A Highly Water- and Air-Stable Iron-Containing MRI Contrast Agent Sensor for H2 O2.

A highly water- and air-stable Fe(II) complex with the quinol-containing macrocyclic ligand H4 qp4 reacts with H2 O2 to yield Fe(III) complexes with less highly chelating forms of the ligand that have either one or two para-quinones. The reaction increases the T1 -weighted relaxivity over four-fold, enabling the complex to detect H2 O2 using clinical MRI technology. The iron-containing sensor differs from its recently characterized manganese analog, which also detects H2 O2 , in that it is the oxidation of the metal center, rather than the ligand, that primarily enhances the relaxivity.

A Macrocyclic Ligand Framework That Improves Both the Stability and T1-Weighted MRI Response of Quinol-Containing H2O2 Sensors.

Previously prepared Mn(II)- and quinol-containing magnetic resonance imaging (MRI) contrast agent sensors for H2O2 relied on linear polydentate ligands to keep the redox-activatable quinols in close proximity to the manganese. Although these provide positive T1-weighted relaxivity responses to H2O2 that result from oxidation of the quinol groups to p-quinones, these reactions weaken the binding affinity of the ligands, promoting dissociation of Mn(II) from the contrast agent in aqueous solution. Here, we report a new ligand, 1,8-bis(2,5-dihydroxybenzyl)-1,4,8,11-tetraazacyclotetradecane, that consists of two quinols covalently tethered to a cyclam macrocycle. The macrocycle provides stronger thermodynamic and kinetic barriers for metal-ion dissociation in both the reduced and oxidized forms of the ligand. The Mn(II) complex reacts with H2O2 to produce a more highly aquated Mn(II) species that exhibits a 130% greater r1, quadrupling the percentile response of our next best sensor. With a large excess of H2O2, there is a noticeable induction period before quinol oxidation and r1 enhancement occurs. Further investigation reveals that, under such conditions, catalase activity initially outcompetes ligand oxidation, with the latter occurring only after most of the H2O2 has been depleted.

Novel Biomarkers of Human GM1 Gangliosidosis Reflect the Clinical Efficacy of Gene Therapy in a Feline Model.

GM1 gangliosidosis is a fatal neurodegenerative disease that affects individuals of all ages. Favorable outcomes using adeno-associated viral (AAV) gene therapy in GM1 mice and cats have prompted consideration of human clinical trials, yet there remains a paucity of objective biomarkers to track disease status. We developed a panel of biomarkers using blood, urine, cerebrospinal fluid (CSF), electrodiagnostics, 7 T MRI, and magnetic resonance spectroscopy in GM1 cats-either untreated or AAV treated for more than 5 years-and compared them to markers in human GM1 patients where possible. Significant alterations were noted in CSF and blood of GM1 humans and cats, with partial or full normalization after gene therapy in cats. Gene therapy improved the rhythmic slowing of electroencephalograms (EEGs) in GM1 cats, a phenomenon present also in GM1 patients, but nonetheless the epileptiform activity persisted. After gene therapy, MR-based analyses revealed remarkable preservation of brain architecture and correction of brain metabolites associated with microgliosis, neuroaxonal loss, and demyelination. Therapeutic benefit of AAV gene therapy in GM1 cats, many of which maintain near-normal function >5 years post-treatment, supports the strong consideration of human clinical trials, for which the biomarkers described herein will be essential for outcome assessment.

Lifelong quercetin enrichment and cardioprotection in Mdx/Utrn+/- mice.

