The architecture of EGFR's basal complexes reveals autoinhibition mechanisms in dimers and oligomers

Our current understanding of epidermal growth factor receptor (EGFR) autoinhibition is based on X-ray structural data of monomer and dimer receptor fragments and does not explain how mutations achieve ligand-independent phosphorylation. Using a repertoire of imaging technologies and simulations we reveal an extracellular head-to-head interaction through which ligand-free receptor polymer chains of various lengths assemble. The architecture of the head-to-head interaction prevents kinase-mediated dimerisation. The latter, afforded by mutation or intracellular treatments, splits the autoinhibited head-to-head polymers to form stalk-to-stalk flexible non-extended dimers structurally coupled across the plasma membrane to active asymmetric tyrosine kinase dimers, and extended dimers coupled to inactive symmetric kinase dimers. Contrary to the previously proposed main autoinhibitory function of the inactive symmetric kinase dimer, our data suggest that only dysregulated species bear populations of symmetric and asymmetric kinase dimers that coexist in equilibrium at the plasma membrane under the modulation of the C-terminal domain

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Very late thrombosis after implantation of sirolimus eluting stent

Stent thrombosis after sirolimus eluting stent implantation has been reported to occur at six hours to 375 days after the procedure and usually within the two weeks after discontinuation of antiplatelet medication. A case is reported of very late stent thrombosis after 17 months of sirolimus eluting stent implantation and eight months after clopidogrel discontinuation despite aspirin continuation. This case underlines the possible need for long term antiplatelet medication among patients receiving sirolimus eluting stents

Hypocalcemic heart failure in thalassemic patients

Hypocalcemic cardiomyopathy in primary or secondary hypoparathyroidism is usually refractory to conventional treatment of cardiac failure. We report the case of a thalassemic patient with severe cardiac failure that might have been attributed to several factors, such as hemosiderosis, hypomagnesemia, and hypocalcemia, refractory to conventional cardiac therapy. Cardiac echocardiography showed impaired biventricular performance, and laboratory analyses revealed hypoparathyroidism due to hemosiderosis. When concomitant treatment of heart failure and calcium supplementation was initiated, correction of hypocalcemia resulted in clinical and laboratory improvement, providing strong evidence in support of our hypothesis about hypocalcemic myocardiopathy

Release of platelet activation markers during coronary angioplasty

Background Authors of several studies have reported that activation of platelets occurs during coronary angioplasty, but consistent results have not been obtained. Levels of serotonin in coronary circulation have been found to be elevated during percutaneous transluminal coronary angioplasty but greater than normal concentrations of beta-thromboglobulin and platelet factor 4 have not been detected. Objective To perform a serial analysis of platelet-activation markers with simultaneous measurements of revels of serotonin, beta-thromboglobulin and platelet factor 4 in blood samples from the coronary artery and coronary sinus of patients undergoing coronary angioplasty. Methods Twenty patients undergoing elective coronary angioplasty were studied. Measurements of levels of beta-thromboglobulin, platelet factor 4, and serotonin in samples from the ostium of the coronary artery and the coronary sinus were performed immediately before angioplasty and after the first balloon deflation. Results Concentrations of beta-thromboglobulin and platelet factor 4 in coronary artery and coronary sinus were elevated in all patients before dilatation, whereas concentrations of serotonin were elevated in 85% of the patients. Concentrations of all markers in coronary sinus decreased after the first inflation. The coronary-sinus: coronary-artery concentration ratios before dilatation for beta-thromboglobulin, platelet factor 4, and serotonin were >1 for the majority of patients, particularly for those with complex culprit lesions, indicating that coronary activation of platelets was occurring. Ratios remained unchanged or decreased after the first inflation, depending on initial values. Conclusions Both systemic and coronary activation occur in patients subjected to percutaneous transluminal coronary angioplasty before the onset of intervention. After balloon deflation the greater than normal baseline coronary-sinus: coronary-artery concentration ratios of ail markers (beta-thromboglobulin, platelet factor 4 and serotonin) tend to decline or remain unchanged, depending on the level of activation. Coron Artery Dis 11:391-398 (C) 2000 Lippincott Williams & Wilkins

