The structure and integrity of DNA is of considerable biological and biomedical importance, and it is therefore critical to identify and to characterize enzymes that alter DNA structure. DNA helicases are ATP-driven motor proteins that unwind DNA. Conversely, HepA-related protein (HARP) protein (also known as SMARCAL1 and DNA-dependent ATPase A) is an annealing helicase that rewinds DNA in an ATP-dependent manner. To date, HARP is the only known annealing helicase. Here we report the identification of a second annealing helicase, which we term AH2, for annealing helicase 2. Like HARP, AH2 catalyzes the ATP-dependent rewinding of replication protein A (RPA)-bound complementary single-stranded DNA, but does not exhibit any detectable helicase activity. Unlike HARP, however, AH2 lacks a conserved RPA-binding domain and does not interact with RPA. In addition, AH2 contains an HNH motif, which is commonly found in bacteria and fungi and is often associated with nuclease activity. AH2 appears to be the only vertebrate protein with an HNH motif. Contrary to expectations, purified AH2 does not exhibit nuclease activity, but it remains possible that AH2 contains a latent nuclease that is activated under specific conditions. These structural and functional differences between AH2 and HARP suggest that different annealing helicases have distinct functions in the cell.

OBJECTIVE

We propose a novel approach for PET respiratory motion correction using tagged-MRI and simultaneous PET-MRI acquisitions.

METHODS

We use a tagged-MRI acquisition followed by motion tracking in the phase domain to estimate the nonrigid deformation of biological tissues during breathing. In order to accurately estimate motion even in the presence of noise and susceptibility artifacts, we regularize the traditional HARP tracking strategy using a quadratic roughness penalty on neighboring displacement vectors (R-HARP). We then incorporate the motion fields estimated with R-HARP in the system matrix of an MLEM PET reconstruction algorithm formulated both for sinogram and list-mode data representations. This approach allows reconstruction of all detected coincidences in a single image while modeling the effect of motion both in the emission and the attenuation maps. At present, tagged-MRI does not allow estimation of motion in the lungs and our approach is therefore limited to motion correction in soft tissues. Since it is difficult to assess the accuracy of motion correction approaches in vivo, we evaluated the proposed approach in numerical simulations of simultaneous PET-MRI acquisitions using the NCAT phantom. We also assessed its practical feasibility in PET-MRI acquisitions of a small deformable phantom that mimics the complex deformation pattern of a lung that we imaged on a combined PET-MRI brain scanner.

RESULTS

Simulations showed that the R-HARP tracking strategy accurately estimated realistic respiratory motion fields for different levels of noise in the tagged-MRI simulation. In simulations of tumors exhibiting increased uptake, contrast estimation was 20% more accurate with motion correction than without. Signal-to-noise ratio (SNR) was more than 100% greater when performing motion-corrected reconstruction which included all counts, compared to when reconstructing only coincidences detected in the first of eight gated frames. These results were confirmed in our proof-of-principle PET-MRI acquisitions, indicating that our motion correction strategy is accurate, practically feasible, and is therefore ready to be tested in vivo.

CONCLUSIONS

This work shows that PET motion correction using motion fields measured with tagged-MRI in simultaneous PET-MRI acquisitions can be made practical for clinical application and that doing so has the potential to remove motion blur in whole-body PET studies of the torso.

