Sustainable self-healing at ultra-low temperatures in structural composites incorporating hollow vessels and heating elements.
Self-healing composites are able to restore their properties automatically. Impressive healing efficiencies can be achieved when conditions are favourable. On the other hand, healing might not be possible under adverse circumstances such as very low ambient temperature. Here, we report a structural composite able to maintain its temperature to provide a sustainable self-healing capability-similar to that in the natural world where some animals keep a constant body temperature to allow enzymes to stay active. The composite embeds three-dimensional hollow vessels with the purpose of delivering and releasing healing agents, and a porous conductive element to provide heat internally to defrost and promote healing reactions. A healing efficiency over 100% at around -60°C was obtained. The effects of the sheets on the interlaminar and tensile properties have been investigated experimentally. The proposed technique can be implemented in a majority of extrinsic self-healing composites to enable automatic recovery at ultra-low temperatures.


Cross-taxon congruence and environmental conditions.
Diversity patterns of different taxa typically covary in space, a phenomenon called cross-taxon congruence. This pattern has been explained by the effect of one taxon diversity on taxon diversity, shared biogeographic histories of different taxa, and/or common responses to environmental conditions. A meta-analysis of the association between environment and diversity patterns found that in 83 out of 85 studies, more than 60% of the spatial variability in species richness was related to variables representing energy, water or their interaction. The role of the environment determining taxa diversity patterns leads us to hypothesize that this would explain the observed cross-taxon congruence. However, recent analyses reported the persistence of cross-taxon congruence when environmental effect was statistically removed. Here we evaluate this hypothesis, analyzing the cross-taxon congruence between birds and mammals in the Brazilian Cerrado, and assess the environmental role on the spatial covariation in diversity patterns. We found a positive association between avian and mammal richness and a positive latitudinal trend for both groups in the Brazilian Cerrado. Regression analyses indicated an effect of latitude, PET, and mean temperature over both biological groups. In addition, we show that NDVI was only associated with avian diversity; while the annual relative humidity, was only correlated with mammal diversity. We determined the environmental effects on diversity in a path analysis that accounted for 73% and 76% of the spatial variation in avian and mammal richness. However, an association between avian and mammal diversity remains significant. Indeed, the importance of this link between bird and mammal diversity was also supported by a significant association between birds and mammal spatial autoregressive model residuals. Our study corroborates the main role of environmental conditions on diversity patterns, but suggests that other important mechanisms, which have not been properly evaluated, are involved in the observed cross-taxon congruence. The approaches introduced here indicate that the prevalence of a significant association among taxa, after considering the environmental determinant, could indicate both the need to incorporate additional processes (e.g. biogeographic and evolutionary history or trophic interactions) and/or the existence of a shared trend in detection biases among taxa and regions.


A review of validation strategies for computational drug repositioning.
Repositioning of previously approved drugs is a promising methodology because it reduces the cost and duration of the drug development pipeline and reduces the likelihood of unforeseen adverse events. Computational repositioning is especially appealing because of the ability to rapidly screen candidates in silico and to reduce the number of possible repositioning candidates. What is unclear, however, is how useful such methods are in producing clinically efficacious repositioning hypotheses. Furthermore, there is no agreement in the field over the proper way to perform validation of in silico predictions, and in fact no systematic review of repositioning validation methodologies. To address this unmet need, we review the computational repositioning literature and capture studies in which authors claimed to have validated their work. Our analysis reveals widespread variation in the types of strategies, predictions made and databases used as 'gold standards'. We highlight a key weakness of the most commonly used strategy and propose a path forward for the consistent analytic validation of repositioning techniques.


Stroke Induces Nuclear Shuttling of Histone Deacetylase 4.
Histone deacetylases (HDACs) 4 and 5 are abundantly expressed in the brain and have been implicated in the regulation of neurodegeneration. Under physiological conditions, HDACs 4 and 5 are expressed in the cytoplasm of brain cells where they cannot directly access chromatin. In response to external stimuli, they can shuttle to the nucleus and regulate gene expression. However, the effect of stroke on nuclear shuttling of HDACs 4 and 5 remains unknown. Using a rat model of middle cerebral artery occlusion, we examined the subcellular localization of HDACs 4 and 5 in the peri-infarct cortex during brain repair after stroke. Stroke significantly increased nuclear HDAC4 immunoreactivity in neurons, but not in astrocytes or in oligodendrocytes, of the peri-infarct cortex at 2, 7, and 14 days after middle cerebral artery occlusion. Neurons with nuclear HDAC4 immunoreactivity distributed across all layers of the peri-infarct cortex and were Ctip2+ excitatory and parvalbumin+ inhibitory neurons. These neurons were not TUNEL or BrdU positive. Furthermore, nuclear HDAC4 immunoreactivity was positively and significantly correlated with increased dendritic, axonal, and myelin densities as determined by microtubule-associated protein 2, phosphorylated neurofilament heavy chain, and myelin basic protein, respectively. Unlike HDAC4, stroke did not alter nuclear localization of HDAC5. Our data show that stroke induces nuclear shuttling of HDAC4 in neurons in the peri-infarct cortex, and that increased nuclear HDAC4 is strongly associated with neuronal remodeling but not with neuronal cell death, suggesting a role for nuclear HDAC4 in promoting neuronal recovery after ischemic injury.


