Development of treatments for dementia is beset by special problems in defining the diagnosis, establishing efficacy criteria, and specifying the necessary duration of study. There is need for agreement among clinicians and scientists on diagnostic subgroups of dementia. Similarly, there is a need for harmonization of the regulatory guidelines in Europe, Japan, and the United States regarding the decision set of variables on which to base efficacy claims. The duration of trials must be based upon the intended claim: transient symptomatic benefit, maintained symptomatic benefit, or a therapeutic effect on disease progression. Claims other than transient benefit require long-term trials, suggested to be of at least six months in duration. Problems with long-term studies include slow patient accrual, high dropout rates, changing milieu, low return on investment, and lack of unanimity regarding regulatory requirements. Regulatory authorities must come to some accord, consonant with current clinical/scientific wisdom and consensus, regarding diagnosis, efficacy criteria, and feasible study duration, in order to attract continued sponsor investment in the development of antidementia treatments.

Background: Ataluren is the first drug to treat the underlying cause of nmDMD. Methods: Phase 2 and 3 studies of ataluren in nmDMD were reviewed, with efficacy and safety/tolerability findings summarized. Results: Ataluren nmDMD trials include: a Phase 2a proof-of-concept study (N=38); a Phase 2b randomized controlled trial (RCT) (N=174); an ongoing US-based open-label safety extension study (N=108); an ongoing non-US-based open-label safety/efficacy extension study (N=94); and a Phase 3 RCT, ACT DMD (N=228), whose primary endpoint was change in six-minute walk distance (6MWD) over 48 weeks. The proof-of-concept study demonstrated increased dystrophin production in post-treatment muscle biopsies from ataluren-treated patients with nmDMD. The Phase 2b results demonstrated an ataluren treatment effect in 6MWD, timed function tests, and other measures of physical functioning, The Phase 3 ACT DMD results demonstrated an ataluren treatment effect in patients with nmDMD in both primary and secondary endpoints, particularly in those with a baseline 6MWD of 300-400m. Ataluren was consistently well-tolerated in all three trials, as well as in the ongoing extension studies. Trial findings will be presented in detail. Conclusions: The totality of the results demonstrates that ataluren enables nonsense mutation readthrough in the dystrophin mRNA, producing functional dystrophin and slowing disease progression.

Supported by: PTC Therapeutics Inc.

Background: Ataluren is the first drug to treat the underlying cause of nmDMD. Methods: ACT DMD is a Phase 3, randomized, double-blind study. Males 7-16 years with nmDMD and a screening six-minute walk distance (6MWD) ≥150 m and <80%-predicted were randomized to ataluren 40 mg/kg/day or placebo for 48 weeks. A pre-specified subgroup included patients with baseline 6MWD 300-400 m. A meta-analysis of the overall ACT DMD population and the ‘ambulatory decline phase’ subgroup of the Phase 2b study (those patients meeting ACT DMD entry criteria) was pre-specified in the statistical plan. Results: In the overall ACT DMD population (N=228), changes in TFTs favored ataluren over placebo: 10-meter walk/run, -1.2s (p=0.117); 4-stair climb, -1.8s (p=0.058); 4-stair descend, -1.8s (p=0.012). In the pre-specified subgroup (n=99), these differences increased to -2.1s, -3.6s, and -4.3s, respectively, and were statistically significant (p<0.01) for 4-stair climb and descend. Results are supported by the meta-analysis (N=291), which demonstrated significant differences (p<0.05) in 10-meter walk/run, 4-stair climb, 4-stair descend. Conclusions: TFT results showed a benefit for ataluren in ACT DMD, and a larger treatment effect in the pre-specified baseline 6MWD 300-400 m subgroup as well as the pre-specified meta-analysis of ACT DMD and the Phase 2b study decline subgroup.

Supported By: PTC Therapeutics Inc.

It is well known that a magnetic field has an inhibiting effect on thermal convection. It is also likely that a magnetic field might have a marked effect on the preferred cell-size and it is therefore of some importance to investigate the effect of such a field on finite amplitude convection. We restrict ourselves to fluids in which the Boussinesq approximation holds. For astrophysical application, especially in a study of the convective layer of the Sun, one should consider the compressible case but unfortunately the full compressible equations are much more difficult to handle numerically. In any case, the integration of the equations for the incompressible case will yield at least an indication of the effect of a magnetic field.

We report on direct numerical simulations of two-dimensional, horizontally periodic Rayleigh–Bénard convection between free-slip boundaries. We focus on the ability of the convection to drive large-scale horizontal flow that is vertically sheared. For the Prandtl numbers ($\mathit{Pr}$) between 1 and 10 simulated here, this large-scale shear can be induced by raising the Rayleigh number ($\mathit{Ra}$) sufficiently, and we explore the resulting convection for $\mathit{Ra}$ up to $10^{10}$. When present in our simulations, the sheared mean flow accounts for a large fraction of the total kinetic energy, and this fraction tends towards unity as $\mathit{Ra}\rightarrow \infty$. The shear helps disperse convective structures, and it reduces vertical heat flux; in parameter regimes where one state with large-scale shear and one without are both stable, the Nusselt number of the state with shear is smaller and grows more slowly with $\mathit{Ra}$. When the large-scale shear is present with $\mathit{Pr}\lesssim 2$, the convection undergoes strong global oscillations on long timescales, and heat transport occurs in bursts. Nusselt numbers, time-averaged over these bursts, vary non-monotonically with $\mathit{Ra}$ for $\mathit{Pr}=1$. When the shear is present with $\mathit{Pr}\gtrsim 3$, the flow does not burst, and convective heat transport is sustained at all times. Nusselt numbers then grow roughly as powers of $\mathit{Ra}$, but the growth rates are slower than any previously reported for Rayleigh–Bénard convection without large-scale shear. We find that the Nusselt numbers grow proportionally to $\mathit{Ra}^{0.077}$ when $\mathit{Pr}=3$ and to $\mathit{Ra}^{0.19}$ when $\mathit{Pr}=10$. Analogies with tokamak plasmas are described.

