A double-blind, randomized, placebo-controlled pilot trial to determine the efficacy and safety of ibudilast, a potential glial attenuator, in chronic migraine

BACKGROUND: Chronic migraine (CM) is problematic, and there are few effective treatments. Recently, it has been hypothesized that glial activation may be a contributor to migraine; therefore, this study investigated whether the potential glial inhibitor, ibudilast, could attenuate CM. METHODS: The study was of double-blind, randomized, placebo-controlled, two-period crossover design. Participants were randomized to receive either ibudilast (40 mg twice daily) or placebo treatment for 8 weeks. Subsequently, the participants underwent a 4-week washout period followed by a second 8-week treatment block with the alternative treatment. CM participants completed a headache diary 4 weeks before randomization throughout both treatment periods and 4 weeks after treatment. Questionnaires assessing quality of life and cutaneous allodynia were collected on eight occasions throughout the study. RESULTS: A total of 33 participants were randomized, and 14 participants completed the study. Ibudilast was generally well tolerated with mild, transient adverse events, principally nausea. Eight weeks of ibudilast treatment did not reduce the frequency of moderate to severe headache or of secondary outcome measures such as headache index, intake of symptomatic medications, quality of life or change in cutaneous allodynia. CONCLUSION: Using the current regimen, ibudilast does not improve migraine with CM participants.Yuen H Kwok, James E Swift, Parisa Gazerani, Paul Rola

Observing the Symmetry of Attractors

We show how the symmetry of attractors of equivariant dynamical systems can be observed by equivariant projections of the phase space. Equivariant projections have long been used, but they can give misleading results if used improperly and have been considered untrustworthy. We find conditions under which an equivariant projection generically shows the correct symmetry of the attractor.Comment: 28 page LaTeX document with 9 ps figures included. Supplementary color figures available at http://odin.math.nau.edu/~jws

Anomalous sea-ice reduction in the Eurasian Basin of the Arctic Ocean during summer 2010

Special Issue: The Second International Symposium on the Arctic Research (ISAR - 2

Shock formation and the ideal shape of ramp compression waves

We derive expressions for shock formation based on the local curvature of the flow characteristics during dynamic compression. Given a specific ramp adiabat, calculated for instance from the equation of state for a substance, the ideal nonlinear shape for an applied ramp loading history can be determined. We discuss the region affected by lateral release, which can be presented in compact form for the ideal loading history. Example calculations are given for representative metals and plastic ablators. Continuum dynamics (hydrocode) simulations were in good agreement with the algebraic forms. Example applications are presented for several classes of laser-loading experiment, identifying conditions where shocks are desired but not formed, and where long duration ramps are desired

Hydrogen Diffusion and Stabilization in Single-crystal VO2 Micro/nanobeams by Direct Atomic Hydrogenation

We report measurements of the diffusion of atomic hydrogen in single crystalline VO2 micro/nanobeams by direct exposure to atomic hydrogen, without catalyst. The atomic hydrogen is generated by a hot filament, and the doping process takes place at moderate temperature (373 K). Undoped VO2 has a metal-to-insulator phase transition at ~340 K between a high-temperature, rutile, metallic phase and a low-temperature, monoclinic, insulating phase with a resistance exhibiting a semiconductor-like temperature dependence. Atomic hydrogenation results in stabilization of the metallic phase of VO2 micro/nanobeams down to 2 K, the lowest point we could reach in our measurement setup. Based on observing the movement of the hydrogen diffusion front in single crystalline VO2 beams, we estimate the diffusion constant for hydrogen along the c-axis of the rutile phase to be 6.7 x 10^{-10} cm^2/s at approximately 373 K, exceeding the value in isostructural TiO2 by ~ 38x. Moreover, we find that the diffusion constant along the c-axis of the rutile phase exceeds that along the equivalent a-axis of the monoclinic phase by at least three orders of magnitude. This remarkable change in kinetics must originate from the distortion of the "channels" when the unit cell doubles along this direction upon cooling into the monoclinic structure. Ab initio calculation results are in good agreement with the experimental trends in the relative kinetics of the two phases. This raises the possibility of a switchable membrane for hydrogen transport.Comment: 23 pages, 4 figs + supporting materia

Association of the 5-HTT Gene-Linked Promoter Region (5-HTTLPR) Polymorphism with Psychiatric Disorders: Review of Psychopathology and Pharmacotherapy

