Secondary acute lymphoblastic leukemia is a distinct clinical entity with prognostic significance.

The effect of prior malignancy on the risk of developing, and prognosis of, acute lymphoblastic leukemia (ALL) is unknown. This observational study utilized the California Cancer Registry to estimate the risk of developing ALL after a prior malignancy using standardized incidence ratios (SIRs, 95% confidence intervals). ALL occurring after a malignancy with an SIR>1 (increased-risk (IR) malignancies) was considered secondary ALL (s-ALL). Adjusted hazard ratios (aHRs, 95% confidence intervals) compared the effect of s-ALL with de novo ALL on overall survival. A total of 14 481 patients with ALL were identified (1988-2012) and 382 (3%) had a known prior malignancy. Any prior malignancy predisposed patients to developing ALL: SIR 1.62 (1.45-1.79). Hematologic malignancies (SIR 5.57, 4.38-6.98) and IR-solid tumors (SIR 2.11, 1.73-2.54) increased the risk of developing ALL. s-ALL increased the risk of death compared with de novo ALL (aHR 1.38 (1.16-1.63)) and this effect was more pronounced among younger patients (age<40 years: aHR 4.80 (3.15-7.30); age⩾40 years: aHR 1.40 (1.16-1.69)) (interaction P<0.001). This population-based study demonstrates that s-ALL is a distinct entity that occurs after specific malignancies and carries a poor prognosis compared with de novo ALL, particularly among patients <40 years of age

Catheter removal versus retention in the management of catheter-associated enterococcal bloodstream infections

