The role of naturally occurring human α1a-Adrenergic Receptor (α1aAR) genetic variants associated with cardiovascular disorders is poorly understood. Here, we present the novel findings that ...expression of human α1aAR-247R (247R) genetic variant in cardiomyoblasts leads to transition of cardiomyoblasts into a fibroblast-like phenotype, evidenced by morphology and distinct de novo expression of characteristic genes. These fibroblast-like cells exhibit constitutive, high proliferative capacity and agonist-induced hypertrophy compared with cells prior to transition. We demonstrate that constitutive, synergistic activation of EGFR, Src and ERK kinases is the potential molecular mechanism of this transition. We also demonstrate that 247R triggers two distinct EGFR transactivation-dependent signaling pathways: 1) constitutive Gq-independent β-arrestin-1/Src/MMP/EGFR/ERK-dependent hyperproliferation and 2) agonist-induced Gq- and EGFR/STAT-dependent hypertrophy. Interestingly, in cardiomyoblasts agonist-independent hyperproliferation is MMP-dependent, but in fibroblast-like cells it is MMP-independent, suggesting that expression of α1aAR genetic variant in cardiomyocytes may trigger extracellular matrix remodeling. Thus, these novel findings demonstrate that EGFR transactivation by α1aAR-247R leads to hyperproliferation, hypertrophy and alterations in cardiomyoblasts, suggesting that these unique genetically-mediated alterations in signaling pathways and cellular function may lead to myocardial fibrosis. Such extracellular matrix remodeling may contribute to the genesis of arrhythmias in certain types of heart failure.
•α1aAR genetic variant triggers cardiomyoblast-to-fibroblast-like cell transition.•α1aAR-247R triggers constitutive hyperproliferation and agonist-induced hypertrophy.•α1aAR-247R-triggered hyperproliferation is Src/MMP/EGFR-transactivation dependent.•α1aAR-247R triggers synergistic activation of EGFR, Src, and ERK kinases.•α1aAR-247R-induced changes may lead to myocardial fibrosis and arrhythmias.
Detecting loss of resistance (LOR) can either be taught with dedicated simulators, with a cost ranging from 1500 to 3000, or with the 'Greengrocer's Model', requiring simply a banana.
The purpose of ...this study was to compare three dedicated epidural puncture training simulators and a banana in their ability to simulate LOR. Our hypothesis was that there was a difference between the four simulators when comparing the detection of LOR.
Single-blinded, randomised, controlled study.
Department of Anaesthesiology and Pain Therapy, Bern University Hospital, Switzerland.
Fifty-five consultant anaesthesiologists.
The participants were asked to insert an epidural catheter in four different epidural puncture training simulators: Lumbar Puncture Simulator II (Kyoto Kagaku, Kyoto, Japan), Lumbar Epidural Injection Trainer (Erler-Zimmer, Lauf, Germany), Normal Adult Lumbar Puncture/Epidural Tissue (Simulab Corp., Seattle, Washington, USA) and a banana. The simulators were placed in identical boxes to blind the participants.
The primary outcome was the detection of LOR rated on a 100-mm visual analogue scale, in which 0 mm represented 'completely unrealistic' and 100 mm represented 'indistinguishable from a real patient'.
The mean visual analogue scale scores for LOR in the four simulators were significantly different: 60 ± 25 mm 95% confidence interval (CI), 55 to 65 mm, 50 ± 29 mm (95% CI, 44 to 55 mm), 64 ± 24 mm (95% CI, 58 to 69 mm) and 49 ± 32 mm (95% CI, 44 to 54 mm); P less than 0.001, Friedman test.
Two of the three dedicated epidural simulators were rated more realistic in detecting LOR than the banana, but some participants preferred the banana to the other three simulators. Given the relative cost of a banana compared with a dedicated simulator, we suggest that a banana be used to teach the technique of LOR for epidural puncture.
KEK Nr: Req-2015-z087.
Summary
We present the use of the SensaScope™, an S‐shaped rigid fibreoptic scope with a flexible distal end, in a series of 13 patients at high risk of, or known to have, a difficult intubation. ...Patients received conscious sedation with midazolam or fentanyl combined with a remifentanil infusion and topical lidocaine to the oral mucosa and to the trachea via a trans‐cricoid injection. Spontaneous ventilation was maintained until confirmation of tracheal intubation. In all cases, tracheal intubation was achieved using the SensaScope. The median (IQR range) insertion time (measured from the time the facemask was taken away from the face until an end‐expiratory CO2 reading was visible on the monitor) was 58 s (38–111 28–300s). In nine of the 13 cases, advancement of the SensaScope into the trachea was easy. Difficulties included a poor view associated with a bleeding diathesis and saliva, transient loss of spontaneous breathing, and difficulty in advancing the tracheal tube in a patient with unforeseen tracheal narrowing. A poor view in two patients was partially improved by a high continuous flow of oxygen. The SensaScope may be a valuable alternative to other rigid or flexible fibreoptic scopes for awake intubation of spontaneously breathing patients with a predicted difficult airway.
