A MHz X-ray diffraction set-up for dynamic compression experiments in the diamond anvil cell.

An experimental platform for dynamic diamond anvil cell (dDAC) research has been developed at the High Energy Density (HED) Instrument at the European X-ray Free Electron Laser (European XFEL). Advantage was taken of the high repetition rate of the European XFEL (up to 4.5 MHz) to collect pulse-resolved MHz X-ray diffraction data from samples as they are dynamically compressed at intermediate strain rates (≤103 s-1), where up to 352 diffraction images can be collected from a single pulse train. The set-up employs piezo-driven dDACs capable of compressing samples in ≥340 µs, compatible with the maximum length of the pulse train (550 µs). Results from rapid compression experiments on a wide range of sample systems with different X-ray scattering powers are presented. A maximum compression rate of 87 TPa s-1 was observed during the fast compression of Au, while a strain rate of ∼1100 s-1 was achieved during the rapid compression of N2 at 23 TPa s-1.

Investigating Serious Adverse Drug Reactions in Patients Receiving Erythropoiesis-Stimulating Agents: A Root Cause Analysis Using the "ANTICIPATE" Framework.

BACKGROUND: Unexpected serious adverse drug reactions (sADRs) affecting patients with chronic kidney disease (CKD) who received erythropoiesis-stimulating agents were identified by study co-authors. These included pure red cell aplasia (PRCA) after administration of the Eprex formulation of epoetin or the epoetin biosimilar HX575 and fatal anaphylaxis associated with peginesatide, an erythropoietin receptor agonist. We developed and applied a structured framework to describe these sADRs, including root cause analyses and eradication efforts. METHODS: A 10-step framework termed "ANTICIPATE," focusing on signal identification, incidence, causality, and eradication guided our evaluations. RESULTS: Initial cases were identified by a hematologist (Eprex), clinical study monitors (HX575), and 4 nurses (peginesatide). The number of persons with individual ADRs was 13 PRCA cases for epoetin, 2 antibody-mediated PRCA cases for HX575, and 5 fatal anaphylaxis cases for peginesatide. Initial incidence estimates per 1000 treated persons were 0.27 for Eprex-associated PRCA, 11 for HX575-associated PRCA, and 0.38 for peginesatide fatalities. Likely causes were subcutaneous administration of epoetin formulated with polysorbate 80 (Eprex), tungsten leaching from pins included in product syringes (HX575), and inclusion of a phenol stabilizer (peginesatide). Eradication strategies included restricting Eprex administration to the intravenous route, excluding tungsten from HX575 syringes, and for peginesatide, proposed eradication was to return to single-dose vials without preservatives. CONCLUSION: Although the number of cases of each sADR was small, eradication was successful for 2 sADRs, and a proposed eradication was developed for a third sADR. The structured framework used to describe the above 3 sADRs in patients with CKD can also be used in other clinical settings.

Therapeutic Outlook of Pyrazole Analogs: A Mini Review.

BACKGROUND: Pyrazole is one of the excellent structural motifs in medicinal chemistry. Various physiological and therapeutic possibilities have been exploited by incorporating different pharmacophoric groups in the pyrazole moiety. OBJECTIVE: This has opened a new arena of pyrazole analogs that can be developed into medicinal agents such as anti-inflammatory, analgesic, antipyretic, antiviral, antibacterial, anticancer, anticonvulsant, hypoglycemic, carbonic anhydrase inhibitors, mono amino oxidase (MAO) inhibitors, etc. Though, pyrazole analogs have proven their clinical efficacy as different pharmacological agents, a few of them have been withdrawn from the market due to their side effects. Thus, research on potential new drug candidates bearing the pyrazole moiety with lesser side effects has fairly increased over the last few years. CONCLUSION: This review explores diverse pharmacological activities exhibited by pyrazole analogs reported recently, which may be of great help for researchers in the area of drug discovery to understand the current scenario of pyrazole based compounds and to design and develop newer drug candidates with improved efficacy.

