The purpose of this study was to assess the feasibility of cardiac magnetic resonance (MR) tagging in rats on a standard clinical 1.5T MR system. Small animal models have been largely used as an experimental model in cardiovascular disease studies but mainly on high field systems (>4T) dedicated to research. Given the larger availability of routine clinical MR systems in centers with active cardiac research programs, it is of great interest to perform small animal imaging on whole-body MR systems of moderate field strength. The feasibility study was performed on 7 rats within 6 to 8 hours after myocardial infarction and 3 normal control rats. Myocardial strain was measured successfully in normal rats using the harmonic phase (ie, HARP) method, and a transmural gradient was demonstrated. In a rat model of acute occlusion/reperfusion, the myocardial circumferential strains were decreased, but the transmural strain gradient was preserved. This study demonstrated the feasibility of cardiac MR tagging in rats with a subendocardial resolution using a clinical 1.5T system.

BACKGROUND

Left ventricular strain may be a more sensitive marker of left ventricular dysfunction than ejection fraction in pediatric cancer survivors after anthracycline therapy, but there is limited validation of strain measurement by feature tracking on cardiovascular magnetic resonance (MR) images.

OBJECTIVE

To compare left ventricular circumferential and radial strain by feature tracking vs. harmonic phase imaging analysis (HARP) in pediatric cancer survivors.

METHODS

Twenty-six patients (20.2 ± 5.6 years old) underwent cardiovascular MR at least 5 years after completing anthracycline therapy. Circumferential and radial strain were measured at the base, midventricle and apex from short-axis myocardial tagged images by HARP, and from steady-state free precession images by feature tracking.

RESULTS

Left ventricular ejection fraction more closely correlated with global circumferential strain by feature tracking (r = -0.63, P = 0.0005) than by HARP (r = -0.39, P = 0.05). Midventricular circumferential strain did not significantly differ by feature tracking or HARP (-20.8 ± 3.4 vs. -19.5 ± 2.5, P = 0.07), with acceptable limits of agreement. Midventricular circumferential strain by feature tracking strongly correlated with global circumferential strain by feature tracking (r = 0.87, P < 0.0001). Radial strain by feature tracking had poor agreement with HARP, particularly at higher values of radial strain. Intraobserver and interobserver reproducibility was excellent for feature tracking circumferential strain, but reproducibility was poor for feature tracking radial strain.

CONCLUSIONS

Midventricular circumferential strain by feature tracking is a reliable and reproducible measure of myocardial deformation in patients status post anthracycline therapy, while radial strain measurements are unreliable. Further studies are necessary to evaluate potential relation to long-term outcomes.

The subalar-tegminal resonance/auditory feedback hypothesis attempts to explain how crickets control the carrier frequency (f(C)), the loudness and the spectral purity of their calls. This model contrasts with the 'clockwork cricket' or escapement model by proposing that f(C) is not controlled by the resonance of the cricket's radiators (the harps) but is instead controlled neurally. It suggests that crickets are capable of driving their harps to vibrate at any frequency and that they use a tunable Helmholtz-like resonator consisting of the tegmina and the air within the subalar space to amplify and filter the f(C). This model predicts that f(C) is variable, that call loudness is related to tegminal position (and subalar volume) and that low-density gases should cause f(C) to increase. In Anurogryllus arboreus, f(C) is not constant and varied by as much as 0.8 % between pulses. Within each sound pulse, the average f(C) typically decreased from the first to the last third of a sound pulse by 9 %. When crickets called in a mixture of heliox and air, f(C) increased 1.07- to 1.14-fold above the value in air. However, if the subalar space were part of a Helmholtz-like resonator, then its resonant frequency should have increased by 40-50 %. Moreover, similar increases occurred in species that lack a subalar space (oecanthines). Experimental reduction of the subalar volume of singing crickets resulted neither in a change in f(C) nor in a change in loudness. Nor did crickets attempt to restore the subalar volume to its original value. These results disprove the presence of a subalar-tegminal resonator. The free resonance of freshly excised Gryllus rubens tegmina shifted by 1.09-fold when moved between air and a mixture of helium and air. Auditory feedback cannot be the cause of this shift, which is similar to the f(C) shifts in intact individuals of other species. Calculations show that the harp is 3.9-1.8 times more massive than the air that moves en masse with the vibrating harps. Replacing air with heliox-air lowers the mass of the vibrating system sufficiently to account for the f(C) shifts. These results re-affirm the 'clockwork cricket' (escapement) hypothesis. However, as realized by others, the harps should be viewed as narrow-band variable-frequency oscillators whose tuning may be controlled by factors that vary the effective mass.

