The sensitivity of chronic lymphocytic leukemia (CLL) cells to current treatments, both in vitro and in vivo, relies on their ability to activate apoptotic death. CLL cells resistant to DNA ...damage-induced apoptosis display deregulation of a specific set of genes.
Microarray hybridization (Human GeneChip, Affymetrix), immunofluorescent in situ labeling coupled with video-microscopy recording/analyses, chromatin-immunoprecipitation (ChIP), polymerase chain reactions (PCR), real-time quantitative PCR (RT-QPCR) and bisulfite genome sequencing were the main methods applied. Statistical analyses were performed by applying GCRMA and SAM analysis (microarray data) and Student's t-test or Mann & Whitney's U-test.
Herein we show that, remarkably, in a resistant male CLL cells the vast majority of genes were down-regulated compared with sensitive cells, whereas this was not the case in cells derived from females. This gene down-regulation was found to be associated with an overall gain of heterochromatin as evidenced by immunofluorescent labeling of heterochromatin protein 1α (HP-1), trimethylated histone 3 lysine 9 (3metH3K9), and 5-methylcytidine (5metC). Notably, 17 genes were found to be commonly deregulated in resistant male and female cell samples. Among these, RELB was identified as a discriminatory candidate gene repressed in the male and upregulated in the female resistant cells.
The molecular defects in the silencing of RELB involve an increase in H3K9- but not CpG-island methylation in the promoter regions. Increase in acetyl-H3 in resistant female but not male CLL samples as well as a decrease of total cellular level of RelB after an inhibition of histone deacetylase (HDAC) by trichostatin A (TSA), further emphasize the role of epigenetic modifications which could discriminate two CLL subsets. Together, these results highlighted the epigenetic RELB silencing as a new marker of the progressive disease in males.
Legislative measures have been identified as one effective way of changing attitude or behaviour towards health care. The aim of this study was to describe trends in patients' complaints for medical ...issues; to evaluate the contribution of a law regarding patients' rights, and to identify factors associated to patients' perception of a medical error.
Patients with a complaint letter for medical issues in a French university hospital were included. Trends in complaint rates were analysed. Comparisons were made between a first (1998-2000) and a second (2001-2004) time period, before and after the diffusion of the law, and according to the perception of a medical error.
Complaints for medical issues increased from 1998 to 2004. Of 164 complaints analysed, 66% were motivated by the perception of a medical error (47% during the first time period vs. 73% during the second time period; p = 0.001). Error or delay in diagnosis/treatment and surgical/medical complication were the main reasons for complaints. Surgical departments had the higher number of complaints. Second time period, substandard care, disability, and adverse effect of a health product were independently associated with the perception of a medical error, positively for the formers, and negatively for the latter.
This study revealed an increase with time in the number of complaints for medical issues in a university hospital, as well as an increase in the perception of a medical error after the passing of a law regarding patients' rights in France.
Abstract Objective Neuropathic pain (NP) in acute conditions has been poorly investigated. A diagnostic score, the DN4 scale (DN4), has been developed to help physicians to detect and treat NP ...appropriately. DN4 is a 10-item questionnaire. If you have 4 or more positive responses out of 10 items, the answer to the questionnaire is positive and you have a neuropathic pain. We aimed to determine the prevalence of NP in emergency department (ED) patients and to describe this population. Methods We used the DN4 in the patients with NP visiting the adult ED of a university hospital. Patients were asked about the characteristics of their pain using a face-to-face questionnaire. Results Among 533 patients with a DN4 score, 114 (21.4%) had NP. Neuropathic pain was independently negatively associated with age of 65 years of older (odds ratio OR, 0.2, 95% confidence interval CI, 0.05-0.8) and positively associated with intense pain (OR, 5.2; 95% CI, 1.5-18.2), located to the limbs (OR, 2.3; 95% CI, 1.2-4.0). Conclusion Neuropathic pain was common in ED patients and associated to a higher level of pain.
To identify predictive factors for irreversible transmural intestinal necrosis (ITIN) in acute mesenteric ischemia (AMI) and establish a risk score for ITIN.
This single-center prospective cohort ...study was performed between 2009 and 2015 in patients with AMI. The primary outcome was the occurrence of ITIN, confirmed by specimen analysis in patients who underwent surgery. Patients who recovered from AMI with no need for intestinal resection were considered not to have ITIN. Clinical, biological and radiological data were compared in a Cox regression model.