It is unclear whether CVC removal is necessary to successfully manage enterococcal CA-BSI. MEthoDs: A 12-month retrospective cohort study of adults with enterococcal CA-BSI was conducted at a tertiary care hospital; clinical, microbiological and outcome data were collected. rEsuLts: A total of 111 patients had an enterococcal CA-BSI. [37.9]; P=0.03), but similar rates of recurrent bacteremia (nine [11.0%] versus two (7.0%); P=0.7) and a similar post-BSI length of hospital stay (median days [range]) (11.1 [1.7 to 63.1 days] versus 9.3 [1.9 to 31.8 days]; P=0.3). Catheter retention was an independent predictor of mortality (OR 3.34 [95% CI 1.21 to 9.26]). ConCLusIons: To the authors' knowledge, the present article describes the largest enterococcal CA-BSI series to date. Mortality was increased among patients who had their catheter retained. Additional prospective studies are necessary to determine the optimal management of enterococcal CA-BSI. [37, Catheter removal versus retention in the management of catheter-associated enterococcal bloodstream infections The aim of the present study was to examine the epidemiology, treatment and subsequent outcomes of patients with enterococcal CA-BSI, comparing patients with retained versus removed catheters. Our hypothesis was that catheter management does not affect patient outcomes. MEthoDs setting Barnes-Jewish Hospital (BJH), a 1250-bed teaching hospital, is the largest hospital in Missouri (USA), and has a referral base that includes the St Louis Metropolitan area, eastern Missouri and western Illinois. It houses all medical specialties, including a stem cell transplantation unit. BJH is affiliated with the Washington University School of Medicine (St Louis, Missiouri, USA). study design A retrospective cohort study of patients with enterococcal CA-BSIs during their hospital stay was performed. CA-BSI was defined as enterococcal bacteremia in a patient with a central venous catheter (CVC) in place for at least 48 h and no alternative source of infection. The hospital's medical informatics database was queried for blood cultures positive for any Enterococcus species; this dataset was merged with a manually collected dataset of CVC usage in the hospital, which is part of the hospital infection control database. Inclusion and exclusion criteria Adult patients admitted to BJH between January 1, 2006 and December 31, 2006, who presented with, or developed, an enterococcal bloodstream infection and had a CVC present at the time of detection of this infection were included. All types and locations of CVCs were included. Blood cultures were obtained during routine care either peripherally and/or from the CVC. Patients who presented to the hospital with a CVC already in place were included. Patient history and physical examination as well as admitting diagnosis and microbiology results were reviewed to determine whether the catheter was the primary focus of the bacteremia. Patients with a primary focus of bacteremia other than the catheter, patients with a CVC in place for <48 h, and patients who died on the day of the positive blood culture were excluded. Polymicrobial infections were included except concurrent Staphylococcus aureus bacteremia or candidemia within ±3 days of the enterococcal bacteremia (n=20) because both entities are established indications for catheter removal. Data collection Demographic characteristics, medical history, clinical presentation, diagnostic and therapeutic procedures, antibiotic treatment and key markers of outcome (recurrence of bloodstream infection, length of hospital stay after the bloodstream infection, crude mortality) were abstracted from the medical records. Admission Charlson comorbidity and McCabe severity of illness scores were determined. Duration of catheter retention time after the bacteremia was recorded. Information on antibiotic lock therapy was collected; however, this treatment modality was not used in patients from this cohort. Postdischarge mortality at both 30 days and three months after bacteremia was obtained from the Social Security Death Index (www. ssdi-search.com). Definitions Renal insufficiency was defined by a serum creatinine level >132.6 μmol/L. Sepsis and sepsis-induced hypotension were defined using established criteria (13). Appropriate therapy was defined as pathogen-directed treatment with antibiotics matching susceptibilities. A catheter was considered to be retained if it was present for the duration of the hospitalization after the first positive blood culture. Recurrence of bacteremia (used here synonymously with intermittent bacteremia) was defined as a second positive blood culture after ≥1 negative blood culture and an interval of ≥1 day during their hospitalization. Community-onset enterococcal bloodstream infection was defined as having the first positive blood culture drawn within 48 h of hospital admission. Data analysis and statistical methods Data entry was performed using Access and Excel (Microsoft Corporation, USA). Data analysis was performed using SPSS 17 (IBM Corporation, USA). Univariate comparisons among categorical variables and outcome measures were performed using the χ 2 test or Fisher's exact test. A two-sided P <0.05 was considered to be statistically significant. Also calculated was the absolute difference in proportion (∆ p ) of rates of outcome measures including the 95% CI of this difference to describe the precision of this point estimate. Analysis of the difference in proportions and 95% CI enabled the interpretation of statistical significance (if the 95% CI did not cross zero) as well as clinical significance (if the upper limit of the 95% CI exceeded a predefined difference). An absolute difference in recurrence of bacteremia and mortality rates of 15% was considered to represent a clinically significant difference; this estimate was chosen based on previous literature regarding catheter management and clinical experience (14,15). Comparisons among continuous independent variables were performed using the Student's t test or Mann-Whitney U test as appropriate. Variables found to have P<0.1 in univariate testing were considered for entry into a forward, stepwise multivariate logistic regression model. The study was approved by the Washington University Human Research Protection Office (#07-0690). rEsuLts Demographics, comorbidities and clinical presentation There were 111 patients with enterococcal CA-BSI who met inclusion criteria. The mean (± SD) age was 58.2±15.3 years; 56 (50.5%) patients were male; and 77 (69.4%) were white. There were 36 (32%) patients admitted to the oncology/bone marrow transplant service. The most frequent comorbidities were malignancies (n=62 [55.9%]), diabetes (n=35 [31.5%]) and renal insufficiency (n=31 [27.9%]). Twenty-five (22.5%) patients had metastatic solid tumours, 28 (25.2%) had leukemia, six (5.4%) had lymphomas and three (2.7%) had nonmetastatic solid tumours. There were 20 (18%) patients who were neutropenic at the time of bloodstream infection. Of all bloodstream infections, 90 (81%) were hospital-acquired. None of the patients were diagnosed with infective endocarditis during the