Background
Previous studies in heart failure with reduced ejection fraction (HFrEF) suggest that skeletal muscle mitochondrial impairments are associated with exercise intolerance in men. However, ...the nature of this relationship in female patients remains to be elucidated. This study aimed to determine the relationship between skeletal muscle mitochondrial impairments and exercise intolerance in male and female patients with HFrEF.
Methods
Mitochondrial respiration, enzyme activity, and gene expression were examined in pectoralis major biopsies from age‐matched male (n = 45) and female (n = 11) patients with HFrEF and healthy‐matched male (n = 24) and female (n = 11) controls. Mitochondrial variables were compared between sex and related to peak exercise capacity.
Results
Compared with sex‐matched controls, complex I mitochondrial oxygen flux was 17% (P = 0.030) and 29% (P = 0.013) lower in male and female patients with HFrEF, respectively, which correlated to exercise capacity (r = 0.71; P > 0.0001). Female HFrEF patients had a 32% (P = 0.023) lower mitochondrial content compared with controls. However, after adjusting for mitochondrial content, male patients demonstrated lower complex I function by 15% (P = 0.030). Expression of key mitochondrial genes regulating organelle dynamics and maintenance (i.e. optic atrophy 1, peroxisome proliferator‐activated receptor γ coactivator‐1α, NADH:ubiquinone oxidoreductase core subunit S1/S3, and superoxide dismutase 2) were selectively lower in female HFrEF patients.
Conclusions
These data provide novel evidence that HFrEF induces divergent sex‐specific mitochondrial phenotypes in skeletal muscle that predispose towards exercise intolerance, impacting mitochondrial ‘quantity' in female patients and mitochondrial ‘quality' in male patients. Therapeutic strategies to improve exercise tolerance in HFrEF should consider targeting sex‐specific mitochondrial abnormalities in skeletal muscle.
Background
Three‐dimensional (3D) multiecho balanced steady‐state free precession (ME‐bSSFP) has previously been demonstrated in preclinical hyperpolarized (HP) 13C‐MRI in vivo experiments, and it ...may be suitable for clinical metabolic imaging of prostate cancer (PCa).
Purpose
To validate a signal simulation framework for the use of sequence parameter optimization. To demonstrate the feasibility of ME‐bSSFP for HP 13C‐MRI in patients. To evaluate the metabolism in PCa measured by ME‐bSSFP.
Study Type
Retrospective single‐center cohort study.
Phantoms/Population
Phantoms containing aqueous solutions of 1‐13C lactate (2.3 M) and 13C urea (8 M). Eight patients (mean age 67 ± 6 years) with biopsy‐confirmed Gleason 3 + 4 (n = 7) and 4 + 3 (n = 1) PCa.
Field Strength/Sequences
1H MRI at 3 T with T2‐weighted turbo spin‐echo sequence used for spatial localization and spoiled dual gradient‐echo sequence used for B0‐field measurement. ME‐bSSFP sequence for 13C MR spectroscopic imaging with retrospective multipoint IDEAL metabolite separation.
Assessment
The primary endpoint was the analysis of pyruvate‐to‐lactate conversion in PCa and healthy prostate regions of interest (ROIs) using model‐free area under the curve (AUC) ratios and a one‐directional kinetic model (kP). The secondary objectives were to investigate the correlation between simulated and experimental ME‐bSSFP metabolite signals for HP 13C‐MRI parameter optimization.
Statistical Tests
Pearson correlation coefficients with 95% confidence intervals and paired t‐tests. The level of statistical significance was set at P < 0.05.
Results
Strong correlations between simulated and empirical ME‐bSSFP signals were found (r > 0.96). Therefore, the simulation framework was used for sequence optimization. Whole prostate metabolic HP 13C‐MRI, observing the conversion of pyruvate into lactate, with a temporal resolution of 6 seconds was demonstrated using ME‐bSSFP. Both assessed metrics resulted in significant differences between PCa (mean ± SD) (AUC = 0.33 ± 012, kP = 0.038 ± 0.014) and healthy (AUC = 0.15 ± 0.10, kP = 0.011 ± 0.007) ROIs.
Data Conclusion
Metabolic HP 13C‐MRI in the prostate using ME‐bSSFP allows for differentiation between aggressive PCa and healthy tissue.