Tetanus, diphtheria, pertussis vaccination coverage before, during, and after pregnancy - 16 States and New York City, 2011.
In June 2011, the Advisory Committee on Immunizations Practices (ACIP) recommended 1 dose of a tetanus, diphtheria, and acellular pertussis (Tdap) vaccine during pregnancy for women who had not received Tdap previously. Before 2011, Tdap was recommended for unvaccinated women either before pregnancy or postpartum. In October 2012, ACIP expanded the 2011 recommendation, advising pregnant women to be vaccinated with Tdap during each pregnancy to provide maternal antibodies for each infant. The optimal time for vaccination is at 27-36 weeks' gestation as recommended by ACIP. In response to ACIP's Tdap recommendation for pregnant women in 2011, CDC added a supplemental question to the Pregnancy Risk Assessment Monitoring System (PRAMS) survey to determine women's Tdap vaccination status before, during, or after their most recent delivery. This report describes overall and state-specific Tdap vaccination coverage around the time of pregnancy using data from 6,852 sampled women who delivered a live-born infant during September-December 2011 in one of 16 states or New York City (NYC). Among the 17 jurisdictions, the median percentage of women with live births who reported any Tdap vaccination was 55.7%, ranging from 38.2% in NYC to 76.6% in Nebraska. The median percentage who received Tdap before pregnancy was 13.9% (range = 7.7%-20.1%), during pregnancy was 9.8% (range = 3.8%-14.2%), and after delivery was 30.9% (range = 13.6%-46.5%). The PRAMS data indicate a wide variation in Tdap vaccination coverage among demographic groups, with generally higher postpartum coverage for non-Hispanic white women, those who started prenatal care in the first trimester, and those who had private health insurance coverage. This information can be used for promoting evidence-based strategies to communicate the importance of ACIP guidelines related to Tdap vaccination coverage to women and their prenatal care providers.


Simulation-based paediatric intensive care unit central venous line maintenance bundle training.
Research has demonstrated that additional reduction in paediatric catheter associated blood stream infection (CA-BSI) rates can be achieved through improving compliance with maintenance bundle care for central venous lines. Our objective was to improve maintenance bundle compliance rates and nursing competency surrounding central venous line (CVL) care in our paediatric intensive care unit (PICU). A multidisciplinary team developed a bedside simulation-based training programme to improve compliance with standard PICU CVL maintenance bundle. We then performed a randomised comparison study comparing a standard CVL bundle training process for bedside PICU nurses in a control group (CG) to an intervention group (IG) receiving bedside training to simulate a CVL dressing change and maintenance bundle followed by intermittent training refreshers. Groups were assessed for compliance with prescribed components of the CVL bundle maintenance (CVL score). At baseline the CG and IG had similar mean CVL scores (p=0.725). At twelve months mean CVL bundle compliance score in the IG was significantly higher than in the CG (p<0.0001). The largest CVL score increase for IG occurred between zero and three months. Coincidentally, CA-BSI rates in the Egleston PICU significantly decreased from 1.9±2.2 BSIsper 1000/CVL days, prior to the study, to 0.6±1.6 BSIsper 1000/CVL days following implementation of the intervention (p=0.034). Bedside simulation based training in CVL dressing change is associated with improved compliance with CVL maintenance bundle practice. Enhanced CVL maintenance bundle practice could contribute to reduction in CA-BSI rates.


