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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.
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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.
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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.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Animales , Ratones , Humanos , Aceite de Oliva/farmacología , Barrera Hematoencefálica/metabolismo , Enfermedad de Alzheimer/prevención & control , Disfunción Cognitiva/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismoRESUMEN
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.
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Medios de Contraste , Hierro , Ligandos , Imagen por Resonancia Magnética , AguaRESUMEN
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.
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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.
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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.
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Prior functional Magnetic Resonance Imaging (fMRI) studies have indicated increased neural activation when zinc nanoparticles are added to odorants in canines. Here we demonstrate that zinc nanoparticles up-regulate directional brain connectivity in parts of the canine olfactory network. This provides an explanation for previously reported enhancement in the odor detection capability of the dogs in the presence of zinc nanoparticles. In this study, we obtained fMRI data from awake and unrestrained dogs while they were being exposed to odorants with and without zinc nanoparticles, zinc nanoparticles suspended in water vapor, as well as just water vapor alone. We obtained directional connectivity between the brain regions of the olfactory network that were significantly stronger for the condition of odorant + zinc nanoparticles compared to just odorants, water vapor + zinc nanoparticles and water vapor alone. We observed significant strengthening of the paths of the canine olfactory network in the presence of zinc nanoparticles. This result indicates that zinc nanoparticles could potentially be used to increase canine detection capabilities in the environments of very low concentrations of the odorants, which would have otherwise been undetected.
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Tay-Sachs disease (TSD) is a fatal neurodegenerative disorder caused by a deficiency of the enzyme hexosaminidase A (HexA). TSD also occurs in sheep, the only experimental model of TSD that has clinical signs of disease. The natural history of sheep TSD was characterized using serial neurological evaluations, 7 Tesla magnetic resonance imaging, echocardiograms, electrodiagnostics, and cerebrospinal fluid biomarkers. Intracranial gene therapy was also tested using AAVrh8 monocistronic vectors encoding the α-subunit of Hex (TSD α) or a mixture of two vectors encoding both the α and ß subunits separately (TSD α + ß) injected at high (1.3 × 1013 vector genomes) or low (4.2 × 1012 vector genomes) dose. Delay of symptom onset and/or reduction of acquired symptoms were noted in all adeno-associated virus-treated sheep. Postmortem evaluation showed superior HexA and vector genome distribution in the brain of TSD α + ß sheep compared to TSD α sheep, but spinal cord distribution was low in all groups. Isozyme analysis showed superior HexA formation after treatment with both vectors (TSD α + ß), and ganglioside clearance was most widespread in the TSD α + ß high-dose sheep. Microglial activation and proliferation in TSD sheep-most prominent in the cerebrum-were attenuated after gene therapy. This report demonstrates therapeutic efficacy for TSD in the sheep brain, which is on the same order of magnitude as a child's brain.
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Dependovirus , Terapia Genética , Enfermedad de Tay-Sachs/terapia , Cadena alfa de beta-Hexosaminidasa/biosíntesis , Cadena beta de beta-Hexosaminidasa/biosíntesis , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/enzimología , Modelos Animales de Enfermedad , Ecocardiografía , Humanos , Imagen por Resonancia Magnética , Microglía/enzimología , Ovinos , Enfermedad de Tay-Sachs/diagnóstico por imagen , Enfermedad de Tay-Sachs/enzimología , Enfermedad de Tay-Sachs/genética , Cadena alfa de beta-Hexosaminidasa/genética , Cadena beta de beta-Hexosaminidasa/genéticaRESUMEN
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.
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Antioxidantes/farmacología , Medios de Contraste/química , Peróxido de Hidrógeno/química , Hidroquinonas/química , Manganeso/farmacología , Compuestos Organometálicos/farmacología , Animales , Antioxidantes/síntesis química , Antioxidantes/química , Muerte Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Imagen por Resonancia Magnética , Manganeso/química , Modelos Moleculares , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Oxidación-Reducción , RatasRESUMEN
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.
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Biomarcadores , Gangliosidosis GM1/genética , Gangliosidosis GM1/metabolismo , Terapia Genética , Animales , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/orina , Gatos , Dependovirus/clasificación , Dependovirus/genética , Modelos Animales de Enfermedad , Electroencefalografía , Gangliosidosis GM1/mortalidad , Gangliosidosis GM1/terapia , Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Humanos , Hipocalcemia/metabolismo , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Resultado del TratamientoRESUMEN
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.
