Alzheimer's disease (AD) is marked by the presence of extracellular amyloid beta (Aβ) plaques, intracellular neurofibrillary tangles (NFTs) and gliosis, activated glial cells, in the brain. It is ...thought that Aβ plaques trigger NFT formation, neuronal cell death, neuroinflammation and gliosis and, ultimately, cognitive impairment. There are increased numbers of reactive astrocytes in AD, which surround amyloid plaques and secrete proinflammatory factors and can phagocytize and break down Aβ. It was thought that neuronal cells were the major source of Aβ. However, mounting evidence suggests that astrocytes may play an additional role in AD by secreting significant quantities of Aβ and contributing to overall amyloid burden in the brain. Astrocytes are the most numerous cell type in the brain, and therefore even minor quantities of amyloid secretion from individual astrocytes could prove to be substantial when taken across the whole brain. Reactive astrocytes have increased levels of the three necessary components for Aβ production: amyloid precursor protein, β-secretase (BACE1) and γ-secretase. The identification of environmental factors, such as neuroinflammation, that promote astrocytic Aβ production, could redefine how we think about developing therapeutics for AD.
Essentials Prothrombin complex concentrates (PCCs) may reverse the effect of factor Xa (FXa) inhibitors. We conducted an open-label, randomized, placebo-controlled, three-period crossover study in 15 ...subjects. Both PCCs rapidly reversed apixaban-mediated decreases in mean endogenous thrombin potential. Four-factor PCC administration had no effect on apixaban pharmacokinetics or anti-FXa activity.
Background Currently, there is no approved reversal agent for direct activated factor Xa (FXa) inhibitors; however, several agents are under investigation, including prothrombin complex concentrates (PCCs). Objective This open-label, randomized, placebo-controlled, three-period crossover study assessed the effect of two four-factor PCCs on apixaban pharmacodynamics and pharmacokinetics in 15 healthy subjects. Methods Subjects received apixaban 10 mg twice daily for 3 days. On day 4, 3 h after apixaban, subjects received a 30-min infusion of 50 IU kg
Cofact, Beriplex P/N (Beriplex), or saline. Change in endogenous thrombin potential (ETP), measured with a thrombin generation assay (TGA), was the primary endpoint. Secondary endpoints included changes in other TGA parameters, prothrombin time (PT), International Normalized Ratio (INR), activated partial thromboplastin time, anti-FXa activity, apixaban pharmacokinetics, and safety. Results Apixaban-related changes in ETP and several other pharmacodynamic measures occurred following apixaban administration. Both PCCs reversed apixaban's effect on ETP; the differences in adjusted mean change from pre-PCC baseline to end of infusion were 425 nm min (95% confidence interval CI 219.8-630.7 nm min; P < 0.001) for Cofact, and 91 nm min (95% CI - 31.3 to 212.4 nm min; P > 0.05) for Beriplex. Both PCCs returned ETP to pre-apixaban baseline levels 4 h after PCC infusion, versus 45 h for placebo. For both PCCs, mean ETP peaked 21 h after PCC initiation, and then slowly decreased over the following 48 h. Both PCCs reversed apixaban's effect on TGA peak height, PT, and INR. Apixaban pharmacokinetic and anti-FXa profiles were consistent across treatments. Conclusions Cofact and Beriplex reversed apixaban's steady-state effects on several coagulation assessments.
Saturn's largest moon, Titan, remains an enigma, explored only by remote sensing from Earth, and by the Voyager and Cassini spacecraft. The most puzzling aspects include the origin of the molecular ...nitrogen and methane in its atmosphere, and the mechanism(s) by which methane is maintained in the face of rapid destruction by photolysis. The Huygens probe, launched from the Cassini spacecraft, has made the first direct observations of the satellite's surface and lower atmosphere. Here we report direct atmospheric measurements from the Gas Chromatograph Mass Spectrometer (GCMS), including altitude profiles of the constituents, isotopic ratios and trace species (including organic compounds). The primary constituents were confirmed to be nitrogen and methane. Noble gases other than argon were not detected. The argon includes primordial 36Ar, and the radiogenic isotope 40Ar, providing an important constraint on the outgassing history of Titan. Trace organic species, including cyanogen and ethane, were found in surface measurements.
