The role of echocardiography in cardiac resynchronization therapy

Echocardiography is the most important imaging tool for managing heart failure patients. With the advent of cardiac resynchronization therapy (CRT), its role has been broadened by data pertaining to patient selection, optimization of device settings, and outcome assessment. Beyond ejection fraction determination, echocardiographic methods that measure tissue velocity and strain may have the capability to determine degree of mechanical dyssynchrony and possibly predict likelihood of benefit with CRT. After implantation (as the ventricles are fully paced, adjusting the atrioventricular delay [atrioventricular optimization]), the timing of the right ventricular and left ventricular lead stimulation (ventricular-ventricular optimization) to achieve maximal cardiac filling or ejection may be clinically important. Atrioventricular and ventricular-ventricular optimization rely on echocardiography to determine optimal values. In long-term follow-up, serial measurement of left ventricular volume has significant correlation with mortality and is a reasonable measure of successful CRT; echocardiography is uniquely suited for this purpose.     

Progastrin and its Products from Patients with Chronic Viral Hepatitis and Liver Cirrhosis

Background: Gastrin and its precursor, progastrin, are synthesized in the stomach, particularly when infected with Helicobacter pylori , and they are metabolized, at least in part, in the liver. However, little is known about their levels in various hepatic diseases. Methods: This study was carried out on 147 patients including chronic hepatitis B ( n &#114 = &#114 35), hepatitis C ( n &#114 = &#114 52) and liver cirrhosis ( n &#114 = &#114 60) of class A ( n &#114 = &#114 38), class B ( n &#114 = &#114 15) and class C ( n &#114 = &#114 7) (Child-Pugh classification) and age- and sex-matched healthy controls ( n &#114 = &#114 65). The diagnosis of chronic hepatitis was confirmed by liver biopsy in all patients, whereas the diagnosis of liver cirrhosis was based on clinical and laboratory findings. Liver biopsy was done in 38 out of 60 patients. Blood samples were collected under basal conditions and separated plasma samples were kept frozen at &#109 70°C until radioimmunoassay of progastrin and its products, including bioactive amidated gastrins. Results: Median (range) plasma concentrations of total progastrin product and amidated gastrin in control subjects were 147.5 (73-345) pM and 33 (15-65), respectively. These concentrations in hepatitis B and C were not significantly different from those in controls. In cirrhosis (classes A, B and C), the concentrations of the progastrin and of gastrin were significantly ( P &#114 < &#114 0.05) higher than in controls reaching, respectively, 253.5 (135-683 &#114 pM) and 47.5 (17-385) pM. Both progastrin and gastrin levels were significantly higher in H. pylori -positive than in negative cirrhotic patients. Antibodies against H. pylori were present in about 50% of controls, 68% of hepatitis B, 57% of hepatitis C and in 83% in cirrhosis patients. The difference in H. pylori prevalence between cirrhosis and controls was statistically significant. Conclusions: Plasma levels of progastrin and gastrin are significantly increased in cirrhotic patients and this could be attributed to reduced metabolism of these peptides in liver cirrhosis and to their increased release due to H. pylori infection rate in this disease.     

Echocardiographic Evaluation of External Iliac Artery Doppler Waveform in Patients with Coronary Artery Disease

Visual interpretation of the Doppler waveform in the common femoral or distal external iliac artery (EIA) was reported to be useful in screening for proximal peripheral artery occlusive disease (PAOD) in patients with lower limb ischemia. Commonly patients with coronary artery disease (CAD) referred for echocardiography have coexistent arterial pathology. Therefore, we decided to study whether echocardiographic evaluation of the distal EIA flow can be useful for detection of PAOD in patients with CAD. We studied 150 consecutive patients (pts) with CAD referred for echocardiography. At the end of an echocardiographic examination, evaluation of the flow in the distal EIA with an echocardiographic probe was performed. The Doppler waveform was classified as normal—with early diastolic flow reversal or abnormal–without early diastolic flow reversal. Echocardiographic findings were compared in a blinded fashion with the results of the ankle brachial index measurements (ABI). Based on the ABI ≤ 0.9, peripheral artery disease was diagnosed in 54 pts (36%) and abnormal external iliac Doppler waveform was found in 27 pts (18%). Sensitivity of abnormal external iliac Doppler waveform in predicting PAOD was 48%, specificity 99%, positive predictive value (PPV) 96%, and negative predictive value 77%. Peripheral arterial occlusive disease is common in patients with CAD referred for echocardiographic study. Echocardiographic assessment of distal EIA Doppler waveform has low sensitivity, but high specificity and high PPV in the diagnosis of peripheral arterial occlusive disease.     