Surveillance of zoonotic pathogens in marine birds and mammals in the Northwest Atlantic revealed a diversity of zoonotic agents. We found amplicons to sequences from Brucella spp., Leptospira spp., Giardia spp. and Cryptosporidium spp. in both marine mammals and birds. Avian influenza was detected in a harp seal and a herring gull. Routine aerobic and anaerobic culture showed a broad range of bacteria resistant to multiple antibiotics. Of 1460 isolates, 797 were tested for resistance, and 468 were resistant to one or more anti-microbials. 73% (341/468) were resistant to 1-4 drugs and 27% (128/468) resistant to 5-13 drugs. The high prevalence of resistance suggests that many of these isolates could have been acquired from medical and agricultural sources and inter-microbial gene transfer. Combining birds and mammals, 45% (63/141) of stranded and 8% (2/26) of by-caught animals in this study exhibited histopathological and/or gross pathological findings associated with the presence of these pathogens. Our findings indicate that marine mammals and birds in the Northwest Atlantic are reservoirs for potentially zoonotic pathogens, which they may transmit to beachgoers, fishermen and wildlife health personnel. Conversely, zoonotic pathogens found in marine vertebrates may have been acquired via contamination of coastal waters by sewage, run-off and agricultural and medical waste. In either case these animals are not limited by political boundaries and are therefore important indicators of regional and global ocean health.

BACKGROUND

Hospitalization is the first cause of functional decline in the elderly: 30 to 60% of elderly patients lose some independence in basic activities of daily living (ADL) during a stay in hospital. This loss of independence results from the acute condition that led to admission, but is also related to the mode of management.

OBJECTIVE

This paper is a review of the literature on functional decline in elderly hospitalized patients. It is the first stage in a project aiming to prevent dependence that is induced during the course of care.

METHODS

During a 2-day workshop in Monaco, a task force of 20 international experts discussed and defined the concept of "iatrogenic disability".

RESULTS

1- "Iatrogenic disability" was defined by the task force as the avoidable dependence which often occurs during the course of care. It involves three components that interact and have a cumulative effect: a) the patient's pre-existing frailty, b) the severity of the disorder that led to the patient's admission, and lastly c) the hospital structure and the process of care. 2- The prevention of "iatrogenic disability" involves successive stages. - becoming aware that hospitalization may induce dependence. Epidemiological studies have identified at-risk populations by the use of composite scores (HARP, ISAR, SHERPA, COMPRI, etc). - considering that functional decline is not a fatality. Quality references have already been defined. Interventions to prevent dependence in targeted populations have been set up: simple geriatric consultation teams, single-factor interventions (aimed for example at mobility, delirium, iatrogenic disorders) or multidomain interventions (such as GEM and ACE units, HELP, Fast Track, NICHE). These interventions are essentially centered on the patient's frailty and have limited results, as they take little account of the way the institution functions, which is not aimed at prevention of functional decline. The process of care reveals shortcomings: lack of geriatric knowledge, inadequate evaluation and management of functional status. The group suggests that interventions must not only identify at-risk patients so that they may benefit from specialized management, but they must also target the hospital structure and the process of care. This requires a graded "quality approach" and rethinking of the organization of the hospital around the elderly person.

Recent studies have added substantially to our knowledge of spatial and temporal trends of persistent organic pollutants and heavy metals in the Canadian Arctic marine ecosystem. This paper reviews the current state of knowledge of contaminants in marine biota in the Canadian Arctic and where possible, discusses biological effects. The geographic coverage of information on contaminants such as persistent organochlorines (OCs) (PCBs, DDT- and chlordane-related compounds, hexachlorocyclohexanes, toxaphene) and heavy metals (mercury, selenium, cadmium, lead) in tissues of marine mammal and sea birds is relatively complete. All major beluga, ringed seal and polar bear stocks along with several major sea bird colonies have been sampled and analysed for OC and heavy metal contaminants. Studies on contaminants in walrus are limited to Foxe Basin and northern Québec stocks, while migratory harp seals have only been studied recently at one location. Contaminant measurements in bearded seal, harbour seal, bowhead whale and killer whale tissues from the Canadian Arctic are very limited or non-existent. Many of the temporal trend data for contaminants in Canadian Arctic biota are confounded by changes in analytical methodology, as well as by variability due to age/size, or to dietary and population shifts. Despite this, studies of OCs in ringed seal blubber at Holman Island and in sea birds at Prince Leopold Island in Lancaster Sound show declining concentrations of PCBs and DDT-related compounds from the 1970s to 1980s then a levelling off during the 1980s and early 1990s. For other OCs, such as chlordane, HCH and toxaphene, limited data for the 1980s to early 1990s suggests few significant declines in concentrations in marine mammals or sea birds. Temporal trend studies of heavy metals in ringed seals and beluga found higher mean concentrations of mercury in more recent (1993/1994) samples than in earlier collections (1981-1984 in eastern Arctic, 1972-1973 in western Arctic) for both species. Rates of accumulation of mercury are also higher in present day animals than 10-20 years ago. Cadmium concentrations in the same animals (eastern Arctic only) showed no change over a 10-year period. No temporal trend data are available for metals in sea birds or polar bears. There have been major advances in knowledge of specific biomarkers in Canadian Arctic biota over the past few years. The species with the most significant risk of exposure to PCBs and OC pesticides may be the polar bear which, based on comparison with EROD activity in other marine mammals (beluga, ringed seal), appears to have elevated CYP1A-mediated activity. The MFO enzyme data for polar bear, beluga and seals suggest that even the relatively low levels of contaminants present in Arctic animals may not be without biological effects, especially during years of poor feeding.