Evidence for the existence of primitive life forms such as lichens and fungi can be based upon the formation of oxalates which are most readily detected using Raman spectroscopy. A comparative study ...of a suite of natural oxalates including weddellite, whewellite, moolooite, humboldtine, glushinskite, natroxalate and oxammite has been undertaken using Raman spectroscopy. The minerals are characterised by the wavenumber of the CO stretching vibration which is cation sensitive. The band is observed at 1468
cm
−1 for weddellite, 1489
cm
−1 for moolooite, 1471
cm
−1 for glushinskite and 1456
cm
−1 for natroxalate. Except for oxammite, the infrared and Raman spectra are mutually exclusive indicating that the minerals are bidentate. Differences are also observed in the wavenumber of the water OH stretching bands of the minerals. The significance of this work rests with the ability of Raman spectroscopy to identify oxalates which often occur as films on host rocks.
C. difficile forms biofilms in vitro Biofilm formation by C. difficile was first reported by Donelli and colleagues where they identified the role of polymicrobial biofilms in clogging of biliary ...stents using confocal and field emission scanning electron microscopy 4. Mutants deficient in stress-related proteins including the SOS response regulator, LexA, the RNA chaperone, Hfq, and the heat stress-associated chaperone, DnaK, have been associated with increased biofilm formation 8–10. In a recent global gene expression analysis of microfermentor biofilms, several genes controlled by the SinR-like regulators CD2214 and CD2215, including pilA1, were differentially expressed in biofilms, although pilA1 appeared to contribute to biofilm/aggregate formation only in c-di-GMP overexpressing strains 12. ...C. difficile forms complex biofilms in vitro which involves multiple regulatory pathways and several virulence-associated proteins. Paradoxically, subinhibitory concentrations of metronidazole and vancomycin induced biofilm formation and seemingly reduced antibiotic susceptibility 5,18. ...it is possible that low levels of antibiotics could induce C. difficile biofilm production, thus promoting persistence and recurrence of infection.
Glucose is an important stimulus for glucagon-like peptide 1 (GLP-1) secretion, but the mechanisms of secretion have not been investigated in integrated physiological models. We studied ...glucose-stimulated GLP-1 secretion from isolated perfused rat small intestine. Luminal glucose (5% and 20% w/v) stimulated the secretion dose dependently, but vascular glucose was without significant effect at 5, 10, 15, and 25 mmol/L. GLP-1 stimulation by luminal glucose (20%) secretion was blocked by the voltage-gated Ca channel inhibitor, nifedipine, or by hyperpolarization with diazoxide. Luminal administration (20%) of the nonmetabolizable sodium-glucose transporter 1 (SGLT1) substrate, methyl-α-D-glucopyranoside (α-MGP), stimulated release, whereas the SGLT1 inhibitor phloridzin (luminally) abolished responses to α-MGP and glucose. Furthermore, in the absence of luminal NaCl, luminal glucose (20%) did not stimulate a response. Luminal glucose-stimulated GLP-1 secretion was also sensitive to luminal GLUT2 inhibition (phloretin), but in contrast to SGLT1 inhibition, phloretin did not eliminate the response, and luminal glucose (20%) stimulated larger GLP-1 responses than luminal α-MGP in matched concentrations. Glucose transported by GLUT2 may act after metabolization, closing KATP channels similar to sulfonylureas, which also stimulated secretion. Our data indicate that SGLT1 activity is the driving force for glucose-stimulated GLP-1 secretion and that KATP-channel closure is required to stimulate a full-blown glucose-induced response.