Serotonin (5-HT) regulates important biological and psychological processes including mood, and may be associated with the development of several psychiatric disorders. An association between psychopathology and genes that regulate 5-HT neurotransmission is a robust area of research. Identification of the genes responsible for the predisposition, development, and pharmacological response of various psychiatric disorders is crucial to the advancement of our understanding of their underlying neurobiology. This review highlights research investigating 5-HT transporter (5-HTTLPR) polymorphism, because studies investigating the impact of the 5-HTTLPR polymorphism have demonstrated significant associations with many psychiatric disorders. Decreased transcriptional activity of the S allele (“risk allele”) may be associated with a heightened amygdala response leading to anxiety-related personality traits, major depressive disorder, suicide attempts, and bipolar disorder. By contrast, increased transcriptional activity of the L allele is considered protective for depression but is also associated with completed suicide, nicotine dependence, and attention deficit hyperactivity disorder. For some disorders, such as post-traumatic stress disorder and major depressive disorder, the research suggests that treatment response may vary by allele (such as an enhanced response to serotonin specific reuptake inhibitors in patients with major depressive disorder and post-traumatic stress disorder with L alleles), and for alcohol dependence, the association and treatment for S or L alleles may vary with alcoholic subtype. While some studies suggest that 5-HTTLPR polymorphism can moderate the response to pharmacotherapy, the association between 5-HTTLPR alleles and therapeutic outcomes is inconsistent. The discovery of triallelic 5-HTTLPR alleles (LA/LG/S) may help to explain some of the conflicting results of many past association studies, while concurrently providing more meaningful data in the future. Studies assessing 5-HTTLPR as the solitary genetic factor contributing to the etiology of psychiatric disorders continue to face the challenges of statistically small effect sizes and limited replication

The Role of Physical, Chemical, and Microbial Heterogeneity on the Field-Scale Transport and Attachment of Bacteria

A field-scale bacterial transport experiment was conducted at the Narrow Channel Focus Area of the South Oyster field site located in Oyster, Virginia. The goal of the field experiment was to determine the relative influence of subsurface heterogeneity and microbial population parameters on flow direction, velocity, and attachment of bacteria at the field scale. The field results were compared with results from laboratory-scale column experiments to develop a method for predicting field-scale bacterial transport. The field site is a shallow, sandy, unconfined, aerobic aquifer that has been characterized by geophysical, sedimentological, and hydrogeological methods. Comamonas sp. strain DA001 and a conservative tracer, bromide (Br), were injected into an area of high permeability for 12 hours. The Br and bacterial concentrations in the groundwater were monitored for 1 week at 192 sampling ports spaced over a 2-m vertical zone located from 0.5 to 7 m down-gradient of the injection well. The bacterial and Br plume was observed to move past 95 sampling ports. The densely characterized field site enabled the comparison of variations in DA001 transport to the aquifer properties. The velocity of the injected plume was correlated with geophysical estimates of hydraulic conductivity. The bacterial and Br plume appeared to follow flow paths not coincident with the hydraulic gradient but through a zone of higher permeability located off the flow axis. The amount of breakthrough of the bacteria was similar in both the high and low permeability layers with only a weak correlation between the observed hydraulic conductivity and amount of bacterial breakthrough. The uniformity in the observed attachment rates across varying grain sizes could be explained by heterogeneity of microbial properties within the single strain of injected bacteria. Application of colloid filtration theory to the field data indicated that variations in the microbial population were described by a lognormal distribution of the collision efficiency (a). Core-scale studies were used to predict the a distribution and field-scale transport distances of DA001. In sandy aquifers, physical heterogeneity may play a secondary role in controlling field-scale bacterial transport, and future research should focus on the microbial factors affecting transport

A rapid in vivo screen for pancreatic ductal adenocarcinoma therapeutics

Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related deaths in the United States, and is projected to be second by 2025. It has the worst survival rate among all major cancers. Two pressing needs for extending life expectancy of affected individuals are the development of new approaches to identify improved therapeutics, addressed herein, and the identification of early markers. PDA advances through a complex series of intercellular and physiological interactions that drive cancer progression in response to organ stress, organ failure, malnutrition, and infiltrating immune and stromal cells. Candidate drugs identified in organ culture or cell-based screens must be validated in preclinical models such as KIC (p48Cre;LSL-KrasG12D;Cdkn2af/f) mice, a genetically engineered model of PDA in which large aggressive tumors develop by 4 weeks of age. We report a rapid, systematic and robust in vivo screen for effective drug combinations to treat Kras-dependent PDA. Kras mutations occur early in tumor progression in over 90% of human PDA cases. Protein kinase and G-protein coupled receptor (GPCR) signaling activates Kras. Regulators of G-protein signaling (RGS) proteins are coincidence detectors that can be induced by multiple inputs to feedback-regulate GPCR signaling. We crossed Rgs16::GFP bacterial artificial chromosome (BAC) transgenic mice withKIC mice and show that the Rgs16::GFP transgene is a KrasG12D-dependent marker of all stages of PDA, and increases proportionally to tumor burden in KIC mice. RNA sequencing (RNA-Seq) analysis of cultured primary PDA cells reveals characteristics of embryonic progenitors of pancreatic ducts and endocrine cells, and extraordinarily high expression of the receptor tyrosine kinase Axl, an emerging cancer drug target. In proof-of-principle drug screens, we find that weanling KIC mice with PDA treated for 2 weeks with gemcitabine (with or without Abraxane) plus inhibitors of Axl signaling (warfarin and BGB324) have fewer tumor initiation sites and reduced tumor size compared with the standard-of-care treatment. Rgs16::GFP is therefore an in vivo reporter of PDA progression and sensitivity to new chemotherapeutic drug regimens such as Axl-targeted agents. This screening strategy can potentially be applied to identify improved therapeutics for other cancers