The relationship between myocardial microstructure and strain in chronic infarction using cardiovascular magnetic resonance diffusion tensor imaging and feature tracking.

BACKGROUND: Cardiac diffusion tensor imaging (cDTI) using cardiovascular magnetic resonance (CMR) is a novel technique for the non-invasive assessment of myocardial microstructure. Previous studies have shown myocardial infarction to result in loss of sheetlet angularity, derived by reduced secondary eigenvector (E2A) and reduction in subendocardial cardiomyocytes, evidenced by loss of myocytes with right-handed orientation (RHM) on helix angle (HA) maps. Myocardial strain assessed using feature tracking-CMR (FT-CMR) is a sensitive marker of sub-clinical myocardial dysfunction. We sought to explore the relationship between these two techniques (strain and cDTI) in patients at 3 months following ST-elevation MI (STEMI). METHODS: 32 patients (F = 28, 60 ± 10 years) underwent 3T CMR three months after STEMI (mean interval 105 ± 17 days) with second order motion compensated (M2), free-breathing spin echo cDTI, cine gradient echo and late gadolinium enhancement (LGE) imaging. HA maps divided into left-handed HA (LHM, - 90 < HA < - 30), circumferential HA (CM, - 30° < HA < 30°), and right-handed HA (RHM, 30° < HA < 90°) were reported as relative proportions. Global and segmental analysis was undertaken. RESULTS: Mean left ventricular ejection fraction (LVEF) was 44 ± 10% with a mean infarct size of 18 ± 12 g and a mean infarct segment LGE enhancement of 66 ± 21%. Mean global radial strain was 19 ± 6, mean global circumferential strain was - 13 ± - 3 and mean global longitudinal strain was - 10 ± - 3. Global and segmental radial strain correlated significantly with E2A in infarcted segments (p = 0.002, p = 0.011). Both global and segmental longitudinal strain correlated with RHM of infarcted segments on HA maps (p < 0.001, p = 0.003). Mean Diffusivity (MD) correlated significantly with the global infarct size (p < 0.008). When patients were categorised according to LVEF (reduced, mid-range and preserved), all cDTI parameters differed significantly between the three groups. CONCLUSION: Change in sheetlet orientation assessed using E2A from cDTI correlates with impaired radial strain. Segments with fewer subendocardial cardiomyocytes, evidenced by a lower proportion of myocytes with right-handed orientation on HA maps, show impaired longitudinal strain. Infarct segment enhancement correlates significantly with E2A and RHM. Our data has demonstrated a link between myocardial microstructure and contractility following myocardial infarction, suggesting a potential role for CMR cDTI to clinically relevant functional impact.

Review of Journal of Cardiovascular Magnetic Resonance 2015.

There were 116 articles published in the Journal of Cardiovascular Magnetic Resonance (JCMR) in 2015, which is a 14 % increase on the 102 articles published in 2014. The quality of the submissions continues to increase. The 2015 JCMR Impact Factor (which is published in June 2016) rose to 5.75 from 4.72 for 2014 (as published in June 2015), which is the highest impact factor ever recorded for JCMR. The 2015 impact factor means that the JCMR papers that were published in 2013 and 2014 were cited on average 5.75 times in 2015. The impact factor undergoes natural variation according to citation rates of papers in the 2 years following publication, and is significantly influenced by highly cited papers such as official reports. However, the progress of the journal's impact over the last 5 years has been impressive. Our acceptance rate is <25 % and has been falling because the number of articles being submitted has been increasing. In accordance with Open-Access publishing, the JCMR articles go on-line as they are accepted with no collating of the articles into sections or special thematic issues. For this reason, the Editors have felt that it is useful once per calendar year to summarize the papers for the readership into broad areas of interest or theme, so that areas of interest can be reviewed in a single article in relation to each other and other recent JCMR articles. The papers are presented in broad themes and set in context with related literature and previously published JCMR papers to guide continuity of thought in the journal. We hope that you find the open-access system increases wider reading and citation of your papers, and that you will continue to send your quality papers to JCMR for publication.

Mouse embryonic phenotyping by morphometric analysis of MR images.

