Prognosis of amyotrophic lateral sclerosis

Two cohorts of amyotrophic lateral sclerosis (ALS) patients were identified. One incidence-based cohort from Harris County, Texas with 97 cases, and the other a clinic referral series from an ALS clinic in Houston, Texas with 439 cases were followed-up to evaluate the prognosis of ALS. The overall Kaplan-Meier 3-year survival after diagnosis was similar, 0.287 for the incidence cohort and 0.313 for the referral cohort. However, the 5-year survival was much lower for the incidence cohort than the referral cohort (0.037 vs. 0.206). The large difference in 5-year survival was thought to be the results of a stronger unfavorable effect of the prognostic factors in the incidence cohort than in the referral cohort.^ Cohort-specific Weibull regression models were derived to evaluate the cohort-specific prognostic factors and survival probability with adjustment of certain prognostic factors.^ The major prognostic factors were: age at diagnosis, bulbar onset, black ethnicity, and positive family history of ALS in both cohorts. Female gender, simultaneous upper and lower extremities onset were specifically unfavorable factors in the incidence cohort. In the incidence cohort the prognosis was relatively favorable for cases with duration from onset to diagnosis longer than 4 months, however in the referral cohort the relatively favorable prognosis only occurred in cases with duration from onset to diagnosis 1 year or longer and was strongest in cases with duration 5 years and longer. Age at diagnosis modified the effect of bulbar onset in the incidence cohort but not in the referral cohort. The estimated survival with presence of an unfavorable prognostic factor identified in the incidence cohort was higher for the referral cohort than for the incidence cohort. Future studies are indicated to investigate the disease heterogeneity issue of ALS based on survival distribution of ALS. ^

STUDYING AGGREGATE FORMATION BY AMYOTROPHIC LATERAL SCLEROSIS-ASSOCIATED MUTANT SOD1 PROTEIN IN DROSOPHILA MODEL

A common pathological hallmark of most neurodegenerative disorders is the presence of protein aggregates in the brain. Understanding the regulation of aggregate formation is thus important for elucidating disease pathogenic mechanisms and finding effective preventive avenues and cures. Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a selective neurodegenerative disorder predominantly affecting motor neurons. The majority of ALS cases are sporadic, however, mutations in superoxide dismutase 1 (SOD1) are responsible for about 20% of familial ALS (fALS). Mutated SOD1 proteins are prone to misfold and form protein aggregates, thus representing a good candidate for studying aggregate formation. The long-term goal of this project is to identify regulators of aggregate formation by mutant SOD1 and other ALS-associated disease proteins. The specific aim of this thesis project is to assess the possibility of using the well-established Drosophila model system to study aggregation by human SOD1 (hSOD1) mutants. To this end, using wild type and the three mutant hSOD1 (A4V, G85R and G93A) most commonly found among fALS, I have generated 16 different SOD1 constructs containing either eGFP or mCherry in-frame fluorescent reporters, established and tested both cell- and animal-based Drosophila hSOD1 models. The experimental strategy allows for clear visualization of ectopic hSOD1 expression as well as versatile co-expression schemes to fully investigate protein aggregation specifically by mutant hSOD1. I have performed pilot cell-transfection experiments and verified induced expression of hSOD1 proteins. Using several tissue- or cell type-specific Gal4 lines, I have confirmed the proper expression of hSOD1 from established transgenic fly lines. Interestingly, in both Drosophila S2 cells and different fly tissues including the eye and motor neurons, robust aggregate formation by either wild type or mutant hSOD1 proteins was not observed. These preliminary observations suggest that Drosophila might not be a good experimental organism to study aggregation and toxicity of mutant hSOD1 protein. Nevertheless this preliminary conclusion implies the potential existence of a potent protective mechanism against mutant hSOD1 aggregation and toxicity in Drosophila. Thus, results from my SOD1-ALS project in Drosophila will help future studies on how to best employ this classic model organism to study ALS and other human brain degenerative diseases.

Robust effect sizes and their confidence intervals for group difference between trajectories in hierarchical linear growth model