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Cardiotónicos/administración & dosificación , Distrofia Muscular de Duchenne/tratamiento farmacológico , Quercetina/administración & dosificación , Animales , Antioxidantes/administración & dosificación , Ciclooxigenasa 2/metabolismo , Dieta , Modelos Animales de Enfermedad , Distrofina/metabolismo , Corazón/efectos de los fármacos , Ratones , Ratones Endogámicos mdx , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Distrofia Muscular Animal/tratamiento farmacológico , Distrofia Muscular Animal/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Miocardio/metabolismo , FN-kappa B/metabolismo , Superóxido Dismutasa/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
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.
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Antioxidantes/farmacología , Corazón/efectos de los fármacos , Distrofia Muscular Animal/fisiopatología , Quercetina/farmacología , Animales , Antígenos de Diferenciación/efectos de los fármacos , Antígenos de Diferenciación/metabolismo , Western Blotting , Citrato (si)-Sintasa/efectos de los fármacos , Citrato (si)-Sintasa/metabolismo , Ciclooxigenasa 2/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Citocromos c/efectos de los fármacos , Citocromos c/metabolismo , Modelos Animales de Enfermedad , Proteínas del Complejo de Cadena de Transporte de Electrón/efectos de los fármacos , Proteínas del Complejo de Cadena de Transporte de Electrón/metabolismo , Fibronectinas/metabolismo , Alimentos Fortificados , Corazón/diagnóstico por imagen , Corazón/fisiopatología , Imagen por Resonancia Magnética , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos mdx , Mitocondrias Musculares/efectos de los fármacos , Mitocondrias Musculares/metabolismo , Actividad Motora , Distrofia Muscular Animal/metabolismo , Distrofia Muscular de Duchenne , Miocardio/metabolismo , Miocardio/patología , Inhibidor NF-kappaB alfa/efectos de los fármacos , Inhibidor NF-kappaB alfa/metabolismo , FN-kappa B/efectos de los fármacos , FN-kappa B/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/efectos de los fármacos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Fosforilación , Receptores de IgG/efectos de los fármacos , Receptores de IgG/metabolismo , Sarcoglicanos/metabolismo , Superóxido Dismutasa/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Factor de Crecimiento Transformador beta1/efectos de los fármacos , Factor de Crecimiento Transformador beta1/metabolismo , Utrofina/genética , Utrofina/metabolismoRESUMEN
BACKGROUND: One of the barriers to studying the behavioral and emotional effects of pain using functional Magnetic Resonance Imaging (fMRI) is the absence of a commercially available, MRI-compatible, pressure-based algometer to elicit pain. The present study sought to address this barrier through creation and validation of a novel MRI-safe apparatus capable of delivering incremental, measurable amounts of pressure inside a scanning bore. NEW METHOD: We introduced an MR-safe device used to administer pressure-based pain. To test against a commercially available, MRI-incompatible algometer (AlgoMed), 199 participants reported their pain tolerance for both devices. A second experiment tested the validity of pressure-based pain in an MRI environment by comparing brain activation with established neural networks for pain. 10 participants performed an identical procedure to test for pain tolerance while being scanned in a 7T MRI scanner. RESULTS: Results support the validity and reliability of our novel device. In Study 1, pain tolerance with this device was strongly correlated with pain tolerance as measured by a commercially available algometer (r=0.78). In Study 2, this device yielded BOLD activation within the insula (BA 13) and anterior cingulate gyrus (BA 24); as pressure increased, activation in these areas parametrically increased. COMPARISON WITH EXISTING METHOD: These findings correspond to other studies using thermal, electrical, or mechanical pain applications. Behavioral and functional data demonstrate that this new device is a valid method of administering pressure-related pain in MRI environments. CONCLUSIONS: Our novel MRI-safe device is a valid instrument to measure and administer pressure-based pain.
