A multicenter evaluation of safety of early extubation in liver transplant recipients.

Small single-institutional studies performed prior to the introduction of organ allocation using the Model for End-Stage Liver Disease (MELD) suggest that early airway extubation of liver transplant recipients is a safe practice. We designed a multicenter study to examine adverse events associated with early extubation in patients selected for liver transplantation using MELD score. A total of 7 institutions extubated all patients meeting study criteria and reported adverse events that occurred within 72 hours following surgery. Adverse events were uncommon: occurring in only 7.7% of 391 patients studied. Most adverse events were pulmonary or surgically related. Pulmonary complications were usually minor, requiring only an increase in ambient oxygen concentration. The majority of surgical adverse events required additional surgery. Analysis of a limited set of perioperative variables suggest that blood transfusions and technical factors were associated with an increased risk of adverse events. In conclusion, while early extubation appears to be safe under specified circumstances, there are performance differences between institutions that remain to be explained.     

Evaluation of 5-(Trifluoromethyl)-1,2,4-oxadiazole-Based Class IIa HDAC Inhibitors for Huntington’s Disease

Using an iterative structure–activity relationship driven approach, we identified a CNS-penetrant 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO, 12) with a pharmacokinetic profile suitable for probing class IIa histone deacetylase (HDAC) inhibition in vivo. Given the lack of understanding of endogenous class IIa HDAC substrates, we developed a surrogate readout to measure compound effects in vivo, by exploiting the >100-fold selectivity compound 12 exhibits over class I/IIb HDACs. We achieved adequate brain exposure with compound 12 in mice to estimate a class I/IIb deacetylation EC₅₀, using class I substrate H4K12 acetylation and global acetylation levels as a pharmacodynamic readout. We observed excellent correlation between the compound 12 in vivo pharmacodynamic response and in vitro class I/IIb cellular activity. Applying the same relationship to class IIa HDAC inhibition, we estimated the compound 12 dose required to inhibit class IIa HDAC activity, for use in preclinical models of Huntington’s disease.     

Salvianolic acid B protects human endothelial progenitor cells against oxidative stress-mediated dysfunction by modulating Akt/mTOR/4EBP1, p38 MAPK/ATF2, and ERK1/2 signaling pathways

The vascular endothelium is specifically sensitive to oxidative stress, and this is one of the mechanisms that causes widespread endothelial dysfunction in most cardiovascular diseases and disorders. Protection against reactive oxygen species (ROS)-mediated oxidative damage via antioxidant mechanisms is essential for tissue maintenance and shows therapeutic potential for patients suffering from cardiovascular and metabolic disorders. Salvianolic acid B (SalB), a natural bioactive component known from Traditional Chinese Medicine, has been reported to exert cellular protection in various types of cells. However, the underlying mechanisms involved are not fully understood. Here, we showed that SalB significantly promoted the migratory and tube formation abilities of human bone marrow derived-endothelial progenitor cells (BM-EPCs) in vitro, and substantially abrogated hydrogen peroxide (H₂O₂)-induced cell damage. SalB down-regulated Nox4 and eNOS, as well as nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase expression upon H₂O₂ induction that in turn prevents oxidative-induced endothelial dysfunction. Moreover, SalB suppressed the Bax/Bcl-xL ratio and caspase-3 activation after H₂O₂ induction. Furthermore, our results provide mechanistic evidence that activation of the mTOR/p70S6K/4EBP1 pathways is required for both SalB-mediated angiogenic and protective effects against oxidative stress-induced cell injury in BM-EPCs. Suppression of MKK3/6-p38 MAPK-ATF2 and ERK1/2 signaling pathways by SalB significantly protected BM-EPCs against cell injury caused by oxidative stress via reduction of intracellular ROS levels and apoptosis. Taken together, by providing a mechanistic insight into the modulation of redox states in BM-EPCs by SalB, we suggest that SalB has a strong potential of being a new proangiogenic and cytoprotective therapeutic agent with applications in the field of endothelial injury-mediated vascular diseases.     

Salidroside exerts angiogenic and cytoprotective effects on human bone marrowderived endothelial progenitor cells via Akt/mTOR/p70S6K and MAPK signalling pathways

Background and Purpose

With the increase of age, increased susceptibility to apoptosis and senescence may contribute to proliferative and functional impairment of endothelial progenitor cells (EPCs). The aim of this study was to investigate whether salidroside (SAL) can induce angiogenic differentiation and inhibit oxidative stress-induced apoptosis in bone marrow-derived EPCs (BM-EPCs), and if so, through what mechanism.

Experimental Approach

BM-EPCs were isolated and treated with different concentrations of SAL for up to 4 days. Cell proliferation, migration and tube formation ability were detected by DNA content quantification, transwell assay and Matrigel-based angiogenesis assay. Gene and protein expression were assessed by qRT-PCR and Western blot respectively.

Key Results

Treatment with SAL promoted cellular proliferation and angiogenic differentiation of BM-EPCs, and increased VEGF and NO secretion, which in turn mediated the enhanced angiogenic differentiation of BM-EPCs. Furthermore, SAL significantly attenuated hydrogen peroxide (H₂O₂)-induced cell apoptosis, reduced the intracellular level of reactive oxygen species and restored the mitochondrial membrane potential of BM-EPCs. Moreover, SAL stimulated the phosphorylation of Akt, mammalian target of rapamycin and p70 S6 kinase, as well as ERK1/2, which is associated with cell migration and capillary tube formation. Additionally, SAL reversed the phosphorylation of JNK and p38 MAPK induced by H₂O₂ and suppressed the changes in the Bax/Bcl-xL ratio observed after stimulation with H₂O₂.

