Stellar winds from Massive Stars

We review the various techniques through which wind properties of massive stars - O stars, AB supergiants, Luminous Blue Variables (LBVs), Wolf-Rayet (WR) stars and cool supergiants - are derived. The wind momentum-luminosity relation (e.g. Kudritzki et al. 1999) provides a method of predicting mass-loss rates of O stars and blue supergiants which is superior to previous parameterizations. Assuming the theoretical sqrt(Z) metallicity dependence, Magellanic Cloud O star mass-loss rates are typically matched to within a factor of two for various calibrations. Stellar winds from LBVs are typically denser and slower than equivalent B supergiants, with exceptional mass-loss rates during giant eruptions Mdot=10^-3 .. 10^-1 Mo/yr (Drissen et al. 2001). Recent mass-loss rates for Galactic WR stars indicate a downward revision of 2-4 relative to previous calibrations due to clumping (e.g. Schmutz 1997), although evidence for a metallicity dependence remains inconclusive (Crowther 2000). Mass-loss properties of luminous (> 10^5 Lo) yellow and red supergiants from alternative techniques remain highly contradictory. Recent Galactic and LMC results for RSG reveal a large scatter such that typical mass-loss rates lie in the range 10^-6 .. 10^-4 Mo/yr, with a few cases exhibiting 10^-3 Mo/yr.Comment: 16 pages, 2 figures, Review paper to appear in Proc `The influence of binaries on stellar population studies', Brussels, Aug 2000 (D. Vanbeveren ed.), Kluwe

A Compensatory Mutation Provides Resistance to Disparate HIV Fusion Inhibitor Peptides and Enhances Membrane Fusion

Fusion inhibitors are a class of antiretroviral drugs used to prevent entry of HIV into host cells. Many of the fusion inhibitors being developed, including the drug enfuvirtide, are peptides designed to competitively inhibit the viral fusion protein gp41. With the emergence of drug resistance, there is an increased need for effective and unique alternatives within this class of antivirals. One such alternative is a class of cyclic, cationic, antimicrobial peptides known as θ-defensins, which are produced by many non-human primates and exhibit broad-spectrum antiviral and antibacterial activity. Currently, the θ-defensin analog RC-101 is being developed as a microbicide due to its specific antiviral activity, lack of toxicity to cells and tissues, and safety in animals. Understanding potential RC-101 resistance, and how resistance to other fusion inhibitors affects RC-101 susceptibility, is critical for future development. In previous studies, we identified a mutant, R5-tropic virus that had evolved partial resistance to RC-101 during in vitro selection. Here, we report that a secondary mutation in gp41 was found to restore replicative fitness, membrane fusion, and the rate of viral entry, which were compromised by an initial mutation providing partial RC-101 resistance. Interestingly, we show that RC-101 is effective against two enfuvirtide-resistant mutants, demonstrating the clinical importance of RC-101 as a unique fusion inhibitor. These findings both expand our understanding of HIV drug-resistance to diverse peptide fusion inhibitors and emphasize the significance of compensatory gp41 mutations. © 2013 Wood et al

Strategy Escalation: An emerging paradigm for safe clinical development of T cell gene therapies

Gene therapy techniques are being applied to modify T cells with chimeric antigen receptors (CARs) for therapeutic ends. The versatility of this platform has spawned multiple options for their application with new permutations in strategies continually being invented, a testimony to the creative energies of many investigators. The field is rapidly expanding with immense potential for impact against diverse cancers. But this rapid expansion, like the Big Bang, comes with a somewhat chaotic evolution of its therapeutic universe that can also be dangerous, as seen by recently publicized deaths. Time-honored methods for new drug testing embodied in Dose Escalation that were suitable for traditional inert agents are now inadequate for these novel "living drugs". In the following, I propose an approach to escalating risk for patient exposures with these new immuno-gene therapy agents, termed Strategy Escalation, that accounts for the molecular and biological features of the modified cells and the methods of their administration. This proposal is offered not as a prescriptive but as a discussion framework that investigators may wish to consider in configuring their intended clinical applications

The factor structure of the Forms of Self-Criticising/Attacking & Self-Reassuring Scale in thirteen distinct populations