Measurement of myocardial strain provides direct information about heart function that can be correlated with disease. We present an MRI pulse sequence that acquires in just six heartbeats both harmonic phase (HARP) and strain-encoded (SENC) images and provides dense measurements of radial, circumferential and longitudinal strains within a single short-axis slice. Normal volunteer data confirm the feasibility of this pulse sequence, and acquired data demonstrate the strain measurement reliability.

In this paper we introduce an improved harmonic phase (HARP) analysis for complementary spatial modulation of magnetization (CSPAMM) tagging of the mouse left ventricular wall, which enables the determination of regional displacement fields with the same resolution as the corresponding CINE anatomical images. CINE MRI was used to measure global function, such as the ejection fraction. The method was tested on two healthy mouse hearts and two mouse hearts with a myocardial infarction, which was induced by a ligation of the left anterior descending coronary artery. We show that the regional displacement fields can be determined. The mean circumferential strain for the left ventricular wall of one of the healthy mice was -0.09 +/- 0.04 (mean +/- standard deviation), while for one of the infarcted mouse hearts strains of -0.02 +/- 0.02 and -0.10 +/- 0.03 were found in the infarcted and remote regions, respectively.

A positive relationship between genetic diversity at neutral markers and juvenile survival has been demonstrated for many vertebrate populations, although the correlation is typically weak and the explanation for it remains controversial. We assessed variation at 9-12 microsatellite loci in 65 juvenile harp seals (Phoca groenlandica) that stranded in poor condition around Long Island, NY, from 2001 to 2004. Compared with seals that died, surviving individuals had slightly higher measures of mean d(2), which reflects the size difference between alleles within an individual and provides an index of outbreeding. In contrast, there were no significant differences between survivors and nonsurvivors in heterozygosity or estimates of internal relatedness. This pattern is attributed to the fact that these microsatellite markers were exceptionally variable in this species (9-22 alleles per locus), and all individuals were heterozygous at most loci. Under these circumstances, mean d(2) may provide a powerful measure for assessing diversity-fitness correlations.

BACKGROUND

Acute lung injury (ALI) is a common devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure. There are in vitro, animal studies and pre-clinical data suggesting that statins may be beneficial in ALI. The Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial is a multicenter, prospective, randomized, allocation concealed, double-blind, placebo-controlled clinical trial which aims to test the hypothesis that treatment with simvastatin will improve clinical outcomes in patients with ALI.

METHODS

Patients fulfilling the American-European Consensus Conference Definition of ALI will be randomized in a 1:1 ratio to receive enteral simvastatin 80 mg or placebo once daily for a maximum of 28 days. Allocation to randomized groups will be stratified with respect to hospital of recruitment and vasopressor requirement. Data will be recorded by participating ICUs until hospital discharge, and surviving patients will be followed up by post at 3, 6 and 12 months post randomization. The primary outcome is number of ventilator-free days to day 28. Secondary outcomes are: change in oxygenation index and sequential organ failure assessment score up to day 28, number of non pulmonary organ failure free days to day 28, critical care unit mortality; hospital mortality; 28 day post randomization mortality and 12 month post randomization mortality; health related quality of life at discharge, 3, 6 and 12 months post randomization; length of critical care unit and hospital stay; health service use up to 12 months post-randomization; and safety. A total of 540 patients will be recruited from approximately 35 ICUs in the UK and Ireland. An economic evaluation will be conducted alongside the trial. Plasma and urine samples will be taken up to day 28 to investigate potential mechanisms by which simvastatin might act to improve clinical outcomes.