The utility of restaging bone marrow biopsy in PET‐negative patients with diffuse large B‐cell lymphoma and baseline bone marrow involvement

Patients with diffuse large B‐cell lymphoma (DLBCL) and pre‐treatment bone marrow (BM) involvement require a restaging BM biopsy to document complete remission (CR). We investigated whether BM assessment by restaging PET‐CT could obviate the need for a repeat BM biopsy. Patients with DLBCL and a positive BM biopsy at diagnosis were identified from the Mayo Clinic Lymphoma Data Base. The concordance of BM status on restaging histopathology and PET‐CT reports and the positive (PPV) and negative predictive value (NPV) of PET‐CT were determined. One thousand eighty patients with DLBCL were evaluated and 69 patients (6%) had DLBCL involving the BM at diagnosis. Of 46 patients who completed frontline chemoimmunotherapy, 34 had a restaging PET‐CT and BM biopsy and were included in the analysis. Thirty‐three patients had a negative BM by both PET‐CT and BM biopsy; one patient had persistent BM involvement by biopsy and PET‐CT. Thus, restaging PET‐CT had 100% PPV and 100% NPV for assessing residual BM disease. The findings were validated in a prospective cohort of 68 DLBCL patients treated on a phase II clinical trial where four patients (6%) had DLBCL involving the BM at diagnosis. All had a negative BM by both restaging BM biopsy and PET‐CT. Compared with the gold standard of BM biopsy, PET‐CT had a 100% NPV to exclude residual BM disease after frontline therapy. If further validated, DLBCL practice guidelines and response criteria could be modified so that BM biopsy is no longer required to document CR if the restaging PET‐CT is negative. Am. J. Hematol. 89:865–867, 2014. © 2014 Wiley Periodicals, Inc.     

Capping protein regulatory cycle driven by CARMIL and V-1 may promote actin network assembly at protruding edges

Although capping protein (CP) terminates actin filament elongation, it promotes Arp2/3-dependent actin network assembly and accelerates actin-based motility both in vitro and in vivo. In vitro, capping protein Arp2/3 myosin I linker (CARMIL) antagonizes CP by reducing its affinity for the barbed end and by uncapping CP-capped filaments, whereas the protein V-1/myotrophin sequesters CP in an inactive complex. Previous work showed that CARMIL can readily retrieve CP from the CP:V-1 complex, thereby converting inactive CP into a version with moderate affinity for the barbed end. Here we further clarify the mechanism of this exchange reaction, and we demonstrate that the CP:CARMIL complex created by complex exchange slows the rate of barbed-end elongation by rapidly associating with, and dissociating from, the barbed end. Importantly, the cellular concentrations of V-1 and CP determined here argue that most CP is sequestered by V-1 at steady state in vivo. Finally, we show that CARMIL is recruited to the plasma membrane and only at cell edges undergoing active protrusion. Assuming that CARMIL is active only at this location, our data argue that a large pool of freely diffusing, inactive CP (CP:V-1) feeds, via CARMIL-driven complex exchange, the formation of weak-capping complexes (CP:CARMIL) at the plasma membrane of protruding edges. In vivo, therefore, CARMIL should promote Arp2/3-dependent actin network assembly at the leading edge by promoting barbed-end capping there.Actin assembly at the interface between the plasma membrane and the cytoplasm is driven by the recruitment of proteins that promote the nucleation of new actin filaments (1). A key nucleating factor driving actin assembly at the leading edge of crawling cells is the Arp2/3 complex, which creates the branched actin networks that comprise lamellipodia (2, 3). Capping protein (CP), which binds the barbed end of the actin filament with very high affinity (∼0.1 nM) to halt elongation (4), is an essential component of Arp2/3-generated branched actin networks (5). Paradoxically, although CP terminates filament elongation, it promotes Arp2/3-dependent actin network assembly and actin-based motility both in vitro and in vivo by increasing the frequency of Arp2/3-dependent nucleation (6–10). Factors that regulate the activity of CP therefore should play important roles in actin assembly and cell motility. One such factor may be the large scaffold protein CARMIL (capping protein Arp2/3 myosin I linker) (11), which contains a region of ∼75 residues that binds CP very tightly (K_d ∼1 nM) (12, 13). This region, which we named CAH3 for CARMIL Homology Domain 3, antagonizes the function of CP in vitro in two ways. First, by binding to free CP, CAH3 reduces CP’s affinity for the barbed end from ∼0.1 to ∼50 nM, thereby creating a weak barbed-end capping complex (CP:CAH3) (12, 13). Second, by binding to CP already present on the barbed end, CAH3 accelerates by ∼300-fold the rate of dissociation of CP from the end; i.e., CAH3 rapidly uncaps CP-capped filaments (12–14).Another potentially important regulator of CP is the protein V-1, also known as myotrophin (15, 16). This 13 kDa, ankyrin-repeat protein binds CP with an affinity of ∼20 nM, creating a 1:1 complex (CP:V-1) that has no affinity for the barbed end (16–18). V-1 has the potential, therefore, to influence polymerization by reducing the extent of barbed-end capping.Full understanding of CP regulation will require an in-depth understanding of how the activities of CARMIL and V-1 are coordinated. Relevant to this, Takeda et al. (17) showed that CAH3-like peptides readily convert the CP:V-1 complex into the CP:CAH3 complex. In terms of the mechanism of this exchange reaction, they postulated that the binding of CAH3 to the CP:V-1 complex results in the transient formation of a CP:V-1:CAH3 ternary complex. A subsequent allosteric change in CP caused by ternary complex formation then drives V-1 dissociation, yielding the CP:CAH3 complex. Importantly, the binding sites on the surface of CP for CAH3 and V-1 are nonoverlapping, consistent with the possibility that these three proteins form a ternary complex (17–21).The first goal of this study was to define precisely how CAH3 catalyzes the exchange of CP from its sequestered state (CP:V-1) into its weak barbed-end–binding state (CP:CAH3). This effort focused on providing direct evidence for the existence of the ternary complex and on determining the relative contributions of allostery versus competitive binding to complex exchange. The second goal was to determine the effect of complex exchange on the rate of barbed-end elongation in vitro, which must be understood to predict the effect of complex exchange on actin assembly in vivo. The third goal was to measure the cellular concentrations of V-1 and CP, as these values are required to gauge the likely significance of the complex exchange reaction in vivo. Finally, the fourth goal was to further define the spatial features and temporal dynamics of CARMIL’s leading-edge localization (11, 12, 22, 23), as this should further pinpoint both the site and the timing of complex exchange. Specifically, we sought to characterize CARMIL’s leading-edge localization relative to other key leading-edge molecules and to the plasma membrane and to determine if CARMIL’s leading-edge accumulation correlates with edge dynamics, i.e., protrusion versus retraction. Overall, our results support a model in which the recruitment of CARMIL to the plasma membrane specifically at sites of active polymerization and edge protrusion drives the exchange of abundant, freely diffusing, inactive CP:V-1 complexes into membrane-bound CP:CARMIL complexes that cap the barbed end weakly. This CARMIL-driven exchange reaction should therefore serve to promote Arp2/3-dependent actin network formation at protruding edges by promoting barbed-end capping there.     

