The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy

Background: Hypertrophic (HCM) and dilated (DCM) cardiomyopathies results from sarcomeric protein mutations, including cardiac troponin T (cTnT, TNNT2). We determined whether TNNT2 mutations cause cardiomyopathies by altering cTnT function or quantity; whether the severity of DCM is related to the ratio of mutant to wildtype cTnT; whether Ca2+ desensitization occurs in DCM; and whether absence of cTnT impairs early embryonic cardiogenesis. Methods and Findings: We ablated Tnnt2 to produce heterozygous Tnnt2+/ mice, and crossbreeding produced homozygous null Tnnt2-/-embryos. We also generated transgenic mice overexpressing wildtype (TGWT) or DCM mutant (TGK210Δ) Tnnt2. Crossbreeding produced mice lacking one allele of Tnnt2, but carrying wildtype (Tnnt2+/-/TGWT) or mutant (Tnnt2+/-/TGK210Δ) transgenes. Tnnt2+/-mice relative to wildtype had significantly reduced transcript (0.82 ± 0.06 [SD] vs. 1.00 ± 0.12 arbitrary units; p = 0.025), but not protein (1.01 ± 0.20 vs. 1.00 ± 0.13 arbitrary units; p = 0.44). Tnnt2+/-mice had normal hearts (histology, mass, left ventricular end diastolic diameter [LVEDD], fractional shortening [FS]). Moreover, whereas Tnnt2+/-/ TGK210Δ mice had severe DCM, TGK210Δ mice had only mild DCM (FS 18 ± 4 vs. 29 ± 7%; p < 0.01). The difference in severity of DCM may be attributable to a greater ratio of mutant to wildtype Tnnt2 transcript in Tnnt2+/-/TGK210Δ relative to TGK210Δ mice (2.42±0.08, p = 0.03). Tnnt2+/-/TGK210Δ muscle showed Ca2+ desensitization (pCa50 = 5.34 ± 0.08 vs. 5.58 ± 0.03 at sarcomere length 1.9 μm. p<0.01), but no difference in maximum force generation. Day 9.5 Tnnt2-/-embryos had normally looped hearts, but thin ventricular walls, large pericardial effusions, noncontractile hearts, and severely disorganized sarcomeres. Conclusions: Absence of one Tnnt2 allele leads to a mild deficit in transcript but not protein, leading to a normal cardiac phenotype. DCM results from abnormal function of a mutant protein, which is associated with myocyte Ca2+ desensitization. The severity of DCM depends on the ratio of mutant to wildtype Tnnt2 transcript. cTnT is essential for sarcomere formation, but normal embryonic heart looping occurs without contractile activity. © 2008 Ahmad et al

Careers in ecstasy use: do ecstasy users cease of their own accord? Implications for intervention development

<p>Abstract</p> <p>Background</p> <p>Ecstasy (MDMA, 3, 4-methylenodioxymethamphetamine) use is widespread in the Netherlands, with a lifetime prevalence of 4.3%, and two-thirds of dance party visitors being ecstasy users. However, research into Dutch ecstasy use patterns is lacking. In addition, recent studies suggest that ecstasy users cease their use automatically, which implies that interventions would do better to better focus on the promotion of harm reduction strategies than on inducing cessation. The current study addresses this process of ecstasy cessation.</p> <p>Methods</p> <p>32 participants from the Dutch dance scene were interviewed, and the results were systematically analysed using NVivo.</p> <p>Results</p> <p>Most ecstasy users had started to use out of curiosity. During use, users applied a host of harm reduction strategies, albeit inconsistently and sometimes incorrectly. Most users appeared to cease ecstasy use automatically because of loss of interest or changing life circumstances (e.g. a new job or relationship).</p> <p>Conclusion</p> <p>It appears that cessation of ecstasy use is largely determined by environmental variables and not by health concerns. This supports the idea that health promotion resources are better spent in trying to promote consistent and correct application of harm reduction practices than in trying to induce cessation.</p

Visual recovery after perinatal stroke evidenced by functional and diffusion MRI: case report

BACKGROUND: After perinatal brain injury, clinico-anatomic correlations of functional deficits and brain plasticity remain difficult to evaluate clinically in the young infant. Thus, new non-invasive methods capable of early functional diagnosis are needed in young infants. CASE PRESENTATION: The visual system recovery in an infant with perinatal stroke is assessed by combining diffusion tensor imaging (DTI) and event-related functional MRI (ER-fMRI). All experiments were done at 1.5T. A first DTI experiment was performed at 12 months of age. At 20 months of age, a second DTI experiment was performed and combined with an ER-fMRI experiment with visual stimuli (2 Hz visual flash). At 20 months of age, ER-fMRI showed significant negative activation in the visual cortex of the injured left hemisphere that was not previously observed in the same infant. DTI maps suggest recovery of the optic radiation in the vicinity of the lesion. Optic radiations in the injured hemisphere are more prominent in DTI at 20 months of age than in DTI at 12 months of age. CONCLUSION: Our data indicate that functional cortical recovery is supported by structural modifications that concern major pathways of the visual system. These neuroimaging findings might contribute to elaborate a pertinent strategy in terms of diagnosis and rehabilitation

Spatiotemporal characterization of neurodegeneration in the visual system upon acute and chronic optic neuropathies using diffusion tensor MRI

Electronic Poster Session - Neuro 2: Neurodegeneration (Not AD Dementia): no. 4717This study determined spatiotemporally the progression of microstructural disorganization in acute and chronic optic neuropathies of different severity using diffusion tensor MRI so as to better understand the mechanisms of pathological processes such as glutamate excitotoxicity, and in neurodegenerative diseases such as ocular hypertension and glaucoma. Our data suggested anterograde degeneration along the visual pathway upon acute glutamate excitotoxic retinal injury with varying rates of λ// and λ┴ changes along time. In addition, mild, early distal axonopathy might be detected in vivo along the visual pathway upon chronic ocular hypertension.link_to_OA_fulltex