Hierarchical linear growth model (HLGM), as a flexible and powerful analytic method, has played an increased important role in psychology, public health and medical sciences in recent decades. Mostly, researchers who conduct HLGM are interested in the treatment effect on individual trajectories, which can be indicated by the cross-level interaction effects. However, the statistical hypothesis test for the effect of cross-level interaction in HLGM only show us whether there is a significant group difference in the average rate of change, rate of acceleration or higher polynomial effect; it fails to convey information about the magnitude of the difference between the group trajectories at specific time point. Thus, reporting and interpreting effect sizes have been increased emphases in HLGM in recent years, due to the limitations and increased criticisms for statistical hypothesis testing. However, most researchers fail to report these model-implied effect sizes for group trajectories comparison and their corresponding confidence intervals in HLGM analysis, since lack of appropriate and standard functions to estimate effect sizes associated with the model-implied difference between grouping trajectories in HLGM, and also lack of computing packages in the popular statistical software to automatically calculate them. ^ The present project is the first to establish the appropriate computing functions to assess the standard difference between grouping trajectories in HLGM. We proposed the two functions to estimate effect sizes on model-based grouping trajectories difference at specific time, we also suggested the robust effect sizes to reduce the bias of estimated effect sizes. Then, we applied the proposed functions to estimate the population effect sizes (d ) and robust effect sizes (du) on the cross-level interaction in HLGM by using the three simulated datasets, and also we compared the three methods of constructing confidence intervals around d and du recommended the best one for application. At the end, we constructed 95% confidence intervals with the suitable method for the effect sizes what we obtained with the three simulated datasets. ^ The effect sizes between grouping trajectories for the three simulated longitudinal datasets indicated that even though the statistical hypothesis test shows no significant difference between grouping trajectories, effect sizes between these grouping trajectories can still be large at some time points. Therefore, effect sizes between grouping trajectories in HLGM analysis provide us additional and meaningful information to assess group effect on individual trajectories. In addition, we also compared the three methods to construct 95% confident intervals around corresponding effect sizes in this project, which handled with the uncertainty of effect sizes to population parameter. We suggested the noncentral t-distribution based method when the assumptions held, and the bootstrap bias-corrected and accelerated method when the assumptions are not met.^

Magnetic properties, grain sizes, XRF Scanner Data of sediment core GeoB9307-3

Geochemical and mineralogical proxies for paleoenvironmental conditions have the underlying assumption that climate variations have an impact on terrestrial weathering conditions. Varying properties of terrigenous sediments deposited at sea are therefore often interpreted in terms of paleoenvironmental change. Also in gravity core GeoB9307-3 (18° 33.99' S, 37° 22.89' E), located off the Zambezi River, environmental changes during Heinrich Stadial 1 (HS 1) and the Younger Dryas (YD) are accompanied by changing properties of the terrigenous sediment fraction. Our study focuses on the relationship of variability in the hydrological system and changes in the magnetic properties, major element geochemistry and granulometry of the sediments. We propose that changes in bulk sedimentary properties concur with environmental change, although not as a direct response of climate driven pedogenic processes. Spatial varying rainfall intensities on a sub-basin scale modify sediment export from different parts of the Zambezi River basin. During humid phases, such as HS 1 and the YD, sediment was mainly exported from the coastal areas, while during more arid phases sediments mirror the hinterland soil and lithological properties and are likely derived from the northern Shire sub-basin. We propose that a de-coupling of sedimentological and organic signals with variable discharge and erosional activity can occur.

(Table 1) Attenuation coefficient of lateral propagating light in sea ice, southern Beaufort Sea

The attenuation property of a lateral propagating light (LPL) in sea ice was measured using an artificial lamp in the Canadian Arctic during the 2007/2008 winter. A measurement method is proposed and applied whereby a recording instrument is buried in the sea ice and an artificial lamp is moved across the instrument. The apparent attenuation coefficient µ(lamda) for the lateral propagating light is obtained from the measured logarithmic relative variation rate. With the exception of blue and red lights, the attenuation coefficient changed little with wavelength, but changed considerably with depth. The vertical decrease of the attenuation coefficient was found to be correlated with salinity: the greater the salinity, the greater the attenuation coefficient. A clear linear relation of salinity and the lateral attenuation coefficient with R2 = 0.939 exists to address the close correlation of the attenuation of LPL with the scattering from the brine. The observed attenuation coefficient of LPL is much larger than that of the vertical propagation light, which we speculate to be caused by scattering. Part of this scattered component is transmitted out of the sea ice from the upper and lower surfaces.

La estimulación gabaérgica del núcleo septal lateral del cerebro de ratas macho incrementa la respuesta agresiva frente a estímulos neutros

El núcleo septal lateral forma parte de estructuras subcorticales del cerebro. La destrucción de dicho núcleo genera lo que se conoce como síndrome de furia septal. En este trabajo demostramos que el agonista GABAérgico muscimol, en dosis no sedativas, indujo una “inhibición del miedo" en ratas macho de la cepa Sprague- Dawley, asociada a un aumento de respuestas agresivas a objetos habitualmente neutros. Estos resultados, sumados al hecho de que el núcleo septal lateral participa en diversas entidades psiquiátricas, hace que sea interesante aportar al conocimiento de su función apelando a moduladores que se sabe están presentes en el en dicha estructura del sistema nervioso central.

Crecimiento y recubrimiento de Azorella monantha Clos (Apiaceae) en los altos Andes Centrales de Mendoza, Argentina

Azorella monantha Clos (Apiaceae) es una planta en cojín que se desarrolla desde 2900 a 4000 m s.n.m. en los Andes Centrales de Mendoza, Argentina. Su población comprende individuos de diferentes formas y tamaño. Estos cojines muestran alta ocurrencia en sitios llanos y base de laderas donde hasta se superponen formando carpetas o alfombras más o menos continuas. Ellos presentan el fenómeno de recubrimiento al cubrir todos los obstáculos que aparecen en la expansión de sus crecimientos como bloques de piedras, ripio, plantas y hasta sus propios individuos. Estos hechos de recubrimientos señalan la alta capacidad de estos cojines de ocupar los espacios disponibles. En el área estudiada su crecimiento en diámetro lateral fue de 1,15 a 1, 90 cm/año (promedio de 1, 52 cm/año). Observaciones y mediciones de los cojines revelan el carácter agresivo de los mismos sobre los obstáculos y plantas invasoras que temporalmente ocupan los sitios de los espacios vacíos abiertos en sus superficies. Con esto último se demuestra su carácter totalmente opuesto al de una verdadera nodriza como se le atribuye a él y a otros cojines andinos.