BACKGROUND

Current Controlled Trials ISRCTN88244364.

The purpose of the study was to examine the association of personality disorders, history of trauma, and posttraumatic stress disorder (PTSD) in a large sample of subjects with anxiety disorders. Categorical and continuous indices of personality disorders were compared in three groups from the Harvard/Brown Anxiety Disorders Research Project (HARP): subjects with no history of trauma (n = 403), subjects with a history of trauma but no history of PTSD (n = 151), and subjects with a current or past diagnosis of PTSD (n = 68). Subjects with PTSD were more likely to meet criteria for borderline or self-defeating personality disorder than subjects in the other two groups. PTSD subjects also had higher scores on the continuous measures (total number of criteria met) for borderline and self-defeating personality disorder than the other two groups. The findings suggest that a diagnosis of PTSD rather than a history of trauma is associated with borderline and self-defeating personality disorder features. Alternative conceptualizations of axis II features in individuals with PTSD are discussed.

OBJECTIVE

The feasibility of a practical solid-state technology for low photon flux imaging applications was investigated. The technology is based on an amorphous selenium photoreceptor with a voltage-controlled avalanche multiplication gain. If this photoreceptor can provide sufficient internal gain, it will be useful for an extensive range of diagnostic imaging systems.

METHODS

The avalanche photoreceptor under investigation is referred to as HARP-DRL. This is a novel concept in which a high-gain avalanche rushing photoconductor (HARP) is integrated with a distributed resistance layer (DRL) and sandwiched between two electrodes. The avalanche gain and leakage current characteristics of this photoreceptor were measured.

RESULTS

HARP-DRL has been found to sustain very high electric field strengths without electrical breakdown. It has shown avalanche multiplication gains as high as 10(4) and a very low leakage current (< or = 20 pA/mm2).

CONCLUSIONS

This is the first experimental demonstration of a solid-state amorphous photoreceptor which provides sufficient internal avalanche gain for photon counting and photon starved imaging applications.

OBJECTIVE

To estimate the risk of functional decline after discharge for older people presenting to, and discharged from, a large emergency department (ED) of a tertiary hospital.

METHODS

The cohort was generated by consecutive sampling of non-Indigenous males and females aged 65 years or over or Aboriginal and Torres Strait Islander males and females aged 45 years or more, without diagnosed dementia, who were living independently in the community before presenting at ED and who were not admitted to hospital as an inpatient after presenting to ED. The hospital assessment risk profile (HARP) was administered to all eligible participants. Sociodemographic information was collected.

RESULTS

Approximately 40 patients per day over two 14-week data collection periods were potentially eligible for inclusion in the study. In total, 597 (17.6% of individuals who presented to ED) were eligible, agreed to participate and continued to be eligible on discharge from ED. Their HARP scores suggested that ~52% were at-risk of functional decline (14.1% high risk, 38.5% intermediate risk).

CONCLUSIONS

Elderly patients present to and are discharged from ED every day. The routinely administered HARP instrument scores suggested that approximately half these individuals were at-risk of functional decline in one large hospital ED. Given this instrument's moderate diagnostic accuracy, the true figure may be higher. We suggest that all over-65 year olds presenting at ED without being admitted as an inpatient should be considered for routine screening for potential downstream functional decline, and for intervention if indicated. What is known about the topic? Older individuals often present to ED in lieu of consulting a general medical practitioner, and are not admitted to a hospital bed. Patient demographics, functional and mental capacity and reasons for presentation may be flags for functional decline in the coming months. These could be used by ED staff to implement targeted assessment and intervention. What does this paper add? This paper highlights the high percentage of older individuals who, at time of ED presentation, are at-risk of downstream functional decline. What are the implications for practitioners? Older people who are discharged from ED without a hospital admission may 'slip through the net', as an ED presentation presents a limited window of opportunity for ED staff to undertake targeted assessment, and intervention, to address the potential for downstream functional decline. The busy nature of ED, resource implications and the range of presenting conditions of older people may preclude this. This research suggests a reality that a large percentage of older people who present at ED but do not require a subsequent hospital admission have the potential for functional decline after discharge. Addressing this, in terms of specific screening processes and interventions, requires a rethink of hospital and community resources, and relationships.

