Background and purpose
Orolingual angioedema (OA) is an uncommon but potentially life‐threatening complication of treatment with recombinant tissue plasminogen activator (rt‐PA; alteplase) during ...acute ischaemic stroke. This study aimed to determine the incidence of rt‐PA‐related OA in an Asian stroke population and the risk of pre‐stroke anti‐hypertensive drug use for development of this complication.
Methods
A multi‐center stroke registry was used to identify the pre‐stroke medications of acute ischaemic stroke patients receiving intravenous rt‐PA from January 2002 to December 2013. The clinical manifestations of rt‐PA‐related OA were recorded and the incidence of this complication was determined. The risks of pre‐stroke use of different anti‐hypertensive agents for the occurrence of rt‐PA‐related OA were determined from this study and from a meta‐analysis.
Results
A total of 559 patients received intravenous rt‐PA over a 12‐year period. Five patients (two males) developed OA after rt‐PA administration. The incidence of OA amongst these patients was 0.89% (95% confidence interval 0.29%–2.09%), which was lower than that obtained by meta‐analysis (1.9%). Amongst pre‐stroke anti‐hypertensive medications, angiotensin‐converting enzyme (ACE) inhibitors were found in this study to have the highest relative risk for rt‐PA‐related OA (17.1; 95% confidence interval 3.0–96.9). Meta‐analysis also revealed that pre‐stroke use of ACE inhibitors was associated with a high relative risk of OA after intravenous rt‐PA (12.9; 95% confidence interval 4.5–37.0).
Conclusions
The incidence of rt‐PA‐related OA in the Asian population is lower than that in the Caucasian population. Pre‐stroke use of ACE inhibitors significantly increases the risk of this complication.
Abstract Using extracellular single unit recordings alone or in combination with neurobiotin juxtacellular labeling and orexin (hypocretin) immunohistochemistry in the mouse, we have recorded a total ...of 452 neurons in the orexin neuron field of the posterior hypothalamus. Of these, 76 exhibited tonic discharge highly specific to wakefulness, referred to as waking-active neurons. They showed differences from each other in terms of spike shape, activity profile, and response to an arousing sound stimulus and could be classified into three groups on the basis of spike shape as: 1) biphasic broad; 2) biphasic narrow; and 3) triphasic. Waking-active neurons characterized by biphasic broad spikes were orexin-immunopositive, whereas those characterized by either biphasic narrow or triphasic broad spikes were orexin-immunonegative. Unlike waking-specific histamine neurons, all orexin and non-orexin waking-active neurons exhibited slow (<10 Hz) tonic discharges during wakefulness and ceased firing shortly after the onset of electroencephalogram (EEG) synchronization (deactivation), the EEG sign of sleep (drowsy state). They remained virtually silent during slow-wave sleep, but displayed transient discharges during paradoxical (or rapid eye movement) sleep. During the transition from sleep to wakefulness, both orexin and triphasic non-orexin neurons fired in clusters prior to the onset of EEG activation, the EEG sign of wakefulness, and responded with a short latency to an arousing sound stimulus given during sleep. In contrast, the biphasic narrow non-orexin neurons fired in single spikes either prior to, or after, EEG activation during the same transition and responded to the stimulus with a longer latency. The activity of all waking-active neurons preceded the return of muscle tonus at the transition from paradoxical sleep to wakefulness. These data support the view that the activity of orexin and non-orexin waking-active neurons in the posterior hypothalamus plays an important wake-promoting role and that their activity antagonizes cortical deactivation and loss of muscle tone.
A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with acute myeloid leukemia (AML). However, comprehensive studies regarding the impact ...of genetic alterations in this group of patients are limited. In this study, we compared relevant mutations in 21 genes between AML patients aged 60 years or older and those younger and exposed their prognostic implications. Compared with the younger patients, the elderly had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A and TP53 mutations but a lower frequency of WT1 mutations. The older patients more frequently harbored one or more adverse genetic alterations. Multivariate analysis showed that DNMT3A and TP53 mutations were independent poor prognostic factors among the elderly, while NPM1 mutation in the absence of FLT3/ITD was an independent favorable prognostic factor. Furthermore, the status of mutations could well stratify older patients with intermediate-risk cytogenetics into three risk groups. In conclusion, older AML patients showed distinct genetic alterations from the younger group. Integration of cytogenetics and molecular mutations can better risk-stratify older AML patients. Development of novel therapies is needed to improve the outcome of older patients with poor prognosis under current treatment modalities.
Superconductivity and charge density waves (CDWs) are competitive, yet coexisting, orders in cuprate superconductors. To understand their microscopic interdependence, a probe capable of discerning ...their interaction on its natural length and time scale is necessary. We use ultrafast resonant soft x-ray scattering to track the transient evolution of CDW correlations in YBa
Cu
O
after the quench of superconductivity by an infrared laser pulse. We observe a nonthermal response of the CDW order characterized by a near doubling of the correlation length within ≈1 picosecond of the superconducting quench. Our results are consistent with a model in which the interaction between superconductivity and CDWs manifests inhomogeneously through disruption of spatial coherence, with superconductivity playing the dominant role in stabilizing CDW topological defects, such as discommensurations.