Duchenne Muscular Dystrophy (DMD) is associated with progressive cardiac pathology; however, the SIRT1/PGC1-α activator quercetin may cardioprotect dystrophic hearts. We tested the extent to which long-term 0.2% dietary quercetin enrichment attenuates dystrophic cardiopathology in Mdx/Utrn+/- mice. At 2 mo, Mdx/Utrn+/- mice were fed quercetin-enriched (Mdx/Utrn+/--Q) or control diet (Mdx/Utrn+/-) for 8 mo. Control C57BL/10 (C57) animals were fed a control diet for 10 mo. Cardiac function was quantified by MRI at 2 and 10 mo. Spontaneous physical activity was quantified during the last week of treatment. At 10 mo hearts were excised for histological and biochemical analysis. Quercetin feeding improved various physiological indexes of cardiac function in diseased animals. Mdx/Utrn+/--Q also engaged in more high-intensity physical activity than controls. Histological analyses of heart tissues revealed higher expression and colocalization of utrophin and α-sarcoglycan. Lower abundance of fibronectin, cardiac damage (Hematoxylin Eosin-Y), and MMP9 were observed in quercetin-fed vs. control Mdx/Utrn+/- mice. Quercetin evoked higher protein abundance of PGC-1α, cytochrome c, ETC complexes I-V, citrate synthase, SOD2, and GPX compared with control-fed Mdx/Utrn+/- Quercetin decreased abundance of inflammatory markers including NFκB, TGF-ß1, and F4/80 compared with Mdx/Utrn+/-; however, P-NFκB, P-IKBα, IKBα, CD64, and COX2 were similar between groups. Dietary quercetin enrichment improves cardiac function in aged Mdx/Utrn+/- mice and increases mitochondrial protein content and dystrophin glycoprotein complex formation. Histological analyses indicate a marked attenuation in pathological cardiac remodeling and indicate that long-term quercetin consumption benefits the dystrophic heart. NEW & NOTEWORTHY: The current investigation provides first-time evidence that quercetin provides physiological cardioprotection against dystrophic pathology and is associated with improved spontaneous physical activity. Secondary findings suggest that quercetin-dependent outcomes are in part due to PGC-1α pathway activation.

Long-term dietary quercetin enrichment as a cardioprotective countermeasure in mdx mice.

NEW FINDINGS: What is the central question of this study? The central question of this study is to understand whether dietary quercetin enrichment attenuates physiologic, histological, and biochemical indices of cardiac pathology. What is the main finding and its importance? Novel findings from this investigation, in comparison to prior published studies, suggest that mouse strain-dependent cardiac outcomes in performance and remodelling exist. Unlike Mdx/Utrn-/+ mice, mdx mice receiving lifelong quercetin treatment did not exhibit improvements cardiac function. Similar to prior work in Mdx/Utrn-/+ mice, histological evidence of remodelling suggests that quercetin consumption may have benefited hearts of mdx mice. Positive outcomes may be related to indirect markers that suggest improved mitochondrial wellbeing and to selected indices of inflammation that were lower in hearts from quercetin-fed mice. Duchenne muscular dystrophy causes a decline in cardiac health, resulting in premature mortality. As a potential countermeasure, quercetin is a polyphenol possessing inherent anti-inflammatory and antioxidant effects that activate proliferator-activated γ coactivator 1α (PGC-1α), increasing the abundance of mitochondrial biogenesis proteins. We investigated the extent to which lifelong 0.2% dietary quercetin enrichment attenuates dystrophic cardiopathology in mdx mice. Dystrophic animals were fed a quercetin-enriched or control diet for 12 months, while control C57 mice were fed a control diet. Cardiac function was assessed via 7 T magnetic resonance imaging at 2, 10 and 14 months. At 14 months, hearts were harvested for histology and Western blotting. The results indicated an mdx strain-dependent decline in cardiac performance at 14 months and that dietary quercetin enrichment did not attenuate functional losses. In contrast, histological analyses provided evidence that quercetin feeding was associated with decreased fibronectin and indirect damage indices (Haematoxylin and Eosin) compared with untreated mdx mice. Dietary quercetin enrichment increased cardiac protein abundance of PGC-1α, cytochrome c, electron transport chain complexes I-V, citrate synthase, superoxide dismutase 2 and glutathione peroxidase (GPX) versus untreated mdx mice. The protein abundance of the inflammatory markers nuclear factor-κB, phosphorylated nuclear factor kappa beta (P-NFκB) and phosphorylated nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (P-IKBα) was decreased by quercetin compared with untreated mdx mice, while preserving nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha( IKBα) compared with mdx mice. Furthermore, quercetin decreased transforming growth factor-ß1, cyclooxygenase-2 (COX2) and macrophage-restricted F4/80 protein (F4/80) versus untreated mdx mice. The data suggest that long-term quercetin enrichment does not impact physiological parameters of cardiac function but improves indices of mitochondrial biogenesis and antioxidant enzymes, facilitates dystrophin-associated glycoprotein complex (DGC) assembly and decreases inflammation in dystrophic hearts.