A total of 67 patients were included. The origin of AMI was arterial, venous, or non-occlusive in 61%, 37%, 2% of cases, respectively. Intestinal resection and ITIN concerned 42% and 34% of patients, respectively. Factors associated with ITIN in multivariate analysis were: organ failure (hazard ratio (HR): 3.1 (95% confidence interval (CI): 1.1-8.5); P=0.03), serum lactate levels >2 mmol/l (HR: 4.1 (95% CI: 1.4-11.5); P=0.01), and bowel loop dilation on computerized tomography scan (HR: 2.6 (95% CI: 1.2-5.7); P=0.02). ITIN rate increased from 3% to 38%, 89%, and 100% in patients with 0, 1, 2, and 3 factors, respectively. Area under the receiver operating characteristics curve for the diagnosis of ITIN was 0.936 (95% CI: 0.866-0.997) depending on the number of predictive factors.
We identified three predictive factors for irreversible intestinal ischemic injury requiring resection in the setting of AMI. Close monitoring of these factors could help avoid unnecessary laparotomy, prevent resection, as well as complications due to unresected necrosis, and possibly lower the overall mortality.
Studies of the responses of hematopoietic stem and progenitor cells (HSPCs) to low doses of ionizing radiation formed an important aspect of the RISK-IR project (
www.risk-ir.eu
). A brief overview ...of these studies is presented here. The findings confirm the sensitivity of HSPCs to radiation even at low doses, and illustrate the substantial impact that differentiation state has upon cell sensitivity. The work provides mechanistic support for epidemiological findings of leukemia risk at dose levels used in diagnostic CT imaging, and further suggests that low-dose irradiation may facilitate bone marrow transplantation, a finding that could lead to refinements in clinical practice.
There is debate over the effects of long-term oral fluoroquinolone therapy in patients with advanced cirrhosis. We performed a randomized controlled trial to evaluate the effects of long-term ...treatment with the fluoroquinolone norfloxacin on survival of patients with cirrhosis.
We performed a double-blind trial of 291 patients with Child-Pugh class C cirrhosis who had not received recent fluoroquinolone therapy. The study was performed at 18 clinical sites in France from April 2010 through November 2014. Patients were randomly assigned to groups given 400 mg norfloxacin (n = 144) or placebo (n = 147) once daily for 6 months. Patients were evaluated monthly for the first 6 months and at 9 months and 12 months thereafter. The primary outcome was 6-month mortality, estimated by the Kaplan–Meier method, censoring spontaneous bacterial peritonitis, liver transplantation, or loss during follow-up.
The Kaplan–Meier estimate for 6-month mortality was 14.8% for patients receiving norfloxacin and 19.7% for patients receiving placebo (P = .21). In competing risk analysis that took liver transplantation into account, the cumulative incidence of death at 6 months was significantly lower in the norfloxacin group than in the placebo group (subdistribution hazard ratio, 0.59; 95% confidence interval, 0.35–0.99). The subdistribution hazard ratio for death at 6 months with norfloxacin vs placebo was 0.35 (95% confidence interval, 0.13–0.93) in patients with ascites fluid protein concentrations <15 g/L and 1.39 (95% confidence interval, 0.42–4.57) in patients with ascites fluid protein concentrations ≥15 g/L. Norfloxacin significantly decreased the incidence of any and Gram-negative bacterial infections without increasing infections caused by Clostridium difficile or multiresistant bacteria.
In a randomized controlled trial of patients with advanced cirrhosis without recent fluoroquinolone therapy, norfloxacin did not reduce 6-month mortality, estimated by the Kaplan–Meier method. Norfloxacin, however, appears to increase survival of patients with low ascites fluid protein concentrations. ClinicalTrials.gov ID: NCT01037959.
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Purpose
Amikacin requires pharmacodynamic targets of peak serum concentration (
C
max
) of 8–10 times the minimal inhibitory concentration, corresponding to a target
C
max
of 60–80 mg/L for the less ...susceptible bacteria. Even with new dosing regimens of 25 mg/kg, 30 % of patients do not meet the pharmacodynamic target. We aimed to identify predictive factors for insufficient
C
max
in a population of critically ill patients.