Abstract We recorded 872 single units across the complete sleep–waking cycle in the mouse preoptic area (POA) and basal forebrain (BFB), which are deeply involved in the regulation of sleep and ...wakefulness (W). Of these, 552 were sleep-active, 96 were waking-active, 106 were active during both waking and paradoxical sleep (PS), and the remaining 118 were state-indifferent. Among the 872, we distinguished slow-wave sleep (SWS)–specific, SWS/PS-specific, PS-specific, W-specific, and W/PS-specific neurons, the last group being further divided into specific tonic type I slow (TI-Ss) and specific tonic type I rapid (TI-Rs) both discharging specifically in association with cortical activation during both W and PS. Both the SWS/PS-specific and PS-specific neurons were distributed throughout a wide region of the POA and BFB, whereas the SWS-specific neurons were mainly located in the middle and ventral half of the POA and adjacent BFB, as were the W-specific and W/PS-specific neurons. At the transition from waking to sleep, the majority of SWS-specific and all SWS/PS-specific neurons fired after the onset of cortical synchronization (deactivation), whereas all W-specific and W/PS-specific neurons showed a significant decrease in firing rate >0.5 s before the onset. At the transition from SWS to W, the sleep-specific neurons showed a significant decrease in firing rate 0.1 s before the onset of cortical activation, while the W-specific and W/PS-specific neurons fired >0.5 s before the onset. TI-Ss neurons were characterized by a triphasic broad action potential, slow single isolated firing, and an antidromic response to cortical stimulation, whereas TI-Rs neurons were characterized by a narrow action potential and high frequency burst discharge in association with theta waves in PS. These data suggest that the forebrain sleep/waking switch is regulated by opposing activities of sleep-promoting (SWS-specific and SWS/PS-specific) and waking-promoting (W-specific and W/PS-specific) neurons, that the initiation of sleep is caused by decreased activity of the waking-promoting neurons (disfacilitation), and that the W/PS-specific neurons are deeply involved in the processes of cortical activation/deactivation.
Uncertainty in equilibrium climate sensitivity impedes accurate climate projections. While the intermodel spread is known to arise primarily from differences in cloud feedback, the exact processes ...responsible for the spread remain unclear. To help identify some key sources of uncertainty, the authors use a developmental version of the next-generation Geophysical Fluid Dynamics Laboratory global climate model (GCM) to construct a tightly controlled set of GCMs where only the formulation of convective precipitation is changed. The different models provide simulation of present-day climatology of comparable quality compared to the model ensemble from phase 5 of CMIP (CMIP5). The authors demonstrate that model estimates of climate sensitivity can be strongly affected by the manner through which cumulus cloud condensate is converted into precipitation in a model’s convection parameterization, processes that are only crudely accounted for in GCMs. In particular, two commonly used methods for converting cumulus condensate into precipitation can lead to drastically different climate sensitivity, as estimated here with an atmosphere–land model by increasing sea surface temperatures uniformly and examining the response in the top-of-atmosphere energy balance. The effect can be quantified through a bulk convective detrainment efficiency, which measures the ability of cumulus convection to generate condensate per unit precipitation. The model differences, dominated by shortwave feedbacks, come from broad regimes ranging from large-scale ascent to subsidence regions. Given current uncertainties in representing convective precipitation microphysics and the current inability to find a clear observational constraint that favors one version of the authors’ model over the others, the implications of this ability to engineer climate sensitivity need to be considered when estimating the uncertainty in climate projections.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Background: Statins are the most commonly prescribed agents for hypercholesterolemia because of their efficacy and tolerability. As the number of patients in need of statin therapy continues ...to increase, information regarding the relative efficacy and safety of statins is required for decision‐making.
Objective: This study will use systematic review to compare the efficacy and safety profiles of different statins at different doses and determine the therapeutically equivalent doses of statins to achieve a specific level of low‐density lipoprotein cholesterol (LDL‐C) lowering effect.
Methods: Publications of head‐to‐head randomized controlled trials (RCTs) of statins were retrieved from the Oregon state database (1966–2004), MEDLINE (2005‐April of 2006), EMBASE (2005‐April of 2006), and the Cochrane Controlled Trials Registry (up to the first quarter of 2006). The publications were evaluated with predetermined criteria by a reviewer before they were included in the review. The mean change in cholesterol level of each statin was calculated and weighted by number of subjects involved in each RCT. Where possible, meta‐analysis was performed to generate pooled estimates of the cholesterol lowering effect of statins and the difference between statins.