Influence of social support on cognitive change and mortality in old age: results from the prospective multicentre cohort study AgeCoDe.
Social support has been suggested to positively influence cognition and mortality in old age. However, this suggestion has been questioned due to inconsistent operationalisations of social support among studies and the small number of longitudinal studies available. This study aims to investigate the influence of perceived social support, understood as the emotional component of social support, on cognition and mortality in old age as part of a prospective longitudinal multicentre study in Germany. A national subsample of 2,367 primary care patients was assessed twice over an observation period of 18 months regarding the influence of social support on cognitive function and mortality. Perceived social support was assessed using the 14-item version of the FSozU, which is a standardised and validated questionnaire of social support. Cognition was tested by the neuropsychological test battery of the Structured Interview for the Diagnosis of Dementia (SIDAM). The influence of perceived support on cognitive change was analysed by multivariate ANCOVA; mortality was analysed by multivariate logistic and cox regression. Sample cognitive change (N = 1,869): Mean age was 82.4 years (SD 3.3) at the beginning of the observation period, 65.9% were female, mean cognition was 49 (SD 4.4) in the SIDAM. Over the observation period cognitive function declined in 47.2% by a mean of 3.4 points. Sample mortality (N = 2,367): Mean age was 82.5 years (SD 3.4), 65.7% were female and 185 patients died during the observation period. Perceived social support showed no longitudinal association with cognitive change (F = 2.235; p = 0.135) and mortality (p = 0.332; CI 0.829-1.743). Perceived social support did not influence cognition and mortality over an 18 months observation period. However, previous studies using different operationalisations of social support and longer observation periods indicate that such an influence may exist. This influence is rather small and the result of complex interaction mechanisms between different components of social support; the emotional component seems to have no or only a limited effect. Further research is needed to describe the complex interactions between components of social support. Longer observation periods are necessary and standardised operationalisations of social support should be applied.


Seeing beyond 2020: an economic evaluation of contemporary and emerging strategies for elimination of Trypanosoma brucei gambiense.
Trypanosoma brucei (T b) gambiense is targeted to reach elimination as a public health problem by 2020 and full elimination by 2030. To achieve these goals, stakeholders need to consider strategies to accelerate elimination. Hence, we aimed to model several options related to current and emerging methods for case detection, treatment, and vector control across settings to assess cost-effectiveness and the probability of elimination. Five intervention strategies were modelled over 30 years for low, moderate, and high transmission settings. Model parameters related to costs, efficacy, and transmission were based on available evidence and parameter estimation. Outcomes included disability-adjusted life-years (DALYs), costs, and long-term prevalence. Sensitivity analyses were done to calculate the uncertainty of the results. To reach elimination targets for 2020 across all settings, approaches combining case detection, treatment, and vector control would be most effective. Elimination in high and moderate transmission areas was probable and cost-effective when strategies included vector control and novel methods, with incremental cost-effectiveness ratios (ICERs) ranging from US$400 to $1500 per DALY averted. In low transmission areas, approaches including the newest interventions alone or in combination with tiny targets (vector control) were cost-effective, with ICERs of $200 or $1800 per DALY averted, respectively, but only strategies including vector control were likely to lead to elimination. Results of sensitivity analyses showed that allowing for biennial surveillance, reducing vector control maintenance costs, or variations of active surveillance coverage could also be cost-effective options for elimination, depending on the setting. Although various strategies might lead to elimination of T b gambiense, cost-effective approaches will include adoption of emerging technologies and, in some settings, increased surveillance or implementation of vector control. Bill & Melinda Gates Foundation.


Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages.
Histone deacetylases (HDACs) regulate inflammatory gene expression, as indicated by the potent antiinflammatory activity of pan-HDAC inhibitors. However, the specific contribution of each of the 11 HDAC proteins to the inflammatory gene expression program is unknown. Using an integrated genomic approach, we found that Hdac3-deficient macrophages were unable to activate almost half of the inflammatory gene expression program when stimulated with LPS. A large part of the activation defect was attributable to loss of basal and LPS-inducible expression of IFN-β, which maintains Stat1 protein levels in unstimulated cells and acts in an autocrine/paracrine manner after stimulation to promote a secondary wave of Stat1-dependent gene expression. Loss of Hdac3-mediated repression of nuclear receptors led to hyperacetylation of thousands of genomic sites and associated gene derepression. The up-regulation of the constitutively expressed prostaglandin endoperoxide synthase, Ptgs1 (Cox-1), a nuclear receptor target, had a causative role in the phenotype because its chemical inhibition reverted, albeit partially, the Ifn-β activation defect. These data indicate a central role for Hdac3 in inflammation and may have relevance for the use of selective Hdac inhibitors as antiinflammatory agents.