Evidence Level
2
Technical Efficacy
Stage 1
Objective To develop a phantom system which can be integrated with an automated injection system, eliminating the experimental variability that arises with manual injection; for the purposes of pulse ...sequence testing and metric derivation in hyperpolarised 13C-MR. Methods The custom dynamic phantom was machined from Ultem and filled with a nicotinamide adenine dinucleotide and lactate dehydrogenase mixture dissolved in phosphate buffered saline. Hyperpolarised 1-13C-pyruvate was then injected into the phantom (n = 8) via an automated syringe pump and the conversion of pyruvate to lactate monitored through a 13C imaging sequence. Results The phantom showed low coefficient of variation for the lactate to pyruvate peak signal heights (11.6%) and dynamic area-under curve ratios (11.0%). The variance for the lactate dehydrogenase enzyme rate constant (kP) was also seen to be low at 15.6%. Conclusion The dynamic phantom demonstrates high reproducibility for quantification of 13C-hyperpolarised MR-derived metrics. Establishing such a phantom is needed to facilitate development of hyperpolarsed 13C-MR pulse sequenced; and moreover, to enable multisite hyperpolarised 13C-MR clinical trials where assessment of metric variability across sites is critical. Advances in knowledge The dynamic phantom developed during the course of this study will be a useful tool in testing new pulse sequences and standardisation in future hyperpolarised work.
Phaeochromocytomas (PCC) and paragangliomas (PGL), cumulatively referred to as PPGLs, are neuroendocrine tumours arising from neural crest-derived cells in the sympathetic and parasympathetic nervous ...systems. Predicting future tumour behaviour and the likelihood of metastatic disease remains problematic as genotype-phenotype correlations are limited, the disease has variable penetrance and, to date, no reliable molecular, cellular or histological markers have emerged. Tumour metabolism quantification can be considered as a method to delineating tumour aggressiveness by utilising hyperpolarised
C-MR (HP-MR). The technique may provide an opportunity to non-invasively characterise disease behaviour. Here, we present the first instance of the analysis of PPGL metabolism via HP-MR in a single case.
Phaeochromocytomas (PCC) and paragangliomas (PGL), cumulatively referred to as PPGLs, are neuroendocrine tumours arising from neural crest-derived cells in the sympathetic and parasympathetic nervous ...systems. Predicting future tumour behaviour and the likelihood of metastatic disease remains problematic as genotype–phenotype correlations are limited, the disease has variable penetrance and, to date, no reliable molecular, cellular or histological markers have emerged. Tumour metabolism quantification can be considered as a method to delineating tumour aggressiveness by utilising hyperpolarised
13
C-MR (HP-MR). The technique may provide an opportunity to non-invasively characterise disease behaviour. Here, we present the first instance of the analysis of PPGL metabolism via HP-MR in a single case.
To develop a phantom system which can be integrated with an automated injection system, eliminating the experimental variability that arises with manual injection; for the purposes of pulse sequence ...testing and metric derivation in hyperpolarised
C-MR.
The custom dynamic phantom was machined from Ultem and filled with a nicotinamide adenine dinucleotide and lactate dehydrogenase mixture dissolved in phosphate buffered saline. Hyperpolarised 1-
C-pyruvate was then injected into the phantom (
= 8) via an automated syringe pump and the conversion of pyruvate to lactate monitored through a
C imaging sequence.
The phantom showed low coefficient of variation for the lactate to pyruvate peak signal heights (11.6%) and dynamic area-under curve ratios (11.0%). The variance for the lactate dehydrogenase enzyme rate constant (kP) was also seen to be low at 15.6%.
The dynamic phantom demonstrates high reproducibility for quantification of
C-hyperpolarised MR-derived metrics. Establishing such a phantom is needed to facilitate development of hyperpolarsed
C-MR pulse sequenced; and moreover, to enable multisite hyperpolarised
C-MR clinical trials where assessment of metric variability across sites is critical.
The dynamic phantom developed during the course of this study will be a useful tool in testing new pulse sequences and standardisation in future hyperpolarised work.