There is considerable evidence that self-criticism plays a major role in the vulnerability to and recovery from psychopathology. Methods to measure this process, and its change over time, are therefore important for research in psychopathology and well-being. This study examined the factor structure of a widely used measure, the Forms of Self-Criticising/Attacking & Self-Reassuring Scale in thirteen nonclinical samples (N = 7510) from twelve different countries: Australia (N = 319), Canada (N = 383), Switzerland (N = 230), Israel (N = 476), Italy (N = 389), Japan (N = 264), the Netherlands (N = 360), Portugal (N = 764), Slovakia (N = 1326), Taiwan (N = 417), the United Kingdom 1 (N = 1570), the United Kingdom 2 (N = 883), and USA (N = 331). This study used more advanced analyses than prior reports: a bifactor item-response theory model, a two-tier item-response theory model, and a non-parametric item-response theory (Mokken) scale analysis. Although the original three-factor solution for the FSCRS (distinguishing between Inadequate-Self, Hated-Self, and Reassured-Self) had an acceptable fit, two-tier models, with two general factors (Self-criticism and Self-reassurance) demonstrated the best fit across all samples. This study provides preliminary evidence suggesting that this two-factor structure can be used in a range of nonclinical contexts across countries and cultures. Inadequate-Self and Hated-Self might not by distinct factors in nonclinical samples. Future work may benefit from distinguishing between self-correction versus shame-based self-criticism.Peer reviewe

HIV-1 Nef Protein Structures Associated with Brain Infection and Dementia Pathogenesis

The difference between regional rates of HIV-associated dementia (HAD) in patients infected with different subtypes of HIV suggests that genetic determinants exist within HIV that influence the ability of the virus to replicate in the central nervous system (in Uganda, Africa, subtype D HAD rate is 89%, while subtype A HAD rate is 24%). HIV-1 nef is a multifunctional protein with known toxic effects in the brain compartment. The goal of the current study was to identify if specific three-dimensional nef structures may be linked to patients who developed HAD. HIV-1 nef structures were computationally derived for consensus brain and non-brain sequences from a panel of patients infected with subtype B who died due to varied disease pathologies and consensus subtype A and subtype D sequences from Uganda. Site directed mutation analysis identified signatures in brain structures that appear to change binding potentials and could affect folding conformations of brain-associated structures. Despite the large sequence variation between HIV subtypes, structural alignments confirmed that viral structures derived from patients with HAD were more similar to subtype D structures than to structures derived from patient sequences without HAD. Furthermore, structures derived from brain sequences of patients with HAD were more similar to subtype D structures than they were to their own non-brain structures. The potential finding of a brain-specific nef structure indicates that HAD may result from genetic alterations that alter the folding or binding potential of the protein

MSH3 polymorphisms and protein levels affect CAG repeat instability in huntington's disease mice

Expansions of trinucleotide CAG/CTG repeats in somatic tissues are thought to contribute to ongoing disease progression through an affected individual's life with Huntington's disease or myotonic dystrophy. Broad ranges of repeat instability arise between individuals with expanded repeats, suggesting the existence of modifiers of repeat instability. Mice with expanded CAG/CTG repeats show variable levels of instability depending upon mouse strain. However, to date the genetic modifiers underlying these differences have not been identified. We show that in liver and striatum the R6/1 Huntington's disease (HD) (CAG)~100 transgene, when present in a congenic C57BL/6J (B6) background, incurred expansion-biased repeat mutations, whereas the repeat was stable in a congenic BALB/cByJ (CBy) background. Reciprocal congenic mice revealed the Msh3 gene as the determinant for the differences in repeat instability. Expansion bias was observed in congenic mice homozygous for the B6 Msh3 gene on a CBy background, while the CAG tract was stabilized in congenics homozygous for the CBy Msh3 gene on a B6 background. The CAG stabilization was as dramatic as genetic deficiency of Msh2. The B6 and CBy Msh3 genes had identical promoters but differed in coding regions and showed strikingly different protein levels. B6 MSH3 variant protein is highly expressed and associated with CAG expansions, while the CBy MSH3 variant protein is expressed at barely detectable levels, associating with CAG stability. The DHFR protein, which is divergently transcribed from a promoter shared by the Msh3 gene, did not show varied levels between mouse strains. Thus, naturally occurring MSH3 protein polymorphisms are modifiers of CAG repeat instability, likely through variable MSH3 protein stability. Since evidence supports that somatic CAG instability is a modifier and predictor of disease, our data are consistent with the hypothesis that variable levels of CAG instability associated with polymorphisms of DNA repair genes may have prognostic implications for various repeat-associated diseases

Multiple populations in globular clusters. Lessons learned from the Milky Way globular clusters

