Fludarabine/2 Gy TBI is Superior to 2 Gy TBI as Conditioning for HLA-Matched Related HCT: A Phase III Randomized Trial.

AbstractThe risks and benefits of adding fludarabine to a 2-Gy total body irradiation (TBI) nonmyeloablative regimen are unknown. For this reason, we conducted a prospective randomized trial comparing 2-Gy TBI alone, or in combination with 90 mg/m2 fludarabine (FLU/TBI), before transplantation of peripheral blood stem cells from HLA-matched related donors. Eighty-five patients with hematological malignancies were randomized to be conditioned with TBI alone (n = 44) or FLU/TBI (n = 41). All patients had initial engraftment. Two graft rejections were observed, both in the TBI group. Infection rates, nonrelapse mortality, and graft-versus-host disease (GVHD) were similar between groups. Three-year overall survival was lower in the TBI group (54% versus 65%; hazard ratio [HR], .57; P = .09), with higher incidences of relapse/progression (55% versus 40%; HR, .55; P = .06), relapse-related mortality (37% versus 28%; HR, .53; P = .09), and a lower progression-free survival (36% versus 53%; HR, .56; P = .05). Median donor T cell chimerism levels were significantly lower in the TBI group at days 28 (61% versus 90%; P < .0001) and 84 (68% versus 92%; P < .0001), as was NK cell chimerism on day 28 (75% versus 96%; P = .0005). In conclusion, this randomized trial demonstrates the importance of fludarabine in augmenting the graft-versus-tumor effect by ensuring prompt and durable high-level donor engraftment early after transplantation

An ERP Assessment of Hemispheric Projections in Foveal and Extrafoveal Word Recognition

The existence and function of unilateral hemispheric projections within foveal vision may substantially affect foveal word recognition. The purpose of this research was to reveal these projections and determine their functionality.Single words (and pseudowords) were presented to the left or right of fixation, entirely within either foveal or extrafoveal vision. To maximize the likelihood of unilateral projections for foveal displays, stimuli in foveal vision were presented away from the midline. The processing of stimuli in each location was assessed by combining behavioural measures (reaction times, accuracy) with on-line monitoring of hemispheric activity using event-related potentials recorded over each hemisphere, and carefully-controlled presentation procedures using an eye-tracker linked to a fixation-contingent display.Event-related potentials 100–150 ms and 150–200 ms after stimulus onset indicated that stimuli in extrafoveal and foveal locations were projected unilaterally to the hemisphere contralateral to the presentation hemifield with no concurrent projection to the ipsilateral hemisphere. These effects were similar for words and pseudowords, suggesting this early division occurred before word recognition. Indeed, event-related potentials revealed differences between words and pseudowords 300–350 ms after stimulus onset, for foveal and extrafoveal locations, indicating that word recognition had now occurred. However, these later event-related potentials also revealed that the hemispheric division observed previously was no longer present for foveal locations but remained for extrafoveal locations. These findings closely matched the behavioural finding that foveal locations produced similar performance each side of fixation but extrafoveal locations produced left-right asymmetries.These findings indicate that an initial division in unilateral hemispheric projections occurs in foveal vision away from the midline but is not apparent, or functional, when foveal word recognition actually occurs. In contrast, the division in unilateral hemispheric projections that occurs in extrafoveal locations is still apparent, and is functional, when extrafoveal word recognition takes place

Functional Foveal Splitting: Evidence from Neuropsychological and Multimodal MRI Investigations in a Chinese Patient with a Splenium Lesion

It remains controversial and hotly debated whether foveal information is double-projected to both hemispheres or split at the midline between the two hemispheres. We investigated this issue in a unique patient with lesions in the splenium of the corpus callosum and the left medial occipitotemporal region, through a series of neuropsychological tests and multimodal MRI scans. Behavioral experiments showed that (1) the patient had difficulties in reading simple and compound Chinese characters when they were presented in the foveal but left to the fixation, (2) he failed to recognize the left component of compound characters when the compound characters were presented in the central foveal field, (3) his judgments of the gender of centrally presented chimeric faces were exclusively based on the left half-face and he was unaware that the faces were chimeric. Functional MRI data showed that Chinese characters, only when presented in the right foveal field but not in the left foveal field, activated a region in the left occipitotemporal sulcus in the mid-fusiform, which is recognized as visual word form area. Together with existing evidence in the literature, results of the current study suggest that the representation of foveal stimuli is functionally split at object processing levels

Phytochemicals as antibiotic alternatives to promote growth and enhance host health