In diving animals, skeletal muscle adaptations to extend underwater time despite selective vasoconstriction include elevated myoglobin (Mb) concentrations, high acid buffering ability (beta) and high aerobic and anaerobic enzyme activities. However, because cardiac muscle is perfused during dives, it may rely less heavily on Mb, beta and anaerobic pathways to support contractile activity. In addition, because cardiac tissue must sustain contractile activity even before birth, it may be more physiologically mature at birth and/or develop faster than skeletal muscles. To test these hypotheses, we measured Mb levels, beta and the activities of citrate synthase (CS), beta-hydroxyacyl-CoA dehydrogenase (HOAD) and lactate dehydrogenase (LDH) in cardiac and skeletal muscle samples from 72 harp and hooded seals, ranging in age from fetuses to adults. Results indicate that in adults cardiac muscle had lower Mb levels (14.7%), beta (55.5%) and LDH activity (36.2%) but higher CS (459.6%) and HOAD (371.3%) activities (all P<0.05) than skeletal muscle. In addition, while the cardiac muscle of young seals had significantly lower [Mb] (44.7%) beta (80.7%) and LDH activity (89.5%) than adults (all P<0.05), it was relatively more mature at birth and weaning than skeletal muscle. These patterns are similar to those in terrestrial species, suggesting that seal hearts do not exhibit unique adaptations to the challenges of an aquatic existence.

The total number, size, topographic distribution, and cell density of ganglion cells were studied in retinal wholemounts of the harp seal Pagophilus groenlandicus. Ganglion cell size varied from 10 to 60 mum. A distinct group were large ganglion cells more than 30-35 mum in diameter which were similar to alpha-cells known in terrestrial mammals. The number of alpha-cells constituted 5.3-5.9% of the total ganglion cell population. The cell size distribution was bimodal, with the second mode composed of alpha-cells. The topographic distribution of ganglion cells showed a definite area of high cell density similar to area centralis of terrestrial carnivores. This area was located in the temporal retinal quadrant, 7-8 mm (16-18 degrees ) from the optic disk. In this area, the peak cell densities in two wholemounts were 2,500 and 1,650 (mean 2,075) cells/mm(2). With a posterior nodal distance of 25.5 mm (underwater), this density corresponded to 495 and 327 (mean 411) cells/deg(2). These values predict a retinal resolution of 2.7-3.3' (11.1-9.0 cycles/deg) in water and 3.6-4.4' (8.3-6.8 cycles/deg) in air. Topographic distributions of alpha-cells was qualitatively similar to that of the total ganglion cell population, but the density of alpha-cells constituted only a few percent (mostly 3-7.5%) of the total ganglion cell density.

The past decade has brought major new developments in the psychopharmacologic management of generalized anxiety disorder and social phobia. We examined medication-prescribing patterns for the treatment of these anxiety disorders for 12 years to assess changes in patients' anti-anxiety psychotropic medication usage during that period of evolving practice guidelines. We examined psychotropic medication use in 305 patients with generalized anxiety disorder and 232 with social phobia enrolled in the Harvard/Brown Anxiety Disorders Research Project (HARP), a prospective, longitudinal study of anxiety disorders. Psychotropic treatment patterns seem to have remained relatively stable over 12 years with benzodiazepines the medications most commonly used for both generalized anxiety disorder and social phobia. Comparatively, selective serotonin reuptake inhibitor (SSRI) and venlafaxine usage as stand-alone medications for these disorders remained low throughout the follow-up period. At the 12-year follow-up, 24% of patients with generalized anxiety disorder and 30% of patients with social phobia were utilizing neither an SSRI/selective norepinephrine reuptake inhibitor (SNRI) nor a benzodiazepine. Treatment recommendations for use of SSRIs and venlafaxine in the management of generalized anxiety disorder and social phobia initially promulgated in 1998 had a modest impact on changes in psychopharmacologic practice 4-5 years later. Difficulties in the implementation of treatment guidelines are discussed.