Electromyographic (EMG) activity of the airway muscles suggest that genioglossus is the primary upper airway dilator muscle. However, EMG data do not necessarily translate into tissue motion and most imaging modalities are limited to assessment of the surfaces of the upper airway. In this study, we hypothesized that genioglossus moves rhythmically during the respiratory cycle and that the motion within is inhomogeneous. A 'tagged' magnetic resonance imaging technique was used to characterize respiratory-related tissue motions around the human upper airway in quiet breathing. Motion of airway tissues at different segments of the eupnoeic respiratory cycle was imaged in six adult subjects by triggering the scanner at the end of inspiration. Displacements of the 'tags' were analysed using the harmonic phase method (HARP). Respiratory timing was monitored by a band around the upper abdomen. The genioglossus moved during the respiratory cycle. During expiration, the genioglossus moved posteriorly and during inspiration, it moved anteriorly. The degree of motion varied between subjects. The maximal anteroposterior movement of a point tracked on the genioglossus was 1.02 +/- 0.54 mm (mean +/- s.d.). The genioglossus moved over the geniohyoid muscle, with minimal movement in other muscles surrounding the airway at the level of the soft palate. Local deformation of the tongue was analysed using two-dimensional strain maps. Across the respiratory cycle, positive strains within genioglossus reached peaks of 17.5 +/- 9.3% and negative strains reached peaks of -16.3 +/- 9.3% relative to end inspiration. The patterns of strains were consistent with elongation and compression within a constant volume structure. Hence, these data suggest that even during respiration, the tongue behaves as a muscular hydrostat.

In this issue of Genes & Development, four papers report that the annealing helicase HepA-related protein (HARP, also known as SMARCAL1 [SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1]) binds directly to the ssDNA-binding protein Replication protein A (RPA) and is recruited to sites of replicative stress. Knockdown of HARP results in hypersensitivity to multiple DNA-damaging agents and defects in fork stability or restart. These exciting insights reveal a key new player in the S-phase DNA damage response.

Sexual-selection theory predicts that multiple signals may reveal male condition at different stages of life, thus allowing females to make a more reliable assessment of male quality. While the effect of current condition on signal design is well established, few studies have experimentally investigated the effects of past condition. We therefore manipulated the nutritional condition of male nymph field crickets Gryllus campestris and assessed the enduring effects on multiple components of the adult calling song. Food-restricted males had longer nymphal development times and smaller adult body sizes than nymphs with ad libitum food access. Nymphal feeding conditions specifically affected the allometric relationship between body size and harp size, as food-restricted males developed comparatively small harps, leading to a calling song of higher carrier frequency than that produced by similar-sized control males. Other calling-song components, notably chirp rate and chirp intensity, were not affected by the nymphal food treatment, exposing carrier frequency as the key component indicating past condition. In a previous study we established chirp rate as the sole indicator of current condition. The combined results represent experimental evidence of a multicomponent sexual signal that provides distinct information on male condition during different stages of life.