Cardiac risks associated with antibiotics: azithromycin and levofloxacin.

INTRODUCTION: Azithromycin and levofloxacin have been shown to be efficacious in treating infections. The adverse drug events associated with azithromycin and levofloxacin were considered rare. However, the US FDA released warnings regarding the possible risk of QT prolongation with azithromycin and levofloxacin. AREAS COVERED: Case reports/case series, observational studies and clinical trials assessing cardiovascular risks associated with azithromycin and levofloxacin were critically reviewed, including 15 case reports/series, 5 observational studies and 5 clinical trials that investigated the cardiac risks associated azithromycin and levofloxacin. EXPERT OPINION: Results are discordant. Two retrospective studies utilizing large databases demonstrated an increased risk of cardiovascular death with azithromycin, when azithromycin was compared with amoxicillin. Two other retrospective studies found no difference in cardiovascular death associated with azithromycin and other antibiotics. For levofloxacin, the increased risk of cardiovascular death was only found in one retrospective study. Therefore, the risks and benefits of antibacterial therapies should be considered when making prescription decisions. This study should not preclude clinicians from avoiding azithromycin and levofloxacin. If a patient has an indication to receive an antibiotic and if azithromycin or levofloxacin is needed, it may be used, but the potential risks must be understood.

Azithromycin and levofloxacin use and increased risk of cardiac arrhythmia and death.

PURPOSE: Azithromycin use has been associated with increased risk of death among patients at high baseline risk, but not for younger and middle-aged adults. The Food and Drug Administration issued a public warning on azithromycin, including a statement that the risks were similar for levofloxacin. We conducted a retrospective cohort study among US veterans to test the hypothesis that taking azithromycin or levofloxacin would increase the risk of cardiovascular death and cardiac arrhythmia compared with persons taking amoxicillin. METHODS: We studied a cohort of US veterans (mean age, 56.8 years) who received an exclusive outpatient dispensation of either amoxicillin (n = 979,380), azithromycin (n = 594,792), or levofloxacin (n = 201,798) at the Department of Veterans Affairs between September 1999 and April 2012. Azithromycin was dispensed mostly for 5 days, whereas amoxicillin and levofloxacin were dispensed mostly for at least 10 days. RESULTS: During treatment days 1 to 5, patients receiving azithromycin had significantly increased risk of death (hazard ratio [HR] = 1.48; 95% CI, 1.05-2.09) and serious arrhythmia (HR = 1.77; 95% CI, 1.20-2.62) compared with patients receiving amoxicillin. On treatment days 6 to 10, risks were not statistically different. Compared with patients receiving amoxicillin, patients receiving levofloxacin for days 1 to 5 had a greater risk of death (HR = 2.49, 95% CI, 1.7-3.64) and serious cardiac arrhythmia (HR = 2.43, 95% CI, 1.56-3.79); this risk remained significantly different for days 6 to 10 for both death (HR = 1.95, 95% CI, 1.32-2.88) and arrhythmia (HR = 1.75; 95% CI, 1.09-2.82). CONCLUSIONS: Compared with amoxicillin, azithromycin resulted in a statistically significant increase in mortality and arrhythmia risks on days 1 to 5, but not 6 to 10. Levofloxacin, which was predominantly dispensed for a minimum of 10 days, resulted in an increased risk throughout the 10-day period.

Altered calsequestrin glycan processing is common to diverse models of canine heart failure.

