Anderson Loundou

Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome

BACKGROUND In patients undergoing mechanical ventilation for the acute respiratory distress syndrome (ARDS), neuromuscular blocking agents may improve oxygenation and decrease ventilator-induced lung injury but may also cause muscle weakness. We evaluated clinical outcomes after 2 days of therapy with neuromuscular blocking agents in patients with early, severe ARDS. METHODS In this multicenter, double-blind trial, 340 patients presenting to the intensive care unit (ICU) with an onset of severe ARDS within the previous 48 hours were randomly assigned to receive, for 48 hours, either cisatracurium besylate (178 patients) or placebo (162 patients). Severe ARDS was defined as a ratio of the partial pressure of arterial oxygen (PaO2) to the fraction of inspired oxygen (FIO2) of less than 150, with a positive end-expiratory pressure of 5 cm or more of water and a tidal volume of 6 to 8 ml per kilogram of predicted body weight. The primary outcome was the proportion of patients who died either before hospital discharge or within 90 days after study enrollment (i.e., the 90-day in-hospital mortality rate), adjusted for predefined covariates and baseline differences between groups with the use of a Cox model. RESULTS The hazard ratio for death at 90 days in the cisatracurium group, as compared with the placebo group, was 0.68 (95% confidence interval [CI], 0.48 to 0.98; P=0.04), after adjustment for both the baseline PaO2:FIO2 and plateau pressure and the Simplified Acute Physiology II score. The crude 90-day mortality was 31.6% (95% CI, 25.2 to 38.8) in the cisatracurium group and 40.7% (95% CI, 33.5 to 48.4) in the placebo group (P=0.08). Mortality at 28 days was 23.7% (95% CI, 18.1 to 30.5) with cisatracurium and 33.3% (95% CI, 26.5 to 40.9) with placebo (P=0.05). The rate of ICU-acquired paresis did not differ significantly between the two groups. CONCLUSIONS In patients with severe ARDS, early administration of a neuromuscular blocking agent improved the adjusted 90-day survival and increased the time off the ventilator without increasing muscle weakness. (Funded by Assistance Publique-Hôpitaux de Marseille and the Programme Hospitalier de Recherche Clinique Régional 2004-26 of the French Ministry of Health; ClinicalTrials.gov number, NCT00299650.)

Global Histone Modifications Predict Prognosis of Resected Non–Small-Cell Lung Cancer

PURPOSE Epigenetic modifications may contribute to the development and progression of cancer. We investigated whether epigenetic changes involving multiple histones influence prognosis of non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS We used immunohistochemistry to assess histone 3 lysine 4 dimethylation (H3K4diMe), and acetylation of histone 2A lysine 5 (H2AK5Ac), histone 2B lysine 12, histone 3 lysine 9 (H3K9Ac), and histone 4 lysine 8 in resected tumor samples of 138 NSCLC patients. Data were analyzed using a recursive partitioning analysis (RPA). RESULTS The RPA classified the patients into seven distinct prognostic groups based on TNM stage (first node), histology, and histone modifications: H3K4diMe (< or 85% tumor cells), H3K9Ac (< or 68% tumor cells), and H2AK5Ac (< or 5% tumor cells). The seven groups were associated with significantly different disease-free (P < .0001) and overall survival (P < .0001). Interestingly, the four groups determined by stage I patients (below the first node) displayed dramatic differences in survival (median, 10 months in adenocarcinoma patients with H3K9Ac 68% v 147 months in nonadenocarcinoma patients with H3K4diMe 85%). A Cox model retained age and RPA groups as the sole independent factors significantly influencing overall survival. CONCLUSION The prognostic influence of epigenetic changes involving multiple histones, in particular H2A and H3, is greater in early NSCLC, and evaluation of these changes may help in selecting early-stage NSCLC patients for adjuvant treatment. Our observations provide a rationale for the use of a combination of standard chemotherapy with drugs interacting with histone modifications, such as histone deacetylase inhibitors.

Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode.

To date, it remains impossible to guarantee that short-term treatment given to a patient suffering from a major depressive episode (MDE) will improve long-term efficacy. Objective biological measurements and biomarkers that could help in predicting the clinical evolution of MDE are still warranted. To better understand the reason nearly half of MDE patients respond poorly to current antidepressive treatments, we examined the gene expression profile of peripheral blood samples collected from 16 severe MDE patients and 13 matched controls. Using a naturalistic and longitudinal design, we ascertained mRNA and microRNA (miRNA) expression at baseline, 2 and 8 weeks later. On a genome-wide scale, we detected transcripts with roles in various biological processes as significantly dysregulated between MDE patients and controls, notably those involved in nucleotide binding and chromatin assembly. We also established putative interactions between dysregulated mRNAs and miRNAs that may contribute to MDE physiopathology. We selected a set of mRNA candidates for quantitative reverse transcriptase PCR (RT-qPCR) to validate that the transcriptional signatures observed in responders is different from nonresponders. Furthermore, we identified a combination of four mRNAs (PPT1, TNF, IL1B and HIST1H1E) that could be predictive of treatment response. Altogether, these results highlight the importance of studies investigating the tight relationship between peripheral transcriptional changes and the dynamic clinical progression of MDE patients to provide biomarkers of MDE evolution and prognosis.

