Harmonic phase magnetic resonance imaging (HARP) is a new technique for measuring the motion of the left ventricle of the heart. HARP uses magnetic resonance tagging, Fourier filtering and special processing algorithms to calculate key indices of myocardial motion including Eulerian and Lagrangian strain. This paper presents several new methods for visualizing myocardial motion based on HARP. Quantities that are computed and visualized include motion grids, velocity fields, strain rates, pathlines, tracked Eulerian strain, and contraction angle. The computations are fast and fully automated and have the potential for clinical application.

Helicobacter pylori is the primary cause of peptic ulcer disease and an etiologic agent in the development of gastric cancer. H. pylori infection is curable with regimens of multiple antimicrobial agents, and antimicrobial resistance is a leading cause of treatment failure. The Helicobacter pylori Antimicrobial Resistance Monitoring Program (HARP) is a prospective, multicenter U.S. network that tracks national incidence rates of H. pylori antimicrobial resistance. Of 347 clinical H. pylori isolates collected from December 1998 through 2002, 101 (29.1%) were resistant to one antimicrobial agent, and 17 (5%) were resistant to two or more antimicrobial agents. Eighty-seven (25.1%) isolates were resistant to metronidazole, 45 (12.9%) to clarithromycin, and 3 (0.9%) to amoxicillin. On multivariate analysis, black race was the only significant risk factor (p < 0.01, hazard ratio 2.04) for infection with a resistant H. pylori strain. Formulating pretreatment screening strategies or providing alternative therapeutic regimens for high-risk populations may be important for future clinical practice.

Proteins with annealing activity are newly identified ATP-dependent motors that can rewind RPA-coated complementary single-stranded DNA bubbles. AH2 (annealing helicase 2, also named as ZRANB3) is the second protein with annealing activity, the function of which is still unknown. Here, we report that AH2 is recruited to stalled replication forks and that cells depleted of AH2 are hypersensitive to replication stresses. Furthermore, AH2 binds to PCNA, which is crucial for its function at stalled replication forks. Interestingly, we identified a HARP-like (HPL) domain in AH2 that is indispensible for its annealing activity in vitro and its function in vivo. Moreover, searching of HPL domain in SNF2 family of proteins led to the identification of SMARCA1 and RAD54L, both of which possess annealing activity. Thus, this study not only demonstrates the in vivo functions of AH2, but also reveals a common feature of this new subfamily of proteins with annealing activity.

OBJECTIVE

The pathophysiology of left ventricular (LV) dysfunction, particularly in the setting of a preserved ejection fraction (EF), remains unclear. Few studies have investigated the relationship between arterial compliance and LV function in humans, and none used cardiovascular MRI.

RESULTS

We sought to determine whether arterial compliance is related to regional myocardial function among participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Arterial compliance was assessed using carotid ultrasound measurements to calculate the distensibility coefficient (DC) and Young's modulus (YM). Circumferential systolic (SR(S)) and diastolic (SR(E)) strain rates were calculated by harmonic phase (HARP) from tagged MRI. Associations between arterial compliance and indices of ventricular function were adjusted for cardiovascular risk factors. We found a significant association between arterial compliance and SR(S) in all myocardial regions (P<0.05); arterial compliance was also associated with SR(E) in the lateral and septal wall regions (P<0.05). Multiple linear regression analyses demonstrated a direct linear relationship between the carotid artery DC and SR(S) across all LV segments and slices, even after adjustment for cardiovascular risk factors and LV mass. In regression analyses, a significant relationship between arterial compliance and SR(E) in the septal and antero-apical walls was also found and remained significant after multivariable adjustment.

CONCLUSIONS

Arterial stiffness is associated with early and asymptomatic impairment of systolic as well as diastolic myocardial function. Further studies are needed to elucidate role of vascular compliance in the development of ventricular dysfunction and failure.

OBJECTIVE

This randomized clinical trial tested whether fish oil supplements can improve human coronary atherosclerosis.

BACKGROUND

Epidemiologic studies of populations whose intake of oily fish is high, as well as laboratory studies of the effects of the polyunsaturated fatty acids in fish oil, support the hypothesis that fish oil is antiatherogenic.