A new method is described for automatic detection of subtle morphological phenotypes in mouse embryos. Based on high-resolution magnetic resonance imaging scanning and nonlinear image alignment, this method is demonstrated by comparing the morphology of two inbred strains, C57BL/6J and 129Sv/S1ImJ, at 15.5 days postconception. Mouse embryo morphology was found to be highly amenable to this kind of analysis with very low levels (on average 110 µm) of residual anatomical variation within strains after linear differences in pose and scale are removed. Mapping of local size differences showed that C57BL/6J embryos were larger than 129Sv/S1ImJ embryos, although these differences were not uniformly distributed across the anatomy. Expressed in terms of organ volumes, heart and lung were larger in C57BL/6J embryos, while brain and liver were comparable in volume between strains. The positive relationship between organ size and embryo size was consistent for the two strains but differed by organ, with the brain and liver being the least variable. Together these findings suggest the power of this technique for detecting subtle phenotypic differences arising from mutated genes.

Availability of metabolic fuels controls estrous cyclicity of Syrian hamsters.

Food deprivation and weight loss inhibit ovulation and estrous behavior in Syrian hamsters. In the present experiments, lean hamsters were more susceptible to starvation-induced anestrus than fat hamsters. However, anestrus was not caused by changes in any dimension of body size per se, but instead by the availability of metabolic fuels. Simultaneous pharmacological blockade of both fatty acid oxidation and glycolysis inhibited reproduction, but, as long as one of these metabolic pathways could be used, estrous cycles continued. Thus, reproduction in female Syrian hamsters is sensitive to the general availability of oxidizable metabolic fuels.

Changes in insulin, glucose and ketone bodies, but not leptin or body fat content precede restoration of luteinising hormone secretion in ewes.

The reproductive system, including pulsatile luteinising hormone (LH) secretion, is inhibited by deficits in energy availability and restored by energy surfeits. Plasma LH, insulin, leptin, ghrelin, glucose, ketone body, and nonesterified fatty acid concentrations were measured in ovariectomised, food-restricted ewes before and after return to ad libitum feeding to determine the factors that change in time to account for the restoration of pulsatile LH secretion. At 07.00 h, blood was sampled every 10 min for 5 h from ovariectomised, hypogonadotrophic, chronically food-restricted and ad libitum-fed ewes (Fed). At 12.00 h, four of the food-restricted sheep were given ad libitum access to food (Re-Fed), while three ewes continued to be food restricted (Restricted). Sampling continued for 5 h and resumed again on the mornings of days 2, 4, and 9. A pulse of LH was seen within 1 h of re-feeding in all Re-Fed ewes, and interpulse interval (IPI) was significantly shorter in Re-Fed compared to Restricted ewes and longer than in Fed ewes during the period after re-feeding. Re-Fed LH IPI was not restored to that of Fed ewes until sometime between days 4 and 9. The first pulse occurred within minutes, whereas restoration of IPI occurred after 4-8 days. Prior to the initial LH pulses seen in Re-Fed ewes, plasma ketone bodies first fell and then rose to levels significantly above those in Restricted ewes. Significant changes in circulating insulin, ghrelin, glucose, and total ketone body concentrations, daily food intake and lean body mass preceded restoration of Re-Fed LH IPI some time between days 4 and 9, but there were no significant changes in adiposity or circulating leptin concentrations, consistent with the hypothesis that LH pulses are reinitiated by changes in the availability of oxidisable metabolic fuels and possibly insulin, but not leptin concentrations.

ASPP2 deficiency causes features of 1q41q42 microdeletion syndrome.

Chromosomal abnormalities are implicated in a substantial number of human developmental syndromes, but for many such disorders little is known about the causative genes. The recently described 1q41q42 microdeletion syndrome is characterized by characteristic dysmorphic features, intellectual disability and brain morphological abnormalities, but the precise genetic basis for these abnormalities remains unknown. Here, our detailed analysis of the genetic abnormalities of 1q41q42 microdeletion cases identified TP53BP2, which encodes apoptosis-stimulating protein of p53 2 (ASPP2), as a candidate gene for brain abnormalities. Consistent with this, Trp53bp2-deficient mice show dilation of lateral ventricles resembling the phenotype of 1q41q42 microdeletion patients. Trp53bp2 deficiency causes 100% neonatal lethality in the C57BL/6 background associated with a high incidence of neural tube defects and a range of developmental abnormalities such as congenital heart defects, coloboma, microphthalmia, urogenital and craniofacial abnormalities. Interestingly, abnormalities show a high degree of overlap with 1q41q42 microdeletion-associated abnormalities. These findings identify TP53BP2 as a strong candidate causative gene for central nervous system (CNS) defects in 1q41q42 microdeletion syndrome, and open new avenues for investigation of the mechanisms underlying CNS abnormalities.

