Reduced expression of GM1 and other major brain gangliosides GD1a, GD1b and GT1b have been reported in Parkinson's disease (PD) brain. Mechanisms underlying these changes are unclear but may be due ...to a deficit in the ganglioside biosynthetic process. The present study examined the extent to which deficits in gene expression of key biosynthetic enzymes involved in synthesis of GM1 and GD1b (B3galt4) and GD1a and GT1b (St3gal2) exist in neuromelanin-containing neurons in the PD substantia nigra (SN). In situ hybridization histochemistry was used to examine gene expression of B3GALT4 and ST3GAL2 in neuromelanin-containing neurons in the SN in 8 normal controls (61-92 yrs.) and 7 PD subjects (77-95 yrs). There was a significant decrease in both B3GALT4 and ST3GAL2 gene expression in residual neuromelanin-containing cells in the SN of PD patients compared to age-matched neurologically normal controls. These changes appeared to be cell-type specific as abundant B3GALT4 and ST3GAL2 gene expression was observed in non-neuromelanin containing neurons located outside of the SN in the PD brain. These data show that residual neuromelanin-containing neurons in the PD SN have decreased expression of the ganglioside biosynthetic genes B3GALT4 and ST3GAL2, consistent with previous reports of decreased levels of gangliosides GM1, GD1a, GD1b and GT1b in the PD SN. These changes may increase the vulnerability of these neurons to degeneration in response to a variety of potential stressors.
Tolerance of infections Ayres, Janelle S; Schneider, David S
Annual review of immunology,
01/2012, Volume:
30
Journal Article
Peer reviewed
A host has two methods to defend against pathogens: It can clear the pathogens or reduce their impact on health in other ways. The first, resistance, is well studied. Study of the second, which ...ecologists call tolerance, is in its infancy. Tolerance measures the dose response curve of a host's health in reaction to a pathogen and can be studied in a simple quantitative manner. Such studies hold promise because they point to methods of treating infections that put evolutionary pressures on microbes different from antibiotics and vaccines. Studies of tolerance will provide an improved foundation to describe our interactions with all microbes: pathogenic, commensal, and mutualistic. One obvious mechanism affecting tolerance is the intensity of an immune response; an overly exuberant immune response can cause collateral damage through immune effectors and because of the energy allocated away from other physiological functions. There are potentially many other tolerance mechanisms, and here we systematically describe tolerance using a variety of animal systems.
Ocean acidification (OA) is generally assumed to negatively impact calcification rates of marine organisms. At a local scale however, biological activity of macrophytes may generate pH fluctuations ...with rates of change that are orders of magnitude larger than the long-term trend predicted for the open ocean. These fluctuations may in turn impact benthic calcifiers in the vicinity. Combining laboratory, mesocosm and field studies, such interactions between OA, the brown alga Fucus vesiculosus, the sea grass Zostera marina and the blue mussel Mytilus edulis were investigated at spatial scales from decimetres to 100s of meters in the western Baltic. Macrophytes increased the overall mean pH of the habitat by up to 0.3 units relative to macrophytefree, but otherwise similar, habitats and imposed diurnal pH fluctuations with amplitudes ranging from 0.3 to more than 1 pH unit. These amplitudes and their impact on mussel calcification tended to increase with increasing macrophyte biomass to bulk water ratio. At the laboratory and mesocosm scales, biogenic pH fluctuations allowed mussels to maintain calcification even under acidified conditions by shifting most of their calcification activity into the daytime when biogenic fluctuations caused by macrophyte activity offered temporal refuge from OA stress. In natural habitats with a low biomass to water body ratio, the impact of biogenic pH fluctuations on mean calcification rates of M. edulis was less pronounced. Thus, in dense algae or seagrass habitats, macrophytes may mitigate OA impact on mussel calcification by raising mean pH and providing temporal refuge from acidification stress.
Disease Tolerance as a Defense Strategy Medzhitov, Ruslan; Schneider, David S.; Soares, Miguel P.
Science (American Association for the Advancement of Science),
02/2012, Volume:
335, Issue:
6071
Journal Article
Peer reviewed
Open access
The immune system protects from infections primarily by detecting and eliminating the invading pathogens; however, the host organism can also protect itself from infectious diseases by reducing the ...negative impact of infections on host fitness. This ability to tolerate a pathogen's presence is a distinct host defense strategy, which has been largely overlooked in animal and human studies. Introduction of the notion of "disease tolerance" into the conceptual tool kit of immunology will expand our understanding of infectious diseases and host pathogen interactions. Analysis of disease tolerance mechanisms should provide new approaches for the treatment of infections and other diseases.
The modern era of drug development for Alzheimer's disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer's disease. Since ...then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here, we review the development of treatments for Alzheimer's disease during the past 30 years, considering the drugs, potential targets, late‐stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late‐stage Alzheimer's disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta‐analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild‐to‐moderate Alzheimer's disease criteria, recently extending to early or prodromal Alzheimer disease or ‘mild cognitive impairment due to Alzheimer's disease’, for drugs considered to be disease modifying. The duration of trials has remained at 6–12 months for drugs intended to improve symptoms; 18‐ to 24‐month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early‐stage Alzheimer's disease trial samples using biomarkers and phase‐specific outcomes. In conclusion, validated drug targets for Alzheimer's disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late‐phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods.