METHODS

Patients with angiographically documented coronary heart disease and normal plasma lipid levels were randomized to receive either fish oil capsules (n = 31), containing 6 g of n-3 fatty acids, or olive oil capsules (n = 28) for an average duration of 28 months. Coronary atherosclerosis on angiography was quantified by computer-assisted image analysis.

RESULTS

Mean (+/- SD) baseline characteristics were age 62 +/- 7 years, plasma total cholesterol concentration 187 +/- 31 mg/dl (4.83 +/- 0.80 mmol/liter) and triglyceride levels 132 +/- 70 mg/dl (1.51 +/- 0.80 mmol/liter). Fish oil lowered triglyceride levels by 30% (p = 0.007) but had no significant effects on other plasma lipoprotein levels. At the end of the trial, eicosapentaenoic acid in adipose tissue samples was 0.91% in the fish oil group compared with 0.20% in the control group (p < 0.0001). At baseline, the minimal lumen diameter of coronary artery lesions (n = 305) was 1.64 +/- 0.76 mm, and percent narrowing was 48 +/- 14%. Mean minimal diameter of atherosclerotic coronary arteries decreased by 0.104 and 0.138 mm in the fish oil and control groups, respectively (p = 0.6 between groups), and percent stenosis increased by 2.4% and 2.6%, respectively (p = 0.8). Confidence intervals exclude improvement by fish oil treatment of>> 0.17 mm, or>> 2.6%.

CONCLUSIONS

Fish oil treatment for 2 years does not promote major favorable changes in the diameter of atherosclerotic coronary arteries.

BACKGROUND

An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance.

METHODS

Fourteen tracers segmented 10 Alzheimer's Disease Neuroimaging Initiative (ADNI) cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on the HarP through a standard web-platform and resegmented following the HarP. The five most accurate tracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 T and 3T.

RESULTS

The agreement among tracers was relatively low with the local protocols (absolute left/right ICC 0.44/0.43) and much higher with the HarP (absolute left/right ICC 0.88/0.89). On the larger set of 15 cases, the HarP agreement within (left/right ICC range: 0.94/0.95 to 0.99/0.99) and among tracers (left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was 0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates (3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variance due to atrophy (33.5%, P < .001), and physiological variability (49.2%, P < .001).

CONCLUSIONS

The HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers. Hippocampi segmented with the HarP can be used as a reference for the qualification of human tracers and automated segmentation algorithms.

OBJECTIVE

To evaluate the outcome of elderly patients with community-acquired pneumonia (CAP) seen at an acute-care hospital, analyzing the importance of CAP severity, functional status, comorbidity, and frailty.

METHODS

Prospective observational study.

METHODS

Emergency department and geriatric medical day hospital of a university teaching hospital.

METHODS

Ninety-nine patients aged 65 and older seen for CAP over a 6-month recruitment period.

METHODS

Clinical data were used to calculate Pneumonia Severity Index (PSI), Barthel Index (BI), Charlson Comorbidity Index, and Hospital Admission Risk Profile (HARP). Patients were then assessed 15 days later to determine functional decline and 30 days and 18 months later for mortality and readmission. Multiple logistic regression was used to analyze outcomes.

RESULTS

Functional decline was observed in 23% of the 93 survivors. Within the 30-day period, case-fatality rate was 6% and readmission rate 11%; 18-month rates were 24% and 59%, respectively. Higher BI was a protective factor for 30-day and 18-month mortality (odds ratio (OR)=0.96, 95% confidence interval (CI)=0.94-0.98 and OR=0.97, 95% CI=0.95-0.99, respectively; P<.01), and PSI was the only predictor for functional decline (OR=1.03, 95% CI=1.01-1.05; P=.01). Indices did not predict readmission. Analyses were repeated for the 74 inpatients and indicated similar results except for 18-month mortality, which HARP predicted (OR=1.73; 95% CI=1.16-2.57; P<.01).

CONCLUSIONS

Functional status was an independent predictor for short- and long-term mortality in hospitalized patients whereas CAP severity predicted functional decline. Severity indices for CAP should possibly thus be adjusted in the elderly population, taking functional status assessment into account.

