Bortezomib combined with low-dose cytarabine in Intermediate-2 and high risk myelodysplastic syndromes. A phase I/II Study by the GFM

Marrow cells from patients with higher-risk myelodysplastic syndrome (MDS) exhibit constitutive nuclear factor (NF)-κB activation. The proteasome inhibitor, bortezomib, has limited efficacy as a single agent in acute myeloid leukaemia. Its activity on leukaemic cell lines is potentiated by chemotherapy. We treated 43 higher-risk MDS patients with bortezomib (1·5 mg/m(2) , days 1, 4, 8 and 11) and low dose cytarabine arabinoside (LDAC; 10 mg/m(2) , then 20 mg/m(2) from days 1-14), every 28 d for four cycles. Median follow-up was 29·7 months. Responses were seen in 12 of the 43 patients (28%), including complete response (CR, n = 1), marrow-CR (n = 3), partial response (PR, n = 5) and haematological improvement (HI, n = 3). Responses were seen in 12 (36%) of the 33 previously untreated patients (11% CR, 13% PR, 2·5% HI), compared to none in the 12 previously treated patients (P < 0·01). Responders had better overall survival (median 18·2 vs. 10 months). One CR and 3 marrow-CRs were seen in patients with complex karyotypes. Main toxicity was haematological, responsible for infection in six patients and bleeding in 3. Three patients with Grade 1-2 pre-treatment haematotoxicity developed Grade 3-4 toxicity. Neuropathy was seen in 12% of patients. The addition of bortezomib to LDAC in higher-risk MDS may improve results obtained with LDAC alone, especially in patients with unfavourable karyotypes.     

IL28B alleles associated with poor hepatitis C virus (HCV) clearance protect against inflammation and fibrosis in patients infected with non-1 HCV genotypes

Genetic polymorphisms near IL28B are associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV), two processes that require the appropriate activation of the host immune responses. Intrahepatic inflammation is believed to mirror such activation, but its relationship with IL28B polymorphisms has yet to be fully appreciated. We analyzed the association of IL28B polymorphisms with histological and follow-up features in 2335 chronically HCV-infected Caucasian patients. Assessable phenotypes before any antiviral treatment included necroinflammatory activity (n = 1,098), fibrosis (n = 1,527), fibrosis progression rate (n = 1,312), and hepatocellular carcinoma development (n = 1,915). Associations of alleles with the phenotypes were evaluated by univariate analysis and multivariate logistic regression, accounting for all relevant covariates. The rare G allele at IL28B marker rs8099917-previously shown to be at risk of treatment failure-was associated with lower activity (P = 0.04), lower fibrosis (P = 0.02) with a trend toward lower fibrosis progression rate (P = 0.06). When stratified according to HCV genotype, most significant associations were observed in patients infected with non-1 genotypes (P = 0.003 for activity, P = 0.001 for fibrosis, and P = 0.02 for fibrosis progression rate), where the odds ratio of having necroinflammation or rapid fibrosis progression for patients with IL28B genotypes TG or GG versus TT were 0.48 (95% confidence intervals 0.30-0.78) and 0.56 (0.35-0.92), respectively. IL28B polymorphisms were not predictive of the development of hepatocellular carcinoma. CONCLUSION: In chronic hepatitis C, IL28B variants associated with poor response to interferon therapy may predict slower fibrosis progression, especially in patients infected with non-1 HCV genotypes.     

Direction of SMR and Beta Change with Attention in Adults

Introduction. The aim of this study was to clarify the interpretation of sensory-motor rhythm (SMR; 13–15 Hz) and beta (16–20 Hz) changes with respect to attention states.

Method. For this purpose, EEG was recorded from 11 participants during (a) a multiple object tracking task (MOT), which required externally directed attention; (b) the retention phase of a visuo-spatial memory task (VSM), which required internally directed attention and avoidance of sensory distraction; and (c) the waiting intervals between trials, which constituted a no-task-imposed control condition. The 2 active tasks were consecutively presented at 2 difficulty levels (i.e., easy and hard). Two analyses of variance were conducted on EEG log spectral amplitudes in the alpha (8–12 Hz), SMR, and beta bands from F3, F4, C3, C4 and P3, P4.