Stenting in acute coronary syndromes: a comparison of radial versus femoral access sites.

OBJECTIVES: The purpose of the present study was to compare the radial approach with the femoral approach for coronary stenting in patients with acute coronary syndromes. BACKGROUND: Aggressive anticoagulation in patients with acute coronary syndromes increases the risk of femoral vascular complications. The transradial approach has the potential to significantly reduce the incidence of access site bleeding complications in this group of patients. METHODS: One hundred forty-two patients with acute coronary syndromes undergoing coronary stenting were prospectively randomized to have their procedure performed from either the radial or femoral access site and the results compared. RESULTS: Nine of 74 patients randomized to the radial group crossed over to the femoral group (6 negative Allen tests, 3 access failures). Patient demographics were the same in both groups. Primary success was identical: 96% radial, 96% femoral, ns. There were no procedural myocardial infarctions or deaths, and no patient was referred for emergency bypass surgery. There were no access site bleeding complications in the radial group as opposed to 3 (4%) in the femoral group, p < 0.01. Postprocedure length of stay, days (1.4+/-0.2 radial vs. 2.3+/-0.4 femoral, p < 0.01) as well as total hospital length of stay (3.0+/-0.3 radial vs. 4.5+/-0.5 femoral, p < 0.01) were significantly reduced in the radial group. Total hospital charge was also significantly lower in the radial group ($20,476+/-811 radial versus $23,389+/-1,180 femoral, p < 0.01). CONCLUSION: Coronary stenting from the radial approach is efficacious in patients with acute coronary syndromes. Access site bleeding complications are less, and early ambulation results in a shorter hospital length of stay. There was a 15% reduction in total hospital charge in the radial group.

Metabolic fuels and reproduction in female mammals.

A complete reproductive cycle of ovulation, conception, pregnancy, and lactation is one of the most energetically expensive activities that a female mammal can undertake. A reproductive attempt at a time when calories are not sufficiently available can result in a reduced return on the maternal energetic investment or even in the death of the mother and her offspring. Numerous physiological and behavioral mechanisms link reproduction and energy metabolism. Reproductive attempts may be interrupted or deferred when food is scarce or when other physiological processes, such as thermoregulation or fattening, make extraordinary energetic demands. Food deprivation suppresses both ovulation and estrous behavior. The neural mechanisms controlling pulsatile release of gonadotropin-releasing hormone (GnRH) and, consequently, luteinizing hormone secretion and ovarian function appear to respond to minute-to-minute changes in the availability of metabolic fuels. It is not clear whether GnRH-secreting neurons are able to detect the availability of metabolic fuels directly or whether this information is relayed from detectors elsewhere in the brain. Although pregnancy is less affected by fuel availability, both lactational performance and maternal behaviors are highly responsive to the energy supply. When a reproductive attempt is made, changes in hormone secretion have dramatic effects on the partitioning and utilization of metabolic fuels. During ovulatory cycles and pregnancy, the ovarian steroids, estradiol and progesterone, induce coordinated changes in the procurement, ingestion, metabolism, storage, and expenditure of metabolic fuels. Estradiol can act in the brain to alter regulatory behaviors, such as food intake and voluntary exercise, as well as adenohypophyseal and autonomic outputs. At the same time, ovarian hormones act on peripheral tissues such as adipose tissue, muscle, and liver to influence the metabolism, partitioning and storage of metabolic fuels. During lactation, the peptide hormones, prolactin and growth hormone, rather than estradiol and progesterone, are the principal hormones controlling partitioning and utilization of metabolic fuels. The interactions between metabolic fuels and reproduction are reciprocal, redundant, and ubiquitous; both behaviors and physiological processes play vital roles. Although there are species differences in the particular physiological and behavioral mechanisms mediating nutrition-reproduction interactions, two findings are consistent across species: 1) Reproductive physiology and behaviors are sensitive to the availability of oxidizable metabolic fuels. 2) When reproductive attempts are made, ovarian hormones play a major role in the changes in ingestion, partitioning, and utilization of metabolic fuels.