With the advent of recombinant DNA techniques, the field of molecular plant pathology witnessed dramatic shifts in the 1970s and 1980s. The new and conventional methodologies of bacterial molecular genetics put bacteria center stage. The discovery in the mid-1980s of the hrp/hrc gene cluster and the subsequent demonstration that it encodes a type III secretion system (T3SS) common to Gram negative bacterial phytopathogens, animal pathogens, and plant symbionts was a landmark in molecular plant pathology. Today, T3SS has earned a central role in our understanding of many fundamental aspects of bacterium-plant interactions and has contributed the important concept of interkingdom transfer of effector proteins determining race-cultivar specificity in plant-bacterium pathosystems. Recent developments in genomics, proteomics, and structural biology enable detailed and comprehensive insights into the functional architecture, evolutionary origin, and distribution of T3SS among bacterial pathogens and support current research efforts to discover novel antivirulence drugs.

The relationships and the zoogeography of the three extant pinniped families, Otariidae (sea lions and fur seals), Odobenidae (one extant species, the walrus), and Phocidae (true seals), have been contentious. Here, we address these topics in a molecular study that includes all extant species of true seals and sea lions, four fur seals and the walrus. Contrary to prevailing morphological views the analyses conclusively showed monophyletic Pinnipedia with a basal split between Otarioidea (Otariidae+Odobenidae) and Phocidae. The northern fur seal was the sister to all remaining otariids and neither sea lions nor arctocephaline fur seals were recognized as monophyletic entities. The basal Phocidae split between Monachinae (monk seals and southern true seals) and Phocinae (northern true seals) was strongly supported. The phylogeny of the Phocinae suggests that the ancestors of Cystophora (hooded seal) and the Phocini (e.g. harp seal, ringed seal) adapted to Arctic conditions and ice-breeding before 12 MYA (million years ago) as supported by the white natal coat of these lineages. The origin of the endemic Caspian and Baikal seals was dated well before the onset of major Pleistocene glaciations. The current findings, together with recent advances in pinniped paleontology, allow the proposal of a new hypothesis for pinniped origin and early dispersal. The hypothesis posits that pinnipeds originated on the North American continent with early otarioid and otariid divergences taking place in the northeast Pacific and those of the phocids in coastal areas of southeast N America for later dispersal to colder environments in the N Atlantic and the Arctic Basin, and in Antarctic waters.

BACKGROUND

Different 2-dimensional speckle-based strain techniques have been developed to overcome the problem of angle dependency with Doppler-based strain. However, their relative accuracy has not been assessed. The aim of this study was to determine the feasibility and accuracy of 2 such techniques (velocity vector imaging [VVI] and automated function imaging [AFI]), using tagged harmonic phase (HARP) magnetic resonance imaging (MRI) as a reference standard.

METHODS

Thirty patients with known or suspected ischemic heart disease underwent measurement of peak systolic longitudinal, radial, and circumferential Lagrangian strain with all 3 techniques using a 16-segment model. The extent of scar tissue in each segment was determined using contrast-enhanced MRI.

RESULTS

The measurement of myocardial strain in all 3 directions was highly feasible with both VVI and AFI. Longitudinal strain was underestimated by both VVI (-11 +/- 8%; P < .01) and AFI (-12 +/- 6%; P < .01) in comparison with HARP MRI (-14 +/- 5%), and radial strain was underestimated by VVI (14 +/- 18% vs 23 +/- 7%; P < .01). All strain measurements with AFI showed better correlation and agreement with HARP MRI compared with VVI. Circumferential strain with AFI had the greatest accuracy (area under the receiver operating characteristic curve = 0.74, P < .001) for the prediction of scar tissue on MRI.

CONCLUSIONS

Two-dimensional strain measured with AFI has significantly better accuracy than VVI. Circumferential strain with AFI has the best discriminative ability for the detection of regional myocardial dysfunction.

Background: In acute respiratory distress syndrome (ARDS) unrelated to COVID-19, two phenotypes, based on the severity of systemic inflammation (hyperinflammatory and hypoinflammatory), have been described. The hyperinflammatory phenotype is known to be associated with increased multiorgan failure and mortality. In this study, we aimed to identify these phenotypes in COVID-19-related ARDS.