This investigation was carried out to characterize the effects of specific dietary marine oils on tissue and plasma fatty acids and their capacity to generate metabolites (prostanoids, lipid peroxides). Young male guinea pigs were fed nonpurified diet (NP), or NP supplemented (10%, w/w) with menhaden fish oil (MO), harp seal oil (SLO), or corn oil (CO, control diet) for 23 to 28 d. Only the plasma showed significant n-3 polyunsaturated fatty acid (PUFA)-induced reductions in triacylglycerol (TAG) or total cholesterol concentration. Proportions of total n-3 PUFA in organs and plasma were elevated significantly in both MO and SLO dietary groups (relative to CO), and in all TAG fractions levels were significantly higher in MO- than SLO-fed animals. The two marine oil groups differed in their patterns of incorporation of eicosapentaenoic acid (EPA). In guinea pigs fed MO, the highest levels of EPA were in the plasma TAG, whereas in SLO-fed animals, maximal incorporation of EPA was in the heart polar lipids (PL). In both marine oil groups, the greatest increases in both docosahexaenoic acid (22:6n-3, DHA) and docosapentaenoic acid (22:5n-3, DPA), relative to the CO group, were in plasma TAG, although the highest proportions of DHA and DPA were in liver PL and heart TAG, respectively. In comparing the MO and SLO groups, the greatest difference in levels of DHA was in heart TAG (MO>> SLO, P < 0.005), and in levels of DPA was in heart PL (SLO>> MO, P < 0.0001). The only significant reduction in proportions of the major n-6 PUFA, arachidonic acid (AA), was in the heart PL of the SLO group (SLO>> MO = CO, P < 0.005). Marine oil feeding altered ex vivo generation of several prostanoid metabolites of AA, significantly decreasing thromboxane A2 synthesis in homogenates of hearts and livers of guinea pigs fed MO and SLO, respectively (P < 0.04 for both, relative to CO). Lipid peroxides were elevated to similar levels in MO- and SLO-fed animals in plasma, liver, and adipose tissue, but not in heart preparations. This study has shown that guinea pigs respond to dietary marine oils with increased organ and plasma n-3 PUFA, and changes in potential synthesis of metabolites. They also appear to respond to n-3 PUFA-enriched diets in a manner that is different from that of rats.

Spectral parameters were used to discriminate between echolocation clicks produced by three dolphin species at Palmyra Atoll: melon-headed whales (Peponocephala electra), bottlenose dolphins (Tursiops truncatus) and Gray's spinner dolphins (Stenella longirostris longirostris). Single species acoustic behavior during daytime observations was recorded with a towed hydrophone array sampling at 192 and 480 kHz. Additionally, an autonomous, bottom moored High-frequency Acoustic Recording Package (HARP) collected acoustic data with a sampling rate of 200 kHz. Melon-headed whale echolocation clicks had the lowest peak and center frequencies, spinner dolphins had the highest frequencies and bottlenose dolphins were nested in between these two species. Frequency differences were significant. Temporal parameters were not well suited for classification. Feature differences were enhanced by reducing variability within a set of single clicks by calculating mean spectra for groups of clicks. Median peak frequencies of averaged clicks (group size 50) of melon-headed whales ranged between 24.4 and 29.7 kHz, of bottlenose dolphins between 26.7 and 36.7 kHz, and of spinner dolphins between 33.8 and 36.0 kHz. Discriminant function analysis showed the ability to correctly discriminate between 93% of melon-headed whales, 75% of spinner dolphins and 54% of bottlenose dolphins.