admission. Microbiology Of the enterococcal bloodstream infections, 45 (40.5%) were caused by E faecalis and 61 (55.0%) by E faecium. Of the bacteremias caused by E faecalis, 10 (22.2%) were due to vancomycin-resistant isolates while 57 (93.4%) of the bacteremias caused by E faecium were vancomycin resistant. An additional five (4.5%) infections were caused by other Enterococcus species. A total of 37 patients (33.3%) had polymicrobial infections in which the most common polymicrobial organism was coagulase-negative Staphylococcus (n=26 [23.4%]). There were 24 (34.9%) polymicrobial E faecalis bacteremias and 10 (27.0%) polymicrobial E faecium bacteremias. Additionally, there was no difference in polymicrobial bacteremias among patients who had their catheter removed versus retained (28 [34.1%] versus nine [31.0%]; P=0.8). Vancomycin-susceptible E faecalis caused 30 (36.6%) of 82 infections in which catheters were removed during the hospitalization and five (17.2%) of 29 infections in which they were retained (P=0.09). Vancomycin-resistant E faecium (VRE) caused 42 (51.2%) of infections in which catheters were removed and 15 (51.7%) in which they were retained (P=0.9). Overall, there was no difference in the number of vancomycin-resistant isolates regardless of whether a catheter was removed Catheter management The CVC was retained during the hospitalization in 29 (26.1%) patients. In univariate analysis, patients with removed CVCs were similar to patients whose CVC was retained DIsCussIon Removal of an intravascular catheter is, with few exceptions, considered to be an essential part of managing CA-BSI. However, robust data to support this approach are only available for a limited number of pathogens responsible for these infections. Despite the lack of sufficient data to provide an evidence-based recommendation with regard to CA-BSI caused by Enterococcus species, national guidelines recommend removing the involved catheters (9). To our knowledge, the present study represents the largest investigation into catheter management and outcomes of enterococcal bloodstream infections. The main finding of the present study was increased mortality in patients whose catheters were retained during the hospitalization. Our findings suggest that catheter removal should be considered to improve patient survival. Also, the difference in the two outcome proportions exceeded the predetermined clinically meaningful difference of 15%, which gives us a quantitative estimate of the impact of catheter removal. The patient groups were very similar with respect to demographic characteristics and comorbidities, including adjunctive antibiotic treatment with the aminoglycoside gentamicin. These findings are congruent with the single study encountered in the scientific literature that scrutinized outcomes of enterococcal CA-BSI and specifically investigated catheter management, albeit in a smaller number of patients (11). There, the authors retrospectively examined 61 enterococcal CA-BSI, with 82% of the episodes due to E faecalis and polymicrobial infections found in 18% of the study population. Of note, they did not exclude patients with concurrent Staphylococcus aureus or yeast bloodstream infections, although these infections likely guided catheter management significantly more than the detection of enterococci. Sandoe et al (11) evaluated whether successful treatment of a bloodstream infection was possible without removal of the catheter, which was achieved in five of 13 cases (38%). If the catheter was removed, the chance for cure was higher (40 of 48 [83%]). They found a combination of a cell wall-active agent with an aminoglycoside to be significantly more effective than monotherapy when the catheter was retained. The authors concluded that, although the removal of the catheter was performed in the majority of cases, it did not appear to be a necessary part of the management as long as antimicrobial treatment was optimized. In our study, even though we did not set cure as an end point, 67 (81.7%) of 82 patients with catheters removed survived the hospital admission and 61 (74.4%) survived at 30 days postbacteremia. These rates were much lower for patients with retained catheters. In summary, these data suggest that although enterococcal CA-BSI are not an absolute indication for catheter removal, removal should be favoured over catheter retention. Reasons for catheter retention may have been that the treating physicians of patients who were severely ill at the time of enterococcal bloodstream infection were reluctant to remove the catheter because it was essential for nonantibiotic medications; that the patients had limited options for alternative intravenous access; or that their comorbidities increased the risk of catheter removal and replacement. Catheter management may have been driven by reasons other than the infection alone, and removing the catheter could have been a lower priority or higher risk in the patients' overall medical management. Because we collected crude mortality data, it is also conceivable that patients died from causes not related to the CA-BSI. Of note, we did not observe a difference in recurrence of infection depending on catheter management; it is possible that the size of the cohort prevented us from noting a statistically significant difference. Our patients are notable for a high percentage of comorbid conditions, including metastatic solid tumours (23%) and leukemia (25%); accordingly, the crude in-hospital mortality rate was high in our study population. An independent factor associated with death was the detection of VRE in the stool, which may be a marker for frequent health care exposure. Despite this finding, CA-BSIs with vancomycinresistant E faecium did not result in increased mortality compared with non-VRE infections. This is different from an earlier prospective study and a more recent meta-analysis, in which vancomycin resistance was found to be associated with increased mortality Limitations of the present study include its retrospective design, the fact that the diagnosis of recurrent infection depended on the treating physician ordering blood cultures and that postdischarge outcomes, including completion of planned antibiotic therapy, follow-up blood cultures, and catheter removal postdischarge, were not studied. In addition, catheter management is potentially influenced by other reasons for retention (difficulty of finding alternative access, bleeding diathesis) and we did not report outcomes for different catheter types. Finally, changes in the usage of daptomycin and linezolid have occurred since the time of the study. Although this was the largest study of enterococcal CA-BSI to date, it is still a relatively small sample to detect rare outcomes. ConCLusIons Based on our study findings, catheter removal is preferable to retention in patients with enterococcal CA-BSI. A large prospective or multicentre study should be performed to identify patients at highest risk for mortality and to add strength to our results. DECLArAtIons: None of the following authors has a conflict of interest to declare: J Marschall, ML Piccirillo, J Doherty