Methods: In this prospective observational study done at two UK intensive care units, we recruited patients with ARDS due to COVID-19. Demographic, clinical, and laboratory data were collected at baseline. Plasma samples were analysed for interleukin-6 (IL-6) and soluble tumour necrosis factor receptor superfamily member 1A (TNFR1) using a novel point-of-care assay. A parsimonious regression classifier model was used to calculate the probability for the hyperinflammatory phenotype in COVID-19 using IL-6, soluble TNFR1, and bicarbonate levels. Data from this cohort was compared with patients with ARDS due to causes other than COVID-19 recruited to a previous UK multicentre, randomised controlled trial of simvastatin (HARP-2).

Findings: Between March 17 and April 25, 2020, 39 patients were recruited to the study. Median ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO₂/FiO₂) was 18 kpa (IQR 15-21) and acute physiology and chronic health evaluation II score was 12 (10-16). 17 (44%) of 39 patients had died by day 28 of the study. Compared with survivors, patients who died were older and had lower PaO₂/FiO₂. The median probability for the hyperinflammatory phenotype was 0·03 (IQR 0·01-0·2). Depending on the probability cutoff used to assign class, the prevalence of the hyperinflammatory phenotype was between four (10%) and eight (21%) of 39, which is lower than the proportion of patients with the hyperinflammatory phenotype in HARP-2 (186 [35%] of 539). Using the Youden index cutoff (0·274) to classify phenotype, five (63%) of eight patients with the hyperinflammatory phenotype and 12 (39%) of 31 with the hypoinflammatory phenotype died. Compared with matched patients recruited to HARP-2, levels of IL-6 were similar in our cohort, whereas soluble TNFR1 was significantly lower in patients with COVID-19-associated ARDS.

Interpretation: In this exploratory analysis of 39 patients, ARDS due to COVID-19 was not associated with higher systemic inflammation and was associated with a lower prevalence of the hyperinflammatory phenotype than that observed in historical ARDS data. This finding suggests that the excess mortality observed in COVID-19-related ARDS is unlikely to be due to the upregulation of inflammatory pathways described by the parsimonious model.

Funding: US National Institutes of Health, Innovate UK, and Randox.

It is becoming increasingly recognized that hydrogen peroxide (HP) plays a role in cell proliferation and migration. In the present study we found that exogenous HP significantly induced human prostate cancer LNCaP cell proliferation and migration. Heparin affin regulatory peptide (HARP) seems to be involved in the stimulatory effect of HP, because the latter had no effect on stably transfected LNCaP cells that did not express HARP. Moreover, HP significantly increased HARP mRNA and protein amounts in a concentration- and time-dependent manner. Curcumin and activator protein-1 (AP-1) decoy oligonucleotides abrogated both HP-induced HARP expression and LNCaP cell proliferation and migration. HP increased luciferase activity of the 5'-flanking region of the HARP gene introduced in a reporter gene vector, an effect that was abolished when even one of the two putative AP-1 binding sites of the HARP promoter was mutated. The effect of HP seems to be due to the binding of Fra-1, JunD, and phospho-c-Jun to the HARP promoter. These results support the notion that HARP is important for human prostate cancer cell proliferation and migration, establish the role of AP-1 in the up-regulation of HARP expression by low concentrations of HP, and characterize the AP-1 dimers involved.

BACKGROUND

Patients with chronic kidney disease are at increased risk for cardiovascular disease, but the efficacy and safety of simvastatin and aspirin are unknown in this patient group.

METHODS

Patients were randomly assigned in a 2 x 2 factorial design to the administration of: (1) 20 mg of simvastatin daily versus matching placebo, and (2) 100 mg of modified-release aspirin daily versus matching placebo.

RESULTS

Overall, 448 patients with chronic kidney disease were randomly assigned (242 predialysis patients with a creatinine level>> or = 1.7 mg/dL >> or =150 micromol/L], 73 patients on dialysis therapy, and 133 patients with a functioning transplant). Compliance with study treatments was 80% at 12 months. Allocation to treatment with 100 mg of aspirin daily was not associated with an excess of major bleeds (aspirin, 4 of 225 patients [2%] versus placebo, 6 of 223 patients [3%]; P = not significant [NS]), although there was a 3-fold excess of minor bleeds (34 of 225 [15%] versus 12 of 223 patients [5%]; P = 0.001). Among those with predialysis renal failure or a functioning transplant at baseline, aspirin did not increase the number of patients who progressed to dialysis therapy (7 of 187 [4%] versus 6 of 188 patients [3%]; P = NS) or experienced a greater than 20% increase in creatinine level (63 of 187 patients [34%] versus 56 of 188 patients [30%]; P = NS). After 12 months of follow-up, allocation to 20 mg of simvastatin daily reduced nonfasting total cholesterol levels by 18% (simvastatin, 163 mg/dL [4.22 mmol/L] versus placebo, 196 mg/dL [5.08 mmol/L]; P < 0.0001), directly measured low-density lipoprotein cholesterol levels by 24% (89 mg/dL [2.31 mmol/L] versus 114 mg/dL [2.96 mmol/L]; P < 0.0001), and triglyceride levels by 13% (166 mg/dL [1.87 mmol/L] versus 186 mg/dL [2.10 mmol/L]; P < 0.01), but there was no significant effect on high-density lipoprotein cholesterol levels (2% increase; P = NS). Allocation to simvastatin therapy was not associated with excess risk for abnormal liver function test results or elevated creatine kinase levels.