Four young harp seals (aged three to five months) were implanted with electrodes for recording electrocorticograms (ECoG) of the two hemispheres, and electrocardiogram, electroculogram, and electromyogram of the neck muscles. In all the seals ECoG slow waves developed simultaneously in both hemispheres, irrespective of whether they slept on land, on the water surface or submerged. Slow-wave sleep (SWS) was present in animals on the water surface and submerged, while paradoxical sleep (PS) occurred only when the animals were submerged. Breathing in SWS could be both regular (pauses less than twenty seconds) and intermittent (pauses lasting up to three minutes alternating with hyperventilation periods). All the PS episodes occurred during single respiratory pauses and ended by waking while the seal ascended to the water surface to breathe. Flipper movements were sometimes observed in SWS, but never in PS. The ability of harp seals to cease respiration during sleep and to sleep under water could be an adaptation to living conditons in the freezing seas.

The trunk of marine mammals is encased in a blubber layer which provides thermal insulation that can be changed by circulatory adjustments. The extremities, on the other hand, are poorly insulated but have vascular arrangements constructed for prevention or promotion of heat loss depending on the thermal state of the animal. We have studied the importance of different body parts as sites for heat dissipation and also assessed the effect of circulatory adjustments on heat transfer through blubber, by combining direct measurements of heat flux from the flippers and trunk with simultaneous recordings of temperature gradients through the blubber and metabolic rates of harp seals (Phoca groenlandica) subjected to water temperatures between 1 and 24 degrees C. We also determined the thermal conductivity of blubber samples from the same animals after death, and compared this with the insulative properties of live blubber. At the lowest water temperatures, the insulative properties of live blubber were similar to those of dead blubber, and heat loss from the flippers only accounted for 2-6% of the metabolic heat production. As heat load increased with increasing water temperatures, the fraction of heat lost from the flippers increased, to 19-48% at 24 degrees C, while the fraction lost from the trunk decreased, despite an increase in the convective (circulatory) heat transfer through the blubber layer.

We describe an example of a variant of Hallervorden-Spatz disease, characterized by hypoprebeta-lipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP syndrome), in an 18-year-old woman who presented with longstanding intellectual subnormality, night blindness, and a 2-year history of orobuccolingual dystonia causing dysarthria and dysphagia. Investigation showed acanthocytosis and hypoprebetalipoproteinemia, and electroretinograms were typical of tapetoretinal degeneration. T2-weighted MRI showed decreased signal intensity in the pallidal nuclei with central hyperintensity, constituting the "eye-of-the-tiger" sign. The patient's sister and mother have a similar lipid disorder but no retinal or neurologic disease. We also report two patients with clinical and radiologic features similar to those of the patient with HARP syndrome but who had normal lipid studies. These various combinations of components of HARP syndrome may be caused by several distinct genetic diseases or may represent variable manifestations of a contiguous gene defect.

Endoscopic techniques have contributed to early recovery and increased quality of life (QOL) of live kidney donors. However, laparoscopic donor nephrectomy (LDN) may have its limitations, and hand-assisted retroperitoneoscopic donor nephrectomy (HARP) has been introduced, mainly as a potentially safer alternative. In a randomized fashion, we explored the feasibility and potential benefits of HARP for right-sided donor nephrectomy in a referral center with longstanding expertise on the standard laparoscopic approach. Forty donors were randomly assigned to either LDN or HARP. Primary outcome was operating time, and secondary outcomes included QOL, complications, pain, morphine requirement, blood loss, warm ischemia time, and hospital stay. Follow-up time was 1 year. Skin-to-skin time did not significantly differ between both groups (162 vs. 158 min, P = 0.98). As compared to LDN, HARP resulted in a shorter warm ischemia time (2.8 vs. 3.9 min, P < 0.001) and increased blood loss (187 vs. 50 ml, P < 0.001). QOL, complication rate, pain, or hospital stay was not significantly different between the groups. Right-sided HARP is feasible but does not confer clear benefits over standard right-sided LDN yet. Further studies should explore the value of HARP in difficult cases such as the obese donor and the value of HARP for transplantation centers starting a live kidney donation program (Dutch Trial Register number: NTR3096). Nevertheless, HARP is a valuable addition to the surgical armamentarium in live donor surgery.