Cytotoxic effects of autoxidative glycation.

Incubation of the RNA phage Q beta at 37 degrees C with a mixture of 100 mM ribose and 10 microM CuSO4 resulted in a complete loss of viable phage after 20 min. This cytotoxic effect required both ribose and cupric ions. There was a direct correlation between the decrease in the percentage of phage survival and: (a) the length of incubation, and (b) the concentrations of both ribose and CuSO4. Addition of the strong chelator diethylenetriaminepentaacetic acid abolished the cytotoxic effect. These results are consistent with an initial production of superoxide free radicals by transition metal catalyzed autoxidation of ribose and Amadori products, followed by dismutation of superoxide to hydrogen peroxide and generation of lethal hydroxyl radicals by the Fenton reaction. RNA isolated from phage incubated with ribose and CuSO4 retained its infectivity, suggesting that the cytotoxic effect may be mediated by a free radical attack on proteinaceous components of the phage through a site specific generation of hydroxyl radicals on protein-bound transition metal ions.

Ascorbate/iron mediation of hydroxyl free radical damage to PBR322 plasmid DNA.

Plasmid PBR322 DNA has been exposed to hydroxyl free radicals generated from an ascorbate/Fe system. Hydroxyl free radical scavengers as well as the iron chelator desferroxamine and catalase inhibit the DNA nicking which occurs, but superoxide dismutase had no effect. The DNA nicking was temperature dependent, occurring more rapidly at higher temperatures. The rate of DNA nicking was accelerated by the addition of hydrogen peroxide. There was an early lag phase in DNA nicking, even though the rate of hydroxyl free radical generation, as assessed by salicylate hydroxylation, showed no lag phase. It is considered that the early hydroxyl free radical damage to DNA may be biologically very important in mutagenic and carcinogenic processes.

Mediation of 8-hydroxy-guanine formation in DNA by thiazin dyes plus light.

We have discovered that methylene blue plus light mediates the formation of 8-OHdG in DNA. Methylene blue is one of several thiazin dyes and we report here that the other thiazin dyes tested, in combination with white light, are effective in mediating 8-OHdG formation in DNA. The effectiveness of light plus the thiazin dyes in forming 8-OHdG in DNA were as follows: methylene blue greater than azure B greater than azure A greater than toluidine blue greater than thionin. Two other compounds tested; riboflavin and fuschin acid, in combination with light, caused formation of very little, if any, 8-OHdG in DNA. Thiazin dye mediated formation of 8-OHdG in DNA was not inhibited by the spin trap alpha-phenyl-t-butyl nitrone, which supports our previous observations that oxygen free radical scavengers did not inhibit methylene blue plus light mediated 8-OHdG formation in DNA. Ascorbate addition to methylene blue plus DNA, in the absence of light, was ineffective in mediating 8-OHdG formation in DNA.

Caudal brain stem plays a role in metabolic control of estrous cycles in Syrian hamsters.

In Syrian hamsters, a critical factor necessary for the occurrence of normal estrous cycles appears to be the cellular availability of oxidizable glucose. For example, estrous cycles are inhibited by food deprivation or treatment with 2-deoxy-D-glucose (2DG), a drug that inhibits cellular glucose utilization. Several lines of evidence suggest that these effects require the participation of neurons in part of the caudal brain stem, the area postrema (AP) and adjacent, reciprocally-innervated nucleus of the solitary tract (NTS). This study was designed to examine the role of the AP in 2DG-induced anestrus. Hamsters received either aspiration lesions directed at the AP or sham operations. Between 12 and 16 days after surgery, both sham-operated and lesioned hamsters showed two consecutive 4-day estrous cycles, as measured by estrous behavior and vaginal discharge. Subsequently, both groups were treated with doses of 2DG known to inhibit the estrous cycle (1750 mg/kg every 6 h on days 1 and 2 of the cycle). Hamsters were tested for measures of estrous cyclicity daily after treatment. Only 9% of the sham-operated hamsters showed estrous cycles within 5 days after the start of 2DG treatment. In contrast, all of the hamsters with confirmed lesions of the AP showed estrous cycles within 5 days of the start of 2DG treatment. Histology showed that most lesions removed the AP plus part of the medial NTS, while two lesions removed part of the AP only.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucoprivic treatments that induce anestrus, but do not affect food intake, increase FOS-like immunoreactivity in the area postrema and nucleus of the solitary tract in Syrian hamsters.

