Can Deflagration-Detonation-Transitions occur in Type Ia Supernovae?

The mechanism for deflagration-detonation-transition (DDT) by turbulent preconditioning, suggested to explain the possible occurrence of delayed detonations in Type Ia supernova explosions, is argued to be conceptually inconsistent. It relies crucially on diffusive heat losses of the burned material on macroscopic scales. Regardless of the amplitude of turbulent velocity fluctuations, the typical gradient scale for temperature fluctuations is shown to be the laminar flame width or smaller, rather than the factor of thousand more required for a DDT. Furthermore, thermonuclear flames cannot be fully quenched in regions much larger than the laminar flame width as a consequence of their simple ``chemistry''. Possible alternative explosion scenarios are briefly discussed.Comment: 8 pages, uses aastex; added references. Accepted by ApJ Letter

Conventional spark versus nanosecond repetitively pulsed discharge for a turbulence facilitated ignition phenomenon

This work applies both conventional-single-spark-discharge (CSSD) at 500-µs pulse duration time and nanosecond-repetitively-pulsed-discharge (NRPD) at various pulsed-repetitive-frequency PRF = 5–70 kHz to explore a turbulence facilitated ignition (TFI) phenomenon using a pair of pin-to-pin electrodes at an inter-electrode gap of 0.8 mm in randomly-stirred lean n-butane/air mixture with Lewis number ≫ 1. For CSSD, measured laminar and turbulent minimum ignition energies (MIE$_{L}$ and MIE$_{T}$) at 50% ignitability show that MIE$_{L}$≈ 23 mJ > the smallest MIE$_{T}$≈ 19.7 mJ at u′ = 0.9 m/s (TFI) and then MIE$_{T}$≈ 28.6/30.8/36.8 mJ at u′ = 1.4/2.1/2.8 m/s (no TFI), where u′ is the r.m.s turbulent fluctuating velocity. For comparison, all NRPD experiments apply the same total ignition energy E$_{tot}$≈ 23 mJ via a fixed train of 11 pulses, each pulse with 2.2 mJ except for the first pulse with 1 mJ. NRPD results show a cumulatively synergistic effect depending on the coherence between PRF and an inward reactant flow recirculation frequency (f$_{RC}$) inside the torus-like kernel induced by the discharge that could enhance ignition. When PRF is approximately synchronizing with f$_{RC}$, the synergistic effect is most profound at PRF = 20-kHz/40-kHz with very high ignition probability P$_{ig}$ = 90%/85% > 50% in quiescence, whereas lower values of P$_{ig}$ = 42%/34% are found at PRF = 10-kHz/60-kHz. Further, P$_{ig}$ = 0 at PRF = 5-kHz even when 5000 pulses (E$_{tot}$≈ 10 J) are applied. We discover that P$_{ig}$ decreases significantly with increasing u′ for most PRFs (no TFI) except at higher PRF ≥ 60 kHz showing possible TFI. These results are attributed to the interactions between turbulent dissipation, differential diffusion, and synergistic influence, which are substantiated by Schlieren images of initial kernel development and the ignition time determined at one half of the flame critical radius that leads to a self-sustained spherical flame propagation