CONCLUSIONS

During a 1-year treatment period, simvastatin, 20 mg/d, produced a sustained reduction of approximately one quarter in low-density lipoprotein cholesterol levels, with no evidence of toxicity, and aspirin, 100 mg/d, did not substantially increase the risk for a major bleeding episode. Much larger trials are now needed to assess whether these treatments can prevent vascular events.

Myocardial tissue tagging using complementary spatial modulation of magnetization (CSPAMM) allows detailed assessment of myocardial motion. To capture the complex 3D cardiac motion pattern, multiple 2D tagged slices are usually acquired in different orientations. These approaches are prone to slice misregistration and associated with long acquisition times. In this work, a fast method for acquiring 3D CSPAMM data is proposed that allows measuring deformation of the whole heart in three breath-holds of 18 heartbeats duration each. Three acquisitions are sequentially performed with line tag preparation in each orthogonal direction. Measurement acceleration is achieved by applying localized tagging preparation and a hybrid multishot, segmented echo-planar imaging sequence. Five healthy volunteers and five patients with myocardial infarction were measured. Midwall contours were tracked throughout the cardiac cycle with an enhanced variant of the harmonic phase (HARP) technique. Circumferential shortening at end-systole ranged from 14.1% (base) to 20.1% (apex) in healthy subjects. Hypokinetic regions in patients corresponded well with regions exhibiting hyperenhancement after contrast injection. Time to maximum circumferential shortening varied more significantly over the left ventricle in patients than in volunteers (P<0.01). The proposed measurement scheme was well tolerated by patients and holds considerable potential to investigate cardiac mechanics in various diseases.

The SNF2 gene family consists of a large group of proteins involved in transcriptional regulation, maintenance of chromosome integrity, and various aspects of DNA repair. We cloned a novel SNF2 family human cDNA, with sequence identity to the Escherichia coli RNA polymerase-binding protein HepA and named the human hepA-related protein (HHARP/SMARCAL1). In addition, the mouse ortholog (Mharp/Smarcal1) was cloned, and the Caenorhabditis elegans ortholog (CEHARP) was identified in the GenBank database. Phylogenetic analysis indicates that the HARP proteins share a high level of sequence similarity to the seven motif helicase core region (SNF2 domain) with identifiable orthologs in other eukaryotic species, except for yeast. Purified His-tagged HARP/SMARCAL1 protein exhibits single-stranded DNA-dependent ATPase activity, consistent with it being a member of the SNF2 family of proteins. Both the human and the mouse genes consist of 17 exons and 16 introns. The human gene maps to chromosome 2q34-q36, and the mouse gene is localized to the syntenic region of chromosome 1 (between markers Gls and Acrg). HARP/SMARCAL1 transcripts are ubiquitously expressed in human and mouse tissues, with testis presenting the highest levels of mRNA expression in humans.