We analyze the pion transition form factor using dispersion theory. We calculate the singly-virtual form factor in the time-like region based on data for the
e
+
e
-
→
3
π
cross section, generalizing ...previous studies on
ω
,
ϕ
→
3
π
decays and
γ
π
→
π
π
scattering, and verify our result by comparing to
e
+
e
-
→
π
0
γ
data. We perform the analytic continuation to the space-like region, predicting the poorly-constrained space-like transition form factor below
1
GeV
, and extract the slope of the form factor at vanishing momentum transfer
a
π
=
(
30.7
±
0.6
)
×
10
-
3
. We derive the dispersive formalism necessary for the extension of these results to the doubly-virtual case, as required for the pion-pole contribution to hadronic light-by-light scattering in the anomalous magnetic moment of the muon.
Summary Objective To provide a consensus-based minimum set of criteria for the diagnosis of malnutrition to be applied independent of clinical setting and aetiology, and to unify international ...terminology. Method The European Society of Clinical Nutrition and Metabolism (ESPEN) appointed a group of clinical scientists to perform a modified Delphi process, encompassing e-mail communications, face-to-face meetings, in group questionnaires and ballots, as well as a ballot for the ESPEN membership. Result First, ESPEN recommends that subjects at risk of malnutrition are identified by validated screening tools, and should be assessed and treated accordingly. Risk of malnutrition should have its own ICD Code. Second, a unanimous consensus was reached to advocate two options for the diagnosis of malnutrition. Option one requires body mass index (BMI, kg/m2 ) <18.5 to define malnutrition. Option two requires the combined finding of unintentional weight loss (mandatory) and at least one of either reduced BMI or a low fat free mass index (FFMI). Weight loss could be either >10% of habitual weight indefinite of time, or >5% over 3 months. Reduced BMI is <20 or <22 kg/m2 in subjects younger and older than 70 years, respectively. Low FFMI is <15 and <17 kg/m2 in females and males, respectively. About 12% of ESPEN members participated in a ballot; >75% agreed; i.e. indicated ≥7 on a 10-graded scale of acceptance, to this definition. Conclusion In individuals identified by screening as at risk of malnutrition, the diagnosis of malnutrition should be based on either a low BMI (<18.5 kg/m2 ), or on the combined finding of weight loss together with either reduced BMI (age-specific) or a low FFMI using sex-specific cut-offs.
Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting millions of patients worldwide. Many therapeutics are available for treating PD symptoms but there is no ...disease-modifying therapeutic that has been unequivocally shown to slow or stop the progression of the disease. There are several factors contributing to the failure of many putative disease-modifying agents in clinical trials and these include the choice of patients and clinical trial designs for disease modification trials. Perhaps more important, however, is the choice of therapeutic, which for the most part, has not taken into account the multiple and complex pathogenic mechanisms and processes involved in PD. This paper discusses some of the factors contributing to the lack of success in PD disease-modification trials, which have mostly investigated therapeutics with a singular mechanism of action directed at one of the many PD pathogenic processes, and suggests that an alternative strategy for success may be to employ multi-functional therapeutics that target multiple PD-relevant pathogenic mechanisms. Evidence is presented that the multi-functional glycosphingolipid GM1 ganglioside may be just such a therapeutic.
In recent years there has been a significant development of novel implant alloys based on β-Ti such as Ti–Nb–Zr and Ti–Nb–Zr–Ta alloys systems. The purpose of this work is to provide characterization ...of Ti–35.3Nb–5.1Ta–7.1Zr and Ti–41.1Nb–7.1Zr alloys, in which Nb will substitute the atomic amount of Ta, with emphasis in the property-microstructure-composition relationships. These alloys are produced from commercially pure materials (Ti, Nb, Zr and Ta) by an arc melting method. All ingots were submitted to sequences of heat treatment (1000
°C/2
h
−
WQ), cold working by swaging procedures and other heat treatment (1000
°C/2
h
−
WQ). Specimens, in as cast and heat-treated condition, were examined by light and scanning electron microscopy (SEM). These results suggested the presence of β- and ω-phases. Mechanical properties were based on tensile and hardness tests. These alloys exhibit a lower modulus than that of conventional Ti alloys and the other mechanical properties are suitable for biomedical applications.
Differences in the equation of state (EOS) of dense matter translate into differences in astrophysical simulations and their multimessenger signatures. Thus, extending the number of EOSs for ...astrophysical simulations allows us to probe the effect of different aspects of the EOS in astrophysical phenomena. In this work, we construct the EOS of hot and dense matter based on the Akmal, Pandharipande, and Ravenhall (APR) model and thereby extend the open-source SROEOS code which computes EOSs of hot dense matter for Skyrme-type parametrizations of the nuclear forces. Unlike Skrme-type models, in which parameters of the interaction are fit to reproduce the energy density of nuclear matter and/or properties of heavy nuclei, the EOS of APR is obtained from potentials resulting from fits to nucleon-nucleon scattering and properties of light nuclei. In addition, this EOS features a phase transition to a spin-isospin ordered state of nucleons, termed a neutral pion condensate, at supranuclear densities. We show that differences in the effective masses between EOSs have consequences for the properties of nuclei in the subnuclear inhomogeneous phase of matter. We also test the new EOS of APR in spherically symmetric core-collapse of massive stars with 15 M-circle dot and 40 M-circle dot, respectively. We find that the phase transition in the EOS of APR speeds up the collapse of the star. However, this phase transition does not generate a second shock wave or another neutrino burst as reported for the hadron-to-quark phase transition. The reason for this difference is that the width of the coexistence region and the latent heat in the EOS of APR are substantially smaller than in the quark-to-hadron transition employed earlier, which results in a significantly smaller softening of the high density EOS.
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