The time-dependent form of the classic, two-dimensional stagnation-point solution of the Navier-Stokes equations is considered. If the viscosity is zero, a class of solutions of the initial-value problem can be found in closed form using Lagrangian coordinates. These solutions exhibit singular behaviour in finite time, because of the infinite domain and unbounded initial vorticity. Thus, the blow-up found by Stuart in three dimensions using the stagnation-point form, also occurs in two. The singularity vanishes under a discrete, finite-dimensional ‘point vortex’ approximation, but is recovered as the number of vortices tends to infinity. We find that a small positive viscosity does not arrest the breakdown, but does strongly alter its form. Similar results are summarized for certain Boussinesq stratified flows.

An investigation is made of the properties of inertial boundary currents in a stably stratified, inviscid, non-diffusive ocean. The Boussinesq and β-plane approximations are adopted. The formalism developed by Robinson (1965) is used: the equations are transformed so that density replaces the vertical coordinate as an independent variable, and after a suitable non-dimensionalization of variables, the various fields are expanded as power series in the downstream co-ordinate η. The motion is shown to conserve potential vorticity. The equations and boundary conditions are obtained to order η2. Solutions are obtained in the region of formation of the coastal jet (i.e. the case of no mass flux through the plane η = 0) for several cases in which the potential vorticity function depends on stream function and density in a simple way. For these cases, it is found that in a constant depth ocean, a boundary current can exist only if the geostrophic drift at the boundary-layer edge is westward at all depths. This constraint is relaxed if the depth increases rapidly enough in the downstream (northward) direction. For slopes just in excess of the critical value, a deep onshore counter-current is predicted. Solutions of the first-order problem, using realistic values of the various parameters, have been computed and are found to be in qualitative agreement with observed features of the Florida Current.

In an appendix, it is shown that the constraint of westward geostrophic drift at all levels must hold in a flat-bottomed ocean for arbitrary potential vorticity distributions consistent with stable stratification.

The surface coat of the 2nd-stage juveniles (J2) of plant-parasitic nematodes is considered to be involved in interactions with microorganisms in the soil and rhizosphere, as well as with the host plant. Characterization of surface antigens might be important in the development of new nematode control strategies. In this study, polyclonal and monoclonal antibodies raised against Meloidogyne javanica, M. incognita and other plant-parasitic nematodes were tested for their binding to the surface coat and secreted–excreted products of M. javanica. Some of the monoclonal and polyclonal antibodies raised against M. incognita showed cross-reactivity with the surface coat of M. javanica. Western blot analysis of M. javanica surface coat extracts revealed labelling of several polypeptides with a 48 kDa main band for the polyclonal antibody IACR-PC Mi 373, and a 55 kDa main band for PC Mj E2. Further characterization of the antigens recognized by the polyclonal antibody PC Mj E2, in planta, showed that they were present in the parasitic stages J2 and J3 and that the surface coat was shed during root penetration. The hypodermis of the infective juveniles was labelled by PC Mj E2 and the monoclonal antibody IACR-Misec 3F.4, suggesting that these surface antigens are produced in the hypodermis. Nematode behaviour was affected by all the antibodies that bound to the surface coat of the pre-parasitic J2, and we demonstrated that the movement pattern of the M. javanica J2 was affected by these antibodies. Continuous binding of the antibodies to the M. javanica surface inhibited the infection of Arabidopsis thaliana roots on agar plates.

Confirming the results obtained for Ti-Co bilayers on Si and in accordance with the phase diagram, the high temperature formation and stability of three ternary silicides Ti0.75Co0.25Si2 (T phase), TiCoSi (E) and Ti4Co4Si7 (V) is reported. The Si rich T phase grows for Ti / CoSi2 and Co / TiSi2 structures. The tetragonal V compound is obtained by annealing Ti (400 Å) / Co (250 Å) / Si (900 Å) / SiO2 whereas orthorhombic TiCoSi is prepared using Ti / CoSi / Si3N4 samples.

Thin films of tungsten silicide with resistivities of 30 – 35 μΩ-cm have been formed by sputter depositing 71 nm of W metal onto (100) oriented, 5 Ω-cm, p-type silicon wafers that were etched in BOE 500 solution. The samples were fast radiatively processed in an RTA system under high vacuum for time anneals ranging from 15 – 50 seconds at a temperature of ∼ 1100°C. The inevitable oxide barrier at the interface is shown to decrease with increasing RTA time.