Displacement-encoded imaging with stimulated echoes (DENSE) and harmonic phase imaging (HARP) employ 1-1 spatial modulation of magnetization to cosine modulate the longitudinal magnetization as a function of position at end diastole. Later in the cardiac cycle they sample the cosine-modulated signal and compute myocardial strain from the signal phase. The sampled signal generally includes three distinct echoes: 1) a displacement-encoded stimulated echo, 2) the complex conjugate of the displacement-encoded echo, and 3) an echo arising from T1 relaxation. If the T1-relaxation and complex conjugate echoes are suppressed, then a phase image representing just the displacement-encoded echo can be reconstructed. In the present study, the use of cosine and sine modulation to eliminate (CANSEL) the T1-relaxation and complex conjugate echoes was investigated. With the use of CANSEL, it was demonstrated that DENSE accurately measures through-plane as well as in-plane components of tissue motion. Also, DENSE with CANSEL artifact suppression can provide increased signal-to-noise ratio (SNR) secondary to reduced intravoxel dephasing by using relatively low displacement-encoding frequencies. For applications that employ DENSE imaging with multiple acquisitions, the CANSEL technique can suppress artifact-generating echoes without placing constraints on the displacement-encoding frequency and direction.

Evolutionary selection has refined the life histories of seven species (three cetacean [narwhal, beluga, and bowhead whales], three pinniped [walrus, ringed, and bearded seals], and the polar bear) to spatial and temporal domains influenced by the seasonal extremes and variability of sea ice, temperature, and day length that define the Arctic. Recent changes in Arctic climate may challenge the adaptive capability of these species. Nine other species (five cetacean [fin, humpback, minke, gray, and killer whales] and four pinniped [harp, hooded, ribbon, and spotted seals]) seasonally occupy Arctic and subarctic habitats and may be poised to encroach into more northern latitudes and to remain there longer, thereby competing with extant Arctic species. A synthesis of the impacts of climate change on all these species hinges on sea ice, in its role as: (1) platform, (2) marine ecosystem foundation, and (3) barrier to non-ice-adapted marine mammals and human commercial activities. Therefore, impacts are categorized for: (1) ice-obligate species that rely on sea ice platforms, (2) ice-associated species that are adapted to sea ice-dominated ecosystems, and (3) seasonally migrant species for which sea ice can act as a barrier. An assessment of resilience is far more speculative, as any number of scenarios can be envisioned, most of them involving potential trophic cascades and anticipated human perturbations. Here we provide resilience scenarios for the three ice-related species categories relative to four regions defined by projections of sea ice reductions by 2050 and extant shelf oceanography. These resilience scenarios suggest that: (1) some populations of ice-obligate marine mammals will survive in two regions with sea ice refugia, while other stocks may adapt to ice-free coastal habitats, (2) ice-associated species may find suitable feeding opportunities within the two regions with sea ice refugia and, if capable of shifting among available prey, may benefit from extended foraging periods in formerly ice-covered seas, but (3) they may face increasing competition from seasonally migrant species, which will likely infiltrate Arctic habitats. The means to track and assess Arctic ecosystem change using sentinel marine mammal species are suggested to offer a framework for scientific investigation and responsible resource management.

Associative learning induces plasticity in the representation of sensory information in sensory cortices. Such high-order associative representational plasticity (HARP) in the primary auditory cortex (A1) is a likely substrate of auditory memory: it is specific, rapidly acquired, long-lasting and consolidates. Because HARP is likely to support the detailed content of memory, it is important to identify the necessary behavioral factors that dictate its induction. Learning strategy is a critical factor for the induction of plasticity (Bieszczad & Weinberger, 2010b). Specifically, use of a strategy that relies on tone onsets induces HARP in A1 in the form of signal-specific decreased threshold and bandwidth. The present study tested the hypothesis that the form and degree of HARP in A1 reflects the amount of use of an "onset strategy". Adult male rats (n=7) were trained in a protocol that increased the use of this strategy from approximately 20% in prior studies to approximately 80%. They developed signal-specific gains in representational area, transcending plasticity in the form of local changes in threshold and bandwidth. Furthermore, the degree of area gain was proportional to the amount of use of the onset strategy. A second complementary experiment demonstrated that use of a learning strategy that specifically did not rely on tone onsets did not produce gains in representational area; but rather produced area loss. Together, the findings indicate that the amount of strategy use is a dominant factor for the induction of learning-induced cortical plasticity along a continuum of both form and degree.

