.04-1.85; p=0.02), and number of decisions to forego life-sustaining treatments in the last week (OR, 1.14; CI, 1.01-1.29; p=0.04). CONCLUSION: One-third of ICU nursing staff had severe BOS. Areas for improvement identified in our study include conflict prevention, participation in ICU research groups, and better management of end-of-life care. Interventional studies are needed to investigate these potentially preventive strategies.

OBJECTIVE: Recurrent digital ulcers are a manifestation of vascular disease in patients with systemic sclerosis (SSc; scleroderma) and lead to pain, impaired function, and tissue loss. We investigated whether treatment with the endothelin receptor antagonist, bosentan, decreased the development of new digital ulcers in patients with SSc. METHODS: This was a randomized, prospective, placebo-controlled, double-blind study of 122 patients at 17 centers in Europe and North America, evaluating the effect of treatment on prevention of digital ulcers. The primary outcome variable was the number of new digital ulcers developing during the 16-week study period. Secondary assessments included healing of existing digital ulcers and evaluation of hand function using the Scleroderma Health Assessment Questionnaire. RESULTS: Patients receiving bosentan had a 48% reduction in the mean number of new ulcers during the treatment period (1.4 versus 2.7 new ulcers; P = 0.0083). Patients who had digital ulcers at the time of entry in the study were at higher risk for the development of new ulcers; in this subgroup the mean number of new ulcers was reduced from 3.6 to 1.8 (P = 0.0075). In patients receiving bosentan, a statistically significant improvement in hand function was observed. There was no difference between treatment groups in the healing of existing ulcers. Serum transaminase levels were elevated to >3-fold the upper limit of normal in bosentan-treated patients; this elevation is comparable with that observed in previous studies of this agent. Other side effects were similar in the 2 treatment groups. CONCLUSION: Endothelins may play an important role in the pathogenesis of vascular disease in patients with SSc. Treatment with the endothelin receptor antagonist bosentan may be effective in preventing new digital ulcers and improving hand function in patients with SSc.

What are the components that control the assembly of subcellular organelles in eukaryotic cells? Although membranes can clearly be distorted by cytosolic factors, very little is known about the intrinsic mechanisms that control the biogenesis, shape, and organization of organellar membranes. Here, we found that the unconventional phospholipid lysobisphosphatidic acid (LBPA) could induce the formation of multivesicular liposomes that resembled the multivesicular endosomes that exist where this lipid is found in vivo. This process depended on the same pH gradient that exists across endosome membranes in vivo and was selectively controlled by Alix. In turn, Alix regulated the organization of LBPA-containing endosomes in vivo.

BACKGROUND: Experimental and clinical evidence suggests that cyclosporine may attenuate reperfusion injury and reduce myocardial infarct size. We aimed to test whether cyclosporine would improve clinical outcomes and prevent adverse left ventricular remodeling. METHODS: In a multicenter, double-blind, randomized trial, we assigned 970 patients with an acute anterior ST-segment elevation myocardial infarction (STEMI) who were undergoing percutaneous coronary intervention (PCI) within 12 hours after symptom onset and who had complete occlusion of the culprit coronary artery to receive a bolus injection of cyclosporine (administered intravenously at a dose of 2.5 mg per kilogram of body weight) or matching placebo before coronary recanalization. The primary outcome was a composite of death from any cause, worsening of heart failure during the initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at 1 year. Adverse left ventricular remodeling was defined as an increase of 15% or more in the left ventricular end-diastolic volume. RESULTS: A total of 395 patients in the cyclosporine group and 396 in the placebo group received the assigned study drug and had data that could be evaluated for the primary outcome at 1 year. The rate of the primary outcome was 59.0% in the cyclosporine group and 58.1% in the control group (odds ratio, 1.04; 95% confidence interval [CI], 0.78 to 1.39; P=0.77). Cyclosporine did not reduce the incidence of the separate clinical components of the primary outcome or other events, including recurrent infarction, unstable angina, and stroke. No significant difference in the safety profile was observed between the two treatment groups. CONCLUSIONS: In patients with anterior STEMI who had been referred for primary PCI, intravenous cyclosporine did not result in better clinical outcomes than those with placebo and did not prevent adverse left ventricular remodeling at 1 year. (Funded by the French Ministry of Health and NeuroVive Pharmaceutical; CIRCUS ClinicalTrials.gov number, NCT01502774; EudraCT number, 2009-013713-99.).