Results: Seventy‐five studies reporting RCTs of head‐to‐head comparisons on statins were included. Most studies had similar baseline characteristics, except the rosuvastatin related studies. A daily dose of atorvastatin 10 mg, fluvastatin 80 mg, lovastatin 40–80 mg, and simvastatin 20 mg could decrease LDL‐C by 30–40%, and fluvastatin 40 mg, lovastatin 10–20 mg, pravastatin 20–40 mg, and simvastatin 10 mg could decrease LDL‐C by 20–30%. The only two statins that could reduce LDL‐C more than 40% were rosuvastatin and atorvastatin at a daily dose of 20 mg or higher. Meta‐analysis indicated a statistically significant but clinically minor difference (<7%) between statins in cholesterol lowering effect. Comparisons of coronary heart disease prevention and safety could not be made because of insufficient data.
Conclusions: At comparable doses, statins are therapeutically equivalent in reducing LDL‐C.
Block of the hERG potassium channel and prolongation of the QT interval are predictors of drug‐induced torsade de pointes. However, drugs that block the hERG potassium channel may also block other ...channels that mitigate torsade risk. We hypothesized that the electrocardiogram can differentiate the effects of multichannel drug block by separate analysis of early repolarization (global J–Tpeak) and late repolarization (global Tpeak–Tend). In this prospective randomized controlled clinical trial, 22 subjects received a pure hERG potassium channel blocker (dofetilide) and three drugs that block hERG and either calcium or late sodium currents (quinidine, ranolazine, and verapamil). The results show that hERG potassium channel block equally prolongs early and late repolarization, whereas additional inward current block (calcium or late sodium) preferentially shortens early repolarization. Characterization of multichannel drug effects on human cardiac repolarization is possible and may improve the utility of the electrocardiogram in the assessment of drug‐related cardiac electrophysiology.
Clinical Pharmacology & Therapeutics (2014); 96 5, 549–558. doi:10.1038/clpt.2014.155
Summary
Background
Peptic ulcer bleeding remains a major healthcare problem despite decreasing prevalence of peptic ulcer disease. The role of chronic obstructive pulmonary disease (COPD) in the risk ...of peptic ulcer bleeding has not yet been established.
Aim
To determine if COPD patients have a higher risk of peptic ulcer bleeding than the general population and to identify the risk factors of peptic ulcer bleeding in COPD patients.
Methods
From Taiwan's National Health Insurance research database, 62 876 patients, including 32 682 COPD and 30 194 age‐gender‐matched non‐COPD controls, were recruited. Cox proportional hazard regression was performed to evaluate independent risk factors for ulcer bleeding in all patients and to identify risk factors in COPD patients.
Results
During the 8‐year follow‐up, COPD patients had a significant higher rate of peptic ulcer bleeding than the control group (P < 0.001, by log‐rank test). By Cox proportional hazard regression analysis, COPD hazard ratio (HR) 1.93, 95% CI 1.73–2.17 was an independent risk factor after adjusting for age, gender, underlying comorbidities and ulcerogenic medication. Age > 65 years, male, comorbidities of hypertension, diabetes, heart failure, history of peptic ulcer disease, and chronic renal disease and use of nonsteroidal anti‐inflammatory drugs were risk factors of ulcer bleeding in COPD patients.
Conclusion
Patients with chronic obstructive pulmonary disease have a higher risk of peptic ulcer bleeding after adjustments for possible confounding factors like underlying comorbidities and ulcerogenic medication.
Summary
Background
Few large population‐based studies have compared the occurrence of peptic ulcer bleeding (PUB) in cirrhotic and noncirrhotic patients.
Aims
To investigate if cirrhotic patients ...have higher risk of PUB than the general population and to identify possible risk factors of PUB in cirrhotic patients.
Methods
Using the National Health Insurance Research Database, a nationwide population‐based dataset in Taiwan and matching age, gender, comorbidities and ulcerogenic medication by propensity score, 4013 cirrhotic patients, 8013 chronic hepatitis patients and 7793 normal controls were compared. The log‐rank test was used to analyse differences in accumulated PUB‐free survival rates between the groups. Cox proportional hazard regressions were performed to evaluate independent risk factors for PUB in all patients and identified risk factors of PUB in cirrhotic patients.
Results
During the 7‐year follow‐up, cirrhotic patients had significantly higher incidences of PUB than chronic hepatitis patients and controls, respectively (P < 0.001 by log‐rank test). By Cox proportional hazard regression analysis, cirrhosis was independently associated with increased risk of PUB (hazard ratio: 4.22; 95% CI 3.37–5.29, P < 0.001) after adjusting for age, gender, economic status, underlying comorbidities and ulcerogenic medication. Age, male, diabetes, chronic renal disease, history of gastro‐oesophageal variceal bleeding and use of nonsteroidal anti‐inflammatory drugs were risk factors for PUB in cirrhotic patients.
Conclusion
Cirrhotic patients have a significantly higher risk of peptic ulcer bleeding after adjustments for possible confounding factors like age, gender, economic status, underlying comorbidities and ulcerogenic medication.
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