Pinnipeds rely primarily on oxygen stores in blood and muscles to support aerobic diving; therefore rapid development of body oxygen stores (TBO(2)) is crucial for pups to transition from nursing to independent foraging. Here, we investigate TBO(2) development in 45 harp (Pagophilus groenlandicus) and 46 hooded (Cystophora cristata) seals ranging in age from neonates to adult females. We found that hooded seal adults have the largest TBO(2) stores yet reported (89.5 ml kg(-1)), while harp seal adults have values more similar to other phocids (71.6 ml kg(-1)). In adults, large TBO(2) stores resulted from large blood volume (harpharp 86.0, hood 94.8 mg g(-1)). In contrast, pups of both species had significantly lower mass-specific TBO(2 )stores than adults, and stores declined rather than increased during the nursing period. This decline was due to a reduction in mass-specific blood volume and the absence of an increase in the low Mb levels (harp 21.0, hood 31.5 mg g(-1)). Comparisons with other phocid species suggests that the pattern of blood and muscle development in the pre- and post-natal periods varies with terrestrial period, and that muscle maturation rates may influence the length of the postweaning fast. However, final maturation of TBO(2) stores does not take place until after foraging begins.

BACKGROUND

Because ECG alterations caused by ischemia cannot be reliably detected in the high-field MRI environment, detection of wall motion abnormalities is often used to ensure patient safety during stress testing. However, an experienced observer is needed to detect these abnormalities. In this study, we investigate the use of fast harmonic phase (FastHARP) MRI for the quantitative, operator-independent detection of the onset of ischemia during acute coronary occlusion.

RESULTS

Eight mongrel dogs underwent an acute 2-minute closed-chest coronary artery occlusion while continuous FastHARP images were acquired. Full regional wall strain was determined every other heartbeat in a single short-axis imaging slice. After 5 minutes of reperfusion, a second 2-minute ischemic episode was induced during the acquisition of conventional cine wall-motion images. The time at which ECG alterations were observed during the first ischemic period was recorded. The time from occlusion to the detection of ischemia, based on a consensus of 2 blinded observers, was determined for MRI. No significant ischemia was present in 2 animals. In the remaining animals, the onset of ischemia was detected significantly earlier by FastHARP than by cine MRI (9.5+/-5 versus 33+/-14 seconds, P<0.01). HARP ischemia detection preceded ECG changes, on average, by 54 seconds.

CONCLUSIONS

The rapid acquisition and detection of induced ischemia with FastHARP MRI shows promise as a nonsubjective method to diagnose significant coronary lesions during MR stress testing.

The present study examined the relationships among impaired psychosocial functioning, comorbidity, and the cumulative probability of future recurrence of anxiety disorders and major depression in recovered patients. Participants were part of the Harvard/Brown Anxiety Disorders Research Program (HARP), a naturalistic, prospective, longitudinal study of anxiety disorders in psychiatric outpatients. Using proportional hazards regressions, worsening psychosocial impairment in general and in specific areas was significantly associated with an increased risk of panic disorder, generalized anxiety disorder, and major depression recurring, even after controlling for diagnostic comorbidity. These results are consistent with and extend similar findings for patients with major depression [Leon, A., Solomon, D. A., Mueller, T. I., Endicott, J., Posternak, M., Judd, L. L., et al. (1999). The range of Impaired Functioning Tool (LIFE-RIFT): a brief measure of functional impairment. Psychological Medicine, 29, 869-878; Leon, A., Solomon, D. A., Mueller, T. I., Endicott, J., Posternak, M., Judd, L. L., et al. (2000). A brief assessment of psychosocial functioning of subjects with bipolar I disorder: The LIFE-RIFT. The Journal of Nervous and Mental Disease, 188, 805-812], and suggest that increased psychosocial impairment may be a risk factor for relapse.