Abstract only
Alpha1‐adrenergic receptors (α1ARs) play an important role in cardiovascular disease. We reported that naturally occurring genetic variant of human α1aAR, with G247R SNP (247R) ...identified in hypertensive patient, leads to constitutive hyperproliferation of fibroblasts via βarrestin/MMP‐dependent EGFR‐transactivation.
Here we examine if the 247R‐triggered hyperproliferation is generalizable in other cell types. Surprisingly, expression of 247R in cardiomyoblasts results in morphological and phenotypical changes to fibroblast‐like cells. RNA and protein expression levels of FSP1, DDR2, MMP2, vimentin, Troponin I, βMHC confirm fibroblast‐like phenotype and cells exhibit agonist‐induced hypertrophy and constitutive, serum‐independent 2–3‐fold increased proliferation. Interestingly, hypertrophy but not proliferation is inhibited by prazosin, an α1aAR‐inverse agonist, suggesting two independent pathways triggered by 247R: proliferation is caused by Gq‐independent, but βarrestin/Src‐dependent EGFR transactivation while hypertrophy is Gq‐dependent.
In summary, our data suggest that the naturally occurring human α1aAR genetic variant triggers βarrestin/MMP/ADAM dependent EGFR transactivation pathway leading to hyperproliferation or hypertrophy in different cardiovascular cell types and is a novel hypertension‐associated signaling mechanism.
Abstract only Hypertensive heart disease is a progressive condition leading to myocardial remodeling, alterations in cardiomyocytes and fibrosis. Three α1 adrenergic receptor (AR) subtypes are ...expressed in human heart (α1a, α1b, α1d). Recently, we reported that human α1aAR with the naturally occurring G247R SNP (247R), originally identified in a hypertensive patient, constitutively couples to EGFR-transactivation pathway in fibroblasts and leads to hyperproliferation. We hypothesized that expression of 247R in cardiomyoblasts plays an important role in their remodeling. We demonstrate that constitutive expression of 247R in H9C2 cardiomyoblasts changes the morphology of myoblasts to fibroblast-like cells (transformed, tr247R); higher 247R expression results in earlier onset of transformation. Expression of α1aAR-WT does not affect cell morphology. Tr247R cells exhibit 2-3 fold increased constitutive proliferation compared to control or WT cells as determined by cell counts and thymidine incorporation assays; pERK is upregulated in tr247R cells as determined by Western blot analyses. Treatment with AraC, a DNA replication inhibitor, eliminates the 247R cells but not the H9C2 myoblasts. Expression of cell-specific markers is being evaluated in tr247R and control cells. RT-PCR and zymograms revealed increased MMP2 mRNA and protein levels in tr247R cells compared to control or WT cells and are comparable to MMP2 levels in fibroblasts. Increased proliferation of tr247R cells is reduced by EGFR specific inhibitor AG1478 but not general MMP inhibitor GM6001. Agonist stimulation of tr247R results in hypertrophy as determined by leucine incorporation. Interestingly, hypertrophy but not cell proliferation is inhibited by prazosin, an α1aAR inverse agonist, suggesting that increased proliferation and hypertrophy observed in transformed cells are two independent pathways triggered by 247R. Our data demonstrate that expression of α1aAR genetic variant triggers alterations in cardiomyoblasts via distinct signaling pathways leading to hyperproliferation, transformation of the cells to fibroblast-like phenotype and hypertrophy. Consequently, these changes may lead to fibrosis in human heart, extracellular matrix remodeling and heart failure.
Pharmacogenetics in palliative care Kleine-Brueggeney, Maren; Musshoff, Frank; Stuber, Frank ...
Forensic science international,
12/2010, Letnik:
203, Številka:
1
Journal Article
Recenzirano
Abstract Response to analgesics, anticancer pharmacotherapy and pharmacotherapy of other cancer related symptoms vary broadly between individuals. Age, disease, comorbidities, concomitant medication, ...organ function and patients’ compliance may partly explain the differences. However, the focus of ongoing research has shifted towards genomic variants of phase I and II drug metabolizing enzymes with one important goal being an individual dose adjustment according to a patient's genotype. Polymorphisms of the cytochrome P 450 2D6 influence the metabolism of many drugs including the analgesics codeine, tramadol, hydrocodone and oxycodone, as well as the metabolism of tricyclic antidepressants and the anticancer drug tamoxifen. Other candidate genes such as (opioid)-receptors, transporters and other molecules important for pharmacotherapy in pain management are discussed. Although pharmacogenetics as a diagnostic tool has the potential to improve patient therapy, study results are often equivocal and limited by small sample sizes and often by their retrospective design. Well designed studies are needed to demonstrate superiority of pharmoacogenetics to conventional dosing regimes.
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