Endovascular Management of Chronic Disabling Ilio-caval Obstructive Lesions: Long-Term Results

OBJECTIVE To report the long-term results of stenting for chronic ilio-caval obstructive lesions. MATERIAL AND METHODS From January 1996 to January 2008, 89 patients (72 women, 17 men; median age 43 years) were admitted for endovascular treatment of chronic disabling non-malignant obstructive ilio-caval lesions. Patients were classified as C2 in 15 cases, C3 in 59, C4 in seven, C5 in two and C6 in six. Median preoperative venous disability score (VDS) and venous clinical severity score (VCSS) were 2 and 9, respectively. Aetiology was primary in 52 patients, secondary in 35 and congenital in two. Lesions were bilateral in seven cases, eight patients had inferior vena cava (IVC) involvement and 18 had common femoral vein (CFV) obstructive lesions. Complete occlusion was found in 30 cases. RESULTS Technical success was achieved in 98%. The median hospital stay was 2 days. During a median follow-up of 38 months (range: 1-144 months), one patient died and five cases of thromboses occurred. Iterative stenting was performed for restenosis in six cases. Primary, assisted-primary and secondary patency rates, in terms of intention to treat, were 83%, 89% and 93%, respectively, at 3 and 10 years, with a median VDS of 1. Univariate analysis found that significant factors affecting patency were CFV involvement for primary patency and history of deep venous thrombosis (DVT) and CFV involvement for secondary patency. The last 46 patients had statistically more severe lesions than the first 43 (higher VDS, more secondary lesions, more occlusions, more stented segments, higher length of stented vein), and in spite of which patency rates are not different. CONCLUSION Endovenous angioplasty, combined with stenting, is a sure, safe, effective and very minimally invasive technique which provides good long-term patency rates. Currently, it is recognised as the technique of choice for the treatment of ilio-caval obstructive lesions. Surgery should be proposed only in case of failure.

Dysembryoplastic Neuroepithelial Tumors Share with Pleomorphic Xanthoastrocytomas and Gangliogliomas BRAFV600E Mutation and Expression

Pediatric cortical glioneuronal benign tumors mainly include gangliogliomas (GG) [differential diagnoses pilocytic astrocytomas (PA) and pleomorphic xanthoastrocytomas (PXA)] and dysembryoplastic neuroepithelial tumor (DNT). DNT include the specific form and the controversial non‐specific form that lack the specific glioneuronal element. Our aims were to search for BRAFV600E mutation and CD34 expression in DNT, PXA, GG and PA to correlate BRAFV600E mutation with BRAFV600E expression and to evaluate their diagnostic and prognostic values. Ninety‐six children were included. BRAFV600E mutation was studied by sequencing and immunohistochemistry; CD34 expression was analyzed by immunohistochemistry. BRAFV600E mutation was detected in PXA (60%), GG (38.7%), DNT (30%, including 3/11 specific and 3/9 non‐specific forms) and PA (12.5%). BRAFV600E expression was recorded in PXA (60%), GG (45.2%) and DNT (30%). CD34 expression was recorded in PXA (60%), GG (58.1%), DNT (25%) and PA (12.5%). Neither CD34 expression nor BRAFV600E status was predictive of prognosis, except for PA tumors where CD34 expression was associated with a shorter overall survival. In conclusion, DNT shared with PXA and GG, BRAFV600E mutation and/or CD34 expression, which represent molecular markers for these tumors, and we recommend searching for CD34 expression and BRAFV600E mutation in all DNT, especially the non‐specific forms.

A nationwide survey of excessive daytime sleepiness in Parkinson's disease in France

To determine the prevalence of excessive daytime sleepiness (EDS) and that of dozing and sudden onset of sleep episodes (SOS) while driving in ambulatory patients with Parkinsons disease (PD) in France, a national sample of private and public neurologists was asked to recruit the first 10 consecutive nondemented PD patients. Each patient completed a questionnaire including the Epworth Sleepiness Scale (ESS) and the likelihood of dozing off and experiencing SOS episodes behind the wheel. Clinical and demographic data were collected. One thousand six hundred and twenty‐five patients with PD were included in the survey. Twenty‐nine percent of the patients suffered from EDS (ESS score ≥10) but only 0.8% declared a high chance of dozing while driving and 0.5% reported totally unpredictable SOS episodes while driving. Risk factors for EDS were male gender, reduced activity of daily living, and a high daily levodopa equivalent dosage. Risk factors for SOS episodes while driving were an ESS score ≥10, male gender, and low Hoehn and Yahr staging. EDS is common in ambulatory patients with PD and is a major risk factor for dozing and for SOS episodes behind the wheel in patients who drive.

Quality of life changes and clinical outcomes in thyroid cancer patients undergoing radioiodine remnant ablation (RRA) with recombinant human TSH (rhTSH): a randomized controlled study

Background  Recombinant human TSH (rhTSH) has become the modality of choice for radioiodine remnant ablation (RRA) in low‐risk thyroid cancer patients.

