111 research outputs found
MERRF/MELAS overlap syndrome: A double pathogenic mutation in mitochondrial tRNA genes
No full textBackground : Myoclonic epilepsy with ragged-red fibres (MERRF) and mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) are established phenotypes of mitochondrial encephalomyopathy. The m.8356T>C transition in the mitochondrial tRNALys gene is a pathogenic mutations of MERRF. The m.3243A>G transition in the mitochondrial tRNALeu gene is detected in most MELAS patients. Although previous analyses of double mutations in mitochondrial DNA (mtDNA) were useful for discussing their nature, many unsolved questions remain. Objective : To describe the clinical and genetic features of a family with the above mtDNA double-point mutations and discuss the role of double mtDNA mutations in diverse clinical features in the family. Patients and methods : The proband was a 23-year-old woman with MERRF harbouring m.8356T>C and m.3243A>G transitions in mitochondrial tRNA genes. We assessed clinical aspects of her and those of her three relatives and performed mutation analyses on their mtDNA. Results : Phenotypes of the four patients were MERRF, MERRF/MELAS overlap syndrome and asymptomatic carrier. We hypothesise that the course of the phenotype of this family begins with MERRF and is followed by MELAS. This double mutation was heteroplasmic in blood of all four patients but with different rates in each patient, while m.8356T>C appeared homoplasmic and m.3243A>G was heteroplasmic in muscle of the two examined cases. No other mutations were detected in the total mtDNA sequence in this family. Conclusions : This is the first reported case of a double-point mutation in mtDNA, both of which were heteroplasmic and pathogenic for the established phenotypes
Therapeutic regimen of l-arginine for MELAS: 9-year, prospective, multicenter, clinical research
No full text© 2018, The Author(s). Objective: To examine the efficacy and safety of the therapeutic regimen using oral and intravenous l-arginine for pediatric and adult patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Methods: In the presence and absence of an ictus of stroke-like episodes within 6 h prior to efficacy assessment, we correspondingly conducted the systematic administration of oral and intravenous l-arginine to 15 and 10 patients with MELAS in two, 2-year, prospective, multicenter clinical trials at 10 medical institutions in Japan. Subsequently, patients were followed up for 7 years. The primary endpoint in the clinical trial of oral l-arginine was the MELAS scale, while that for intravenous l-arginine was the improvement rates of headache and nausea/vomiting at 2 h after completion of the initial intravenous administration. The relationships between the ictuses of stroke-like episodes and plasma arginine concentrations were examined. Results: Oral l-arginine extended the interictal phase (p = 0.0625) and decreased the incidence and severity of ictuses. Intravenous l-arginine improved the rates of four major symptoms—headache, nausea/vomiting, impaired consciousness, and visual disturbance. The maximal plasma arginine concentration was 167 μmol/L when an ictus developed. Neither death nor bedriddenness occurred during the 2-year clinical trials, and the latter did not develop during the 7-year follow-up despite the progressively neurodegenerative and eventually life-threatening nature of MELAS. No treatment-related adverse events occurred, and the formulations of l-arginine were well tolerated. Conclusions: The systematic administration of oral and intravenous l-arginine may be therapeutically beneficial and clinically useful for patients with MELAS
Therapeutic regimen of l-arginine for MELAS: 9-year, prospective, multicenter, clinical research
No full text© 2018, The Author(s). Objective: To examine the efficacy and safety of the therapeutic regimen using oral and intravenous l-arginine for pediatric and adult patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Methods: In the presence and absence of an ictus of stroke-like episodes within 6 h prior to efficacy assessment, we correspondingly conducted the systematic administration of oral and intravenous l-arginine to 15 and 10 patients with MELAS in two, 2-year, prospective, multicenter clinical trials at 10 medical institutions in Japan. Subsequently, patients were followed up for 7 years. The primary endpoint in the clinical trial of oral l-arginine was the MELAS scale, while that for intravenous l-arginine was the improvement rates of headache and nausea/vomiting at 2 h after completion of the initial intravenous administration. The relationships between the ictuses of stroke-like episodes and plasma arginine concentrations were examined. Results: Oral l-arginine extended the interictal phase (p = 0.0625) and decreased the incidence and severity of ictuses. Intravenous l-arginine improved the rates of four major symptoms—headache, nausea/vomiting, impaired consciousness, and visual disturbance. The maximal plasma arginine concentration was 167 μmol/L when an ictus developed. Neither death nor bedriddenness occurred during the 2-year clinical trials, and the latter did not develop during the 7-year follow-up despite the progressively neurodegenerative and eventually life-threatening nature of MELAS. No treatment-related adverse events occurred, and the formulations of l-arginine were well tolerated. Conclusions: The systematic administration of oral and intravenous l-arginine may be therapeutically beneficial and clinically useful for patients with MELAS
