Dynamic walking features and improved walking performance in multiple sclerosis patients treated with fampridine (4-aminopyridine)

Background: Impaired walking capacity is a frequent confinement in Multiple Sclerosis (MS). Patients are affected by limitations in coordination, walking speed and the distance they may cover. Also abnormal dynamic walking patterns have been reported, involving continuous deceleration over time. Fampridine (4-aminopyridine), a potassium channel blocker, may improve walking in MS. The objective of the current study was to comprehensively examine dynamic walking characteristics and improved walking capacity in MS patients treated with fampridine. Methods: A sample of N = 35 MS patients (EDSS median: 4) underwent an electronic walking examination prior to (Time 1), and during treatment with fampridine (Time 2). Patients walked back and forth a distance of 25 ft for a maximum period of 6 min (6-minute 25-foot-walk). Besides the total distance covered, average speed on the 25-foot distance and on turns was determined separately for each test minute, at Time 1 and Time 2. Results: Prior to fampridine administration, 27/35 patients (77 %) were able to complete the entire 6 min of walking, while following the administration, 34/35 patients (97 %) managed to walk for 6 min. In this context, walking distance considerably increased and treatment was associated with faster walking and turning across all six test minutes (range of effect sizes: partial eta squared = .34-.72). Importantly, previously reported deceleration across test minutes was consistently observable at Time 1 and Time 2. Discussion: Fampridine administration is associated with improved walking speed and endurance. Regardless of a treatment effect of fampridine, the previously identified, abnormal dynamic walking feature, i.e. the linear decline in walking speed, may represent a robust feature. Conclusions: The dynamic walking feature might hence be considered as a candidate for a new outcome measure in clinical studies involving interventions other than symptomatic treatment, such as immune-modulating medication. Trial registration: DRKS00009228 (German Clinical Trials Register). Date obtained: 25.08.2015

Evolutionary and pulsational properties of white dwarf stars

Abridged. White dwarf stars are the final evolutionary stage of the vast majority of stars, including our Sun. The study of white dwarfs has potential applications to different fields of astrophysics. In particular, they can be used as independent reliable cosmic clocks, and can also provide valuable information about the fundamental parameters of a wide variety of stellar populations, like our Galaxy and open and globular clusters. In addition, the high densities and temperatures characterizing white dwarfs allow to use these stars as cosmic laboratories for studying physical processes under extreme conditions that cannot be achieved in terrestrial laboratories. They can be used to constrain fundamental properties of elementary particles such as axions and neutrinos, and to study problems related to the variation of fundamental constants. In this work, we review the essentials of the physics of white dwarf stars. Special emphasis is placed on the physical processes that lead to the formation of white dwarfs as well as on the different energy sources and processes responsible for chemical abundance changes that occur along their evolution. Moreover, in the course of their lives, white dwarfs cross different pulsational instability strips. The existence of these instability strips provides astronomers with an unique opportunity to peer into their internal structure that would otherwise remain hidden from observers. We will show that this allows to measure with unprecedented precision the stellar masses and to infer their envelope thicknesses, to probe the core chemical stratification, and to detect rotation rates and magnetic fields. Consequently, in this work, we also review the pulsational properties of white dwarfs and the most recent applications of white dwarf asteroseismology.Comment: 85 pages, 28 figures. To be published in The Astronomy and Astrophysics Revie

Finite element modeling and in vivo analysis of electrode configurations for selective stimulation of pudendal afferent fibers

<p>Abstract</p> <p>Background</p> <p>Intraurethral electrical stimulation (IES) of pudendal afferent nerve fibers can evoke both excitatory and inhibitory bladder reflexes in cats. These pudendovesical reflexes are a potential substrate for restoring bladder function in persons with spinal cord injury or other neurological disorders. However, the complex distribution of pudendal afferent fibers along the lower urinary tract presents a challenge when trying to determine the optimal geometry and position of IES electrodes for evoking these reflexes. This study aimed to determine the optimal intraurethral electrode configuration(s) and locations for selectively activating targeted pudendal afferents to aid future preclinical and clinical investigations.</p> <p>Methods</p> <p>A finite element model (FEM) of the male cat urethra and surrounding structures was generated to simulate IES with a variety of electrode configurations and locations. The activating functions (AFs) along pudendal afferent branches innervating the cat urethra were determined. Additionally, the thresholds for activation of pudendal afferent branches were measured in α-chloralose anesthetized cats.</p> <p>Results</p> <p>Maximum AFs evoked by intraurethral stimulation in the FEM and in vivo threshold intensities were dependent on stimulation location and electrode configuration.</p> <p>Conclusions</p> <p>A ring electrode configuration is ideal for IES. Stimulation near the urethral meatus or prostate can activate the pudendal afferent fibers at the lowest intensities, and allowed selective activation of the dorsal penile nerve or cranial sensory nerve, respectively. Electrode location was a more important factor than electrode configuration for determining stimulation threshold intensity and nerve selectivity.</p