Radio Emission from Ultra-Cool Dwarfs

The 2001 discovery of radio emission from ultra-cool dwarfs (UCDs), the very low-mass stars and brown dwarfs with spectral types of ~M7 and later, revealed that these objects can generate and dissipate powerful magnetic fields. Radio observations provide unparalleled insight into UCD magnetism: detections extend to brown dwarfs with temperatures <1000 K, where no other observational probes are effective. The data reveal that UCDs can generate strong (kG) fields, sometimes with a stable dipolar structure; that they can produce and retain nonthermal plasmas with electron acceleration extending to MeV energies; and that they can drive auroral current systems resulting in significant atmospheric energy deposition and powerful, coherent radio bursts. Still to be understood are the underlying dynamo processes, the precise means by which particles are accelerated around these objects, the observed diversity of magnetic phenomenologies, and how all of these factors change as the mass of the central object approaches that of Jupiter. The answers to these questions are doubly important because UCDs are both potential exoplanet hosts, as in the TRAPPIST-1 system, and analogues of extrasolar giant planets themselves.Comment: 19 pages; submitted chapter to the Handbook of Exoplanets, eds. Hans J. Deeg and Juan Antonio Belmonte (Springer-Verlag

Cystatin C, a marker for successful aging and glomerular filtration rate, is not influenced by inflammation

Abstract Background. The plasma level of cystatin C is a better marker than plasma creatinine for successful aging. It has been assumed that the advantage of cystatin C is not only due to it being a better marker for glomerular filtration rate (GFR) than creatinine, but also because an inflammatory state of a patient induces a raised cystatin C level. However, the observations of an association between cystatin C level and inflammation stem from large cohort studies. The present work concerns the cystatin C levels and degree of inflammation in longitudinal studies of individual subjects without inflammation, who undergo elective surgery. Methods. Cystatin C, creatinine, and the inflammatory markers CRP, serum amyloid A (SAA), haptoglobin and orosomucoid were measured in plasma samples from 35 patients the day before elective surgery and subsequently during seven consecutive days. Results. Twenty patients had CRP-levels below 1 mg/L before surgery and low levels of the additional inflammatory markers. Surgery caused marked inflammation with high peak values of CRP and SAA on the second day after the operation. The cystatin C level did not change significantly during the observation period and did not correlate significantly with the level of any of the four inflammatory markers. The creatinine level was significantly reduced on the first postoperative day but reached the preoperative level towards the end of the observation period. Conclusion. The inflammatory status of a patient does not influence the role of cystatin C as a marker of successful aging, nor of GFR

Identification of Combinatorial Patterns of Post-Translational Modifications on Individual Histones in the Mouse Brain

Post-translational modifications (PTMs) of proteins are biochemical processes required for cellular functions and signalling that occur in every sub-cellular compartment. Multiple protein PTMs exist, and are established by specific enzymes that can act in basal conditions and upon cellular activity. In the nucleus, histone proteins are subjected to numerous PTMs that together form a histone code that contributes to regulate transcriptional activity and gene expression. Despite their importance however, histone PTMs have remained poorly characterised in most tissues, in particular the brain where they are thought to be required for complex functions such as learning and memory formation. Here, we report the comprehensive identification of histone PTMs, of their combinatorial patterns, and of the rules that govern these patterns in the adult mouse brain. Based on liquid chromatography, electron transfer, and collision-induced dissociation mass spectrometry, we generated a dataset containing a total of 10,646 peptides from H1, H2A, H2B, H3, H4, and variants in the adult brain. 1475 of these peptides carried one or more PTMs, including 141 unique sites and a total of 58 novel sites not described before. We observed that these PTMs are not only classical modifications such as serine/threonine (Ser/Thr) phosphorylation, lysine (Lys) acetylation, and Lys/arginine (Arg) methylation, but also include several atypical modifications such as Ser/Thr acetylation, and Lys butyrylation, crotonylation, and propionylation. Using synthetic peptides, we validated the presence of these atypical novel PTMs in the mouse brain. The application of data-mining algorithms further revealed that histone PTMs occur in specific combinations with different ratios. Overall, the present data newly identify a specific histone code in the mouse brain and reveal its level of complexity, suggesting its potential relevance for higher-order brain functions

