Genome-wide methylation profiling in decitabine-treated patients with acute myeloid leukemia

The outcome of older (≥ 60 years) acute myeloid leukemia (AML) patients is poor, and novel treatments are needed. In a phase 2 trial for older AML patients, low-dose (20 mg/m(2) per day for 10 days) decitabine, a DNA hypomethylating azanucleoside, produced 47% complete response rate with an excellent toxicity profile. To assess the genome-wide activity of decitabine, we profiled pretreatment and post treatment (day 25/course 1) methylomes of marrow samples from patients (n = 16) participating in the trial using deep-sequencing analysis of methylated DNA captured by methyl-binding protein (MBD2). Decitabine significantly reduced global methylation compared with pretreatment baseline (P = .001). Percent marrow blasts did not correlate with global methylation levels, suggesting that hypomethylation was related to the activity of decitabine rather than to a mere decrease in leukemia burden. Hypomethylation occurred predominantly in CpG islands and CpG island-associated regions (P ranged from .03 to .04) A significant concentration (P < .001) of the hypomehtylated CpG islands was found in chromosome subtelomeric regions, suggesting a differential activity of decitabine in distinct chromosome regions. Hypermethylation occurred much less frequently than hypomethylation and was associated with low CpG content regions. Decitabine-related methylation changes were concordant with those previously reported in distinct genes. In summary, our study supports the feasibility of methylome analyses as a pharmacodynamic endpoint for hypomethylating therapies.     

Addition of chlorine during water purification reduces iodine content of drinking water and contributes to iodine deficiency

Drinking water is the major natural source of iodine in many European countries. In the present study, we examined possible sites of iodine loss during the usual water purification process.Water samples from 6 sites during the technological process were taken and analyzed for iodine content. Under laboratory circumstances, prepared iodine in water solution has been used as a model to test the effect of the presence of chlorine. Samples from the purification sites revealed that in the presence of chlorine there is a progressive loss of iodine from the water. In the chlorine concentrations employed in the purification process, 24-h chlorine exposure eliminated more than 50% of iodine when the initial iodine concentration was 250 μg/l or less. Iodine was completely eliminated if the starting concentration was 16 μg/l.We conclude that chlorine used during water purification may be a major contributor to iodine deficiency in European communities.     

The Isolation of Numerals at the Semantic Level

Abstract

In this study, we examine the case of a patient (NM) who could comprehend and produce numerals despite impairment on comprehension tasks and a high degree of anomia for other categories of words. It will be claimed that NM suffered from an impairment to the semantic system affecting all categories except numerals and the series of days and months. The case of a patient presenting with the exact reverse dissociation has been described a few years ago by Cipolotti et al. (Brain 1991; 114: 619–37). We conclude that NM's pattern of performance provides evidence that numerals constitute a relevant and perhaps a distinct category at the semantic level.     

Chapter 2: Medical Tests Guidance (2) Developing the Topic and Structuring Systematic Reviews of Medical Tests: Utility of PICOTS,Analytic Frameworks,Decision Trees,and Other Frameworks

Topic development and structuring a systematic review of diagnostic tests are complementary processes. The goals of a medical test review are to identify and synthesize evidence to evaluate the impacts alternative testing strategies on health outcomes and to promote informed decisionmaking. A common challenge is that the request for a review may state the claim for the test ambiguously. Due to the indirect impact of medical tests on clinical outcomes, reviewers need to identify which intermediate outcomes link a medical test to improved clinical outcomes. In this paper, we propose the use of five principles to deal with challenges: the PICOTS typology (patient population, intervention, comparator, outcomes, timing, setting), analytic frameworks, simple decision trees, other organizing frameworks and rules for when diagnostic accuracy is sufficient.     

Haemolytic-uraemic syndrome during severe lupus nephritis: efficacy of plasma exchange

Systemic lupus erythematosus (SLE) has been described as a cause of thrombotic microangiopathy, especially thrombotic thrombocytopenic purpura (TTP). Haemolytic-uraemic syndrome (HUS) is less frequent in SLE. We report a case of such an association during an episode of severe lupus nephritis in a young woman, who was successfully treated with steroids, cyclophosphamide and especially plasma exchange with plasma replacement. This report highlights the importance of recognising atypical HUS in SLE patients by looking for schistocytes in case of haemolytic anemia with a negative antiglobulin test, in order to begin plasma exchange.     

Cationised gelatin and hyaluronic acid coating enhances polyethylene terephthalate artificial ligament graft osseointegration in porcine bone tunnels

Purpose

The aim of this study was to investigate whether cationised gelatin and hyaluronic acid (CH) coating could induce polyethylene terephthalate (PET) artificial ligament graft osseointegration in the bone tunnel.

Methods

Surface modification of PET artificial ligament graft was performed by layer-by-layer (LBL) self-assembly CH coating. Six pigs underwent anterior cruciate ligament (ACL) reconstruction on the right knees, with three pigs receiving the CH-coated PET grafts and the other three pigs non-CH-coated PET grafts as controls. They were sacrificed at three months after surgery and the graft-bone complexes were acquired for computed tomography (CT) scan and histological examination.

Results

CT scans showed a significant difference at the distal femoral site (p = 0.031) or at the distal tibial site (p = 0.0078), but no significant difference in the bone tunnel areas’ enlargement at other sites (p > 0.05) between the CH group and the control group. Histologically, application of CH coating induced new bone formation between graft and bone at three months compared with the controls at the distal site. The interface width of the CH group was significantly lower than that of the control group at the distal femoral site (p = 0.0327) and at the distal tibial site (p = 0.0047).

Conclusions

The study has shown that CH coating on the PET artificial ligament surface has a positive biological effect in the induction of artificial ligament osseointegration within the bone tunnel at the distal site of the bone tunnel.     

Neuroprotection with glatiramer acetate: evidence from the PreCISe trial

The phase III, multicenter, randomized, placebo-controlled PreCISe trial assessed glatiramer acetate (GA) effects in patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS). To assess the neuroprotective effect of GA in a subset of patients in the PreCISe trial, we used proton magnetic resonance spectroscopy (MRS) to measure N-acetylaspartate (NAA), a marker of neuronal integrity, in a large central volume of brain. Thirty-four CIS patients randomized to GA 20 mg/day (n = 19) SC or placebo (n = 15) were included. Patients who relapsed (developed clinically definite MS [CDMS]) were removed from the substudy. NAA/creatine (NAA/Cr) ratios were compared between GA-treated and placebo-treated patients. Twenty patients with CIS had not converted to CDMS and were still in the double-blind phase of the trial at 12 months of follow-up. Paired changes in NAA/Cr differed significantly in patients treated with GA (+0.14, n = 11) compared with patients receiving placebo (?0.33, n = 9, p = 0.03) at 12 months, consistent with a neuroprotective effect of GA in vivo. Patients with CIS who received GA showed improvement in brain neuroaxonal integrity, as indicated by increased NAA/Cr, relative to comparable patients treated with placebo, who showed a decline in NAA/Cr consistent with findings from natural history studies.