Phaeochromocytomas (PCC) and paragangliomas (PGL), cumulatively referred to as PPGLs, are neuroendocrine tumours arising from neural crest-derived cells in the sympathetic and parasympathetic nervous ...systems. Predicting future tumour behaviour and the likelihood of metastatic disease remains problematic as genotype-phenotype correlations are limited, the disease has variable penetrance and, to date, no reliable molecular, cellular or histological markers have emerged. Tumour metabolism quantification can be considered as a method to delineating tumour aggressiveness by utilising hyperpolarised 13 C-MR (HP-MR). The technique may provide an opportunity to non-invasively characterise disease behaviour. Here, we present the first instance of the analysis of PPGL metabolism via HP-MR in a single case.
Inelastic neutron scattering techniques have been used to study the low energy phonon excitations in superconducting RENi$\sb2$B$\sb2$C (RE=Lu, Y) to further characterize the anomalous features ...observed by Kawano et al. (Phys. Rev. Lett., 77, 4628 (1996)) for RE=Y and Stassis et al. (Phys. Rev. B, 55, R8678 (1997)) for RE=Lu, when these systems enter the superconducting ground state. We find that above T$\sb{\rm c}$ the frequencies of the $\Delta\sb4\lbrack\xi 00\rbrack$ lowest-lying acoustic and optic phonon modes decrease with decreasing temperature, for $\xi$ close to the nesting vector $\xi\sb{m}.$ In addition there is a shift of intensity from the upper to the lower mode, an effect characteristic of mode coupling. At temperatures below approximately 100K only a single unresolved peak is observed. The observed anticrossing behavior of these modes above T$\sb{\rm c}$ can be described satisfactorily in both compounds by a coupled-mode model. Below T$\sb{\rm c}$ the observed spectrum changes dramatically: it consists of a sharp peak at approximately 4 meV with a broad weak shoulder at higher energies. The experimental results unambiguously show that this dramatic change is due to the onset of superconductivity in these compounds. In this temperature region, the results are in qualitative agreement with recent theoretical calculations.
Mr Glenn Hubbard writes: "Offshoring . . . may boost productivity enough to raise the wages of low-skilled as well as high-skilled workers." One wonders how he arrived at this conclusion, or what ...real-life experiences he has encountered. Workers in a Thai factory labouring for Dollars 7 per day making bras for Victoria's Secret, Calvin Klein and Charming Shoppes have physically fought for this "decent pay" and better conditions. The management of the factory - a model of quality, productivity and worker-management relations - claim that the plant is moving to China because the US retailers demanded lower unit cost.
Cytoplasmic dynein is an approximately 1.4 MDa multi‐protein complex that transports many cellular cargoes towards the minus ends of microtubules. Several in vitro studies of mammalian dynein have ...suggested that individual motors are not robustly processive, raising questions about how dynein‐associated cargoes can move over long distances in cells. Here, we report the production of a fully recombinant human dynein complex from a single baculovirus in insect cells. Individual complexes very rarely show directional movement in vitro. However, addition of dynactin together with the N‐terminal region of the cargo adaptor BICD2 (BICD2N) gives rise to unidirectional dynein movement over remarkably long distances. Single‐molecule fluorescence microscopy provides evidence that BICD2N and dynactin stimulate processivity by regulating individual dynein complexes, rather than by promoting oligomerisation of the motor complex. Negative stain electron microscopy reveals the dynein–dynactin–BICD2N complex to be well ordered, with dynactin positioned approximately along the length of the dynein tail. Collectively, our results provide insight into a novel mechanism for coordinating cargo binding with long‐distance motor movement.
Synopsis
Cargo adaptor BICD2 converts dynein from a non‐processive to a highly processive motor in presence of dynactin. This might coordinate long‐distance movement with cargo availability.
Production of the 1.4 MDa recombinant mammalian dynein complex using a single baculovirus.
The dynactin complex and the N‐terminus of the cargo adaptor BICD2 (BICD2N) are sufficient to convert dynein into a highly processive motor.
In the presence of BICD2N, dynactin forms a well‐ordered complex with the dynein tail.
Results suggest a mechanism for coupling cargo availability to the activation of long‐distance transport.
Cargo adaptor BICD2 converts dynein from a non‐processive to a highly processive motor in presence of dynactin. This might coordinate long‐distance movement with cargo availability.
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