DNA replication occurs in a defined temporal order known as the replication-timing (RT) program. RT is regulated during development in discrete chromosomal units, coordinated with transcriptional activity and 3D genome organization. Here, we derived distinct cell types from F1 hybrid musculus × castaneus mouse crosses and exploited the high single-nucleotide polymorphism (SNP) density to characterize allelic differences in RT (Repli-seq), genome organization (Hi-C and promoter-capture Hi-C), gene expression (total nuclear RNA-seq), and chromatin accessibility (ATAC-seq). We also present HARP, a new computational tool for sorting SNPs in phased genomes to efficiently measure allele-specific genome-wide data. Analysis of six different hybrid mESC clones with different genomes (C57BL/6, 129/sv, and CAST/Ei), parental configurations, and gender revealed significant RT asynchrony between alleles across ∼12% of the autosomal genome linked to subspecies genomes but not to parental origin, growth conditions, or gender. RT asynchrony in mESCs strongly correlated with changes in Hi-C compartments between alleles but not as strongly with SNP density, gene expression, imprinting, or chromatin accessibility. We then tracked mESC RT asynchronous regions during development by analyzing differentiated cell types, including extraembryonic endoderm stem (XEN) cells, four male and female primary mouse embryonic fibroblasts (MEFs), and neural precursor cells (NPCs) differentiated in vitro from mESCs with opposite parental configurations. We found that RT asynchrony and allelic discordance in Hi-C compartments seen in mESCs were largely lost in all differentiated cell types, accompanied by novel sites of allelic asynchrony at a considerably smaller proportion of the genome, suggesting that genome organization of homologs converges to similar folding patterns during cell fate commitment.

The purpose of this investigation was to determine whether diets supplemented with oils from three different marine sources, all of which contain high proportions of long-chain n-3 polyunsaturated fatty acids (PUFA), result in qualitatively distinct lipid and fatty acid profiles in guinea pig heart. Albino guinea pigs (14 days old) were fed standard, nonpurified guinea pig diets (NP) or NP supplemented with menhaden fish oil (MO), harp seal oil (SLO) or porbeagle shark liver oil (PLO) (10%, w/w) for 4-5 weeks. An n-6 PUFA control group was fed NP supplemented with corn oil (CO). All animals appeared healthy, with weight gains marginally lower in animals fed the marine oils. Comparison of relative organ weights indicated that only the livers responded to the diets, and that they were heavier only in the marine-oil fed guinea pigs. Heart total cholesterol levels were unaffected by supplementing NP with any of the oils, whereas all increased the triacylglycerol (TAG) content. The fatty-acid profiles of total phospholipid (TPL), TAG and free fatty acid (FFA) fractions of heart lipids showed that feeding n-3 PUFA significantly altered the proportions of specific fatty-acid classes. For example, all marine-oil-rich diets were associated with increases in total monounsaturated fatty acids in TPL (p < 0.05), and with decreases in total saturates in TAG (p < 0.05). Predictably, the n-3 PUFA enriched regimens significantly increased the cardiac content of n-3 PUFA and decreased that of n-6 PUFA, although the extent varied among the diets. As a result, n-6/n-3 ratios were significantly lower in all myocardial lipid classes of marine-oil-fed guinea pigs. Analyses of the profiles of individual PUFA indicated that quantitatively, the fatty acids of the three marine oils were metabolized and/or incorporated into TPL, TAG and FFA in a diet-specific manner. In animals fed MO-enriched diets in which eicosapentaenoic acid (EPA)>> docosahexacnoic acid (DHA), ratios of DHA/EPA in the hearts were 1.2, 2.2 and 1.5 in TPL, TAG and FFA, respectively. In SLO-fed guinea pigs in which dietary EPA approximately DHA, ratios of DHA/EPA were 0.9, 3.4 and 2.1 in TPL, TAG and FFA, respectively. Feeding NP + PLO (DHA/EPA = 4.8), resulted in values for DHA/EPA in cardiac tissue of 2.1, 10.6 and 2.9 in TPL, TAG and FFA, respectively. In the TAG and FFA, proportions of n-3 docosapentaenoic acid (n-3 DPA) were equal to or higher than EPA in the SLO- and PLO-fed animals. The latter group exhibited the greatest difference between the DHA/n-3 DPA ratio in the diet and in cardiac TAG and FFA fractions (7, 3.4 and 3.1, respectively). Quantitative analysis indicated that>> or = 85% of the n-3 PUFA were in TPL, 7-11% were in TAG, and 2-6% were FFA. Specific patterns of distribution of EPA, DPA and DHA depended on the dietary oil. Both the qualitative and quantitative results of this study demonstrated that in guinea pigs, n-3 PUFA in different marine oils are metabolized and/or incorporated into cardiac lipids in distinct manners. In support of the concept that the diet-induced alterations reflect changes specifically in cardiomyocytes, we observed that direct supplementation of cultured guinea pig myocytes for 2-3 weeks with EPA or DHA produced changes in the PUFA profiles of their TPL that were qualitatively similar to those observed in tissue from the dietary study. The factors that regulate specific deposition of n-3 PUFA from either dietary oils or individual PUFA are not yet known, however the differences that we observed could in some manner be related to cardiac function and thus their relative potentials as health-promoting dietary fats.