Inter- and intraclonal diversity in the antibody response to influenza hemagglutinin.
This study focuses on 10 BALB/c anti-influenza virus (A/PR/8/34) hemagglutinin antibodies that have light chains encoded by the same variable region kappa chain (V kappa) gene, V kappa 21C. A comparison of antibodies from lymphocytes of independent origin reveals the contribution of germline diversity (combinatorial joining and association) to this response. Although combinatorial joining and association contribute to sequence diversity, they appear to have little effect on the fine specificity of these antibodies. Somatic mutation, in addition to contributing to the sequence diversity of these antibodies, creates differences in their fine specificity. The extent of mutation and its effect on fine specificity can be seen by comparing antibodies of lymphocytes from the same clone. These intraclonal comparisons also indicate that somatic mutation is an ongoing process occurring at a high rate (estimated to be at least 10(-3) mutations per base pair per division) in the expressed V region heavy chain (VH) and V kappa genes. Furthermore, both the nature and distribution of these mutations suggest that amino acid replacement mutations in the light but not the heavy chain are selected for by antigen.


MORE: mixed optimization for reverse engineering--an application to modeling biological networks response via sparse systems of nonlinear differential equations.
Reverse engineering is the problem of inferring the structure of a network of interactions between biological variables from a set of observations. In this paper, we propose an optimization algorithm, called MORE, for the reverse engineering of biological networks from time series data. The model inferred by MORE is a sparse system of nonlinear differential equations, complex enough to realistically describe the dynamics of a biological system. MORE tackles separately the discrete component of the problem, the determination of the biological network topology, and the continuous component of the problem, the strength of the interactions. This approach allows us both to enforce system sparsity, by globally constraining the number of edges, and to integrate a priori information about the structure of the underlying interaction network. Experimental results on simulated and real-world networks show that the mixed discrete/continuous optimization approach of MORE significantly outperforms standard continuous optimization and that MORE is competitive with the state of the art in terms of accuracy of the inferred networks.


Exome sequencing and cis-regulatory mapping identify mutations in MAK, a gene encoding a regulator of ciliary length, as a cause of retinitis pigmentosa.
A fundamental challenge in analyzing exome-sequence data is distinguishing pathogenic mutations from background polymorphisms. To address this problem in the context of a genetically heterogeneous disease, retinitis pigmentosa (RP), we devised a candidate-gene prioritization strategy called cis-regulatory mapping that utilizes ChIP-seq data for the photoreceptor transcription factor CRX to rank candidate genes. Exome sequencing combined with this approach identified a homozygous nonsense mutation in male germ cell-associated kinase (MAK) in the single affected member of a consanguineous Turkish family with RP. MAK encodes a cilium-associated mitogen-activated protein kinase whose function is conserved from the ciliated alga, Chlamydomonas reinhardtii, to humans. Mutations in MAK orthologs in mice and other model organisms result in abnormally long cilia and, in mice, rapid photoreceptor degeneration. Subsequent sequence analyses of additional individuals with RP identified five probands with missense mutations in MAK. Two of these mutations alter amino acids that are conserved in all known kinases, and an in vitro kinase assay indicates that these mutations result in a loss of kinase activity. Thus, kinase activity appears to be critical for MAK function in humans. This study highlights a previously underappreciated role for CRX as a direct transcriptional regulator of ciliary genes in photoreceptors. In addition, it demonstrates the effectiveness of CRX-based cis-regulatory mapping in prioritizing candidate genes from exome data and suggests that this strategy should be generally applicable to a range of retinal diseases.


Mass spectrometry informs the structure and dynamics of membrane proteins involved in lipid and drug transport.
Membrane proteins are important macromolecules that play crucial roles in many cellular and physiological processes. Over the past two decades, the use of mass spectrometry as a biophysical tool to characterise membrane proteins has grown steadily. By capturing these dynamic complexes in the gas phase, many unknown small molecule interactions have been revealed. One particular application of this research has been the focus on antibiotic resistance with considerable efforts being made to understand underlying mechanisms. Here we review recent advances in the application of mass spectrometry that have yielded both structural and dynamic information on the interactions of antibiotics with proteins involved in bacterial cell envelope biogenesis and drug efflux.