Adding a Second Quinol to a Redox-Responsive MRI Contrast Agent Improves Its Relaxivity Response to H2O2.

The overproduction of reactive oxygen species has been linked to a wide array of health disorders. The ability to noninvasively monitor oxidative stress in vivo could provide substantial insight into the progression of these conditions and, in turn, could facilitate the development of better diagnosis and treatment options. A mononuclear Mn(II) complex with the redox-active ligand N,N'-bis(2,5-dihydroxybenzyl)-N,N'-bis(2-pyridinylmethyl)-1,2-ethanediamine (H4qtp2) was made and characterized. A previously prepared Mn(II) complex with a ligand containing a single quinol subunit was found to display a modest T1-derived relaxivity response to H2O2. The introduction of a second redox-active quinol both substantially improves the relaxivity response of the complex to H2O2 and reduces the cytotoxicity of the sensor but renders the complex more susceptible to transmetalation. The addition of H2O2 partially oxidizes the quinol subunits to para-quinones, concomitantly increasing the r1 from 5.46 mM-1 s-1 to 7.17 mM-1 s-1. The oxidation of the ligand enables more water molecules to coordinate to the metal ion, providing an explanation for the enhanced relaxivity. That the diquinol complex is only partially oxidized by H2O2 is attributed to its activity as an antioxidant; the complex can both catalytically degrade superoxide and serve as a hydrogen atom donor.

Enhancement of Odor-Induced Activity in the Canine Brain by Zinc Nanoparticles: A Functional MRI Study in Fully Unrestrained Conscious Dogs.

Using noninvasive in vivo functional magnetic resonance imaging (fMRI), we demonstrate that the enhancement of odorant response of olfactory receptor neurons by zinc nanoparticles leads to increase in activity in olfaction-related and higher order areas of the dog brain. To study conscious dogs, we employed behavioral training and optical motion tracking for reducing head motion artifacts. We obtained brain activation maps from dogs in both anesthetized state and fully conscious and unrestrained state. The enhancement effect of zinc nanoparticles was higher in conscious dogs with more activation in higher order areas as compared with anesthetized dogs. In conscious dogs, voxels in the olfactory bulb and hippocampus showed higher activity to odorants mixed with zinc nanoparticles as compared with pure odorants, odorants mixed with gold nanoparticles as well as zinc nanoparticles alone. These regions have been implicated in odor intensity processing in other species including humans. If the enhancement effect of zinc nanoparticles observed in vivo are confirmed by future behavioral studies, zinc nanoparticles may provide a way for enhancing the olfactory sensitivity of canines for detection of target substances such as explosives and contraband substances at very low concentrations, which would otherwise go undetected.

Mucopolysaccharidosis-like phenotype in feline Sandhoff disease and partial correction after AAV gene therapy.

Sandhoff disease (SD) is a fatal neurodegenerative disease caused by a mutation in the enzyme ß-N-acetylhexosaminidase. Children with infantile onset SD develop seizures, loss of motor tone and swallowing problems, eventually reaching a vegetative state with death typically by 4years of age. Other symptoms include vertebral gibbus and cardiac abnormalities strikingly similar to those of the mucopolysaccharidoses. Isolated fibroblasts from SD patients have impaired catabolism of glycosaminoglycans (GAGs). To evaluate mucopolysaccharidosis-like features of the feline SD model, we utilized radiography, MRI, echocardiography, histopathology and GAG quantification of both central nervous system and peripheral tissues/fluids. The feline SD model exhibits cardiac valvular and structural abnormalities, skeletal changes and spinal cord compression that are consistent with accumulation of GAGs, but are much less prominent than the severe neurologic disease that defines the humane endpoint (4.5±0.5months). Sixteen weeks after intracranial AAV gene therapy, GAG storage was cleared in the SD cat cerebral cortex and liver, but not in the heart, lung, skeletal muscle, kidney, spleen, pancreas, small intestine, skin, or urine. GAG storage worsens with time and therefore may become a significant source of pathology in humans whose lives are substantially lengthened by gene therapy or other novel treatments for the primary, neurologic disease.

