The newly developed CRF1-receptor antagonists, NGD 98-2 and NGD 9002, suppress acute stress-induced stimulation of colonic motor function and visceral hypersensitivity in rats.

Corticotropin releasing factor receptor 1 (CRF1) is the key receptor that mediates stress-related body responses. However to date there are no CRF1 antagonists that have shown clinical efficacy in stress-related diseases. We investigated the inhibitory effects of a new generation, topology 2 selective CRF1 antagonists, NGD 98-2 and NGD 9002 on exogenous and endogenous CRF-induced stimulation of colonic function and visceral hypersensitivity to colorectal distension (CRD) in conscious rats. CRF1 antagonists or vehicle were administered orogastrically (og) or subcutaneously (sc) before either intracerebroventricular (icv) or intraperitoneal (ip) injection of CRF (10 µg/kg), exposure to water avoidance stress (WAS, 60 min) or repeated CRD (60 mmHg twice, 10 min on/off at a 30 min interval). Fecal pellet output (FPO), diarrhea and visceromotor responses were monitored. In vehicle (og)-pretreated rats, icv CRF stimulated FPO and induced diarrhea in >50% of rats. NGD 98-2 or NGD 9002 (3, 10 and 30 mg/kg, og) reduced the CRF-induced FPO response with an inhibitory IC50 of 15.7 and 4.3 mg/kg respectively. At the highest dose, og NGD 98-2 or NGD 9002 blocked icv CRF-induced FPO by 67-87% and decreased WAS-induced-FPO by 23-53%. When administered sc, NGD 98-2 or NGD 9002 (30 mg/kg) inhibited icv and ip CRF-induced-FPO. The antagonists also prevented the development of nociceptive hyper-responsivity to repeated CRD. These data demonstrate that topology 2 CRF1 antagonists, NGD 98-2 and NGD 9002, administered orally, prevented icv CRF-induced colonic secretomotor stimulation, reduced acute WAS-induced defecation and blocked the induction of visceral sensitization to repeated CRD

Natural history of a visceral leishmaniasis outbreak in highland Ethiopia

In May 2005, visceral leishmaniasis (VL) was recognized for the first time in Libo Kemken, Ethiopia, a highland region where only few cases had been reported before. We analyzed records of VL patients treated from May 25, 2005 to December 13, 2007 by the only VL treatment center in the area, maintained by Médecins Sans Frontières-Ethiopia, Operational Center Barcelona-Athens. The median age was 18 years; 77.6% were male. The overall case fatality rate was 4%, but adults 45 years or older were five times as likely to die as 5-29 year olds. Other factors associated with increased mortality included HIV infection, edema, severe malnutrition, pneumonia, tuberculosis, and vomiting. The VL epidemic expanded rapidly over a several-year period, culminating in an epidemic peak in the last third of 2005, spread over two districts, and transformed into a sustained endemic situation by 2007

The Digital Astronaut Project Bone Remodeling Model

Under the conditions of microgravity, astronauts lose bone mass at a rate of 1% to 2% a month, particularly in the lower extremities such as the proximal femur: (1) The most commonly used countermeasure against bone loss has been prescribed exercise, (2) However, current exercise countermeasures do not completely eliminate bone loss in long duration, 4 to 6 months, spaceflight, (3,4) leaving the astronaut susceptible to early onset osteoporosis and a greater risk of fracture later in their lives. The introduction of the Advanced Resistive Exercise Device, coupled with improved nutrition, has further minimized the 4 to 6 month bone loss. But further work is needed to implement optimal exercise prescriptions, and (5) In this light, NASA's Digital Astronaut Project (DAP) is working with NASA physiologists to implement well-validated computational models that can help understand the mechanisms of bone demineralization in microgravity, and enhance exercise countermeasure development

Continental rift architecture and patterns of magma migration: a dynamic analysis based on centrifuge models.