Recent progress in studies of globular clusters has shown that they are not simple stellar populations, being rather made of multiple generations. Evidence stems both from photometry and spectroscopy. A new paradigm is then arising for the formation of massive star clusters, which includes several episodes of star formation. While this provides an explanation for several features of globular clusters, including the second parameter problem, it also opens new perspectives about the relation between globular clusters and the halo of our Galaxy, and by extension of all populations with a high specific frequency of globular clusters, such as, e.g., giant elliptical galaxies. We review progress in this area, focusing on the most recent studies. Several points remain to be properly understood, in particular those concerning the nature of the polluters producing the abundance pattern in the clusters and the typical timescale, the range of cluster masses where this phenomenon is active, and the relation between globular clusters and other satellites of our Galaxy.Comment: In press (The Astronomy and Astrophysics Review

Pharmaceutical Cost Management in an Ambulatory Setting Using a Risk Adjustment Tool

© 2014 Vivas-Consuelo et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Background Pharmaceutical expenditure is undergoing very high growth, and accounts for 30% of overall healthcare expenditure in Spain. In this paper we present a prediction model for primary health care pharmaceutical expenditure based on Clinical Risk Groups (CRG), a system that classifies individuals into mutually exclusive categories and assigns each person to a severity level if s/he has a chronic health condition. This model may be used to draw up budgets and control health spending. Methods Descriptive study, cross-sectional. The study used a database of 4,700,000 population, with the following information: age, gender, assigned CRG group, chronic conditions and pharmaceutical expenditure. The predictive model for pharmaceutical expenditure was developed using CRG with 9 core groups and estimated by means of ordinary least squares (OLS). The weights obtained in the regression model were used to establish a case mix system to assign a prospective budget to health districts. Results The risk adjustment tool proved to have an acceptable level of prediction (R2 0.55) to explain pharmaceutical expenditure. Significant differences were observed between the predictive budget using the model developed and real spending in some health districts. For evaluation of pharmaceutical spending of pediatricians, other models have to be established. Conclusion The model is a valid tool to implement rational measures of cost containment in pharmaceutical expenditure, though it requires specific weights to adjust and forecast budgets.This study was financed by a grant from the Fondo de Investigaciones de la Seguridad Social Instituto de Salud Carlos III, the Spanish Ministry of Health (FIS PI12/0037). The authors would like to thank members (Juan Bru and Inma Saurf) of the Pharmacoeconomics Office of the Valencian Health Department. The opinions expressed in this paper are those of the authors and do not necessary reflect those of the afore-named. Any errors are the authors' responsibility. We would also like to thank John Wright for the English editing.Vivas Consuelo, DJJ.; Usó Talamantes, R.; Guadalajara Olmeda, MN.; Trillo Mata, JL.; Sancho Mestre, C.; Buigues Pastor, L. (2014). Pharmaceutical Cost Management in an Ambulatory Setting Using a Risk Adjustment Tool. 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The Armeo Spring as training tool to improve upper limb functionality in multiple sclerosis: a pilot study

<p>Abstract</p> <p>Background</p> <p>Few research in multiple sclerosis (MS) has focused on physical rehabilitation of upper limb dysfunction, though the latter strongly influences independent performance of activities of daily living. Upper limb rehabilitation technology could hold promise for complementing traditional MS therapy. Consequently, this pilot study aimed to examine the feasibility of an 8-week mechanical-assisted training program for improving upper limb muscle strength and functional capacity in MS patients with evident paresis.</p> <p>Methods</p> <p>A case series was applied, with provision of a training program (3×/week, 30 minutes/session), supplementary on the customary maintaining care, by employing a gravity-supporting exoskeleton apparatus (Armeo Spring). Ten high-level disability MS patients (Expanded Disability Status Scale 7.0-8.5) actively performed task-oriented movements in a virtual real-life-like learning environment with the affected upper limb. Tests were administered before and after training, and at 2-month follow-up. Muscle strength was determined through the Motricity Index and Jamar hand-held dynamometer. Functional capacity was assessed using the TEMPA, Action Research Arm Test (ARAT) and 9-Hole Peg Test (9HPT).</p> <p>Results</p> <p>Muscle strength did not change significantly. Significant gains were particularly found in functional capacity tests. After training completion, TEMPA scores improved (<it>p </it>= 0.02), while a trend towards significance was found for the 9HPT (<it>p </it>= 0.05). At follow-up, the TEMPA as well as ARAT showed greater improvement relative to baseline than after the 8-week intervention period (<it>p </it>= 0.01, <it>p </it>= 0.02 respectively).</p> <p>Conclusions</p> <p>The results of present pilot study suggest that upper limb functionality of high-level disability MS patients can be positively influenced by means of a technology-enhanced physical rehabilitation program.</p