Who's been framed? Framing effects are reduced in financial gambles made for others

Background: Decisions made on behalf of other people are sometimes more rational than those made for oneself. In this study we used a monetary gambling task to ask if the framing effect in decision-making is reduced in surrogate decision-making. Methods: Participants made a series of choices between a predetermined sure option and a risky gambling option of winning a proportion of an initial stake. Trials were presented as either a gain or a loss relative to that initial stake. In half of the trials participants made choices to earn money for themselves and in the other half they earned money for another participant. Framing effects were measured as risk seeking in loss frames and risk aversion in gain frames. Results: Significant framing effects were observed both in trials in which participants earned money for themselves and those in which they earned money for another person; however, these framing effects were significantly reduced when making decisions for another person. It appears that the reduced emotional involvement when the decision-maker is not affected by the outcome of the decision thus lessens the framing effect without eradicating it altogether. Conclusions: This suggests that the deviation from rational choices in decision-making can be significantly reduced when the emotional impact on the decision maker is lessened. These results are discussed in relation to Somatic Distortion Theory

N-terminally cleaved Bcl-x(L) mediates ischemia-induced neuronal death

Transient global ischemia in rats induces delayed death of hippocampal CA1 neurons. Early events include caspase activation, cleavage of anti-death Bcl-2 family proteins and large mitochondrial channel activity. However, whether these events have a causal role in ischemia-induced neuronal death is unclear. We found that the Bcl-2 and Bcl-xL inhibitor ABT-737, which enhances death of tumor cells, protected rats against neuronal death in a clinically relevant model of brain ischemia. Bcl-xL is prominently expressed in adult neurons and can be cleaved by caspases to generate a pro-death fragment, ΔN-Bcl-xL. We found that ABT-737 administered before or after ischemia inhibited ΔN-Bcl-xL–induced mitochondrial channel activity and neuronal death. To establish a causal role for ΔN-Bcl-xL, we generated knock-in mice expressing a caspase-resistant form of Bcl-xL. The knock-in mice exhibited markedly reduced mitochondrial channel activity and reduced vulnerability to ischemia-induced neuronal death. These findings suggest that truncated Bcl-xL could be a potentially important therapeutic target in ischemic brain injury

AMP-Activated Protein Kinase (AMPK) Mediates Nutrient Regulation of Thioredoxin-Interacting Protein (TXNIP) in Pancreatic Beta-Cells

Thioredoxin-interacting protein (TXNIP) regulates critical biological processes including inflammation, stress and apoptosis. TXNIP is upregulated by glucose and is a critical mediator of hyperglycemia-induced beta-cell apoptosis in diabetes. In contrast, the saturated long-chain fatty acid palmitate, although toxic to the beta-cell, inhibits TXNIP expression. The mechanisms involved in the opposing effects of glucose and fatty acids on TXNIP expression are unknown. We found that both palmitate and oleate inhibited TXNIP in a rat beta-cell line and islets. Palmitate inhibition of TXNIP was independent of fatty acid beta-oxidation or esterification. AMP-activated protein kinase (AMPK) has an important role in cellular energy sensing and control of metabolic homeostasis; therefore we investigated its involvement in nutrient regulation of TXNIP. As expected, glucose inhibited whereas palmitate stimulated AMPK. Pharmacologic activators of AMPK mimicked fatty acids by inhibiting TXNIP. AMPK knockdown increased TXNIP expression in presence of high glucose with and without palmitate, indicating that nutrient (glucose and fatty acids) effects on TXNIP are mediated in part via modulation of AMPK activity. TXNIP is transcriptionally regulated by carbohydrate response element-binding protein (ChREBP). Palmitate inhibited glucose-stimulated ChREBP nuclear entry and recruitment to the Txnip promoter, thereby inhibiting Txnip transcription. We conclude that AMPK is an important regulator of Txnip transcription via modulation of ChREBP activity. The divergent effects of glucose and fatty acids on TXNIP expression result in part from their opposing effects on AMPK activity. In light of the important role of TXNIP in beta-cell apoptosis, its inhibition by fatty acids can be regarded as an adaptive/protective response to glucolipotoxicity. The finding that AMPK mediates nutrient regulation of TXNIP may have important implications for the pathophysiology and treatment of diabetes