Mycophenolate Mofetil Monotherapy in Membranous Nephropathy: A 1-Year Randomized Controlled Trial

BACKGROUND Treatment of patients with membranous glomerulonephritis (MGN) is controversial because of the lack of clear benefit of the immunosuppressive regimens on patient or renal survival. The objective of this study is to evaluate the efficacy and safety of mycophenolate mofetil (MMF) for patients with MGN. STUDY DESIGN 1-year prospective, randomized, and controlled clinical trial. SETTING & PARTICIPANTS 36 patients with biopsy-proven idiopathic MGN and nephrotic syndrome. INTERVENTION 19 patients received MMF (2 g/d) for 12 months and 17 patients were in the control group. All patients had the same conservative treatment based on renin-angiotensin blockers, statins, low-salt and low-protein diet, and diuretics in case of edema. OUTCOMES & MEASUREMENTS End points were the mean proteinuria over creatinuria ratio in mg/g throughout the study and numbers of complete and partial remissions at 1 year (month 12). Data were analyzed on an intention-to-treat analysis. RESULTS Mean proteinuria over creatinuria ratio was stable in both groups throughout the study (P = 0.1). Mean proteinuria over creatinuria ratio was 4,690 +/- 2,212 mg/g in the MMF group and 6,548 +/- 4,601 mg/g in the control group (95% confidence interval of the difference, -619 to +4,247; P = 0.1). Remission was complete in 3 patients (1 in the MMF group, 2 in the control group; P = 0.5) and partial in 11 patients (6 in the MMF group, 5 in the control group; P = 0.9). The probability of complete or partial remission did not differ between the 2 groups after 12 months (relative risk, 0.92; 95% confidence interval, 0.48 to 1.75; P = 0.7). Kidney function was stable in the 2 groups according to estimated glomerular filtration rate and serum creatinine level. LIMITATIONS The small number of patients and short follow-up prevent generalizations. CONCLUSIONS A 12-month regimen of MMF did not decrease mean proteinuria over creatinuria ratio or increase partial and complete remissions. Serious adverse effects were observed in 4 patients (20%) receiving MMF.

Clinical variations modulate patterns of gene expression and define blood biomarkers in major depression

The aim of the study is to compare the expression level of candidate genes between patients suffering from a severe major depressive episode (MDE) and controls, and also among patients during MDE evolution. After a comprehensive review of the biological data related to mood disorders, we initiated a hypothesis-driven exploration of candidate mRNAs. Using RT-qPCR, we analyzed peripheral blood mononuclear cells (PBMCs) mRNA obtained from a homogeneous population of 11 patients who suffered from severe melancholic MDE. To assess the evolution of MDE, we analyzed PBMC mRNAs that were collected on Day 1 and 8 weeks later. Data from these patient samples were analyzed in comparison to age- and sex-matched healthy controls. Among 40 candidate genes consistently transcribed in PBMCs, 10 were differentially expressed in at least one comparison. We found that variations of mRNA levels for NRG1, SORT1 and TPH1 were interesting state-dependent biological markers of the disease. We also observed that variations in other mRNA expression were associated with treatment efficacy or clinical improvement (CREB1, HDAC5, HSPA2, HTR1B, HTR2A, and SLC6A4/5HTT). Significantly, 5HTT exhibited a strong correlation with clinical score evolution. We also found a state-independent marker, IL10. Moreover, the analysis of 2 separate MDEs concerning a same patient revealed comparable results for the expression of CREB1, HSPA2, HTR1B, NRG1 and TPH1. Overall, our results indicate that PBMCs obtained at different time points during MDE progression represent a promising avenue to discover biological markers for depression.

The development of the S-QoL 18: A shortened quality of life questionnaire for patients with schizophrenia

OBJECTIVE The S-QoL 41 is a French self-administered questionnaire that assesses quality of life (QoL) among people with schizophrenia. This study aims to validate a shortened version of the S-QoL for more widespread use in clinical practice. METHODS We used data from four studies conducted in four psychiatric hospitals in France (n=507). The item reduction and validation processes were based on both item response theory and classical test theory. The final version of the S-QoL was tested for construct validity, reliability, external validity, reproducibility and sensitivity to change. In addition, differential item functioning (DIF) analyses were performed to see whether all items behave in the same way in subgroups divided by age, gender, educational level and clinical form. RESULTS The S-QoL 18 evaluates eight dimensions: psychological well-being, self-esteem, family relationships, relationships with friends, resilience, physical well-being, autonomy and sentimental life. The factor structure accounted for 78% of the total variance. Internal consistency was satisfactory (item-internal consistency greater than 0.40; Cronbachs alpha coefficients ranged from 0.72 to 0.84). The scalability was satisfactory, with INFIT statistics within an acceptable range. In addition, the results confirmed the absence of DIF and supported the invariance of the item calibrations. CONCLUSIONS The S-QoL 18 is a short self-administered QoL instrument that has a high degree of comparability with S-QoL 41 and presents satisfactory psychometric properties. Future studies should confirm its sensitivity to change.