Exploiting Size-Dependent Drag and Magnetic Forces for Size-Specific Separation of Magnetic Nanoparticles.

Realizing the full potential of magnetic nanoparticles (MNPs) in nanomedicine requires the optimization of their physical and chemical properties. Elucidation of the effects of these properties on clinical diagnostic or therapeutic properties, however, requires the synthesis or purification of homogenous samples, which has proved to be difficult. While initial simulations indicated that size-selective separation could be achieved by flowing magnetic nanoparticles through a magnetic field, subsequent in vitro experiments were unable to reproduce the predicted results. Magnetic field-flow fractionation, however, was found to be an effective method for the separation of polydisperse suspensions of iron oxide nanoparticles with diameters greater than 20 nm. While similar methods have been used to separate magnetic nanoparticles before, no previous work has been done with magnetic nanoparticles between 20 and 200 nm. Both transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis were used to confirm the size of the MNPs. Further development of this work could lead to MNPs with the narrow size distributions necessary for their in vitro and in vivo optimization.

A mononuclear manganese(II) complex demonstrates a strategy to simultaneously image and treat oxidative stress.

A manganese(II) complex with a ligand containing an oxidizable quinol group serves as a turn-on sensor for H2O2. Upon oxidation, the relaxivity of the complex in buffered water increases by 0.8 mM(-1) s(-1), providing a signal that can be detected and quantified by magnetic resonance imaging. The complex also serves as a potent antioxidant, suggesting that this and related complexes have the potential to concurrently visualize and alleviate oxidative stress.

Hip thrust and back squat training elicit similar gluteus muscle hypertrophy and transfer similarly to the deadlift.

Purpose: We examined how set-volume equated resistance training using either the back squat (SQ) or hip thrust (HT) affected hypertrophy and various strength outcomes. Methods: Untrained college-aged participants were randomized into HT or SQ groups. Surface electromyograms (sEMG) from the right gluteus maximus and medius muscles were obtained during the first training session. Participants completed nine weeks of supervised training (15-17 sessions), before and after which we assessed muscle cross-sectional area (mCSA) via magnetic resonance imaging and strength via three-repetition maximum (3RM) testing and an isometric wall push test. Results: Glutei mCSA growth was similar across both groups. Estimates [(-) favors HT; (+) favors SQ] modestly favored the HT compared to SQ for lower [effect ± SE, -1.6 ± 2.1 cm2], mid [-0.5± 1.7 cm2], and upper [-0.5 ± 2.6 cm2], but with appreciable variance. Gluteus medius+minimus [-1.8 ± 1.5 cm2] and hamstrings [0.1 ± 0.6 cm2] mCSA demonstrated little to no growth with small differences between groups. Thigh mCSA changes were greater in SQ for the quadriceps [3.6 ± 1.5 cm2] and adductors [2.5 ± 0.7 cm2]. Squat 3RM increases favored SQ [14 ± 2.5 kg] and hip thrust 3RM favored HT [-26 ± 5 kg]. 3RM deadlift [0 ± 2 kg] and wall push strength [-7 ± 13 N] similarly improved. All measured gluteal sites showed greater mean sEMG amplitudes during the first bout hip thrust versus squat set, but this did not consistently predict gluteal hypertrophy outcomes. Conclusion: Nine weeks of squat versus hip thrust training elicited similar gluteal hypertrophy, greater thigh hypertrophy in SQ, strength increases that favored exercise allocation, and similar strength transfers to the deadlift and wall push.

Hip thrust and back squat training elicit similar gluteus muscle hypertrophy and transfer similarly to the deadlift.