Animals make a wide variety of physiological and behavioral adjustments in order to maintain caloric homeostasis. For example, most animals increase food intake when the availability of cellular metabolic fuels is low. The area postrema (AP) and adjacent, reciprocally-innervated nucleus of the solitary tract (NTS) are important brain areas for metabolic control of food intake in rats. However, in Syrian hamsters, food intake is not affected by decreases in metabolic fuel availability such as those that occur with food deprivation or with pharmacological inhibitors of metabolic fuels. Hamsters make other adjustments that conserve energy when the availability of metabolic fuels is low. Estrous cycles are inhibited by treatment with a high dose of 2-deoxy-D-glucose (2DG), a drug that inhibits cellular glucose utilization, but not by treatment with methyl palmoxirate (MP) a drug that inhibits fatty acid utilization. Recent data suggest that the AP/NTS is critical for the effects of glucoprivation on estrous cycles. Lesions of the AP/NTS prevent 2DG-induced anestrus. If the AP/NTS is involved in anestrus induced by glucoprivation, it might be predicted that glucoprivic treatments that induce anestrus would change patterns of neural activation, as measured by FOS-like immunoreactivity (FOS-li), in the AP/NTS. We examined FOS-li in females that were either food deprived or fed ad libitum, and in females treated with 2DG, MP or the appropriate vehicle. FOS-li was increased in the AP/NTS only in hamsters food deprived or treated with 2DG, the two treatments that induce anestrus but have no effect on food intake. These results are consistent with the notion that metabolic control of estrous cycles involves detection of decreases in the availability of metabolic fuels in the AP/NTS.

Q beta bacteriophage photoinactivated by methylene blue plus light involves inactivation of its genomic RNA.

Methylene blue (MB) is being used as a sensitizer for the photodynamic inactivation of viral contaminants, including the human immunodeficiency virus, in blood and blood components used in medical treatment. We recently showed that oxygen-dependent photodynamic inactivation of the RNA bacteriophage Q beta with MB plus light (MB + L) is associated with the formation of 8-oxo-7,8-dihydroguanine, protein carbonyls, RNA-protein crosslinkages and minor amounts of RNA strand breaks. We report herein, with the use of infectious RNA assays, that the lethal lesions in Q beta phage following MB + L exposure can be accounted for, and thereby most likely reside in, the RNA component of the phage but that the protein component of the virion contributes to the inactivation. The formation of RNA-protein crosslinkages as the primary inactivating type of lesion is put forth as the most probable model of the inactivation mechanism due to the sensitivity with which RNA-protein crosslinks are formed in response to MB + L exposure and the expectation of the powerful inactivating power of this type of lesion.

Potential mechanisms of photodynamic inactivation of virus by methylene blue. I. RNA-protein crosslinks and other oxidative lesions in Q beta bacteriophage.

A spectrum of oxidative lesions was observed in a bacteriophage-based model system that is very sensitive to the photodynamic activity of selected dyes. When suspensions of the intact bacteriophage Q beta were exposed to methylene blue plus light (MB + L), inactivating events, or "hits" occurred that were oxygen-dependent and that were associated with the formation of several specific lesions: (1) carbonyl moieties on proteins, (2) 8-oxo-7,8-dihydroguanine (8-oxoGua), and (3) single-strand breaks (ssb) in the RNA genome and (4) RNA-protein crosslinks. Formation of carbonyl groups associated with protein in the Q beta phage preparation correlated positively with photoinactivation of the phage with increasing doses of either of the sensitizers MB or rose bengal. Strand breaks in the Q beta genomic RNA were observable at high MB concentrations but appeared not to be significant at the lower concentrations of MB, as full-length Q beta RNA was observable well beyond the 99% inactivation point in MB dosage. It was shown that the number of 8-oxoGua lesions were unlikely to be sufficient to account for the number of lethal events. Following exposure to MB + L, crosslink formation between Q beta RNA and protein was observed by virtue of the location of RNA at the interface of phenol-aqueous extractions of phage suspensions. A significant increase over background of RNA-protein complexes (including full-length Q beta RNA) was observed at the lowest concentration of MB tested (0.5 microM), which corresponded roughly to an average of 2 lethal hits per phage or approximately 13% survival compared to the zero MB control (100% survival). Due to its close correlation with Q beta inactivation and its expected lethality, RNA-protein crosslink formation may be important as an inactivating lesion in bacteriophage Q beta following MB + L exposure.