Conclusions and Implications

These findings identify novel mechanisms that regulate EPC function and suggest that SAL has therapeutic potential as a new agent to enhance vasculogenesis as well as protect against oxidative endothelial injury.     

Embolic events in patients with atrial fibrillation and effective anticoagulation: value of transesophageal echocardiography to guide direct-current cardioversion. Final results of the Ludwigshafen Observational Cardioversion Study

OBJECTIVES: The primary objective was to evaluate the usefulness of transesophageal echocardiography (TEE)-guided cardioversion to prevent thromboembolic complications in patients with atrial fibrillation (AF) and effective anticoagulation (International Normalized Ratio of 2 or 3) at least three weeks before cardioversion. BACKGROUND: Transesophageal echocardiography has been proposed as a method of screening patients for left atrial thrombi before direct-current cardioversion of AF. The usefulness of TEE as a screening tool has always been evaluated in patients without long-term anticoagulation before cardioversion. METHODS: This prospective, single-center, observational study, performed on an intention-to-cardiovert basis, comprised 1,076 consecutive, unselected patients with AF. The initial two years were designed to be the control phase, during which the conventional approach was used. After that, cardioversion guided by TEE was performed in consecutive patients. RESULTS: The prevalence of left atrial thrombi was 7.7% in patients with persistent AF and effective anticoagulation. During the first four weeks after electrical cardioversion, six thromboembolic complications were observed in patients in whom the TEE-guided approach was employed (6 [0.8%] of 719 patients), compared with three thromboembolic complications in patients in whom the conventional approach was used (3 [0.8%] of 357 patients). None of the patients in whom electrical cardioversion was not performed experienced an embolic event. CONCLUSIONS: There were no differences in the rate of embolic events between the two treatment groups. In patients with AF and effective anticoagulation, TEE-guided electrical cardioversion does not reduce the embolic risk. However, TEE revealed left atrial thrombi in 7.7% of patients with AF and effective anticoagulation, before direct-current cardioversion.     

Evoked acoustic emissions and cochlear microphonics in the mustache bat, Pteronotus parnellii

In the echolocating bat, Pteronotus parnellii, otoacoustic responses at a frequency of 62 kHz are measurable in the external ear canal during continuous and after transient acoustic stimulation. These responses are interpreted to represent emissions from the cochlea. They can reach an amplitude as large as 70 dB SPL and occur in the frequency range most important for echolocation, namely on the average about 700 Hz above the constant frequency component of the orientation calls. A sharp maximum of the amplitude of cochlear microphonic potentials at about 62 kHz could be correlated with the emission frequency. In one bat an evoked otoacoustic response changed to a spontaneous otoacoustic emission. The frequency and amplitude of the evoked otoacoustic responses reversibly decreased after exposure for 1 min to continuous sounds of more than 85 dB SPL with frequencies of about 2.5-7.5 kHz above the emission frequency. Similar effects occurred during anaesthesia or cooling. A possible relation between the existence of otoacoustic emissions and morphological specializations of the cochlea is discussed.     

Variable sensitivity to noxious heat is mediated by differential expression of the CGRP gene

Heat sensitivity shows considerable functional variability in humans and laboratory animals, and is fundamental to inflammatory and possibly neuropathic pain. In the mouse, at least, much of this variability is genetic because inbred strains differ robustly in their behavioral sensitivity to noxious heat. These strain differences are shown here to reflect differential responsiveness of primary afferent thermal nociceptors to heat stimuli. We further present convergent behavioral and electrophysiological evidence that the variable responses to noxious heat are due to strain-dependence of CGRP expression and sensitivity. Strain differences in behavioral response to noxious heat could be abolished by peripheral injection of CGRP, blockade of cutaneous and spinal CGRP receptors, or long-term inactivation of CGRP with a CGRP-binding Spiegelmer. Linkage mapping supports the contention that the genetic variant determining variable heat pain sensitivity across mouse strains affects the expression of the Calca gene that codes for CGRPalpha.     

Cognitive strategies versus self-management skills as adjunct to vocational rehabilitation

Cognitive dysfunctions and negative symptoms are "rate-limiting factors" for community outcome and response to psychosocial intervention in people with schizophrenia. Therefore, two cognitive-behavioral group therapies were developed-computer-assisted cognitive strategy training (CAST) and training of self-management skills for negative symptoms (TSSN)-to target these barriers to rehabilitation readiness. One hundred thirty-eight DSM-IV schizophrenia inpatients on a rehabilitation ward were randomly assigned to CAST plus vocational rehabilitation, TSSN plus vocational rehabilitation, or vocational rehabilitation alone. CAST included computer-based training in coping strategies focusing on deficits in attention, verbal memory, and planning. TSSN focused on social withdrawal/social anhedonia, lack of drive/volition, and affect flattening using techniques such as time scheduling, mastery, and pleasure techniques. Treatment outcome was assessed at intake and at discharge after 8 weeks. Analyses of covariance controlling for basis-level functioning demonstrated that patients receiving CAST plus vocational rehabilitation showed greater improvement on attention and verbal memory but not on planning ability. Patients receiving TSSN plus vocational rehabilitation failed to demonstrate improvement in negative symptoms. CAST plus vocational rehabilitation was found to be associated with a higher rate of successful job placement at the 12-month followup interval. Hierarchical logistic regression analyses demonstrated that improvement in short- and long-term verbal memory predicted a higher proportion of variance of successful job placement in the followup than pretreatment history of employment alone. Cognitive training as an adjunct to inpatient vocational rehabilitation demonstrated cognitive improvement, which was found to be associated with successful job placement in the followup. TSSN's efficacy was less clear; reasons for this uncertainty are provided.