Magnetic resonance tagging has proven useful in the visualization and quantification of cardiac motion. Traditionally, tags are designed to have crisp geometric profiles in order to enhance both visualization and detection of tags. Recent image acquisition and analysis methods, however, have been designed to exploit sinusoidal tag profiles. This paper presents a method based on harmonic phase (HARP) concepts to synthesize tag lines that have both crisp profiles and alternative orientations from the original sinusoidal patterns. Results are demonstrated on images acquired with SPAMM, CSPAMM, and fast-HARP pulse sequences.

BACKGROUND

The aim of this study is to determine the test-retest reliability of the measurement of regional myocardial function by cardiovascular magnetic resonance (CMR) tagging using spatial modulation of magnetization.

METHODS

Twenty-five participants underwent CMR tagging twice over 12 ± 7 days. To assess the role of slice orientation on strain measurement, two healthy volunteers had a first exam, followed by image acquisition repeated with slices rotated ±15 degrees out of true short axis, followed by a second exam in the true short axis plane. To assess the role of slice location, two healthy volunteers had whole heart tagging. The harmonic phase (HARP) method was used to analyze the tagged images. Peak midwall circumferential strain (Ecc), radial strain (Err), Lambda 1, Lambda 2, and Angle α were determined in basal, mid and apical slices. LV torsion, systolic and early diastolic circumferential strain and torsion rates were also determined.

RESULTS

LV Ecc and torsion had excellent intra-, interobserver, and inter-study intra-class correlation coefficients (ICC range, 0.7 to 0.9). Err, Lambda 1, Lambda 2 and angle had excellent intra- and interobserver ICC than inter-study ICC. Angle had least inter-study reproducibility. Torsion rates had superior intra-, interobserver, and inter-study reproducibility to strain rates. The measurements of LV Ecc were comparable in all three slices with different short axis orientations (standard deviation of mean Ecc was 0.09, 0.18 and 0.16 at basal, mid and apical slices, respectively). The mean difference in LV Ecc between slices was more pronounced in most of the basal slices compared to the rest of the heart.

CONCLUSIONS

Intraobserver and interobserver reproducibility of all strain and torsion parameters was excellent. Inter-study reproducibility of CMR tagging by SPAMM varied between different parameters as described in the results above and was superior for Ecc and LV torsion. The variation in LV Ecc measurement due to altered slice orientation is negligible compared to the variation due to slice location.

BACKGROUND

This trial is registered as NCT00005487 at National Heart, Lung and Blood institute.

The avirulence gene matching the R2 gene for resistance to halo-blight disease in Phaseolus was cloned and sequenced from race 4 strain 1302A of Pseudomonas syringae pv. phaseolicola. The predicted 41-kDa AvrPphE protein is hydrophilic, has no features that indicate function, and no similarity to other protein sequences. The promoter region of avrPphE contains a "harp box" motif. The gene was expressed more strongly in minimal than in nutrient-rich media. Lower concentrations of the phytoalexin phaseollin accumulated in tissue undergoing the hypersensitive reaction (HR) determined by avrPphE than by avrPphB. Homologs of avrPphE were detected in strains representing eight races of P. s. pv. phaseolicola including those virulent on cultivars with the R2 resistance gene, and in P. s. pv. tabaci but not in P. cichorii or P. s. pvs. coronafaciens, glycinea, maculicola, pisi, or syringae. Disruption of avrPphE prevented induction of the HR but did not appear to affect basic pathogenicity. Transposon mutagenesis and DNA sequencing showed that avrPphE was linked to hrpY a hrp locus identified at the left end of the hrp gene cluster. Sequence analysis showed that the region linked to avrPphE was very similar to DNA containing hrp genes from P. s. pv. syringae including hrpJ, hrpL, and hrpK.