There are heightened concerns globally on emerging drug-resistant superbugs and the lack of new antibiotics for treating human and animal diseases. For the agricultural industry, there is an urgent need to develop strategies to replace antibiotics for food-producing animals, especially poultry and livestock. The 2nd International Symposium on Alternatives to Antibiotics was held at the World Organization for Animal Health in Paris, France, December 12-15, 2016 to discuss recent scientific developments on strategic antibiotic-free management plans, to evaluate regional differences in policies regarding the reduction of antibiotics in animal agriculture and to develop antibiotic alternatives to combat the global increase in antibiotic resistance. More than 270 participants from academia, government research institutions, regulatory agencies, and private animal industries from >25 different countries came together to discuss recent research and promising novel technologies that could provide alternatives to antibiotics for use in animal health and production; assess challenges associated with their commercialization; and devise actionable strategies to facilitate the development of alternatives to antibiotic growth promoters (AGPs) without hampering animal production. The 3-day meeting consisted of four scientific sessions including vaccines, microbial products, phytochemicals, immune-related products, and innovative drugs, chemicals and enzymes, followed by the last session on regulation and funding. Each session was followed by an expert panel discussion that included industry representatives and session speakers. The session on phytochemicals included talks describing recent research achievements, with examples of successful agricultural use of various phytochemicals as antibiotic alternatives and their mode of action in major agricultural animals (poultry, swine and ruminants). Scientists from industry and academia and government research institutes shared their experience in developing and applying potential antibiotic-alternative phytochemicals commercially to reduce AGPs and to develop a sustainable animal production system in the absence of antibiotics.Fil: Lillehoj, Hyun. United States Department of Agriculture. Agricultural Research Service; ArgentinaFil: Liu, Yanhong. University of California; Estados UnidosFil: Calsamiglia, Sergio. Universitat Autònoma de Barcelona; EspañaFil: Fernandez Miyakawa, Mariano Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Patobiología; ArgentinaFil: Chi, Fang. Amlan International; Estados UnidosFil: Cravens, Ron L.. Amlan International; Estados UnidosFil: Oh, Sungtaek. United States Department of Agriculture. Agricultural Research Service; ArgentinaFil: Gay, Cyril G.. United States Department of Agriculture. Agricultural Research Service; Argentin

The influence of age, delay of repair, and tendon involvement in acute rotator cuff tears: Structural and clinical outcomes after repair of 42 shoulders

Background and purpose Few authors have considered the outcome after acute traumatic rotator cuff tears in previously asymptomatic patients. We investigated whether delay of surgery, age at repair, and the number of cuff tendons involved affect the structural and clinical outcome. Patients and methods 42 patients with pseudoparalysis after trauma and no previous history of shoulder symptoms were included. A full-thickness tear in at least 1 of the rotator cuff tendons was diagnosed in all patients. Mean time to surgery was 38 (6-91) days. Follow-up at a mean of 39 (12-108) months after surgery included ultrasound, plain radiographs, Constant-Murley score, DASH score, and western Ontario rotator cuff (WORC) score. Results At follow-up, 4 patients had a full-thickness tear and 9 had a partial-thickness tear in the repaired shoulder. No correlation between the structural or clinical outcome and the time to repair within 3 months was found. The patients with a tendon defect at follow-up had a statistically significantly lower Constant-Murley score and WORC index in the injured shoulder and were significantly older than those with intact tendons. The outcomes were similar irrespective of the number of tendons repaired. Interpretation A delay of 3 months to repair had no effect on outcome. The patients with cuff defects at follow-up were older and they had a worse clinical outcome. Multi-tendon injury did not generate worse outcomes than single-tendon tears at follow-up

NeuN/Rbfox3 Nuclear and Cytoplasmic Isoforms Differentially Regulate Alternative Splicing and Nonsense-Mediated Decay of Rbfox2

Anti-NeuN (Neuronal Nuclei) is a monoclonal antibody used extensively to specifically detect post-mitotic neurons. Anti-NeuN reactivity is predominantly nuclear; by western it detects multiple bands ranging in molecular weight from 45 kDa to >75 kDa. Expression screening putatively identified R3hdm2 as NeuN; however immunoprecipitation and mass spectrometry of the two major NeuN species at 45–50 kDa identified both as the RNA binding protein Rbfox3 (a member of the Fox family of alternative splicing factors), confirming and extending the identification of the 45 kDa band as Rbfox3 by Kim et al. Mapping of the anti-NeuN reactive epitopes in both R3hdm2 and Rbfox3 reveals a common proline- and glutamine-rich domain that lies at the N-terminus of the Rbfox3 protein. Our data suggests that alternative splicing of the Rbfox3 pre-mRNA itself leads to the production of four protein isoforms that migrate in the 45–50 kDa range, and that one of these splicing choices regulates Rbfox3/NeuN sub-cellular steady-state distribution, through the addition or removal of a short C-terminal extension containing the second half of a bipartite hydrophobic proline-tyrosine nuclear localization signal. Rbfox3 regulates alternative splicing of the Rbfox2 pre-mRNA, producing a message encoding a dominant negative form of the Rbfox2 protein. We show here that nuclear Rbfox3 isoforms can also enhance the inclusion of cryptic exons in the Rbfox2 mRNA, resulting in nonsense-mediated decay of the message, thereby contributing to the negative regulation of Rbfox2 by Rbfox3 through a novel mechanism

NeuN/Rbfox3 Nuclear and Cytoplasmic Isoforms Differentially Regulate Alternative Splicing and Nonsense-Mediated Decay of Rbfox2