Results. The first 15 analysis compared the MOT to the VSM by difficulty levels and revealed a significant task effect (p < .0005) but no effect of difficulty. The results showed that externally directed attention (MOT) resulted in lower values than internally directed attention (VSM) in all three bands. The second analysis averaged the difficulty levels together and added the no-task-imposed reference condition. The results again showed a significant task effect that did not interact with site, hemisphere, or, more important, band. Post hoc tests revealed that both MOT and VSM produced significantly smaller means than the no-task-imposed condition. This pattern of log-amplitude means and the lack of task interaction with any other factor indicate that task-induced attention reduces EEG power in the same proportion across the 3 bands and the 6 channels studied.

Conclusions. These results contradict a frequent interpretation concerning the relationship between the brain's aptitude to increase low beta in neurofeedback programs and improved sustain attention capacities.     

Factors associated with hospital mortality in community-acquired legionellosis in France

The aims of this study were to describe the clinical, biological and radiological features of community-acquired (CA) Legionnaires' disease (LD) and identify the predictors of mortality in hospitalised patients. Demographic data, risk factors, clinical and biological features, medical management, complications, and outcome from 540 hospitalised patients with confirmed CA LD were prospectively recorded. 8.1% of patients (44 out of 540) died. The predictors of survival after Kaplan-Meier analysis were male sex (p = 0.01), age <60 yrs (p = 0.02), general symptoms (p = 0.006), intensive care unit (ICU) stay (p<0.001), and class II-III Pneumonia Severity Index score (p = 0.004). Six predictors of death were identified by multivariate analysis: age (per 10-yr increment) (relative hazard (RH) 1.50, 95% CI 1.21-1.87), female sex (RH 2.00, 95% CI 1.08-3.69), ICU admission (RH 3.31, 95% CI 1.67-6.56), renal failure (RH 2.73, 95% CI 1.42-5.27), corticosteroid therapy (RH 2.54, 95% CI 1.04-6.20) and C-reactive protein (CRP) >500 mg · L(-1) (RH 2.14, 95% CI 1.02-4.48). Appropriate antibiotic therapy was prescribed for 70.8% (292 out of 412) of patients after admission and for 99.8% (537 out of 538) of patients after diagnosis confirmation. In conclusion, female sex, age, ICU stay, renal failure, corticosteroid treatment and increased level of CRP are significant risk factors for mortality in CA LD.     

Implementation of HIV early infant diagnosis and HIV type 1 RNA viral load determination on dried blood spots in Cameroon: challenges and propositions

The testing of dried blood spots (DBSs) for human immunodeficiency type 1 (HIV-1) proviral DNA by PCR is a technology that has proven to be particularly valuable in diagnosing exposed infants. We implemented this technology for HIV-1 early infant diagnosis (EID) and HIV-1 RNA viral load determination in infants born of HIV-1-seropositive mothers from remote areas in Cameroon. The samples were collected between December 2007 and September 2010. Fourteen thousand seven hundred and sixty-three (14,763) DBS samples from infants born of HIV-positive mothers in 108 sites nationwide were tested for HIV. Of these, 1452 were positive on first PCR analyses (PCR1), giving an overall infection rate of 12.30%. We received only 475 DBS specimen for a second PCR testing (PCR2); out of these, 145 were positive. The median HIV-1 RNA viral load for 169 infant DBS samples tested was 6.85 log copies/ml, with values ranging from 3.37 to 8 log copies/ml. The determination of the viral load on the same DBS as that used for PCR1 allowed us to bypass the PCR2. The viral load values were high and tend to decrease with age but with a weak slope. The high values of viral load among these infants call for early and effective administration of antiretroviral therapy (ART). The findings from this study indicate that the use of DBS provides a powerful tool for perinatal screening programs, improvement on the testing algorithm, and follow-up during treatment, and thus should be scaled up to the entire nation.     