We examined how set-volume equated resistance training using either the back squat (SQ) or hip thrust (HT) affected hypertrophy and various strength outcomes. Untrained college-aged participants were randomized into HT (n = 18) or SQ (n = 16) groups. Surface electromyograms (sEMG) from the right gluteus maximus and medius muscles were obtained during the first training session. Participants completed 9 weeks of supervised training (15-17 sessions), before and after which gluteus and leg muscle cross-sectional area (mCSA) was assessed via magnetic resonance imaging. Strength was also assessed prior to and after the training intervention via three-repetition maximum (3RM) testing and an isometric wall push test. Gluteus mCSA increases were similar across both groups. Specifically, estimates [(-) favors HT (+) favors SQ] modestly favored the HT versus SQ for lower [effect ±SE, -1.6 ± 2.1 cm2; CI95% (-6.1, 2.0)], mid [-0.5 ± 1.7 cm2; CI95% (-4.0, 2.6)], and upper [-0.5 ± 2.6 cm2; CI95% (-5.8, 4.1)] gluteal mCSAs but with appreciable variance. Gluteus medius + minimus [-1.8 ± 1.5 cm2; CI95% (-4.6, 1.4)] and hamstrings [0.1 ± 0.6 cm2; CI95% (-0.9, 1.4)] mCSA demonstrated little to no growth with small differences between groups. mCSA changes were greater in SQ for the quadriceps [3.6 ± 1.5 cm2; CI95% (0.7, 6.4)] and adductors [2.5 ± 0.7 cm2; CI95% (1.2, 3.9)]. Squat 3RM increases favored SQ [14 ± 2 kg; CI95% (9, 18),] and hip thrust 3RM favored HT [-26 ± 5 kg; CI95% (-34, -16)]. 3RM deadlift [0 ± 2 kg; CI95% (-4, 3)] and wall push strength [-7 ± 12N; CI95% (-32, 17)] similarly improved. All measured gluteal sites showed greater mean sEMG amplitudes during the first bout hip thrust versus squat set, but this did not consistently predict gluteal hypertrophy outcomes. Squat and hip thrust training elicited similar gluteal hypertrophy, greater thigh hypertrophy in SQ, strength increases that favored exercise allocation, and similar deadlift and wall push strength increases.

Adeno-associated virus serotype 9 administered systemically after reperfusion preferentially targets cardiomyocytes in the infarct border zone with pharmacodynamics suitable for the attenuation of left ventricular remodeling.

BACKGROUND: Adeno-associated virus serotype 9 (AAV9) vectors provide efficient and uniform gene expression to normal myocardium following systemic administration, with kinetics that approach steady-state within 2-3 weeks. However, as a result of the delayed onset of gene expression, AAV vectors have not previously been administered intravenously after reperfusion for post-infarct gene therapy applications. The present study evaluated the therapeutic potential of post-myocardial infarction gene delivery using intravenous AAV9. METHODS: AAV9 vectors expressing firefly luciferase, enhanced green fluorescent protein (eGFP) or extracellular superoxide dismutase genes from the cardiac troponin-T (cTnT) promoter (AcTnTLuc, AcTnTeGFP, AcTnTEcSOD) were employed. AcTnTLuc was administered intravenously at 10 min and at 1, 2 and 3 days post-ischemia/reperfusion (IR), and the kinetics of luciferase expression were assessed with bioluminescence imaging. AcTnTeGFP was used to evaluate the distribution of eGFP expression. High-resolution echocardiography was used to evaluate the effects of AcTnTEcSOD on left ventricular (LV) remodeling when injected 10 min post-IR. RESULTS: Compared to sham animals, luciferase expression at 2 days after vector administration was elevated by four-, 24-, 210- and 213-fold in groups injected at 10 min, 1 day, 2 days and 3 days post-IR, respectively. The expression of cTnT-driven eGFP was strongest in cardiomyocytes bordering the infarct zone. In the efficacy study of EcSOD, post-infarct LV end-systolic and end-diastolic volumes at days 14 and 28 were significantly smaller in the EcSOD group compared to the control. CONCLUSIONS: Systemic administration of AAV9 vectors after IR both elevates and accelerates gene expression that preferentially targets cardiomyocytes in the border zone with pharmacodynamics suitable for the attenuation of LV remodeling.