NOX4 is an enigmatic member of the NOX (NADPH oxidase) family of ROS (reactive oxygen species)-generating NADPH oxidases. NOX4 has a wide tissue distribution, but the physiological function and activation mechanisms are largely unknown, and its pharmacology is poorly understood. We have generated cell lines expressing NOX4 upon tetracycline induction. Tetracycline induced a rapid increase in NOX4 mRNA (1 h) followed closely (2 h) by a release of ROS. Upon tetracycline withdrawal, NOX4 mRNA levels and ROS release decreased rapidly (<24 h). In membrane preparations, NOX4 activity was selective for NADPH over NADH and did not require the addition of cytosol. The pharmacological profile of NOX4 was distinct from other NOX isoforms: DPI (diphenyleneiodonium chloride) and thioridazine inhibited the enzyme efficiently, whereas apocynin and gliotoxin did not (IC(50)>100 muM). The pattern of NOX4-dependent ROS generation was unique: (i) ROS release upon NOX4 induction was spontaneous without need for a stimulus, and (ii) the type of ROS released from NOX4-expressing cells was H(2)O(2), whereas superoxide (O(2)(-)) was almost undetectable. Probes that allow detection of intracellular O(2)(-) generation yielded differential results: DHE (dihydroethidium) fluorescence and ACP (1-acetoxy-3-carboxy-2,2,5,5-tetramethylpyrrolidine) ESR measurements did not detect any NOX4 signal, whereas a robust signal was observed with NBT. Thus NOX4 probably generates O(2)(-) within an intracellular compartment that is accessible to NBT (Nitro Blue Tetrazolium), but not to DHE or ACP. In conclusion, NOX4 has a distinct pharmacology and pattern of ROS generation. The close correlation between NOX4 mRNA and ROS generation might hint towards a function as an inducible NOX isoform.

BACKGROUND: Patients with primary biliary cholangitis who have an inadequate response to therapy with ursodeoxycholic acid are at high risk for disease progression. Fibrates, which are agonists of peroxisome proliferator-activated receptors, in combination with ursodeoxycholic acid, have shown potential benefit in patients with this condition. METHODS: In this 24-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 100 patients who had had an inadequate response to ursodeoxycholic acid according to the Paris 2 criteria to receive bezafibrate at a daily dose of 400 mg (50 patients), or placebo (50 patients), in addition to continued treatment with ursodeoxycholic acid. The primary outcome was a complete biochemical response, which was defined as normal levels of total bilirubin, alkaline phosphatase, aminotransferases, and albumin, as well as a normal prothrombin index (a derived measure of prothrombin time), at 24 months. RESULTS: The primary outcome occurred in 31% of the patients assigned to bezafibrate and in 0% assigned to placebo (difference, 31 percentage points; 95% confidence interval, 10 to 50; P<0.001). Normal levels of alkaline phosphatase were observed in 67% of the patients in the bezafibrate group and in 2% in the placebo group. Results regarding changes in pruritus, fatigue, and noninvasive measures of liver fibrosis, including liver stiffness and Enhanced Liver Fibrosis score, were consistent with the results of the primary outcome. Two patients in each group had complications from end-stage liver disease. The creatinine level increased 5% from baseline in the bezafibrate group and decreased 3% in the placebo group. Myalgia occurred in 20% of the patients in the bezafibrate group and in 10% in the placebo group. CONCLUSIONS: Among patients with primary biliary cholangitis who had had an inadequate response to ursodeoxycholic acid alone, treatment with bezafibrate in addition to ursodeoxycholic acid resulted in a rate of complete biochemical response that was significantly higher than the rate with placebo and ursodeoxycholic acid therapy. (Funded by Programme Hospitalier de Recherche Clinique and Arrow Génériques; BEZURSO ClinicalTrials.gov number, NCT01654731 .).