Kinetics of atrial repolarization alternans in a free-behaving ovine model

Kinetics of Atrial Repolarization Alternans. Introduction: Repolarization alternans (Re‐ALT), a beat‐to‐beat alternation in action potential repolarization, promotes dispersion of repolarization, wavebreaks, and reentry. Recently, Re‐ALT has been shown to play an important role in the transition from rapid pacing to atrial fibrillation (AF) in humans. The detailed kinetics of atrial Re‐ALT, however, has not been reported so far. We developed a chronic free‐behaving ovine pacing model to study the kinetics of atrial Re‐ALT as a function of pacing rate. Methods: Thirteen sheep were chronically implanted with 2 pacemakers for the recording of broadband right atrial unipolar electrograms and delivery of rapid pacing protocols. Beat‐to‐beat differences in the atrial T‐wave apex amplitude as a measure of Re‐ALT and activation time were analyzed at incremental pacing rates until the effective refractory period (ERP) defined as stable 2:1 capture. Results: Atrial Re‐ALT appeared intermittently but without periodicity, and increased in amplitude as a function of pacing rate until ERP. Intermittent 2:1 atrial capture was observed at pacing cycle lengths 40 ms above ERP, and increased in duration as a function of pacing rate. Episodes of rapid pacing‐induced AF were rare, and were preceded by Re‐ALT or complex oscillations of atrial repolarization, but without intermittent capture. Conclusion: We show in vivo that atrial Re‐ALT developed and increased in magnitude with rate until stable 2:1 capture. In rare instances where capture failure did not occur, Re‐ALT and complex oscillations of repolarization surged and preceded AF initiation. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1003‐1012, September 2012)     

A role for vesicular glutamate transporter 1 in synaptic vesicle clustering and mobility

Synaptic vesicles (SVs) from excitatory synapses carry vesicular glutamate transporters (VGLUTs) that fill the vesicles with neurotransmitter. Although the essential function of VGLUTs as glutamate transporters has been well established, the evidence for additional cell‐biological functions is more controversial. Both VGLUT1 and VGLUT2 disruptions in mice result in a reduced number of SVs away from release sites, flattening of SVs, and the appearance of tubular structures. Therefore, we analysed the morphology, biochemical composition and trafficking of SVs at synapses of VGLUT1^?/? mice in order to test for a function of VGLUTs in the formation or clustering of SVs. Analyses with high‐pressure freezing immobilisation and electron tomography pointed to a role of VGLUT1 transport function in the tonicity of excitatory SVs, explaining the aldehyde‐induced flattening of SVs observed in VGLUT1^?/? synapses. We confirmed the steep reduction in the number of SVs previously observed in VGLUT1^?/? presynaptic terminals, but did not observe accumulation of endocytotic intermediates. Furthermore, SV proteins of adult VGLUT1^?/? mouse brain tissue were expressed at normal levels in all subcellular fractions, suggesting that they were not displaced to another organelle. We thus assessed the mobility of the recently documented superpool of SVs. Synaptobrevin2–enhanced green fluorescent protein time lapse experiments revealed an oversized superpool of SVs in VGLUT1^?/? neurons. Our results support the idea that, beyond glutamate loading, VGLUT1 enhances the tonicity of excitatory SVs and stabilises SVs at presynaptic terminals.     

Noninvasive quantitation of blood flow turbulence in patients with aortic valve disease using online digital computer analysis of Doppler velocity data.

Previous experimental studies have demonstrated that aortic valve disease is associated with significant downstream turbulence (T). In this study, we developed a noninvasive method on the basis of Doppler velocity recording for quantitating aortic blood flow T in patients with aortic valve disease. The instantaneous blood velocity at a point in the aorta is equal to the sum of a mean periodic velocity component with a random or turbulent velocity component. According to the ensemble average method, time mean absolute T intensity is the root-mean-square value of turbulent velocity averaged over time and T is better quantitated by the relative T intensity (TIr), which is the ratio of absolute T intensity to the ensemble average velocity averaged over time. We computed TIr in 18 patients with mild to severe aortic stenosis and in 13 healthy volunteers from instantaneous modal velocities of 70 cycle length-matched heart beats recorded in the proximal part of the descending aorta by pulsed Doppler using an ultrasound system with an output port for online digital data transfer into a microcomputer. TIr was greater in patients with aortic valve disease (18.4 +/- 5.1%, range 11.2%-28.9%) than in control patients (7.9 +/- 1.9%, range 4.8%-9.8%; P =.0001). In patients with aortic valve disease, TIr was better linearly related to the ratio of postvalvular aorta to valvular orifice cross-sectional areas (r = 0.89, P =.0001) than to other parameters of valve restriction: transvalvular pressure gradient (r = 0.78, P =.0001); valve area (r = -0.56, P =.01); and valve resistance (r = 0.72, P =.0002). Thus, T that can be computed noninvasively from direct digital transfer of Doppler velocity data appears to be linearly related to indices of aortic valve restriction. Our data support the concept of the postvalvular aorta to valvular orifice cross-sectional areas ratio as a new important hemodynamic parameter in patients with aortic valve disease.