Distinction between signaling mechanisms in lipid rafts vs. caveolae

The relative importance of lipid rafts vs. specialized rafts termed caveolae to influence signal transduction is not known. Here we show that in cells lacking caveolae, the dually acylated protein, endothelial nitric oxide synthase (eNOS), localizes to cholesterol-rich lipid raft domains of the plasma membrane. In these cells, expression of caveolin-1 (cav-1) stimulates caveolae biogenesis, promotes the interaction of cav-1 with eNOS, and the inhibition of NO release from cells. Interestingly, in cells where cav-1 does not drive caveolae assembly, despite equal levels of cav-1 and eNOS and localization of both proteins to raft domains of the plasmalemma, the physical interaction of eNOS with cav-1 is dramatically less resulting in less inhibition of NO release. Thus, cav-1 concentrated in caveolae, not in rafts, is in closer proximity to eNOS and is necessary for negative regulation of eNOS function, thereby providing the first clear example of spatial regulation of signaling in this organelle that is distinct from raft domains.     

Effect of SiC Addition to Al2O3 Ceramics Used in Cutting Tools

In this study, the effect of the addition of silicon carbide to alumina ceramics commonly used in cutting tool applications is addressed. Performance of Al₂O₃–SiC composite cutting inserts during the machining of hardened steels and ductile iron was compared to the results obtained for a cutting tool made out of 99 wt.% Al₂O₃, Al₂O₃–TiC, Al₂O₃–TiC–ZrO₂, and Al₂O₃–TiN. In almost all tests, the composite with silicon carbide demonstrated better wear resistance, longer tool lifetime, and the ability to cut at higher speeds. The enhanced properties of cutting tools with SiC can be attributed to the morphology and dimensions of the inclusions in the matrix as well as to the strength of the interphase boundaries, small porosity, and lack of high inner stresses in the volume.     

Numerical and Metallurgical Analysis of Laser Welded,Sealed Lap Joints of S355J2 and 316L Steels under Different Configurations

This paper presents the results of laser welding of dissimilar joints, where low-carbon and stainless steels were welded inthe lap joint configuration. Performed welding of austenitic and ferritic-pearlitic steels included a sealed joint, where only partial penetration of lower material was obtained.The authors presented acomparative study of the joints under different configurations. The welding parameters for the assumed penetration were estimated via anumericalsimulation. Moreover, a stress–strain analysis was performed based on theestablished model. Numerical analysis showed significant differences in joint properties, therefore, further study was conducted. Investigation of the fusion mechanism in the obtained joints wascarried out using electron dispersive spectroscopy (EDS) and metallurgical analysis. The study of the lap joint under different configurations showed considerable dissimilarities in stress–strain distribution and relevant differences in the fusion zone structure. The results showed advantages of using stainless steel as the upper material of a microstructure, and uniform chemical element distribution and stress analysis is considered.