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"Martin, Claire"
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The Viking and Anglo-Saxon struggle for England
\"From the first settlers in Britain to the invation of the Normals in 1066, this series guides readers through the exciting events of early British history.\"--Page 4 of cover.
Book
Pathophysiology, diagnosis and treatment of tachycardiomyopathy
Correspondence to Dr Pier D Lambiase, UCL Institute of Cardiovascular Science & Barts Heart Centre Cardiology Department Barts Heart Centre W. Smithfield, London EC1 7EB, UK; pierlambiase@hotmail.com, p.lambiase@ucl.ac.uk Learning objectives Recognise the diagnosis of tachycardiomyopathy (TCMP) Understand the pathophysiology Determine treatment strategies to restore left ventricular function The role of TCMP in non-responders to cardiac resynchronisation Introduction Tachycardiomyopathies (TCMP) are an important cause of left ventricular (LV) dysfunction that should be recognised by physicians as they are potentially reversible and have a significant impact on morbidity and prognosis. Two categories of the condition exist: the arrhythmia is the only reason for ventricular dysfunction (arrhythmia-induced), and another where the arrhythmia exacerbates ventricular dysfunction and/or worsens heart failure (HF) in a patient with concomitant heart disease (arrhythmia-mediated).4 The exclusion of underlying structural heart disease can be challenging as current imaging techniques, for example, MRI cannot easily identify diffuse fibrosis which may itself be primary or secondary to the effects of arrhythmia promoting ventricular wall dyskinesis and stretch or valvular regurgitation. Other factors that point to a diagnosis of TCMP include: (i) evidence of a previously normal ejection fraction (EF) and a degree of LV dysfunction out of proportion to other comorbidities, (ii) no other cause of non-ischaemic cardiomyopathy found (eg, hypertension, alcohol or drug use, stress, etc), (iii) absence of left ventricular hypertrophy, (iv) relatively normal LV dimensions (LV end-diastolic dimension below 5.5 cm), (v) recovery of LV function after control of tachycardia (by rate control, cardioversion or radiofrequency ablation within 1–6 months) and (vi) rapid decline in LV ejection fraction (LVEF) following recurrence of tachycardia in a patient with recovered LV function after previous control of tachycardia. Cardiac imaging provides important information in TCMP to identify underlying structural disease—patients initially have smaller LV end-diastolic diameters and LV volume adjusted for body surface area and LV mass compared with patients with idiopathic dilated cardiomyopathy.10 The presence of gadolinium late enhancement can be an indicator of structural pathology pointing to a reduced likelihood to response in the context of PVC ablation.11 In an electro-anatomical mapping study of PVC cases, patients with irreversible cardiomyopathy had greater areas of low amplitude signals, a reduced unipolar voltage area ≥32% of LV endocardium predicted the irreversibility of cardiomyopathy with >95% sensitivity and specificity, but prospective validation is lacking.12 Serial assessment of the N-terminal pro-B-type natriuretic peptide (NT-proBNP) ratio (NT-BNP at baseline/NT-BNP during follow-up) can differentiate TCMP from irreversible dilated cardiomyopathy.
Journal Article
Low energy cost for optimal speed and control of membrane fusion
Membrane fusion is the cell’s delivery process, enabling its many compartments to receive cargo and machinery for cell growth and intercellular communication. The overall activation energy of the process must be large enough to prevent frequent and nonspecific spontaneous fusion events, yet must be low enough to allow it to be overcome upon demand by specific fusion proteins [such as soluble N-ethylmaleimide–sensitive factor attachment protein receptors (SNAREs)]. Remarkably, to the best of our knowledge, the activation energy for spontaneous bilayer fusion has never been measured. Multiple models have been developed and refined to estimate the overall activation energy and its component parts, and they span a very broad range from 20 kBT to 150 kBT, depending on the assumptions. In this study, using a bulk lipid-mixing assay at various temperatures, we report that the activation energy of complete membrane fusion is at the lowest range of these theoretical values. Typical lipid vesicles were found to slowly and spontaneously fully fuse with activation energies of ∼30 kBT. Our data demonstrate that the merging of membranes is not nearly as energy consuming as anticipated by many models and is ideally positioned to minimize spontaneous fusion while enabling rapid, SNARE-dependent fusion upon demand.
Journal Article
Characterization of a novel disease-associated mutation within NPHS1 and its effects on nephrin phosphorylation and signaling
Mutations in the transmembrane protein nephrin (encoded by NPHS1) underlie nearly half of all cases of congenital nephrotic syndrome (CNS), which is caused by aberrations in the blood filtering function of glomerular podocytes. Nephrin directly contributes to the structure of the filtration barrier, and it also serves as a signaling scaffold in podocytes, undergoing tyrosine phosphorylation on its cytoplasmic tail to recruit intracellular effector proteins. Nephrin phosphorylation is lost in several human and experimental models of glomerular disease, and genetic studies have confirmed its importance in maintenance of the filtration barrier. To date, however, the effect of CNS-associated NPHS1 variants on nephrin phosphorylation remains to be determined, which hampers genotype-phenotype correlations. Here, we have characterized a novel nephrin sequence variant, A419T, which is expressed along with C623F in a patient presenting with CNS. Nephrin localization is altered in kidney biopsies, and we further demonstrate reduced surface expression and ER retention of A419T and C623F in cultured cells. Moreover, we show that both mutations impair nephrin tyrosine phosphorylation, and they exert dominant negative effects on wildtype nephrin signaling. Our findings thus reveal that missense mutations in the nephrin extracellular region can impact nephrin signaling, and they uncover a potential pathomechanism to explain the spectrum of clinical severity seen with mild NPHS1 mutations.
Journal Article
Actual fusion efficiency in the lipid mixing assay - Comparison between nanodiscs and liposomes
Lipid exchange occurs between membranes during fusion or active lipid transfer. These processes are necessary
in vivo
for the homeostasis of the cell at the level of the membranes, the organelles and the cell itself. They are also used by the cell to interact with the surrounding medium. Several assays have been developed to characterize
in vitro
these processes on model systems. The most common one, relying on fluorescence dequenching, measures lipid mixing between small membranes such as liposomes or nanodiscs in bulk. Usually, relative comparisons of the rate of lipid exchange are made between measurements performed in parallel. Here, we establish a quantitative standardization of this assay to avoid any bias resulting from the temperatures, the chosen fluorescent lipid fractions and from the various detergents used to normalize the measurements. We used this standardization to quantitatively compare the efficiency of SNARE-induced fusion in liposome-liposome and liposome-nanodisc configurations having similar collision frequency. We found that the initial yield of fusion is comparable in both cases, 1 per 2–3 million collisions in spite of a much larger dequenching signal with nanodiscs. Also, the long-term actual fusion rate is slightly lower with nanodiscs than in the liposome-liposome assay.
Journal Article
Martin Luther King, Jr.
Recounts the life of Martin Luther King, Jr. and his dream of freedom, equality, and justice for all up to his 1968 assassination.
BOOK
Pleuritic chest pain postcatheter ablation procedure
Following admission, he underwent chest radiography (CXR) (figure 1B) and transthoracic echocardiography (TTE) (figure 1C) but was not referred for coronary angiography. (A) ECG, (B) chest radiography, (C) transthoracic echocardiography on presentation to the hospital. Surgical repair reduces mortality of AOF from 97% to 33%.2 While in this patient the fistula extended only between the oesophagus and the pericardial sac, their deteriorating state should have led to aggressive management of sepsis, drainage of the effusion and referral to cardiothoracic surgery.
Journal Article