Trans-Epithelial Immune Cell Transfer during Suckling Modulates Delayed-Type Hypersensitivity in Recipients as a Function of Gender

INTRODUCTION: Breast feeding has long term effects on the developing immune system which outlive passive immunization of the neonate. We have investigated the transfer of milk immune cells and examined the result of transfer once the recipients were adult. METHODS: Non-transgenic mouse pups were foster-nursed by green fluorescent protein (GFP) transgenic dams for 3 weeks and the fate of GFP+ cells was followed by FACS analysis, immunohistochemistry and RT-PCR for GFP and appropriate immune cell markers. Pups suckled by non-transgenic dams served as controls. RESULTS: Despite a preponderance of B cells and macrophages in the stomach contents of the pups, most cells undergoing trans-epithelial migration derived from the 3-4% of milk cells positive for T lymphocyte markers. These cells homed to the spleen and thymus, with maximal accumulation at 3-4 weeks. By sensitizing dams with an antigen which elicits a T cell-mediated delayed-type-hypersensitivity (DTH) response, we determined that nursing by a sensitized dam (compared to a non-sensitized dam) amplified a subsequent DTH response in females and yet suppressed one in males. DISCUSSION: These results suggest that clinical evaluation weighing the pros and cons of nursing male versus female children by mothers with genetically-linked hypersensitivity diseases, such as celiac disease and eczema, or those in regions of the world with endemic DTH-eliciting diseases, such as tuberculosis, may be warranted

Meiotic Chromosome Pairing Is Promoted by Telomere-Led Chromosome Movements Independent of Bouquet Formation

Chromosome pairing in meiotic prophase is a prerequisite for the high fidelity of chromosome segregation that haploidizes the genome prior to gamete formation. In the budding yeast Saccharomyces cerevisiae, as in most multicellular eukaryotes, homologous pairing at the cytological level reflects the contemporaneous search for homology at the molecular level, where DNA double-strand broken ends find and interact with templates for repair on homologous chromosomes. Synapsis (synaptonemal complex formation) stabilizes pairing and supports DNA repair. The bouquet stage, where telomeres have formed a transient single cluster early in meiotic prophase, and telomere-promoted rapid meiotic prophase chromosome movements (RPMs) are prominent temporal correlates of pairing and synapsis. The bouquet has long been thought to contribute to the kinetics of pairing, but the individual roles of bouquet and RPMs are difficult to assess because of common dependencies. For example, in budding yeast RPMs and bouquet both require the broadly conserved SUN protein Mps3 as well as Ndj1 and Csm4, which link telomeres to the cytoskeleton through the intact nuclear envelope. We find that mutants in these genes provide a graded series of RPM activity: wild-type>mps3-dCC>mps3-dAR>ndj1Δ>mps3-dNT = csm4Δ. Pairing rates are directly correlated with RPM activity even though only wild-type forms a bouquet, suggesting that RPMs promote homologous pairing directly while the bouquet plays at most a minor role in Saccharomyces cerevisiae. A new collision trap assay demonstrates that RPMs generate homologous and heterologous chromosome collisions in or before the earliest stages of prophase, suggesting that RPMs contribute to pairing by stirring the nuclear contents to aid the recombination-mediated homology search

Structural and molecular correlates of cognitive aging in the rat

Aging is associated with cognitive decline. Herein, we studied a large cohort of old age and young adult male rats and confirmed that, as a group, old  rats display poorer spatial learning and behavioral flexibility than younger adults. Surprisingly, when animals were clustered as good and bad performers, our data revealed that while in younger animals better cognitive performance was associated with longer dendritic trees and increased levels of synaptic markers in the hippocampus and prefrontal cortex, the opposite was found in the older group, in which better performance was associated with shorter dendrites and lower levels of synaptic markers. Additionally, in old, but not young individuals, worse performance correlated with increased levels of BDNF and the autophagy substrate p62, but decreased levels of the autophagy complex protein LC3. In summary, while for younger individuals "bigger is better", "smaller is better" is a more appropriate aphorism for older subjects.Portuguese Foundation for Science and Technology (FCT) with fellowships granted to: Cristina Mota (SFRH/BD/81881/2011), Susana Monteiro (SFRH/BD/69311/2010), Sofia Pereira das Neves and Sara Monteiro-Martins (PIC/IC/83213/2007); and by the European Commission within the 7th framework program, under the grant agreement: Health-F2-2010-259772 (Switchbox). In addition, this work was co-funded by the Northern Portugal Regional Operational Programme (ON.2 SR&TD Integrated Program – NORTE-07-0124-FEDER-000021), through the European Regional Development Fund (FEDER) and by national funds granted by FCT (PEst-C/SAU/LA0026/2013), and FEDER through the COMPETE (FCOMP-01-0124-FEDER-037298)