Author response to the letter regarding the publication titled "Major cerebral vessels involvement in patients with MELAS syndrome: worth a scan? A systematic review"
No full textWe appreciate the interest in our systematic review, which revealed that dilatation or stenosis of major vessel caliber is present in 59% (27/46) of patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS) and underlined the importance of imaging intracranial vessels during prospective study protocols of patients with MELAS. We share the view that pathogenic mechanisms of (SLEs) are not fully understood and a variety of mechanisms has been proposed, including metabolically impaired mitochondrial energy production, as well as micro- and macrovascular angiopathy. A substantial degree of evidence has indicated that patients with MELAS have an inability to efficiently produce mitochondrial energy. In particular, a previous in vitro study of cybrid cell lines composed of cytoplasts from patients with MELAS bearing an A>G transition (nucleotide position 3243 in the tRNA(Leu(UUR)) gene of the mitochondrial genome) fused with human cells lacking endogenous mitochondrial DNA (mtDNA) demonstrated impaired mitochondrial translation and protein synthesis. Consequently, the inability to efficiently produce mitochondrial energy is a biochemical feature of MELAS syndrome, which may periodically exacerbate during SLEs.
Furthermore, microangiopathy of small blood vessels can occur in patients with MELAS that may show abnormal staining of succinate dehydrogenase, a mitochondrial enzyme, as well as mitochondrial proliferation in smooth muscle and endothelial cells of small blood vessels.
Therefore, blood vessels’ impaired energy metabolism may intrinsically contribute to abnormal perfusion during SLEs. Notably, several studies have indicated increased perfusion in patients with MELAS using computed tomography (CT), magnetic resonance imaging (MRI) perfusion, and single photon emission computed tomography (SPECT) during SLEs.
As suggested, we reviewed the possible influence of mtDNA mutations and pharmacological treatment on the vessel caliber alterations.
It is well known that in patients harboring mtDNA mutations, both mutant and wild type mtDNA molecules may coexist within the same cell, defining a condition called heteroplasmy, which may vary widely among different tissues. Importantly, the skeletal muscle and blood heteroplasmy levels of the m.3243A>G mutation are correlated with disease severity in patients with MELAS.
Interestingly, a recent study of our group identified a common diffuse pattern of brain biochemical alterations detected in vivo by proton magnetic resonance spectroscopy, which correlated with mtDNA heteroplasmy in patients with MELAS. Unfortunately, in the reviewed studies, the percentage of mutated mtDNA was reported in only one third of them (n = 8/23, 35%). Heteroplasmy ranged from 22% to 76%, and was measured in different tissues such as skeletal muscle, fibroblasts, and blood cells
Optimal investment decisions in static and dynamic environments
No full textThis thesis addresses three optimisation problems. The first problem concerns static portfolio optimization. Empirical evidence suggests that asset dynamics can be characterised by a multifactor representation of asset returns. In this context, investors can capture the premium or hedge the risk associated with a particular factor through factor-mimicking portfolios. We examine different methods for constructing optimal factor-mimicking portfolios. We provide analytical considerations in the construction of factor-mimicking portfolios, along with empirical evidence. Also, we illustrate potential practical applications of factor-mimicking portfolios in the institutional investment process. The second problem addresses continuous time optimal consumption and investment for an agent investing in a complete arbitrage-free market consisting of several risky assets and a bank account. In particular, we consider a general model in which the agent's preferences exhibit a linear habit formation pattern that captures the effect of past consumption on current utility. Using duality methods, we establish the existence of an optimal consumption and investment strategy. We also prove that the optimal portfolio consumption pair can be expressed in terms of the solution to the Hamilton-Jacobi-Bellman equation that the problem's value function satisfies. The third problem concerns a general one-dimensional lro diffusion which must be maintained within an externally specified bounded interval by means of an impulse control process. We minimise a long-term average criterion that penalises deviations of the state process from a given nominal point within this region as well as the use of impulsive control effort. We solve the resulting optimisation problem and we provide an explicit optimal control strategy under general assumptions. The model that we study is motivated by several applications, including the problem of determining an optimal central bank intervention strategy aiming at the control of an exchange rate or an inflation rate, as well as the problem of designing optimal contribution policies in defined benefit pension plans.EThOS - Electronic Theses Online ServiceGBUnited Kingdo
Quantitative measurement of cerebral oxygen extraction fraction using MRI in patients with MELAS.