Anti-NeuN (Neuronal Nuclei) is a monoclonal antibody used extensively to specifically detect post-mitotic neurons. Anti-NeuN reactivity is predominantly nuclear; by western it detects multiple bands ranging in molecular weight from 45 kDa to >75 kDa. Expression screening putatively identified R3hdm2 as NeuN; however immunoprecipitation and mass spectrometry of the two major NeuN species at 45–50 kDa identified both as the RNA binding protein Rbfox3 (a member of the Fox family of alternative splicing factors), confirming and extending the identification of the 45 kDa band as Rbfox3 by Kim et al. Mapping of the anti-NeuN reactive epitopes in both R3hdm2 and Rbfox3 reveals a common proline- and glutamine-rich domain that lies at the N-terminus of the Rbfox3 protein. Our data suggests that alternative splicing of the Rbfox3 pre-mRNA itself leads to the production of four protein isoforms that migrate in the 45–50 kDa range, and that one of these splicing choices regulates Rbfox3/NeuN sub-cellular steady-state distribution, through the addition or removal of a short C-terminal extension containing the second half of a bipartite hydrophobic proline-tyrosine nuclear localization signal. Rbfox3 regulates alternative splicing of the Rbfox2 pre-mRNA, producing a message encoding a dominant negative form of the Rbfox2 protein. We show here that nuclear Rbfox3 isoforms can also enhance the inclusion of cryptic exons in the Rbfox2 mRNA, resulting in nonsense-mediated decay of the message, thereby contributing to the negative regulation of Rbfox2 by Rbfox3 through a novel mechanism

Regional differences in multidimensional aspects of health: findings from the MRC cognitive function and ageing study

BACKGROUND: Differences in mortality and health experience across regions are well recognised and UK government policy aims to address this inequality. Methods combining life expectancy and health have concentrated on specific areas, such as self-perceived health and dementia. Few have looked within country or across different areas of health. Self-perceived health, self-perceived functional impairment and cognitive impairment are linked closely to survival, as well as quality of life. This paper aims to describe regional differences in healthy life expectancy using a variety of states of health and wellbeing within the MRC Cognitive Function and Ageing Study (MRC CFAS). METHODS: MRC CFAS is a population based study of health in 13,009 individuals aged 65 years and above in five centres using identical study methodology. The interviews included self-perceived health and measures of functional and cognitive impairment. Sullivan's method was used to combine prevalence rates for cognitive and functional impairment and life expectancy to produce expectation of life in various health states. RESULTS: The prevalence of both cognitive and functional impairment increases with age and was higher in women than men, with marked centre variation in functional impairment (Newcastle and Gwynedd highest impairment). Newcastle had the shortest life expectancy of all the sites, Cambridgeshire and Oxford the longest. Centre differences in self-perceived health tended to mimic differences in life expectancy but this did not hold for cognitive or functional impairment. CONCLUSION: Self-perceived health does not show marked variation with age or sex, but does across centre even after adjustment for impairment burden. There is considerable centre variation in self-reported functional impairment but not cognitive impairment. Only variation in self-perceived health relates to the ranking of life expectancy. These data confirm that quite considerable differences in life experience exist across regions of the UK beyond basic life expectancy

Macrophage Migration Inhibitory Factor Activates Hypoxia-Inducible Factor in a p53-Dependent Manner

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The Role of Fibrocytes in Sickle Cell Lung Disease

<div><h3>Background</h3><p>Interstitial lung disease is a frequent complication in sickle cell disease and is characterized by vascular remodeling and interstitial fibrosis. Bone marrow-derived fibrocytes have been shown to contribute to the pathogenesis of other interstitial lung diseases. The goal of this study was to define the contribution of fibrocytes to the pathogenesis of sickle cell lung disease.</p> <h3>Methodology/Principal Findings</h3><p>Fibrocytes were quantified and characterized in subjects with sickle cell disease or healthy controls, and in a model of sickle cell disease, the NY1DD mouse. The role of the chemokine ligand CXCL12 in trafficking of fibrocytes and phenotype of lung disease was examined in the animal model. We found elevated concentration of activated fibrocytes in the peripheral blood of subjects with sickle cell disease, which increased further during vaso-occlusive crises. There was a similar elevations in the numbers and activation phenotype of fibrocytes in the bone marrow, blood, and lungs of the NY1DD mouse, both at baseline and under conditions of hypoxia/re-oxygenation. In both subjects with sickle cell disease and the mouse model, fibrocytes expressed a hierarchy of chemokine receptors, with CXCR4 expressed on most fibrocytes, and CCR2 and CCR7 expressed on a smaller subset of cells. Depletion of the CXCR4 ligand, CXCL12, in the mouse model resulted in a marked reduction of fibrocyte trafficking into the lungs, reduced lung collagen content and improved lung compliance and histology.</p> <h3>Conclusions</h3><p>These data support the notion that activated fibrocytes play a significant role in the pathogenesis of sickle cell lung disease.</p> </div