BACKGROUND: The authors conducted a patient-based survey of practices to fully describe the assessment and the management of pain and sedation of a large cohort of mechanically ventilated patients during their first week of intensive care unit (ICU) stay. METHODS: A total of 1,381 adult patients were included in a prospective, observational study in 44 ICUs in France. Pain and sedation assessment, analgesic and sedative use, and analgesic management during procedural pain were collected on days 2, 4, and 6 of the ICU stay. RESULTS: The observed rates of assessment on day 2 for sedation (43%) and analgesia (42%) were significantly smaller than that of use of sedatives (72%) and opioids (90%), also noted on days 4 and 6. The use of protocols/guidelines for sedation/analgesia in the ICU reduced the proportion of patients who were treated, although not evaluated. A large proportion of assessed patients were in a deep state of sedation (40-50%). Minor changes in the dosages of the main prescribed agents for sedation (midazolam, propofol) and analgesia (sufentanil, fentanyl, morphine, remifentanil) were found across 6 days of the patient's ICU stay. Procedural pain was specifically managed for less than 25% of patients; during those procedures, the proportion of patients with pain significantly increased from the baseline pain evaluation. CONCLUSIONS: Excessively deep states of sedation and a lack of analgesia during painful procedures must be prevented. To facilitate systematic pain and sedation assessment and to adjust daily drug dosages accordingly, it seems crucial to promote educational programs and elaboration of protocols/guidelines in the ICU.

BACKGROUND: Treatment with interferon prolongs survival in chronic myelogenous leukemia. We conducted a clinical trial to assess the efficacy of treatment with a combination of interferon and cytarabine. METHODS: Previously untreated patients with chronic myelogenous leukemia were randomly assigned to receive either hydroxyurea (50 mg per kilogram of body weight per day) and interferon alfa-2b (5 million units per square meter of body-surface area per day), or hydroxyurea and interferon in the same dosages plus monthly courses of cytarabine (20 mg per square meter per day, for 10 days). The end points were overall survival, complete hematologic remission at 6 months, and major cytogenetic response (less than 35 percent Philadelphia chromosome-positive cells in the bone marrow) at 12 months. RESULTS: The trial was stopped when a sequential analysis showed a benefit of interferon and cytarabine. A significant improvement in survival was observed in the interferon-cytarabine group (360 patients) as compared with the interferon group (361 patients) (P=0.02; relative risk of death, 0.64; 95 percent confidence interval, 0.44 to 0.93). After three years, the survival rate was 85.7 percent with interferon and cytarabine and 79.1 percent with interferon alone. The rate of hematologic response was higher in the interferon-cytarabine group than in the interferon group (P=0.003). Major cytogenetic responses were observed 12 months after randomization in 126 of 311 patients treated with interferon and cytarabine (41 percent) and in 75 of 314 patients treated with interferon only (24 percent, P<0.001). CONCLUSIONS: The combination of interferon and cytarabine, as compared with interferon alone, increases the rate of major cytogenetic response and prolongs survival in patients with the chronic phase of chronic myelogenous leukemia.

INTRODUCTION: A previous trial in renal transplantation comparing sirolimus (rapamycin) to cyclosporine (CsA) in a triple-drug therapy regimen with azathioprine and corticosteroids found that the incidence of acute rejection was similar (approximately 40%) with a trend for better renal function with sirolimus. METHODS: In 14 European centers, first cadaveric renal allograft recipients were randomized to receive sirolimus (n = 40) or CsA (n = 38) in an open-label design. All patients received corticosteroids and mycophenolate mofetil 2 g/day. Sirolimus and CsA were concentration controlled; trough levels of mycophenolic acid and prednisolone were also measured. RESULTS: At 12 months, graft survival (92.5% sirolimus vs. 89.5% CsA), patient survival (97.5% sirolimus vs. 94.7% CsA), and the incidence of biopsy-proven acute rejection (27.5% sirolimus vs. 18.4% CsA) were not statistically different. The use of antibodies to treat suspected rejection episodes was also similar (7.5% sirolimus vs. 5.3% CsA). More sirolimus patients received bolus steroid therapy (20 vs. 11, P = 0.068). From month 2 onward, the calculated glomerular filtration rate was consistently higher in sirolimus-treated patients. The adverse events reported more frequently with sirolimus were thrombocytopenia (45% vs. 8%) and diarrhea (38% vs. 11%). In the CsA group, increased creatinine (18% vs. 39%), hyperuricemia (3% vs. 18%), cytomegalovirus infection (5% vs. 21%), and tremor (5% vs. 21%) were observed significantly more often. DISCUSSION: Patient and graft survival and the incidence of biopsy-proven acute rejection at 12 months were comparable between sirolimus and CsA, whereas safety profiles were different. These data suggest that sirolimus may be used as primary therapy for the prevention of acute rejection.