No full textOBJECTIVE: To quantify the cerebral OEF at different phases of stroke-like episodes in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) by using MRI. METHODS: We recruited 32 patients with MELAS confirmed by gene analysis. Conventional MRI scanning, as well as functional MRI including arterial spin labeling and oxygen extraction fraction imaging, was undertaken to obtain the pathological and metabolic information of the brains at different stages of stroke-like episodes in patients. A total of 16 MRI examinations at the acute and subacute phase and 19 examinations at the interictal phase were performed. In addition, 24 healthy volunteers were recruited for control subjects. Six regions of interest were placed in the anterior, middle, and posterior parts of the bilateral hemispheres to measure the OEF of the brain or the lesions. RESULTS: OEF was reduced significantly in brains of patients at both the acute and subacute phase (0.266 ± 0.026) and at the interictal phase (0.295 ± 0.009), compared with normal controls (0.316 ± 0.025). In the brains at the acute and subacute phase of the episode, 13 ROIs were prescribed on the stroke-like lesions, which showed decreased OEF compared with the contralateral spared brain regions. Increased blood flow was revealed in the stroke-like lesions at the acute and subacute phase, which was confined to the lesions. CONCLUSION: MRI can quantitatively show changes in OEF at different phases of stroke-like episodes. The utilization of oxygen in the brain seems to be reduced more severely after the onset of episodes in MELAS, especially for those brain tissues involved in the episodes
Simulations of Coastal Atmospheric Dynamics and Transport Processes
No full textThe marine atmosphere can be highly variable in space and time, and the coastal terrain plays a crucial role in influencing its properties. These, in turn, determine the atmospheric transport in the coastal zone.The rapid collapse of a cloud-topped Marine Atmospheric Boundary Layer (MABL) is studied using aircraft observations of the same, made off the south-eastern coast of Sweden, and mesoscale atmospheric model simulations. The study reveals distortion of the vertical turbulent eddy structure due to the rapid evolution, a new mode of initiation of low-level wind jet due to the collapse, as well as how the jet strength and location are affected by the blocking by coastal terrain. Marine atmospheric variability and the coastal terrain continue to play a central role in the rest of the thesis focussing on coastal atmospheric transport. A Lagrangian Random Particle dispersion model (LAP) is developed and used to quantify this transport. Dispersion calculations using particle models are subject to errors and uncertainties. A method to characterize these is proposed and used with the LAP model, with three different turbulence parameterizations. Simulated dispersion is shown to agree well with measurements from a field program.The LAP model, in conjunction with Mesoscale Model 5 (MM5) simulations, is applied to examine the inland transport of marine air along the California coast during a period of dramatic and rare wind rotation in June 1996. The impact of this wind field rotation on the spatial structure of marine air penetration, blocking by the coastal terrain, and the diurnal impact on penetration are revealed. A simple method of quantification of marine air transport using the particle model is proposed and shows interesting features of penetration. During the commonly seen northerly winds along the California coast during summer, the air flow is considered dynamically blocked by the terrain. Marine air transport during five such typical days of June 1996 is examined using MM5 and LAP model simulations. A significant amount of cross-coast transport is shown to occur on all the days at specific coastal locations. Diurnal enhancement of the transport, as well as daily variations in the same are also revealed.</p
Evaluation of numerical mesoscale modeling of surface fluxes in a heterogeneous boreal forest region
No full textAn ergodic impulse control model with applications
No full textWorld leading experts give their accounts of the modern mathematical models in the field: Markov Decision Processes, controlled diffusions, piece-wise deterministic processes etc, with a wide range of performance functionals. One of the aims is to give a general view on the state-of-the-art. The authors use Dynamic Programming, Convex Analytic Approach, several numerical methods, index-based approach and so on. Most chapters either contain well developed examples, or are entirely devoted to the application of the mathematical control theory to real life problems from such fields as Insurance, Portfolio Optimization and Information Transmission. The book will enable researchers, academics and research students to get a sense of novel results, concepts, models, methods, and applications of controlled stochastic processes
- …