Antiendothelial cell antibodies in patients with coronary artery ectasia

BACKGROUND: The mechanisms involved in the pathogenesis of coronary artery ectasia (CAE) have not been elucidated. Circulating antiendothelial cell antibodies (AECA) are often detectable in systemic vasculitis and have been implicated in the pathogenesis of endothelial injury. Their prevalence in CAE is not known. METHODS AND Results: Out of 475 consecutive patients subjected to coronary angiography, 27 patients were diagnosed with CAE. Thirty patients matched for age, body mass index, sex, and coronary artery disease prevalence, served as controls. Serum AECA of IgG, IgM, and IgA isotypes were detected using a cell-based enzyme-linked immunosorbent assay (ELISA). Antinuclear antibodies (ANA) and antineutrophil cytoplasmic antibodies (ANCA) were detected using indirect immunofluorescence. IgG and IgM anticardiolipin antibodies (aCL) were detected using commercial ELISA. The prevalence of ANA and ANCA was similar in CAE patients and controls (33.3 vs. 43.3%, and 3.3 vs. 7.4%, respectively). There was no significant difference in IgG or IgM aCL reactivity between patients and controls. Both CAE patients and controls were negative for IgG AECA. The frequency of IgM AECA positivity was similar in CAE patients and controls. The prevalence of AECA of the IgA isotype was significantly higher in CAE patients (37.0 vs. 10%, P<0.05). Conclusion: There is increased prevalence of circulating AECA of the IgA isotype in patients with CAE. This provides evidence for a role of autoimmunity in the pathogenesis of certain cases of CAE. Copyright © 2010 Lippincott Williams & Wilkins

Anatomic characteristics of culprit sites in acute coronary syndromes

Background: A detailed analysis of the anatomic relationships of the site of culprit lesions that have resulted in acute coronary syndromes (ACS) has not been reported. Methods: Coronary angiograms of consecutive patients who presented with ACS were analyzed according to multiple anatomic criteria. Results: In left anterior descending artery (LAD) (n = 85), 85% of culprit lesions were located in the first 40 mm from the ostium. The presence of angulation on the lesion increased the risk of an ACS 1.92 times (95% confidence interval [CI] 1.9-3.07), and the presence of bifurcation after the lesion increased the risk 1.65 times (95% CI 1.04-2.62). Angulated lesions located within the first 40 mm from the ostium and before a bifurcation presented an 11-fold increased risk for an ACS. In right coronary artery (RCA) (n = 58), the risk of plaque rupture was almost 2.5 times higher in lesions located between 10 and 50 mm from the ostium compared to those located in 90-130 mm (relative risk [RR] 2.38, 95% CI 1.25-4.56). In left circumflex (LCx) (n = 40), the risk of plaque rupture was almost 4.5 and 5 times higher in the first 20 mm, and between 20 and 40 mm from the ostium, respectively, compared to 60 and 80 mm (relative risk [RR] 4.58, 95% CI 1.01-20.68 for 0-20 mm, and RR 4.95, 95% CI 1.14-21.47 for 20-40 mm) after adjustment for the presence of curve on the lesion. The presence of lesion angulation increased the risk of plaque rupture almost three times (RR 3.22, 95% CI 1.49-6.93). Conclusion: Specific anatomic features of the coronary arteries predispose to development and/or subsequent rupture of vulnerable plaques. © 2008, the Authors

Patient dosimetry during coronary interventions: A comprehensive analysis

Background We performed a detailed analysis of patient radiation during coronary interventions, comparing dose measurements to established dose reference levels, assessing coronary artery doses, and estimating total radiation risk of fatal cancer. Methods We prospectively examined 281 patients who were subjected to 307 percutaneous coronary interventions. Results The mean kerma area product (KAP) per procedure was 82.1 +/- 47.9 Gy. cm(2). Corresponding values for fluoroscopy and digital cineangiography were 28.3 +/- 25.5 Gy cm(2) and 53.8 +/- 35.5 Gy. cm(2), respectively, and exposure times were 13.1 +/- 6.8 minutes (87%) and 2.0 +/- 1.5 minutes (13%), respectively. The right anterior oblique caudal and left anterior oblique cranial projections accounted for the highest amount of KAP (24.0% and 23.1%, respectively) compared with other projections. The maximum recorded skin-dose was 182 mGy. Performing a representative procedure on a phantom, the effective dose was 14.9 mSv. The mean coronary dose was 61.7 +/- 38.2 mGy, with a highest calculated dose of 220.1 mGy. The third quartile of KAP measurements was 105 Gy. cm(2), the 95th percentile was 175 Gy. cm(2), and the mean value of KAP measurements was 82 Gy.cm(2). The total risk for the development of fatal cancer was calculated as 83 cases for every 100,000 patients subjected to coronary intervention. Conclusions A detailed analysis of patient radiation during coronary interventions is presented. Coronary doses and total radiation risk of fatal cancer are also calculated, and a method for establishing dose reference level values is proposed

Multilocalized pyomyositis in a previously healthy subject

A case of pyomyositis is presented. This case is unique in the literature as at least 29 abscesses were detected, affecting the vast majority of big muscle groups. We outline the origin of this disease entity which selectively affects striated muscles. We also discuss its natural history and management strategy