Non-synonymous variant (Gly307Ser) in CD226 is associated with susceptibility to multiple autoimmune diseases.
Recently, a non-synonymous (Gly307Ser) variant, rs763361, in the CD226 gene was shown to be associated with multiple autoimmune diseases (ADs) in European Caucasian populations. However, shared autoimmunity with CD226 has not been evaluated in non-European populations. The aim of the present study is to assess the association of this single nucleotide polymorphism (SNP) with ADs in non-European populations. To replicate this association in non-European populations, we evaluated case-control association between rs763361 and coeliac disease (CED) samples from Argentina; SLE, RA, type-1 diabetes (T1D) and primary SS (pSS) from Colombia; and SLE samples from China and Japan. We genotyped rs763361 and evaluated its genetic association with multiple ADs, using chi(2)-test. For each association, odds ratio (OR) and 95% CI were calculated. We show that rs763361 is significantly associated with Argentinean CED (P = 0.0009, OR = 1.60). We also observed a trend of possible association with Chinese SLE (P = 0.01, OR = 1.19), RA (P = 0.047, OR = 1.25), SLE (P = 0.0899, OR = 1.24) and pSS (P = 0.09, OR = 1.33) in Colombians. Meta-analyses for SLE (using our three populations) and T1D (our population and three published populations) yielded significant association with rs763361, P = 0.009 (OR = 1.16) and P = 1.1.46 x 10(-9) (OR = 1.14), respectively. Our results demonstrate that the coding variant rs763361 in CD226 gene is associated with multiple ADs in non-European populations.


Valve type and long-term outcomes after aortic valve replacement in older patients.
To compare outcomes after aortic valve replacement (AVR) according to valve type specifically in older patients since valve-related risks are age-dependent; two randomised trials comparing mechanical and bioprosthetic valves found better outcomes with mechanical valves, but the samples were small and the patients were considerably younger than most who undergo AVR. Cohort study. 1199 US hospitals. Patients 65 years and older undergoing AVR during 1991-2003 (n = 307 054) identified through Medicare claims data. Relative hazard ratios associated with bioprosthetic valves of (1) death (n = 131,719); (2) readmission for haemorrhage (n = 31,186), stroke (n = 25,051) or embolism (n = 5870); (3) reoperation (n = 4216); and (4) death or reoperation (reoperation free survival) in Cox regression analyses adjusting for demographic and clinical factors and hospital-level effects. Overall, 36% of AVR patients received bioprosthetic valves. Bioprosthetic valve recipients were older (77 vs 75 years, p<0.001) and generally had higher comorbidity. Bioprosthetic valve recipients had a slightly lower adjusted hazard ratios of death (HR = 0.97; 95% CI 0.95 to 0.98); readmission for haemorrhage, stroke or embolism (HR = 0.90, 95% CI 0.88 to 0.92); and death or reoperation (HR = 0.97, 95% CI 0.96 to 0.98), but a higher hazard ratio of reoperation (HR = 1.25, 95% CI 1.16 to 1.35). However, overall mortality and complication rates were more than 20 and 10 times higher, respectively, than the overall reoperation rate. In older patients undergoing AVR, bioprosthetic valve recipients had slightly lower risks of death and complications, but a higher risk of reoperation. Given the low reoperation rate, these data suggest that bioprosthetic valves may be preferred in older patients.


Conscious brain-to-brain communication in humans using non-invasive technologies.
Human sensory and motor systems provide the natural means for the exchange of information between individuals, and, hence, the basis for human civilization. The recent development of brain-computer interfaces (BCI) has provided an important element for the creation of brain-to-brain communication systems, and precise brain stimulation techniques are now available for the realization of non-invasive computer-brain interfaces (CBI). These technologies, BCI and CBI, can be combined to realize the vision of non-invasive, computer-mediated brain-to-brain (B2B) communication between subjects (hyperinteraction). Here we demonstrate the conscious transmission of information between human brains through the intact scalp and without intervention of motor or peripheral sensory systems. Pseudo-random binary streams encoding words were transmitted between the minds of emitter and receiver subjects separated by great distances, representing the realization of the first human brain-to-brain interface. In a series of experiments, we established internet-mediated B2B communication by combining a BCI based on voluntary motor imagery-controlled electroencephalographic (EEG) changes with a CBI inducing the conscious perception of phosphenes (light flashes) through neuronavigated, robotized transcranial magnetic stimulation (TMS), with special care taken to block sensory (tactile, visual or auditory) cues. Our results provide a critical proof-of-principle demonstration for the development of conscious B2B communication technologies. More fully developed, related implementations will open new research venues in cognitive, social and clinical neuroscience and the scientific study of consciousness. We envision that hyperinteraction technologies will eventually have a profound impact on the social structure of our civilization and raise important ethical issues.