We have previously described the purification of a heparin binding growth factor from adult bovine brain named heparin affin regulatory peptide (HARP), which was identical to an uterus derived growth factor named pleiotrophin and to a developmentally regulated neurite promoting factor named heparin-binding growth associated molecule. However, for yet unclear reasons, the mitogenic activity of this purified polypeptide following isolation from animal tissue extracts is a subject of controversy, due to conflicting and irreproducible data when produced by recombinant DNA technologies in E. coli or insect cells. The purified protein was inactive in mitogenic assays but the natural molecule was active in assay of neurite outgrowth. In order to clarify these conflicting results and to obtain a recombinant protein free from other contaminating heparin-binding growth factors, we have cloned human cDNA encoding human HARP, engineered its expression in NIH 3T3 cells and characterised the resulting recombinant polypeptide. Purified recombinant HARP displayed mitogenic activity for capillary endothelial cells with half-maximal stimulation at approximately 1 ng/ml (55 pM) and induced angiogenesis in an in vitro model. Interestingly, while the NH2 terminal sequence of tissue purified HARP was NH2-GKKEKPEKK, the NH2 terminal sequence of the biologically active recombinant protein was NH2-AEAGKKEKPEKK, corresponding to a three amino acid extended form.

Preliminary findings from a long-term, prospective, longitudinal, naturalistic treatment study of adults with social anxiety disorder (SAD) demonstrate that this illness has a chronic course and a greater adverse impact on social functioning than do depressive symptoms or chronic medical illnesses. Comorbid anxiety, depressive, and personality disorders are common in patients with SAD. Only 35% of patients with SAD recovered after 10 years of prospective follow-up. Whereas, the relapse rate, once recovery is achieved, is 34% during this 10-year follow-up. Treatment is underutilized in patients with SAD, and a long-term treatment approach may be needed to improve the likelihood of recovery from SAD.

BACKGROUND

Evaluating the effects of decreasing low-density lipoprotein (LDL) cholesterol levels requires large randomized trials. In preparation for such a trial, we assessed the biochemical efficacy, safety, and tolerability of adding ezetimibe, 10 mg/d, to simvastatin, 20 mg/d, as initial therapy for such patients.

METHODS

Two hundred three patients (152 predialysis patients with creatinine levels>> or = 1.7 mg/dL >> or = 150 micromol/L], 18 patients on peritoneal dialysis therapy, and 33 patients on hemodialysis therapy) were randomly assigned to the administration of simvastatin, 20 mg/d, plus ezetimibe, 10 mg/d; or simvastatin, 20 mg, plus placebo ezetimibe daily.

RESULTS

After 6 months, allocation to simvastatin monotherapy was associated with a 31-mg/dL (0.8-mmol/L) decrease in nonfasting LDL cholesterol levels compared with baseline. Allocation to simvastatin plus ezetimibe produced an additional 18-mg/dL (0.47-mmol/L) decrease in LDL cholesterol level, representing an incremental 21% reduction over that achieved with simvastatin monotherapy (P < 0.0001). There were no statistically significant effects of the addition of ezetimibe to simvastatin on triglyceride or high-density lipoprotein cholesterol levels. Ezetimibe was not associated with an excess risk of abnormal liver function test results or of elevated creatine kinase levels and did not impair absorption of fat-soluble vitamins. There were no serious adverse events caused by study treatment.

CONCLUSIONS

This 6-month study shows that the addition of ezetimibe to simvastatin, 20 mg/d, as initial therapy for patients with chronic kidney disease was well tolerated and produced an additional 21% decrease in LDL cholesterol levels. The clinical efficacy and safety of combination therapy in this population are now being assessed in a large randomized trial.