T2 -weighted MRI of post-infarct myocardial edema in mice.

T(2) -weighted, cardiac magnetic resonance imaging (T(2) w CMR) can be used to noninvasively detect and quantify the edematous region that corresponds to the area at risk (AAR) following myocardial infarction (MI). Previously, CMR has been used to examine structure and function in mice, expediting the study of genetic manipulations. To date, CMR has not been applied to imaging of post-MI AAR in mice. We developed a whole-heart, T(2) w CMR sequence to quantify the AAR in mouse models of ischemia and infarction. The ΔB(0) and ΔB(1) environment around the mouse heart at 7 T were measured, and a T(2) -preparation sequence suitable for these conditions was developed. Both in vivo T(2) w and late gadolinium enhanced CMR were performed in mice after 20-min coronary occlusions, resulting in measurements of AAR size of 32.5 ± 3.1 (mean ± SEM)% left ventricular mass, and MI size of 50.1 ± 6.4% AAR size. Excellent interobserver agreement and agreement with histology were also found. This T(2) w imaging method for mice may allow for future investigations of genetic manipulations and novel therapies affecting the AAR and salvaged myocardium following reperfused MI.

A magnetic resonance imaging contrast agent capable of detecting hydrogen peroxide.

The redox-active ligand N-(2-hydroxy-5-methylbenzyl)-N,N',N'-tris(2-pyridinylmethyl)-1,2-ethanediamine (Hptp1) was prepared and complexed to manganese(II). The isolated [Mn(Hptp1)(MeCN)](2+) serves as a magnetic resonance imaging contrast agent, with an r(1) value comparable to those of other mononuclear gadolinium(III) and manganese(II) complexes. The metal and ligand are stable in aerated aqueous solutions, but the addition of H(2)O(2) causes the complex to oxidatively couple to itself through a bimolecular reaction involving the phenol groups of two Hptp1 ligands. The binuclear product is less paramagnetic per manganese(II) than its mononuclear precursor, lowering the measured r(1) per manganese(II). The manganese(II) complex with Hptp1 can thereby serve as a sensor for oxidative stress.

Extra-Virgin Olive Oil Enhances the Blood-Brain Barrier Function in Mild Cognitive Impairment: A Randomized Controlled Trial.

Mild cognitive impairment (MCI) and early Alzheimer's disease (AD) are characterized by blood-brain barrier (BBB) breakdown leading to abnormal BBB permeability ahead of brain atrophy or dementia. Previous findings in AD mouse models have reported the beneficial effect of extra-virgin olive oil (EVOO) against AD, which improved BBB and memory functions and reduced brain amyloid-ß (Aß) and related pathology. This work aimed to translate these preclinical findings to humans in individuals with MCI. We examined the effect of daily consumption of refined olive oil (ROO) and EVOO for 6 months in MCI subjects on BBB permeability (assessed by contrast-enhanced MRI), and brain function (assessed using functional-MRI) as the primary outcomes. Cognitive function and AD blood biomarkers were also assessed as the secondary outcomes. Twenty-six participants with MCI were randomized with 25 participants completed the study. EVOO significantly improved clinical dementia rating (CDR) and behavioral scores. EVOO also reduced BBB permeability and enhanced functional connectivity. While ROO consumption did not alter BBB permeability or brain connectivity, it improved CDR scores and increased functional brain activation to a memory task in cortical regions involved in perception and cognition. Moreover, EVOO and ROO significantly reduced blood Aß42/Aß40 and p-tau/t-tau ratios, suggesting that both altered the processing and clearance of Aß. In conclusion, EVOO and ROO improved CDR and behavioral scores; only EVOO enhanced brain connectivity and reduced BBB permeability, suggesting EVOO biophenols contributed to such an effect. This proof-of-concept study justifies further clinical trials to assess olive oil's protective effects against AD and its potential role in preventing MCI conversion to AD and related dementias.

