Safety and feasibility of high-dose dobutamine-atropine stress cardiovascular magnetic resonance for diagnosis of myocardial ischaemia: experience in 1000 consecutive cases.

AIMS: To determine the safety of high-dose dobutamine-atropine stress cardiovascular magnetic resonance (stress-CMR), which recently emerged as a highly accurate modality for diagnosis of inducible myocardial ischaemia. METHOD AND RESULTS: From 1997 to 2002, 1000 consecutive stress-CMR examinations were performed. Images were acquired at rest and during a high-dose dobutamine-atropine protocol in 3 short-axis, a 4- and a 2-chamber view. Stress testing was discontinued when > or =85% of age-predicted heart rate was reached, on patient request, maximum pharmacologic infusion, or when new or worsening wall motion abnormalities, severe angina, dyspnoea, increase or decrease in blood pressure, or severe arrhythmias occurred. Stress-CMR was successfully performed in all but four patients (0.4%; insufficient ECG-triggering). Target heart rate was not reached in 95 cases (9.5%), due to maximum pharmacologic infusion in submaximal negative examinations in 21 cases (2.1%), and limiting side effects in 74 (7.4%). Side effects included one case (0.1%) of sustained and four cases (0.4%) of non-sustained ventricular tachycardia, 16 cases (1.6%) of atrial fibrillation, and two cases (0.2%) of transient second degree AV block. CONCLUSION: The safety profile of stress-CMR is similar to other methodologies using dobutamine infusions. Patients must be closely monitored, and resuscitation equipment and trained personnel must be available.     

Effect of Alkylureas on the Polymerization of Hemoglobin S

Alkylureas (methyl-, ethyl-, propyl-, and butyl-) can inhibit both the gelation of deoxyhemoglobin S and red cell sickling without denaturation of the hemoglobin or intrinsic alteration of its oxygen affinity. This effect is directly proportional to the length of the alkyl chain and substantiates the importance of hydrophobic interactions in the polymerization of hemoglobin S. In addition, it opens the possibility that further systematic investigations with these compounds will help quantitate the role of hydrophobic interactions in this system so as to further our understanding of the polymerization of deoxyhemoglobin S.     

Differentiation in lacunary directions

Let {θ_j} be a lacunary sequence going to zero. Let [Formula: see text]. Define [Formula: see text]. We prove [Formula: see text].     

Functional proteomics of nonalcoholic steatohepatitis: mitochondrial proteins as targets of S-adenosylmethionine

Recent work shows that S-adenosylmethionine (AdoMet) helps maintain normal liver function as chronic hepatic deficiency results in spontaneous development of steatohepatitis and hepatocellular carcinoma. The mechanisms by which these nontraditional functions of AdoMet occur are unknown. Here, we use knockout mice deficient in hepatic AdoMet synthesis (MAT1A(-/-)) to study the proteome of the liver during the development of steatohepatitis. One hundred and seventeen protein spots, differentially expressed during the development of steatohepatitis, were selected and identified by peptide mass fingerprinting. Among them, 12 proteins were found to be affected from birth, when MAT1A(-/-) expression is switched on in WT mouse liver, to the rise of histological lesions, which occurs at approximately 8 months. Of the 12 proteins, 4 [prohibitin 1 (PHB1), cytochrome c oxidase I and II, and ATPase beta-subunit] have known roles in mitochondrial function. We show that the alteration in expression of PHB1 correlates with a loss of mitochondrial function. Experiments in isolated rat hepatocytes indicate that AdoMet regulates PHB1 content, thus suggesting ways by which steatohepatitis may be induced. Importantly, we found the expression of these mitochondrial proteins was abnormal in obob mice and obese patients who are at risk for nonalcoholic steatohepatitis.     

PET/CT and MR imaging biomarker of lipid-rich plaques using [Cu]-labeled scavenger receptor (CD68-Fc)

Continued uptake of modified low-density lipoproteins (LDL) by the scavenger receptor, CD68, of activated macrophages is a crucial process in the development of atherosclerotic plaques and leads to the formation of foam cells. Eight-weeks-old male Apolipoprotein E-deficient (ApoE^-/-) mice (n=6) were fed a high-fat diet for 12 weeks. C57BL/6J wildtype (WT) mice served as controls (n=6). Positron emission tomography (PET) with an acquisition time of 1800s (NanoPET/CT scanner; Mediso, Hungary & Bioscan, USA) was carried out 24h after intravenous tail vein administration of 50µl ⁶⁴Cu-CD68-Fc (~20-30µg labeled protein/mouse containing approximately 10-12MBq ⁶⁴Cu-CD68-Fc per mouse). Three days after PET/CT, all mice received an intravenous administration of 0.2 mmol/kg body weight of a gadolinium-based elastin-binding contrast agent to assess plaque burden and vessel wall remodeling. Two hours after injection, mice were imaged in a 3T clinical MR scanner (Philips Healthcare, Best, NL) using a dedicated single loop surface coil (23mm). Enhanced ⁶⁴Cu-CD68-Fc uptake was found in the aortic arches of ApoE^-/- compared to WT mice (ApoE^-/- mice:10.5±1.5Bq/cm³ vs. WT mice: 2.1±0.3Bq/cm³; P=0.002). Higher gadolinium-based elastin-binding contrast agent uptake was also detected in the aortic arch of ApoE^-/- compared to WT mice using R¹ maps (R¹=1.47±0.06 s^-1 vs. 0.92±0.05 s^-1; P <0.001). Radiolabeled scavenger receptor (⁶⁴Cu-CD68-Fc) may help to target foam cell rich plaques with high content of oxidized LDL. This novel imaging biomarker tool may have potential to identify unstable plaques and for risk stratification.     