Small-scale centrifuge models were used to investigate the role of continental rift structure in controlling patterns of magma migration and emplacement. Experiments considered the reactivation of weakness zones in the lower crust and the presence of magma at Moho depths. Results suggest that surface deformation, which reflects the weakness zone geometry, exerts a major control on patterns of magma migration. In the case of a single rift segment, the experimental lower crust and magma were both transferred in an extension-parallel direction toward the rift flanks. This lateral migration reflected the dominance of far-field stresses over extension-induced buoyancy forces. Local pressure gradients favored the raise of experimental magma in correspondence of marginal grabens. The lateral migration gave rise to major accumulations below the footwall of major boundary faults, providing the magma source able to feed off-axis volcanoes in nature, as inferred for the Main Ethiopian Rift. In the case of two offset rift segments, a major transfer zone developed. This transfer zone was characterized by prominent experimental lower crust doming and strong magma accumulation. Dynamic analysis showed that the transfer zone development caused a strong pressure difference in a rift-parallel direction, which dominated over the farfield thinning. Owing to this pressure gradient, almost all the underplated experimental magma collected below the lower crust dome, suggesting a rift-parallel (extension-orthogonal) migration. This process has a direct relevance for the localization of magmatic activity at transfer zones in natural continental rifts, such as in the Western Branch of the East African Rift System. Copyright 2004 by the American Geophysical Union

Stratigraphy and geochronology of the Tambien Group, Ethiopia: evidence for globally synchronous carbon isotope change in the Neoproterozoic

The Neoproterozoic Era was an interval characterized by profound environmental and biological transitions. Existing age models for Neoproterozoic nonglacial intervals largely have been based on correlation of carbonate carbon isotope values, but there are few tests of the assumed synchroneity of these records between basins. In contrast to the ash-poor successions typically targeted for Neoproterozoic chemostratigraphy, the Tonian to Cryogenian Tambien Group (Tigray region, Ethiopia) was deposited in an arc-proximal basin where volcanic tuffs suitable for U-Pb geochronology are preserved within the mixed carbonate-siliciclastic sedimentary succession. The Tambien Group culminates in a diamictite interpreted to correlate to the ca. 717–662 Ma Sturtian snowball Earth glaciation. New physical stratigraphic data and high-precision U-Pb dates from intercalated tuffs lead to a new stratigraphic framework for the Tambien Group that confirms identification of negative δ13C values from Assem Formation limestones with the ca. 800 Ma Bitter Springs carbon isotope stage. Integration with data from the Fifteenmile Group of northwestern Canada constitutes a positive test for the global synchroneity of the Bitter Spring Stage and constrains the stage to have started after 811.51 ± 0.25 Ma and to have ended before 788.72 ± 0.24 Ma. These new temporal constraints strengthen the case for interpreting Neoproterozoic carbon isotope variation as a record of large-scale changes to the carbon cycle and provide a framework for age models of paleogeographic change, geochemical cycling, and environmental evolution during the radiation of early eukaryotes

Contractual and Relational Governances: Are they Complementary or Substitutable in the Context of Value Chains

Interactions among value chain actors can be governed either through contractual or relational governance mechanisms or through the use of both at the same time. The question of complementarity or substitutability of these two governance mechanisms has already attracted the attentions of researchers nowadays. This essay is the review of selected scientific journals in the area of contractual and relational governance mechanisms. The purpose is to compile the research findings in a way it assists readers to better understand whether contractual and relational governance mechanisms are complementary or substitutable. Keywords: contractual governance, relational governance, complementary, substitutabilit

Stress control of frictional hangingwall accommodation above thrust ramps

Experimental models are used to study the stress control of frictional hangingwall accomodation above rigid flat-ramp-flat footwalls. Hangingwall accommodation involves shear or kink-band nucleation above the lower fault bend and migration of these as the hangingwalls climb over the underthrusting footwall. The kinkbands change shape and localise to thrusts as they migrate over the flat-ramp-flat footwall. When the shear stress to gravity stress ratio is low the thrusts reactivate to normal faults. With increase in the shear stress to gravity stress ratio reactivation of the kink bands was by tensile failure, at the upper fault bend. The models show that by changing the strength of materials deforming under otherwise similar conditions it is possible to study the geometry of frictional hangingwall accommodation, at different scales. In nature, hangingwall accommodation by thrust nucleation above thrust ramps and their subsequent normal reactivation may be anticipated in frictional sediments at shallow crustal levels, where temperatures and pressures are low