Angiographic trials of coronary atherosclerosis treatment have demonstrated that lowering low density lipoprotein (LDL) cholesterol concentrations improves coronary artery stenosis. Most patients in previous trials have had at least mildly elevated LDL. Recently, however, the Harvard Atherosclerosis Reversibility Project (HARP) did not find such benefit in patients with lower baseline LDL levels compared with previous trials. We reviewed and analyzed all cholesterol-lowering trials that used angiographic endpoints. Unifactorial trials of hypocholesterolemic dietary or drug therapy demonstrated that the higher the baseline LDL, the greater the improvement in quantitatively determined stenosis in the treatment group compared with the controls (r = .83). Considering the change in stenosis in the treatment group alone, regression was more common in trials in which baseline mean LDL was>> 170 mg/dl >> 4.4 mmol/liter), whereas progression occurred when baseline mean LDL was < 170 mg/dl (< 4.4 mmol/liter). HARP had the lowest baseline LDL (137 mg/dl [3.54 mmol/liter]), and showed no tendency for improvement in lesions. In contrast to the influence of baseline LDL levels, neither a low LDL level achieved on treatment nor a large percentage reduction in LDL was related to improvement in lesions. Sample size differences between HARP and the other trials are unlikely to be a major explanatory factor, since trials of comparable sample size to HARP, but with higher initial LDL, demonstrated favorable results. We conclude that coronary lesions that develop in the context of average LDL levels show less angiographic improvement in response to substantial LDL reduction than lesions in hypercholesterolemic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

We isolated and cultivated 31 strains of free-living heterolobosean flagellates and amoebae from freshwater, brackish, and marine sediments with low concentrations of oxygen. Phylogenetic analysis of small subunit (SSU) rDNA showed that the strains constitute a single clade, the Psalteriomonadidae. According to combined light-microscopic morphology plus molecular phylogeny, our isolates belong to seven species and five genera, from which three species and two genera are new. In addition, previously described anaerobic species Percolomonas descissus and Vahlkampfia anaerobica are transferred to the Psalteriomonadidae. We identified a flagellate stage of Monopylocystis visvesvarai which was reported to produce only amoebae. Two environmental sequences previously obtained from acidic environments belong to the Psalteriomonadidae as well, suggesting a broad ecological importance of the Psalteriomonadidae. The ultrastructure of two psalteriomonadid species was also studied. Unifying features of the Psalteriomonadidae are acristate mitochondrial derivates, flagellates with a ventral groove and four flagella, and a harp-like structure in the mastigont. A new overall classification of the Psalteriomonadidae is proposed. Our data show that the Psalteriomonadidae are much more diverse than previously thought and constitute the main anaerobic lineage within the Heterolobosea.