Effects of High-Volume Versus High-Load Resistance Training on Skeletal Muscle Growth and Molecular Adaptations.

We evaluated the effects of higher-load (HL) versus (lower-load) higher-volume (HV) resistance training on skeletal muscle hypertrophy, strength, and muscle-level molecular adaptations. Trained men (n = 15, age: 23 ± 3 years; training experience: 7 ± 3 years) performed unilateral lower-body training for 6 weeks (3× weekly), where single legs were randomly assigned to HV and HL paradigms. Vastus lateralis (VL) biopsies were obtained prior to study initiation (PRE) as well as 3 days (POST) and 10 days following the last training bout (POSTPR). Body composition and strength tests were performed at each testing session, and biochemical assays were performed on muscle tissue after study completion. Two-way within-subject repeated measures ANOVAs were performed on most dependent variables, and tracer data were compared using dependent samples t-tests. A significant interaction existed for VL muscle cross-sectional area (assessed via magnetic resonance imaging; interaction p = 0.046), where HV increased this metric from PRE to POST (+3.2%, p = 0.018) whereas HL training did not (-0.1%, p = 0.475). Additionally, HL increased leg extensor strength more so than HV training (interaction p = 0.032; HV < HL at POST and POSTPR, p < 0.025 for each). Six-week integrated non-myofibrillar protein synthesis (iNon-MyoPS) rates were also higher in the HV versus HL condition, while no difference between conditions existed for iMyoPS rates. No interactions existed for other strength, VL morphology variables, or the relative abundances of major muscle proteins. Compared to HL training, 6 weeks of HV training in previously trained men optimizes VL hypertrophy in lieu of enhanced iNon-MyoPS rates, and this warrants future research.

Manganese(II)-containing MRI contrast agent employing a neutral and non-macrocyclic ligand.

The ligand N,N'-bis(2-pyridylmethyl)-bis(ethylacetate)-1,2-ethanediamine (debpn) coordinates divalent transition metal ions in either a pentadentate or hexadentate fashion. The coordination number correlates with the ionic radius of the metal ion, with larger cations being heptacoordinate as assessed by solid-state analysis. With Mn(II), the debpn ligand is hexadentate and remains bound to the oxophilic metal ion, even when dissolved in water. The ligand's incomplete coordination of the manganous ion allows water molecules to coordinate to the metal center. These two properties, coupled with the high paramagnetism associated with the S = 5/2 metal center, enable [Mn(debpn)(H(2)O)](ClO(4))(2) to serve as a stable and effective magnetic resonance imaging contrast agent despite the ligand's lack of both a macrocyclic component and an anionic charge.

7T MRI Predicts Amelioration of Neurodegeneration in the Brain after AAV Gene Therapy.

GM1 gangliosidosis (GM1) is a fatal neurodegenerative lysosomal storage disease that occurs most commonly in young children, with no effective treatment available. Long-term follow-up of GM1 cats treated by bilateral thalamic and deep cerebellar nuclei (DCN) injection of adeno-associated virus (AAV)-mediated gene therapy has increased lifespan to 8 years of age, compared with an untreated lifespan of ~8 months. Due to risks associated with cerebellar injection in humans, the lateral ventricle was tested as a replacement route to deliver an AAVrh8 vector expressing feline ß-galactosidase (ß-gal), the defective enzyme in GM1. Treatment via the thalamus and lateral ventricle corrected storage, myelination, astrogliosis, and neuronal morphology in areas where ß-gal was effectively delivered. Oligodendrocyte number increased, but only in areas where myelination was corrected. Reduced AAV and ß-gal distribution were noted in the cerebellum with subsequent increases in storage, demyelination, astrogliosis, and neuronal degeneration. These postmortem findings were correlated with endpoint MRI and magnetic resonance spectroscopy (MRS). Compared with the moderate dose with which most cats were treated, a higher AAV dose produced superior survival, currently 6.5 years. Thus, MRI and MRS can predict therapeutic efficacy of AAV gene therapy and non-invasively monitor cellular events within the GM1 brain.