Measurement of human faces is fundamental to many applications from recognition to genetic phenotyping. While anthropometric landmarks provide a conventional set of homologous measurement points, ...digital scans are increasingly used for facial measurement, despite the difficulties in establishing their homology. We introduce an alternative basis for facial measurement, which 1) provides a richer information density than discrete point measurements, 2) derives its homology from shared facial topography (ridges, folds, etc.), and 3) quantifies local morphological variation following the conventions and practices of anatomical description. A parametric model that permits matching a broad range of facial variation by the adjustment of 71 parameters is demonstrated by modeling a sample of 80 adult human faces. The surface of the parametric model can be adjusted to match each photogrammetric surface mesh generally to within 1 mm, demonstrating a novel and efficient means for facial shape encoding. We examine how well this scheme quantifies facial shape and variation with respect to geographic ancestry and sex. We compare this analysis with a more conventional, landmark-based geometric morphometric (GMM) study with 43 landmarks placed on the same set of scans. Our multivariate statistical analysis using the 71 attribute values separates geographic ancestry groups and sexes with a high degree of reliability, and these results are broadly similar to those from GMM, but with some key differences that we discuss. This approach is compared with conventional, non-parametric methods for the quantification of facial shape, including generality, information density, and the separation of size and shape. Potential uses for phenotypic and dysmorphology studies are also discussed.
Alzheimer's disease (AD) is marked by the presence of amyloid beta (Aβ) plaques, neurofibrillary tangles (NFT), neuronal death and synaptic loss, and inflammation in the brain. AD research has, in ...large part, been dedicated to the understanding of Aβ and NFT deposition as well as to the pharmacological reduction of these hallmarks. However, recent GWAS data indicates neuroinflammation plays a critical role in AD development, thereby redirecting research efforts toward unveiling the complexities of AD-associated neuroinflammation. It is clear that the innate immune system is intimately associated with AD progression, however, the specific roles of glia and neuroinflammation in AD pathology remain to be described. Moreover, inflammatory processes have largely been painted as detrimental to AD pathology, when in fact, many immune mechanisms such as phagocytosis aid in the reduction of AD pathologies. In this review, we aim to outline the delicate balance between the beneficial and detrimental aspects of immune activation in AD as a more thorough understanding of these processes is critical to development of effective therapeutics for AD.
To improve collaboration in software development teams, IBM Research and IBM Rational software engineers have been working on the Jazz project. Jazz sets out to define a vision for the way products ...can integrate to support collaborative work, and to create a technology platform on which to build products to deliver on this vision. It focuses on developing better team-building strategies, managerial processes, architectural designs, collaborative coding techniques, and software development practices. Jazz aims to be a scalable platform that can integrate tasks across the software life cycle. As such, it will consist of a set of plug-ins to Eclipse, IBM's Java-based, extensible open source development platform. Unlike Eclipse, however, which seeks to increase individual programmers' productivity, Jazz aims to make teams and teams of teams more productive. By building on prior experience with Eclipse, Jazz's developers hope to address IBM customers' evolving application-development requirements.
Traumatic brain injury (TBI) is a significant public-health concern. To understand the extent of TBI, it is important to assess the prevalence of TBI in the general population. However, the ...prevalence of TBI in the general population can be difficult to measure because of differing definitions of TBI, differing TBI severity levels, and underreporting of sport-related TBI. Additionally, prevalence reports vary from study to study. In this present study, we used meta-analytic methods to estimate the prevalence of TBI in the adult general population. Across 15 studies, all originating from developed countries, which included 25,134 adults, 12% had a history of TBI. Men had more than twice the odds of having had a TBI than did women, suggesting that male gender is a risk factor for TBI. The adverse behavioral, cognitive and psychiatric effects associated with TBI coupled with the high prevalence of TBI identified in this study indicate that TBI is a considerable public and personal-health problem.
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