Calsequestrin-2 (CSQ2) is a resident glycoprotein of junctional sarcoplasmic reticulum that functions in the regulation of SR Ca(2+) release. CSQ2 is biosynthesized in rough ER around cardiomyocyte nuclei and then traffics transversely across SR subcompartments. During biosynthesis, CSQ2 undergoes N-linked glycosylation and phosphorylation by protein kinase CK2. In mammalian heart, CSQ2 molecules subsequently undergo extensive mannose trimming by ER mannosidase(s), a posttranslational process that often regulates protein breakdown. We analyzed the intact purified CSQ2 from mongrel canine heart tissue by electrospray mass spectrometry. The average molecular mass of CSQ2 in normal mongrel dogs was 46,306 ± 41 Da, corresponding to glycan trimming of 3-5 mannoses, depending upon the phosphate content. We tested whether CSQ2 glycan structures would be altered in heart tissue from mongrel dogs induced into heart failure (HF) by two very different experimental treatments, rapid ventricular pacing or repeated coronary microembolizations. Similarly dramatic changes in mannose trimming were found in both types of induced HF, despite the different cardiomyopathies producing the failure. Unique to all samples analyzed from HF dog hearts, 20-40 % of all CSQ2 contained glycans that had minimal mannose trimming (Man9,8). Analyses of tissue samples showed decreases in CSQ2 protein levels per unit levels of mRNA for tachypaced heart tissue, also indicative of altered turnover. Quantitative immunofluorescence microscopy of frozen tissue sections suggested that no changes in CSQ2 levels occurred across the width of the cell. We conclude that altered processing of CSQ2 may be an adaptive response to the myocardium under stresses that are capable of inducing heart failure.

Ticlopidine-, clopidogrel-, and prasugrel-associated thrombotic thrombocytopenic purpura: a 20-year review from the Southern Network on Adverse Reactions (SONAR).

Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year of marketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrel-associated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ.

Statin therapy significantly reduces risk of ventricular tachyarrhythmias in patients with an implantable cardioverter defibrillator.

A few observational studies have shown the protective effect of statins on preventing ventricular tachycardia/ventricular fibrillation (VT/VF). However, the disparate study results prompt further exploration of this concept. We performed a meta-analysis to assess whether statin therapy is associated with a decrease in the incidence or recurrence of VT/VF in patients with an implantable cardioverter-defibrillator (ICD).The MEDLINE(®) and Cochrane databases were searched from 1980 to July 2009 for studies examining the effect of statins on VT/VF in recipients of ICDs. We retrieved all prospective cohort studies that examined this association. The endpoint was defined as appropriate ICD therapy for VT/VF. The quality of individual studies was assessed using the Newcastle Ottawa Scale.Seven prospective cohort studies met our inclusion criteria with a total of 2278 patients with a mean follow-up of 19.7 months. Pooled analysis of the eligible studies revealed that statin therapy was associated with a 45% reduction in the risk of developing VT/VF in recepients of ICDs [pooled odds ratio (pOR): 0.55; 95% confidence interval: 0.34-0.90; heterogeneity I(2) = 81%, P = 0.02]. In a subgroup analysis, the magnitude of the risk reduction in patients with ischemic cardiomyopathy was 54% (pOR: 0.46, P = 0.05). Sensitivity analysis including studies with higher methodological qualities alone showed a significant protective effect (pOR: 0.48, P = 0.01). There was no evidence of publication bias in the analysis.Our meta-analysis suggests an association between the use of statin and a reduction in the VT/VF occurrence in recipients of ICDs, mainly in patients with ischemic cardiomyopathy.

Phantom shocks unmasked: clinical data and proposed mechanism of memory reactivation of past traumatic shocks in patients with implantable cardioverter defibrillators.

BACKGROUND: Implantable cardioverter defibrillators (ICD), despite an unequivocal clinical benefit, are known to have a complex psychosocial impact on the patients. ICD shocks and the resultant psychobiological changes are known to contribute to increased levels of anxiety, depression, and post-shock stress symptoms in these patients. Phantom shock is a patient-reported perception of an ICD shock in the absence of any actual shock; however, its pathophysiological understanding is poor. METHODS: A retrospective chart review of the University hospital ICD patients' database from June 2006 to April 2010 was conducted. A total of 38 patients with documented phantom shocks as cases and 76 age- and sex-matched patients with no phantom shocks as controls were selected from the database. Patient characteristics were analyzed for their potential association with the occurrence of phantom shocks. RESULTS: Phantom shock patients had higher prevalence of documented depression (31.6%), anxiety (23.7%), and cocaine use (42.1%). Additionally, patients who had previous ICD shock storms were more likely to have phantom shocks (39.5%; p = 0.001). More importantly, no phantom shocks were reported in patients who did not receive defibrillation threshold testing or past ICD shock storms. CONCLUSIONS: Phantom shocks are primarily observed in ICD patients who had prior exposure to traumatic device shocks and are more common in patients with a history of depression, anxiety, or substance abuse. A pathophysiological mechanism is proposed as a guide to potential prevention.