Phenotypic Variability of Childhood Charcot-Marie-Tooth Disease

IMPORTANCE: Disease severity of childhood Charcot-Marie-Tooth disease (CMT) has not been extensively characterized, either within or between types of CMT to date. OBJECTIVE: To assess the variability of disease severity in a large cohort of children and adolescents with CMT. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study was conducted among 520 children and adolescents aged 3 to 20 years at 8 universities and hospitals involved in the Inherited Neuropathies Consortium between August 6, 2009, and July 31, 2014, in Australia, Italy, the United Kingdom, and the United States. Data analysis was conducted from August 1, 2014, to December 1, 2015. MAIN OUTCOMES AND MEASURES: Scores on the Charcot-Marie-Tooth Disease Pediatric Scale (CMTPedS), a well-validated unidimensional clinical outcome measure to assess disease severity. This instrument includes 11 items assessing fine and gross motor function, sensation, and balance to produce a total score ranging from 0 (unaffected) to 44 (severely affected). RESULTS: Among the 520 participants (274 males) aged 3 to 20 years, CMT type 1A (CMT1A) was the most prevalent type (252 [48.5%]), followed by CMT2A (31 [6.0%]), CMT1B (15 [2.9%]), CMT4C (13 [2.5%]), and CMTX1 (10 [1.9%]). Disease severity ranged from 1 to 44 points on the CMTPedS (mean [SD], 21.5 [8.9]), with ankle dorsiflexion strength and functional hand dexterity test being most affected. Participants with CMT1B (mean [SD] CMTPedS score, 24.0 [7.4]), CMT2A (29.7 [7.1]), and CMT4C (29.8 [8.6]) were more severely affected than those with CMT1A (18.9 [7.7]) and CMTX1 (males: 15.3 [7.7]; females: 13.0 [3.6]) (P < .05). Scores on the CMTPedS tended to worsen principally during childhood (ages, 3-10 years) for participants with CMT4C and CMTX1 and predominantly during adolescence for those with CMT1B and CMT2A (ages, 11-20 years), while CMT1A worsened consistently throughout childhood and adolescence. For individual items, participants with CMT4C recorded more affected functional dexterity test scores than did those with all other types of CMT (P < .05). Participants with CMT1A and CMTX1 performed significantly better on the 9-hole peg test and balance test than did those with all other types of CMT (P < .05). Participants with CMT2A had the weakest grip strength (P < .05), while those with CMT2A and CMT4C exhibited the weakest ankle plantarflexion and dorsiflexion strength, as well as the lowest long jump and 6-minute walk test distances (P < .05). Multiple regression modeling identified increasing age (r = 0.356, β = 0.617, P < .001) height (r = 0.251, β = 0.309, P = .002), self-reported foot pain (r = 0.162, β = .114, P = .009), and self-reported hand weakness (r = 0.243, β = 0.203, P < .001) as independent predictors of disease severity. CONCLUSIONS AND RELEVANCE: These results highlight the phenotypic variability within CMT genotypes and mutation-specific manifestations between types. This study has identified distinct functional limitations and self-reported impairments to target in future therapeutic trials

CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis

BACKGROUND: The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them. METHODS: We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES). RESULTS: 997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported. CONCLUSIONS: Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT. CLINICAL TRIAL REGISTRATION ID NUMBER: NCT0119307

Two novel missense mutations in the myelin protein zero gene causes Charcot-Marie-Tooth type 2 and Déjérine-Sottas syndrome

<p>Abstract</p> <p>Background</p> <p>The Charcot-Marie-Tooth (CMT) phenotype caused by mutation in the <it>myelin protein zero (MPZ) </it>gene varies considerably, from early onset and severe forms to late onset and milder forms. The mechanism is not well understood. The myelin protein zero (P₀) mediates adhesion in the spiral wraps of the Schwann cell's myelin sheath. The crystalline structure of the extracellular domain of the myelin protein zero (P₀ex) is known, while the transmembrane and intracellular structure is unknown.</p> <p>Findings</p> <p>One novel missense mutation caused a milder late onset CMT type 2, while the second missense mutation caused a severe early onset phenotype compatible with Déjérine-Sottas syndrome.</p> <p>Conclusions</p> <p>The phenotypic variation caused by different missense mutations in the <it>MPZ </it>gene is likely caused by different conformational changes of the MPZ protein which affects the functional tetramers. Severe changes of the MPZ protein cause dysfunctional tetramers and predominantly uncompacted myelin, i.e. the severe phenotypes congenital hypomyelinating neuropathy and Déjérine-Sottas syndrome, while milder changes cause the phenotypes CMT type 1 and 2.</p

Reliability of the Charcot-Marie-Tooth functional outcome measure

The CMT‐FOM is a 13‐item clinical outcome assessment (COA) that measures physical ability in adults with Charcot‐Marie‐Tooth disease (CMT). Test‐retest reliability, internal consistency and convergent validity have been established for the CMT‐FOM. This current study sought to establish inter‐rater reliability. Following an in‐person training of six international clinical evaluators we recruited 10 participants with genetically diagnosed CMT1A, (aged 18‐74 years, 6 female). Participants were evaluated using the CMT‐FOM over 2 days. Participants were given at least a 3 hour rest between evaluations, and were assessed twice each day. Following the provision of training by master trainers, all 13 items of the CMT‐FOM exhibited excellent inter‐rater reliability for raw scores (ICC1,1 0.825‐0.989) and z‐scores (ICC1,1 0.762‐0.969). Reliability of the CMT‐FOM total score was excellent (ICC1,1 0.983, 95% CI 0.958‐0.995). The CMT‐FOM is a reliable COA used by clinical evaluators internationally. The next steps are to establish further validation through psychometric evaluation of the CMT‐FOM in the Accelerate Clinical Trials in CMT (ACT‐CMT) study