Lipid-lowering therapy ameliorates coronary atherosclerosis in patients with raised concentrations of low-density-lipoprotein (LDL) cholesterol. We have investigated whether a similar benefit can be obtained in normocholesterolaemic patients. We studied 79 normocholesterolaemic patients with coronary heart disease (70 male, 9 female), mean age 58 years, all non-smokers, with mean total cholesterol concentration 5.5 mmol/L. All patients received diet therapy and were randomly assigned placebo (39) or active treatment (40) with pravastatin, nicotinic acid, cholestyramine, and gemfibrozil stepwise as needed to reach the specified goal (total cholesterol < or = 4.1 mmol/L, ratio of LDL/high-density-lipoprotein [HDL] cholesterol < or = 2.0). Coronary angiograms at baseline and after 2.5 years of treatment were analysed by computer-assisted quantitative techniques. There was no significant difference in coronary atherosclerosis during follow-up between the active treatment and placebo groups; the mean minimum diameter narrowed significantly but to the same extent in both groups (change baseline to 2.5 years 0.14 [SD 0.42] and 0.15 [0.42] mm, respectively, both p < 0.001). Similarly, the change in percentage stenosis did not differ between the groups (2.1 [10.6] vs 2.4 [10.3]%). By multiple regression analysis, the adjusted difference between the groups was a 0.04 mm (95% CI -0.04 to 0.12 mm) increase in minimum diameter and a 0% (-1.7 to 1.7) change in percentage stenosis. The groups differed significantly in plasma lipids (% change in active minus % change in placebo group: -28% total cholesterol, -41% LDL-cholesterol, 13% HDL-cholesterol, -26% triglycerides, -31% apolipoprotein B, all p < 0.001). Thus, intensive pharmacological treatment of normocholesterolaemic patients has significant effects on plasma lipid concentrations but no angiographically measurable benefit on the coronary arteries.

The objective of this study was to validate a deformable image registration technique, termed Hyperelastic Warping, for left ventricular strain measurement during systole using cine-gated, non-tagged MR images with strains measured from tagged MRI. The technique combines deformation from high resolution, non-tagged MR image data with a detailed computational model, including estimated myocardial material properties, fiber direction, and active fiber contraction, to provide a comprehensive description of myocardial contractile function. A normal volunteer (male, age 30) with no history of cardiac pathology was imaged with a 1.5 T Siemens Avanto clinical scanner using a TrueFISP imaging sequence and a 32-channel cardiac coil. Both tagged and non-tagged cine MR images were obtained. The Hyperelastic Warping solution was evolved using a series of non-tagged images in ten intermediate phases from end-diastole to end-systole. The solution may be considered as ten separate warping problems with multiple templates and targets. At each stage, an active contraction was initially applied to a finite element model, and then image-based warping penalty forces were utilized to generate the final registration. Warping results for circumferential strain (R(2)=0.75) and radial strain (R(2)=0.78) were strongly correlated with results obtained from tagged MR images analyzed with a Harmonic Phase (HARP) algorithm. Results for fiber stretch, LV twist, and transmural strain distributions were in good agreement with experimental values in the literature. In conclusion, Hyperelastic Warping provides a unique alternative for quantifying regional LV deformation during systole without the need for tags.

The harmonic phase (HARP) method provides automatic and rapid analysis of tagged magnetic resonance (MR) images for quantification and visualization of myocardial strain. In this article, the development and implementation of a pulse sequence that acquires HARP images in real time are described. In this pulse sequence, a CINE sequence of images with 1-1 spatial modulation of magnetization (SPAMM) tags are acquired during each cardiac cycle, alternating between vertical and horizontal tags in successive heartbeats. An incrementing train of imaging RF flip angles is used to compensate for the decay of the harmonic peaks due to both T(1) relaxation and the applied imaging pulses. The magnitude images displaying coarse anatomy are automatically reconstructed and displayed in real time after each heartbeat. HARP strain images are generated offline at a rate of four images per second; real-time processing should be possible with faster algorithms or computers. A comparison of myocardial contractility in non-breath-hold and breath-hold experiments in normal humans is presented.