Magnetic resonance (MR) tagging is capable of accurate, noninvasive quantification of regional myocardial function. Routine clinical use, however, is hindered by cumbersome and time-consuming postprocessing procedures. We propose a fast, semiautomatic method for tracking three-dimensional (3-D) cardiac motion from a temporal sequence of short- and long-axis tagged MR images. The new method, called 3-D-HARmonic Phase (3D-HARP), extends the HARP approach, previously described for two-dimensional (2-D) tag analysis, to 3-D. A 3-D material mesh model is built to represent a collection of material points inside the left ventricle (LV) wall at a reference time. Harmonic phase, a material property that is time-invariant, is used to track the motion of the mesh through a cardiac cycle. Various motion-related functional properties of the myocardium, such as circumferential strain and left ventricular twist, are computed from the tracked mesh. The correlation analysis of 3D-HARP and FINDTAGS + Tag Strain(E) Analysis (TEA), which are well-established tag analysis techniques, shows that the regression coefficients of circumferential strain (E(CC)) and twist angle are r2 = 0.8605 and r2 = 0.8645, respectively. The total time required for tracking 3-D cardiac motion is approximately 10 min in a 9 timeframe tagged MRI dataset and has the potential to be much faster.

The new SinMod method extracts motion from magnetic resonance imaging (MRI)-tagged (MRIT) image sequences. Image intensity in the environment of each pixel is modeled as a moving sine wavefront. Displacement is estimated at subpixel accuracy. Performance is compared with the harmonic-phase analysis (HARP) method, which is currently the most common method used to detect motion in MRIT images. SinMod can handle line tags, as well as speckle patterns. In artificial images (tag distance six pixels), SinMod detects displacements accurately (error < 0.02 pixels). Effects of noise are suppressed effectively. Sharp transitions in motion at the boundary of an object are smeared out over a width of 0.6 tag distance. For MRIT images of the heart, SinMod appears less sensitive to artifacts, especially later in the cardiac cycle when image quality deteriorates. For each pixel, the quality of the sine-wave model in describing local image intensity is quantified objectively. If local quality is low, artifacts are avoided by averaging motion over a larger environment. Summarizing, SinMod is just as fast as HARP, but it performs better with respect to accuracy of displacement detection, noise reduction, and avoidance of artifacts.

Heparin affin regulatory peptide (HARP) is an 18-kDa secreted growth factor that has a high affinity for heparin and a potent role on tumor growth and angiogenesis. We have previously reported that HARP is mitogenic for different types of endothelial cells and also affects cell migration and differentiation (12). In this study we examined the signaling pathways involved in the migration and tube formation on matrigel of human umbilical vein endothelial cells (HUVEC) induced by HARP. We report for the first time that receptor-type protein-tyrosine phosphatase beta/zeta (RPTPbeta/zeta), which is a receptor for HARP in neuronal cell types, is also expressed in HUVEC. We also document that HARP signaling through RPTPbeta/zeta leads to activation of Src kinase, focal adhesion kinase, phosphatidylinositol 3-kinase, and Erk1/2. Sodium orthovanadate, chondroitin sulfate-C, PP1, wortmannin, LY294002, and U0126 inhibit HARP-mediated signaling and HUVEC migration and tube formation. In addition, RPTPbeta/zeta suppression using small interfering RNA technology interrupts intracellular signals and HUVEC migration and tube formation induced by HARP. These results establish the role of RPTPbeta/zeta as a receptor of HARP in HUVEC and elucidate the HARP signaling pathway in endothelial cells.

Heparin affin regulatory peptide (HARP) is an heparin-binding molecule involved in the regulation of cell proliferation and differentiation. Here, we report that HARP inhibited the biological activity induced by the 165-amino-acid form of vascular endothelial growth factor (VEGF165) on human umbilical vein endothelial cells. Endothelial-cell proliferation induced by VEGF165 showed about 50% inhibition in the presence of HARP in a concentration of 3 nM. In similar range of concentrations, HARP blocked tube formation induced by VEGF165 in three-dimensional angiogenesis assay. In vivo studies showed that HARP inhibited the VEGF165-induced Matrigel trade mark infiltration of endothelial cells. We then investigated the mechanisms of this inhibition and shown that HARP inhibited the binding of 125I-VEGF165 to the VEGF receptors of endothelial cells. Additional studies using VEGF soluble receptors indicated that binding of 125I-VEGF165 to kinase insert domain-containing receptor and neuropilin receptor was inhibited by HARP, but conversely the binding of 125I-VEGF165 to fms-like tyrosine kinase I receptor was unaffected. A competitive affinity-binding assay demonstrated that HARP interacted directly with VEGF165 with a dissociation coefficient of 1.38 nM. Binding assay using deletion mutants of HARP revealed that the thrombospondin type-1 repeats domains were involved in this interaction. These data demonstrate for the first time that the angiogenic factor HARP can also negatively regulates the angiogenic activity of VEGF165.