Methods
Prospective observational monocentric study of patients admitted to a general ICU and requiring a loading dose of amikacin. Amikacin was administered intravenously at the dose of 25 mg/kg of total body weight. Independent determinants of
C
max
< 60 mg/L were identified by mixed model multivariate analysis.
Results
Over a 1-year period, 181 episodes in 146 patients (SAPS 2 = 51 41–68) were included. At inclusion, the SOFA score was 8 6–12, 119 (66 %) episodes required vasopressors, 150 (83 %) mechanical ventilation, and 81 (45 %) renal replacement therapy. The amikacin
C
max
was 69 54.9–84.4 mg/L. Overall, 60 (33 %) episodes had a
C
max
< 60 mg/L. The risk of
C
max
< 60 mg/L associated with BMI < 25 kg/m
2
varied across quarters of inclusion. Independent risk factors for
C
max
< 60 mg/L were a BMI < 25 kg/m
2
over the first quarter (odds ratio (OR) 15.95, 95 % confidence interval (CI) 3.68–69.20,
p
< 0.001) and positive 24-h fluid balance (OR per 250-mL increment 1.06, 95 % CI 1.01–1.11,
p
= 0.018).
Conclusions
Despite an amikacin dose of 25 mg/kg of total body weight, 33 % of patients still had an amikacin
C
max
< 60 mg/L. Positive 24-h fluid balance was identified as a predictive factor of
C
max
< 60 mg/L. When total body weight is used, low BMI tended to be associated with amikacin underdosing. These results suggest the need for higher doses in patients with a positive 24-h fluid balance in order to reach adequate therapeutic targets.
To describe the frequency of clinical signs and the accuracy of video diagnosis of sport-related concussion.
An observational cross-sectional study.
Videos from a database of all suspected ...sport-related concussion in TOP14 matches (French professional male rugby Championship) were used, from 2012 to 2015 seasons. The videos were analyzed by 4 observers, blinded to the concussion diagnosis, after a training phase, and an inter-rater reliability analysis.
N/A.
Video analysis for clinical signs and presumed diagnosis of sport-related concussion. The observer's diagnosis was compared with the team physicians' diagnosis.
Four hundred seventeen videos were analyzed with 142 concussed players. Sport-related concussions happened mostly from an impact to the head (seen by the observers in 98.4%), against an opponent (73.2%), and during a tackle (74.6%). Video signs were observable in 98.6% for suspected loss of consciousness, tonic posturing (95%), ataxia (77.2%), dazed look (35.7%), abnormal behavior (18.2%), and seizures (96.2%). Ataxia was seen in 77.7% of concussed players, suspected loss of consciousness in 61.4%, dazed look in 63.2%, abnormal behavior in 55%, and tonic posturing in 7.1%. The observers diagnosed 79.8% of concussions.
We described the frequency of video clinical signs of sport-related concussion, with a good accuracy of the blinded observers for the diagnosis. This emphasizes the importance of pitch-side video analysis as an extra tool for sport-related concussion diagnosis.
INTRODUCTIONStudies have shown that the PD-1/PD-L1 immunomodulatory pathway slows down anti-tumor immunity in a number of cancers. The description of the expression of these molecules has never been ...performed in anal low-grade/high grade squamous intra-epithelial lesions (LSIL/HSIL respectively). MATERIALS AND METHODSPatients followed in the AIN3 cohort were routinely sampled. For each selected sample, an immunohistochemical study was performed with anti-CD8, PD-1, PD-L1 antibodies. The presence and distribution of CD8+ lymphocytes, and the presence of PD-1+ lymphocytes and PD-L1+ epithelial cells were assessed. The comparison of these characteristics was performed between the HSIL and LSIL groups. RESULTS33 patients were included and 78 samples selected (60 HSIL and 18 LSIL). CD8+ lymphocytes were observed more frequently in HSIL versus LSIL in the lamina propria or intra epithelial (respectively 90% vs. 60%, p = 0.01; and 62% vs. 33%, p = 0.04). PD-1+ lymphocytes were observed more frequently in HSIL versus LSIL (41% vs 11%, p = 0.03). There was no difference between HSIL and LSIL for PD-L1+ epithelial cells. CONCLUSIONSAnal dysplastic lesions are accompanied by an inflammatory lymphocytic infiltrate expressing CD8 and PD-1, more frequent in high-grade lesions. These results highlight the involvement of the PD-1/PD-L1 pathway in the natural history of anal dysplasia.
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