The efficacy and safety of venetoclax therapy in elderly patients with relapsed,refractory chronic lymphocytic leukaemia

Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.     

Impact of Antimicrobial Stewardship Intervention on Coagulase-Negative Staphylococcus Blood Cultures in Conjunction with Rapid Diagnostic Testing

Rapid diagnostic testing with matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) decreases the time to organism identification by 24 to 36 h compared to the amount of time required by conventional methods. However, there are limited data evaluating the impact of MALDI-TOF with real-time antimicrobial stewardship team (AST) review and intervention on antimicrobial prescribing and outcomes for patients with bacteremia and blood cultures contaminated with coagulase-negative Staphylococcus (CoNS). A quasiexperimental study was conducted to analyze the impact of rapid diagnostic testing with MALDI-TOF plus AST review and intervention for adult hospitalized patients with blood cultures positive for CoNS. Antibiotic prescribing patterns and clinical outcomes were compared before and after implementation of MALDI-TOF with AST intervention for patients with CoNS bacteremia and CoNS contamination. A total of 324 patients with a positive CoNS blood culture were included; 246 were deemed to have contaminated cultures (117 in the preintervention group and 129 in AST the intervention group), and 78 patients had bacteremia (46 in the preintervention group and 32 in the AST intervention group). No differences in demographics were seen between the groups, and similar rates of contamination occurred between the preintervention and AST intervention groups (64.3% versus 72.6%, P = 0.173). Patients with bacteremia were initiated on optimal therapy sooner in the AST intervention group (58.7 versus 34.4 h, P = 0.030), which was associated with a similarly decreased mortality (21.7% versus 3.1%, P = 0.023). Patients with CoNS-contaminated cultures had similar rates of mortality, lengths of hospitalization, recurrent bloodstream infections, and 30-day hospital readmissions, but the AST intervention group had a decreased duration of unnecessary antibiotic therapy (1.31 versus 3.89 days, P = 0.032) and a decreased number of vancomycin trough assays performed (0.88 versus 1.95, P < 0.001). In patients with CoNS bacteremia, rapid pathogen identification integrated with real-time stewardship interventions improved timely organism identification and initiation of antibiotic therapy. Patients in the AST group with blood cultures contaminated with CoNS had decreased inappropriate antimicrobial prescribing and decreased unnecessary serum vancomycin trough assays.     

Long-term outcome after fetal transfusion for hydrops associated with parvovirus B19 infection

OBJECTIVE: To evaluate neurodevelopmental status of children treated with intrauterine red blood cell and platelet transfusion for fetal hydrops caused by parvovirus B19. METHODS: Maternal and neonatal records of all intrauterine transfusions for congenital parvovirus B19 infection in our center between 1997 and 2005 were reviewed. Congenital B19 virus infection was confirmed by the presence of parvovirus B19-specific immunoglobulin M or parvovirus B19 DNA in fetal blood samples. All children underwent a general pediatric and neurological examination. Primary outcome measure was neurodevelopmental status (developmental index by Bayley Scales of Infant Development or Snijders-Oomen test). Secondary outcome measure was general health status of surviving children. RESULTS: A total of 25 intrauterine transfusions were performed in 24 hydropic fetuses. Median fetal hemoglobin concentration, platelet count, and blood pH before intrauterine transfusions were 4.5 g/dL (range 2.4-11.4 g/dL), 79x10(9)/L (range 37-238x10(9)/L) and 7.36 (range 7.31-7.51), respectively. Sixteen survivors aged 6 months to 8 years were included in the follow-up study. Eleven children (68%) were normal, and 5 children (32%) demonstrated a delayed psychomotor development with an suboptimal neurological examination (mild delay n=3, severe delay n=2). Neurodevelopmental status did not correlate with pre-intrauterine transfusion hemoglobin, platelet, or blood pH values. Growth and general health status were normal in all. Two children had minor congenital defects. CONCLUSION: Neurodevelopmental status was abnormal in 5 of 16 survivors and was not related to the severity of fetal anemia and acidemia. We hypothesize that fetal parvovirus B19 infection may induce central nervous system damage. LEVEL OF EVIDENCE: III.