Helicases are enzymes that use ATP-driven motor force to unwind double-stranded DNA or RNA. Recently, increasing evidence demonstrates that some helicases also possess rewinding activity-in other words, they can anneal two complementary single-stranded nucleic acids. All five members of the human RecQ helicase family, helicase PIF1, mitochondrial helicase TWINKLE, and helicase/nuclease Dna2 have been shown to possess strand-annealing activity. Moreover, two recently identified helicases-HARP and AH2 have only ATP-dependent rewinding activity. These findings not only enhance our understanding of helicase enzymes but also establish the presence of a new type of protein: annealing helicases. This paper discusses what is known about these helicases, focusing on their biochemical activity to zip and unzip double-stranded DNA and/or RNA, their possible regulation mechanisms, and biological functions.

The utility of harmonic phase (HARP) analysis was recently demonstrated in humans and large animals as a technique for rapid and automatic analysis of tagged magnetic resonance images. In the current study, the applicability and accuracy of HARP analysis for automatic strain quantification in small animals were investigated. A validation study was performed on seven postinfarct rats and seven age-matched controls. A method for direct computation of 2D Lagrangian strain fields from spatial derivatives of HARP images was also developed in this paper. The results of HARP analysis were evaluated by comparison with those of homogeneous strain analysis employing finite element method and manual tag tracking. Both methods were validated with simulated digital images. Compared to conventional homogeneous strain analysis, HARP analysis yielded similar results in the assessment of regional strain patterns in both control and infarct rats. Both methods detected a reduction in maximal stretch and shortening in infarct rats. Our results suggest that HARP analysis can also be applied to quantify alterations in regional myocardial wall motion in small animals.

OBJECTIVE

To introduce a true three-dimensional (3D) tagging technique for the assessment of myocardial tissue motion.

METHODS

To generate a 3D tagging grid, a complementary spatial modulation of magnetization (CSPAMM) was applied in three spatial directions. Imaging was performed using a conventional fast 3D gradient-echo sequence. For automatic analysis of the 3D-CSPAMM data set, evaluation software, based on a 3D extension of the HARP technique, was used.

RESULTS

Successful application of the 3D-CSPAMM technique in healthy subjects allowed the accurate determination of quantitative 3D motion patterns in the human heart.

CONCLUSIONS

3D-CSPAMM may contribute to the quantification of the local 3D myocardial motion pattern throughout the cardiac cycle.

A cine series of tagged magnetic resonance (MR) images of the tongue is used to measure tongue motion and its internal deformation during speech. Tagged images are collected in three slice orientations (sagittal, coronal, and axial) during repetitions of the utterance "disouk" (/disuk/). A new technique called harmonic phase MRI (HARP-MRI) is used to process the tagged MR images to measure the internal deformation of the tongue. The measurements include displacement and velocity of tissue points, principal strains, and strain in the line-of-action of specific muscles. These measurements are not restricted to tag intersections, but can be calculated at every pixel in the image. The different motion measurements complement each other in understanding the tongue kinematics and in hypothesizing the internal muscle activity of the tongue.

In traumatic brain injury (TBI) rapid deformation of brain tissue leads to axonal injury and cell death. In vivo quantification of such fast deformations is extremely difficult, but important for understanding the mechanisms of degeneration post-trauma and for development of numerical models of injury biomechanics. In this paper, strain fields in the brain of the perinatal rat were estimated from data obtained in vivo during rapid indentation. Tagged magnetic resonance (MR) images were obtained with high spatial (0.2 mm) and temporal (3.9 ms) resolution by gated image acquisition during and after impact. Impacts were repeated either 64 or 128 times to obtain images of horizontal and vertical tag lines in coronal and sagittal planes. Strain fields were estimated by harmonic phase (HARP) analysis of the tagged images. The original MR data was filtered and Fourier-transformed to obtain HARP images, following a method originally developed by Osman et al. (IEEE Trans. Med. Imaging 19(3) (2000) 186). The displacements of material points were estimated from intersections of HARP contours and used to generate estimates of the deformation gradient and Lagrangian strain tensors. Maximum principal Lagrangian strains of >0.20 at strain rates >40/s were observed during indentations of 2 mm depth and 21 ms duration.