Effects of maternal diet, body weight and body composition on infanticide in Syrian hamsters.

We examined the idea that female hamsters kill and eat their own offspring as part of an organized mechanism that balances litter size with metabolic energy supply. In Experiment 1, females fed diets that made them lighter and leaner cannibalized more offspring and maintained smaller litters than females fed diets that made them heavier and fatter. A greater supply of metabolic energy from the diet and/or from body fat stores may have attenuated cannibalism in heavier mothers. In Experiment 2, food restriction during lactation increased the level of cannibalism to a greater degree in lighter, leaner mothers. Heavier, fatter mothers may have eaten fewer offspring because they were better able to mobilize fatty acids from adipose tissue as an alternative fuel source during food restriction. These results suggest that an important factor influencing cannibalism of pups is the general availability of metabolic fuels from both external (food supply) and internal (adipose tissue) sources.

Effects of ambient temperature and body fat content on maternal litter reduction in Syrian hamsters.

Reproduction in Syrian hamsters is sensitive to the general availability of metabolic energy. For example, females often modify their litter size by cannibalism on days 1-7 postpartum, and the number of young eaten is a function of the total supply of metabolic energy as determined by both food supply and body fat content. If the level of cannibalism is a function of energy availability, it might be expected that a drop in ambient temperature would increase cannibalism, since cold acclimation demands greater energy expenditure. We found that hamsters ate significantly more of their offspring when housed at 10 compared to 22 degrees C during lactation. The effect of cold on cannibalism was attenuated in hamsters fattened prior to cold exposure and exaggerated in hamsters that were lean prior to cold exposure. Thus, the litter size maintained by Syrian hamsters is a function of the total supply of metabolic fuels as determined by energy sources, such as food supply and adipose tissue, and by energetic costs of thermoregulatory and other processes.

Inhibition of fatty acid oxidation and glucose metabolism does not affect food intake or hunger motivation in Syrian hamsters.

We examined the interaction of the metabolic fuels, glucose and free fatty acids (FFA), in the control of food intake in Syrian hamsters. Hamsters were treated with a 2-deoxy-D-glucose (2DG) which inhibits glucose utilization, and methyl palmoxirate (MP), which inhibits fatty acid oxidation. The 2DG and MP, alone or in combination did not enhance food intake in hamsters fed a standard rodent chow diet. Determination of the circulating glucose, FFAs, and ketones confirmed that the drugs were having the intended metabolic effects. The 2DG caused marked hyperglycemia and decreased ketones consistent with an inhibition of glycolysis, and the MP caused increased FFAs and decreased ketones indicating inhibition of fatty acid oxidation. A third experiment examined the hamsters' willingness to ingest a diet made highly unpalatable with NaCl, another measure of hunger motivation. Although food-deprived hamsters ingested more of a salt-adulterated diet than did control animals, hamsters treated with MP and 2DG did not. These experiments provide further evidence that the control of food intake in Syrian hamsters is appreciably different than that of laboratory rats.

Genetic association between progesterone-induced and maternal nesting in mice.

Increases in nesting during pregnancy may be mediated by progesterone in mice. If the behaviors, maternal nesting (MN) and nesting induced by exogenous progesterone (PN), are controlled by the same physiological mechanism, it would be expected that they share a common genetic basis. The present experiment was designed to quantify the extent of genetic association between PN and MN. At Wesleyan University, baseline nesting was measured on females of 4 inbred strains. Subsequently, half of the mice in each strain received progesterone implants. There were significant increases in nesting due to progesterone treatment. After 21 days, implants were removed and nesting levels returned to baseline. The mice were mated and nesting measured throughout pregnancy. The strain rank order was the same for levels of PN and MN. The genetic correlation between PN and MN estimated from analysis of covariance within and between strains was not significantly different from 1.0. These results were replicated at the University of Iowa. The high genetic correlation implies a common physiological mechanism underlying PN and MN.