Effects of chronic ocular hypertension and hypotensive drug treatment on ocular physiology and biotransport using dynamic gadolinium-enhanced MRI

Electronic Poster Session - Perfusion: Perfusion & Permeability: no. 4589Balanced aqueous humor flow dynamics is crucial to maintain healthy ocular physiology. Imbalanced aqueous humor flow dynamics would lead to altered intraocular pressure and retinal damage or visual loss in glaucoma disease. To date, the relationships between eye pressure, aqueous humor flow and glaucoma are not fully evaluated. Gd-enhanced MRI may non-invasively visualize flow dynamics of aqueous humor. In this study, dynamic Gd-enhanced MRI was employed to evaluate in vivo the ocular physiology and biotransport in a rat model of microbead-induced ocular hypertension and in healthy, normotensive rats after topical applications of 3 different ophthalmic hypotensive eye drops.link_to_OA_fulltex

In vivo assessment of aqueous humor dynamics upon chronic ocular hypertension and hypotensive drug treatment using gadolinium-enhanced MRI

Purpose. Although glaucoma treatments alter aqueous humor (AH) dynamics to lower intraocular pressure, the regulatory mechanisms of AH circulation and their contributions to the pathogenesis of ocular hypertension and glaucoma remain unclear. We hypothesized that gadolinium-enhanced magnetic resonance imaging (Gd-MRI) can visualize and assess AH dynamics upon sustained intraocular pressure elevation and pharmacologic interventions. Methods. Gadolinium contrast agent was systemically administered to adult rats to mimic soluble AH components entering the anterior chamber (AC) via blood-aqueous barrier. Dynamic Gd-MRI was applied to examine the signal enhancement in AC and vitreous body upon microbead-induced ocular hypertension and unilateral topical applications of latanoprost, timolol maleate, and brimonidine tartrate to healthy eyes. Results. Gadolinium signal time courses in microbead-induced hypertensive eyes possessed faster initial gadolinium uptake and higher peak signals in AC than control eyes, reflective of reduced gadolinium clearance upon microbead occlusion. Opposite trends were observed in latanoprost- and timolol-treated eyes, indicative of their respective drug actions on increased uveoscleral outflow and reduced AH production. The slowest initial gadolinium uptake but strongest peak signals were found in AC of both brimonidine-treated and untreated fellow eyes. These findings drew attention to the systemic effects of topical hypotensive drug treatment. Gadolinium leaked into the vitreous of microbead-induced hypertensive eyes and brimonidine-treated and untreated fellow eyes, suggestive of a compromise of aqueous-vitreous or blood-ocular barrier integrity. Conclusions. Gadolinium-enhanced MRI allows spatiotemporal and quantitative evaluation of altered AH dynamics and ocular tissue permeability for better understanding the physiological mechanisms of ocular hypertension and the efficacy of antiglaucoma drug treatments.School of Optometr

Structural-physiological relationships in the visual system upon glutamate excitotoxicity in the eye using diffusion tensor imaging and manganese-enhanced MRI

Scientific Session: Cell Memories: Cell Tracking & MEMRI: no. 0697Summa Cum Laude Merit AwardExcitotoxicity has been linked to the pathogenesis of ocular diseases and injuries and may involve early degeneration of both anterior and posterior visual pathways. To date, the spatiotemporal patterns of neurodegeneration in the visual system and the relationships with excitotoxic retinal injury and optic neuropathy are not fully elucidated. In this study, we employed DTI and MEMRI to study the microstructural alterations, anterograde Mn transport and their correlations along the visual pathway upon N-methyl-D-aspartate (NMDA)-induced glutamate excitotoxicity in the eye, in order to determine the pathophysiological events and structural-physiological relationships in the injured visual pathways

Structural-physiological relationships in the visual system upon glutamate excitotoxicity in the eye using diffusion tensor imaging and manganese-enhanced MRI

Scientific Session: Cell Memories: Cell Tracking & MEMRI: no. 0697Summa Cum Laude Merit AwardExcitotoxicity has been linked to the pathogenesis of ocular diseases and injuries and may involve early degeneration of both anterior and posterior visual pathways. To date, the spatiotemporal patterns of neurodegeneration in the visual system and the relationships with excitotoxic retinal injury and optic neuropathy are not fully elucidated. In this study, we employed DTI and MEMRI to study the microstructural alterations, anterograde Mn transport and their correlations along the visual pathway upon N-methyl-D-aspartate (NMDA)-induced glutamate excitotoxicity in the eye, in order to determine the pathophysiological events and structural-physiological relationships in the injured visual pathways

Morphological and microstructural changes in the eye and the brain in an experimental glaucoma model induced by crosslinking hydrogel injection

Traditional Poster Session: Neuro 2 - Novel Brain & Eye: no. 2284Glaucoma is the second leading cause of blindness in the world and is an irreversible neurodegenerative disease of the visual system. To date, limited models have been available to provide sustained intraocular pressure elevation while keeping a clear visual axis for normal visual input to the eye. In this study, we characterized a novel experimental glaucoma model in rats using a crosslinking hydrogel that gives sustained intraocular pressure elevation and a transparent medium after intracameral injection. In vivo anatomical MRI, magic angle-enhanced MRI and diffusion tensor imaging were employed to determine the morphological and microstructural changes in the whole eye and the brain in this model