Inhibition of Calpains by Calpastatin: Implications for Cellular and Functional Damage Following Traumatic Brain Injury

Traumatic brain injury (TBI) is a devastating health problem based on its high incidence, economic burden, and lack of effective pharmacological treatment. Individuals who suffer an injury often experience lifelong disability. TBI results in abrupt, initial cell damage leading to delayed neuronal death. The calcium-activated proteases, calpains, are known to contribute to this secondary neurodegenerative cascade. Prolonged activation of calpains results in proteolysis of numerous cellular substrates including cytoskeletal components, membrane receptors, and cytosolic proteins, contributing to cell demise despite coincident expression of calpastatin, the specific inhibitor of calpains. A comprehensive analysis using two separate calpastatin transgenic mouse lines was performed to test the hypothesis that calpastatin overexpression will reduce posttraumatic calpain activity affording neuroprotection and behavioral efficacy. Increased calpastatin expression was achieved using transgenic mice that overexpress the human calpastatin (hCAST) construct under control of a neuron-specific calcium-calmodulin dependent kinase II alpha or a ubiquitous prion protein promoter. Both transgenic lines exhibited enhanced calpastatin expression within the brain, extending into peripheral tissues under the prion protein promoter. hCAST overexpression significantly reduced protease activity confirmed by reductions in acute calpain-mediated substrate proteolysis in the cortex and hippocampus following controlled cortical impact brain injury. Aspects of posttraumatic motor and cognitive behavioral deficits were also lessened in hCAST transgenic mice compared to their wildtype littermates. However, volumetric analyses of neocortical contusion revealed no histological neuroprotection at either acute or long-term time points in either transgenic line. Partial hippocampal neuroprotection observed at a moderate injury severity in neuron-specific calpastatin overexpressing transgenic mice was lost after severe TBI. Greater levels of calpastatin under the prion protein promoter line failed to protect against hippocampal cell loss after severe brain injury. This study underscores the effectiveness of calpastatin overexpression in reducing calpain-mediated proteolysis and behavioral impairment after TBI, supporting the therapeutic potential for calpain inhibition. However, the reduction in proteolysis without accompanied neocortical neuroprotection suggests the involvement of other factors that are critical for neuronal survival after contusion brain injury. Augmenting calpastatin levels may be an effective method for calpain inhibition and may have efficacy in reducing behavioral morbidity after TBI and neurodegenerative disorders

Demonstration of angular anisotropy in the output of Thematic Mapper

There is a dependence of TM output (proportional to scene radiance in a manner which will be discussed) upon season, upon cover type and upon view angle. The existence of a significant systematic variation across uniform scenes in p-type (radiometrically and geometrically pre-processed) data is demonstrated. Present pre-processing does remove the effects and the problem must be addressed because the effects are large. While this is in no way attributable to any shortcomings in the thematic mapper, it is an effect which is sufficiently important to warrant more study, with a view to developing suitable pre-processing correction algorithms

Correlation effects in the density of states of annealed GaMnAs

We report on an experimental study of low temperature tunnelling in hybrid NbTiN/GaMnAs structures. The conductance measurements display a root mean square V dependence, consistent with the opening of a correlation gap in the density of states of GaMnAs. Our experiment shows that low temperature annealing is a direct empirical tool that modifies the correlation gap and thus the electron-electron interaction. Consistent with previous results on boron-doped silicon we find, as a function of voltage, a transition across the phase boundary delimiting the direct and exchange correlation regime.Comment: Replaced with revised version. To appear in Phys. Rev.

A new species of Conoryctella (Mammalia: Taeniodonta) from the Paleocene of the San Juan Basin, New Mexico, and a revision of the genus

Specimens from Paleocene strata of the Nacimiento Formation in Kutz Canyon, San Juan Basin, New Mexico, add to our knowledge of the poorly known taeniodont genus Conoryctella Gazin, 1939 and provide evidence for its taxonomic revision. C. dragonensis Gazin, 1939 is only known with certainty from its type specimen from the Dragon local fauna, North Horn Formation in east-central Utah, although a poorly preserved maxillary fragment and canine of uncertain provenance from the San Juan Basin, New Mexico, may pertain to this taxon. C. pattersoni, new species, differs from C. dragonensis in its smaller size, less molariform P4 and relatively narrow upper molars. It is known from: dental remains from the Dragon local fauna previously referred to C. dragonensis by Gazin (1939, 1941); dental remains from Torrejonian strata in Kutz Canyon referred by Wilson (1956, p. 82) to conoryctine, n. gen. and sp. ; and newly discovered dental and postcranial remains from a horizon in Kutz Canyon that, based on magnetostratigraphy (Tomida and Butler, 1980), is temporally equivalent to the Dragon local fauna. The occurrences of Conoryctella in the San Juan Basin extend the geographic range of the genus and also extend its time-stratigraphic range into a typical Torrejonian horizon. These extensions further reduce the distinctiveness of the Dragon local fauna, supporting recent arguments that the Dragon local fauna should be considered early Torrejonian in age

Variations in vascular access flows in haemodialysis can depend on needle orientation

Introduction: While using the Transonic Qc[TM] machine to assess access flow in arteriovenous fistulae (AVF), we observed that when compared to antegrade arterial needle insertion, retrograde arterial needle insertion could regularly produce lower access flow measurements. This study sought to explore this phenomenon. Method: 23 patients entered and 20 finished the study. Patient selection criteria included: functioning AVF and an adequate AVF length for either retrograde or antegrade arterial needle insertion. After ensuring stable and similar blood pressures, 3 flow measurements were taken during the first 2 hours on the same dialysis day of 3 consecutive weeks using antegrade needle insertion then were repeated on 3 further consecutive weeks using retrograde insertion. Results: Overall, access flows measured with retrograde insertion were significantly lower by a mean difference of 107.15 ml/min (57-484 ml/min) than the flows measured with antegrade needle placement. In 5/20, 3 recorded minimal difference and 2 had a higher access flows during retrograde insertion. No recirculation was observed during either antegrade or retrograde needle insertion. The paired t-test showed that there was significant difference between the antegrade versus retrograde mean measurements (p = 0.005). Conclusion: Although the sample size is small and the number of measurements limited, we conclude that access flows may be greater with an antegrade arterial orientation compared to flows recorded with a retrograde orientation. The phenomenon behind this conclusion is yet to be investigated. We suggest that when using the Transonic Qc[TM] access measurement device the arterial needle should always be in the same direction for each measurement for each individual patient.<br /