Tab. 2: Grain-sizes of cobble on the surface of sanderwurzel

yResults of 13 field investigations between 1966 and 1990 of the southwestern to eastern margin of Kötlujökull and its proglacial area are summarized with respect to sandar and their formation. Generally, the results are based on sedimentological examinations in the field and laboratory, on analyses of aerial photographs, and investigations of the glacier slope. The methods permitted a more detailed reconstruction of sandar evolution in the proglacial area of Kötlujökull since 1945, of tendencies in development and of single data going back until the last decades of the 19th century. Accordingly, there existed special periods of "flachsander"-formations with raised coarsegrained "sanderwurzels" resultant from the outbreak of subglacial meltwater tunneloutlets and other periods with "hochsander-"formations by supraglacial drainage. At present the belts of hochsanders in front of the glacier come up to more than 4 m in thickness and 1000 m in width, therefore containing perhaps more sediment direct in front of Kötlujökull than the old belts of flachsanderwurzels. In one case the explosion-like subglacial meltwater outburst combined with the genesis of a sanderwurzel could be observed for a time and is thoroughly discussed. The event is referred to the outburst of a sub- to inglacial meltwater body being under extreme hydrostatic press ures which is combined with the genesis of a new subglacial tunneloutlet as a new flachsander. Often these outbursts led to the destruction of a morainic belt more than 1000 m in width. Presumably the whole event was finished in not more than a few days. In addition to a characteristic pear-shaped form and water-moved stones up to diameters of 1 m the wurzels possess a single "main-channel" with rectangular cross-sections as far as 4 m deep and 50 m wide just as small flat channels resembling fish bones in connection with the main channel. Presumably, they have been active only in the last stage of wurzel formation. With regard to the subglacial tunnel gates long-living L-meltwater outlets are distinguished from short-living K-meltwater outlets. These are always combined with a raised coarse-grained sanderwurzel, but its meltwater discharge is generally decreasing and ceases after some years, whereas the discharge of L-meltwater outlets continues unchanged for long times (except seasonal differences). The material of flachsanders is preponderantly composed of mugearitic and andesitic cobble extending at least for some kilometres from the glacier margin, whereas the hochsanders correspond to medium to coarse sands without clay and without alternations into the direction of flow. The hochsander fans are covered with small braidet channels. Their sedimentary structures are determined by the short time changing of supraglacial meltwater discharge and the upper flow regime combined with the development of antidunes, which rule the channel-flows during the main activity periods in summer. Unlike the subglacial drainage the supraglacial drainage led to only weak effects of erosion on the glacier foreland. So the hochsanders refilled depressions of morainic areas or grew up on older flachsanderwurzels. Whereas all large flachsanders developed in front of approximate stationary glacier margins, the evolution of coherent belts of hochsanders were combined with progressive glacier fronts. On the other hand, there was obviously no evolution at all of large sandar in front of back-melting margins of Kötlujökull. Based on examinations of the glacier surface and on analyses of aerial photographs the different types of sandar are referred to different structures of the glacier snout. Finally chances of surviving of sandar in the proglacial area of Kötlujökull are shortly discussed just as the possibility of an application of the Islandic research results on Pleistocene sandar in northern Germany.

Magnetic properties, grain sizes and minerals at DSDP Site 83-504B

Twenty-seven samples from the Leg 83 section of Hole 504B have been investigated using magnetic, optical, and electron optical methods. The primary magnetic mineral to crystallize was titanomagnetite of approximate composition Fe2.4Ti0.6O4 (TM60), but none survives, nor is there evidence of titanomaghemite produced by oxidation of TM60. The average measured magnetic properties can be interpreted in terms of magnetite, Fe3O4, having average grain size of <1 µm and present in average volume concentration of - 0.5%. The intensity of the natural remanent magnetization (NRM) of the rocks could also be accounted for as being a thermoremanence carried by this mineral. Although the heterogeneity of the titanomagnetite grains could be detected optically, the texture of the intergrown phases is poorly developed. In some samples from the massive units of the lower part of the section, trellis patterns were visible. The Fe3O4 present in the intergrowths is too intimately mixed with the other intergrown phases to be revealed by electron microprobe analysis that simply returns the bulk composition of the intergrowth (oxidized TM60). The path by which the mineral assemblage evolved from TM60 to an Fe304-containing intergrowth, under the temperature and pressure conditions obtaining in the Leg 83 section, makes interesting speculation. Deuteric oxidation, maghemitization/inversion, or some hypothetical low-temperature/high-pressure oxidation by a leaching-of-iron process may all play roles.