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Imagen por Resonancia Magnética/instrumentación , Dimensión del Dolor/instrumentación , Dolor/diagnóstico , Dolor/fisiopatología , Presión , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Mapeo Encefálico/instrumentación , Diseño de Equipo , Femenino , Humanos , Masculino , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
BACKGROUND: Ivabradine selectively inhibits the pacemaker current of the sinoatrial node, slowing heart rate. Few studies have examined the effects of ivabradine on the mechanical properties of the heart after reperfused myocardial infarction (MI). Advances in ultrasound speckle-tracking allow strain analyses to be performed in small-animal models, enabling the assessment of regional mechanical function. METHODS AND RESULTS: After 1 hour of coronary occlusion followed by reperfusion, mice received 10 mg/kg per day of ivabradine dissolved in drinking water (n=10), or were treated as infarcted controls (n=9). Three-dimensional high-frequency echocardiography was performed at baseline and at days 2, 7, 14, and 28 post-MI. Speckle-tracking software was used to calculate intramural longitudinal myocardial strain (Ell) and strain rate. Standard deviation time to peak radial strain (SD Tpeak Err) and temporal uniformity of strain were calculated from short-axis cines acquired in the left ventricular remote zone. Ivabradine reduced heart rate by 8% to 16% over the course of 28 days compared to controls (P<0.001). On day 28 post-MI, the ivabradine group was found to have significantly smaller end-systolic volumes, greater ejection fraction, reduced wall thinning, and greater peak Ell and Ell rate in the remote zone, as well as globally. Temporal uniformity of strain and SD Tpeak Err were significantly smaller in the ivabradine-treated group by day 28 (P<0.05). CONCLUSIONS: High-frequency ultrasound speckle-tracking demonstrated decreased left ventricular remodeling and dyssynchrony, as well as improved mechanical performance in remote myocardium after heart rate reduction with ivabradine.
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Benzazepinas/uso terapéutico , Frecuencia Cardíaca/efectos de los fármacos , Contracción Miocárdica/fisiología , Infarto del Miocardio/tratamiento farmacológico , Daño por Reperfusión Miocárdica/complicaciones , Función Ventricular Izquierda/fisiología , Remodelación Ventricular/efectos de los fármacos , Animales , Fármacos Cardiovasculares/uso terapéutico , Modelos Animales de Enfermedad , Ecocardiografía , Frecuencia Cardíaca/fisiología , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/fisiopatología , Ivabradina , Imagen por Resonancia Cinemagnética , Masculino , Ratones , Ratones Endogámicos C57BL , Contracción Miocárdica/efectos de los fármacos , Infarto del Miocardio/etiología , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/diagnóstico , Daño por Reperfusión Miocárdica/fisiopatología , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
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.
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Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Estado de Conciencia/fisiología , Imagen por Resonancia Magnética , Nanopartículas del Metal/administración & dosificación , Odorantes , Zinc/administración & dosificación , Animales , Mapeo Encefálico , Perros , Neuronas Receptoras Olfatorias/fisiología , Zinc/farmacologíaRESUMEN
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.
Asunto(s)
Compuestos Férricos/química , Nanopartículas de Magnetita/análisis , Nanopartículas de Magnetita/química , Dispersión Dinámica de Luz , Campos Magnéticos , Microscopía Electrónica de Transmisión , Tamaño de la PartículaRESUMEN
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.
Asunto(s)
Terapia Genética , Enfermedad de Sandhoff/genética , Enfermedad de Sandhoff/terapia , beta-N-Acetilhexosaminidasas/genética , beta-N-Acetilhexosaminidasas/uso terapéutico , Adenoviridae/genética , Estructuras Animales/patología , Animales , Gatos , Modelos Animales de Enfermedad , Vectores Genéticos , Humanos , Mucopolisacaridosis/genética , Mucopolisacaridosis/patología , Mucopolisacaridosis/terapia , Fenotipo , Enfermedad de Sandhoff/fisiopatología , Enfermedad de Sandhoff/orinaRESUMEN
OBJECTIVE: To determine whether exercise on alternative terrain affects the development of the digital cushion and bony structures of the bovine foot. ANIMALS: 20 weaned bull calves. PROCEDURES: Two-month-old calves were randomly allocated to an exercise or control group. For 4 months, the control group was maintained in grass paddocks, and the exercise group was maintained in a 0.8-km lane with a mixed terrain of dirt, stones (0.32- to 0.95-cm pea gravel and 5-cm crusher run), and grass. Water and food for the exercise group were located at opposite ends of the lane; calves were fed twice daily, which ensured they walked 3.2 km/d. Pedometers were applied to all calves to measure distance traveled. All calves were slaughtered at 6 months of age. The right forefeet and hind feet were harvested for MRI and CT evaluation. RESULTS: Control calves walked a mean of 1.1 km daily, whereas the exercised calves walked a mean of 3.2 km daily. Mean digital cushion volume and surface area were 25,335 mm(3) and 15,647 mm(2), respectively, for the exercised calves and 17,026 mm(3) and 12,745 mm(2), respectively, for the control calves. When weight was controlled, mean digital cushion volume and surface area for the exercise group were increased by 37.10% and 18.25%, respectively, from those for the control group. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that exercise on alternative terrain increased the volume and surface area of the digital cushion of the feet of dairy calves, which should make them less susceptible to lameness.