Relationship between red cell distribution width and microalbuminuria: a population-based study of multiethnic representative US adults.

INTRODUCTION: Microalbuminuria (MA), a renal marker of vascular injury, is an independent predictor of cardiovascular (CV) events. Red cell distribution width (RDW), an emerging CV risk predictor, has not been evaluated for its association with MA. METHODS: We evaluated 8,499 participants of the National Health and Nutrition Examination Survey (NHANES) 1999-2006, where RDW was evaluated as a continuous variable and in quartiles (Q(1) ≤ 12.1, Q(2) 12.2-12.5, Q(3) 12.6-13 and Q(4) >13). Multivariate adjusted logistic regression analysis was performed to estimate the odds of having MA (n = 1,736; adjusted for traditional CV risk factors, race, BMI, estimated glomerular filtration rate, hemoglobin, mean corpuscular volume, high-sensitivity C-reactive protein and nutritional factors deficiencies of iron, folate and vitamin B(12)). RESULTS: The prevalence of MA increased with increasing RDW (13.52% in Q(1) vs. 30.02% in Q(4), p < 0.001). The odds of having MA for those in Q(4) was 2.49 (95% CI: 1.95-3.18, p < 0.001) compared to those in Q(1) after the adjustments. No effect modification was observed by covariates on the association between RDW and MA. CONCLUSION: Elevated RDW is independently associated with a higher risk of MA. An interaction between chronic inflammation, oxidative stress, neurohumoral overactivity and endothelial dysfunction may explain this association and the attendant elevated CV/renal risk.

The efficacy of sotalol in preventing postoperative atrial fibrillation: a meta-analysis.

OBJECTIVE: Supraventricular tachyarrhythmias including atrial fibrillation are common and troubling complications after cardiac surgery, and thus considerable interest in pharmacologic prophylaxis has developed. The aim of this study was to evaluate the efficacy of sotalol in the prevention of postoperative supraventricular tachyarrhythmias. METHODS: Standard methods of meta-analysis were used. Randomized clinical trials published in English language were eligible for the meta-analysis. RESULTS: A systematic review revealed 15 eligible publications that provided 20 comparisons of sotalol with a control group. The incidence and relative risk (RR) with 95% confidence interval (CI) of developing postoperative supraventricular tachyarrhythmias while taking sotalol were sotalol (n=489) versus placebo (n=499): 22.5% versus 41.5%, RR=0.55 (CI, 0.454-0.667, P<.001); sotalol (n=304) versus no treatment (n=311): 12% versus 39%, RR=0.329 (CI, 0.236-0.459, P<.001); sotalol (n=488) versus beta-blocker (n=555): 14% versus 23%, RR=0.644 (CI, 0.495-0.838, P<.001); sotalol (n=139) versus amiodarone (n=146): no significant differences in supraventricular tachyarrhythmia prevention; and sotalol (n=51) versus magnesium (n=54): no significant differences in supraventricular tachyarrhythmia prevention. Initiating sotalol orally or intravenously had no significant effect on efficacy. Initiating sotalol after surgery showed a trend toward less adverse events (before: RR=1.700 [CI, 0.903-3.200] and after: RR=0.767 [CI, 0.391-1.505]). CONCLUSION: Sotalol is more effective in the prevention of supraventricular tachyarrhythmia than placebo or beta-blockers. Initiating sotalol before cardiac surgery has no advantage compared with initiating sotalol shortly after surgery. Starting sotalol intravenously after surgery may be a more reliable method than administering via a nasogastric tube or delaying treatment until the patient can take oral medication.