Beneficial Effects of ragi (Finger Millet) on Hematological Parameters, Body Mass Index, and Scholastic Performance among Anemic Adolescent High-School Girls (AHSG).
Adolescence is a period characterized by rapid physical, emotional, and mental growth and changes potentially resulting in health challenges. Anemia, which is a fairly common complication in this age group, is reported to negatively affect the cognitive ability of adolescents. Traditionally, ragi (Finger millet: Eleusine coracana), a cereal available in India, has been recommended as nutritional supplement to combat anemia because of its high protein and mineral content as well as anti-microbial property. This study sought to establish the effect of ragi in improving hematological parameters, body mass index, and scholastic performance among adolescent school girls. Sixty adolescent girls were randomly selected and divided into intervention (n = 30) and control groups (n = 30). The effect of dietary supplementation of ragi porridge on hematological parameters was evaluated on the intervention group at 45 and 90 days. Both groups were monitored for changes in body mass index and scholastic performance. A statistically significant increase in hemoglobin levels was observed in the intervention group after 90 days (from a mean of 11.3 g% to 12.54 g%; t (29) = 7.514, p < .0001), with no significant changes in the control group. No statistically significant differences between the two groups were observed for mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, red cell distribution width, body mass index, and scholastic performance. The data show that daily dietary supplementation with ragi porridge has a positive effect on hemoglobin levels in adolescent high schools girls. A well planned nutrition education with dietary supplementation is thus recommended for better outcomes.


Semi-artificial mouse skin membrane feeding technique for adult tick, Haemaphysalis longicornis.
An in vitro artificial feeding technique for hard ticks is quite useful for studying the tick-pathogen interactions. Here, we report a novel semi-artificial feeding technique for the adult parthenogenetic tick, Haemaphysalis longicornis, using mouse skin membrane. Skin with attached adult ticks was removed from the mouse body at 4 to 5 days post-infestation for the construction of the feeding system. This system supplied with rabbit blood was kept in >95% relative humidity at 30°C during the feeding, and ticks were fully engorged (artificially engorged, AE) within 12 to 48 h. For comparison, ticks were fed to engorgement solely on rabbit or mouse for 5 days as controls (naturally engorged on rabbit, NEr, or mouse, NEm). Blood digestion-related gene expression in the midgut and reproductive fitness were compared. Body weight, egg mass weight, egg conversion ratio, and hatchability of eggs did not show any significant differences. We analyzed transcription profiles of selected genes assayed by quantitative RT-PCR and revealed similar patterns of expression between NEr and AE but some differences between NEm and AE or NEm and NEr. Our results demonstrate that this semi-artificial feeding technique mimics natural feeding processes of ticks and can be utilized as a standardized method to inoculate pathogens, especially Babesia protozoa, into H. longicornis and possibly other tick species as well.


Results of imatinib mesylate therapy in patients with refractory or recurrent acute myeloid leukemia, high-risk myelodysplastic syndrome, and myeloproliferative disorders.
Imatinib mesylate is a selective tyrosine kinase inhibitor of c-abl, bcr/abl, c-kit, and platelet-derived growth factor-receptor (PDGF-R). c-kit is expressed in most patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) and PDGF has been implicated in the pathogenesis of myeloproliferative disorders (MPD). The authors investigated the efficacy of imatinib in patients with these disorders. Forty-eight patients with AML (n = 10), MDS (n = 8), myelofibrosis (n = 18), atypical chronic myeloid leukemia (CML; n = 7), chronic myelomonocytic leukemia (CMML; n = 3), or polycythemia vera (n = 2) were treated with imatinib 400 mg daily. None of the patients with AML or MDS responded. Among patients with myelofibrosis, 10 of 14 patients with splenomegaly (71%) had a 30% or greater reduction in spleen size, 1 patient had trilineage hematologic improvement, 2 had erythroid hematologic improvement, and 1 had improvement in platelet count. One patient with atypical CML had erythroid hematologic improvement. Both patients with polycythemia vera needed fewer phlebotomies (from 2-3 per year to none during the 8 months of therapy and from 3-6 per year to 1 during 9 months of therapy). None of the three patients with CMML responded. Treatment was well tolerated. The side effects were similar to those observed in patients with CML. Within these small subgroups of disease types, single-agent imatinib did not achieve a significant clinical response among patients with AML, MDS, atypical CML, or CMML without PDGF-R fusion genes. Preliminary data on polycythemia vera are promising and deserve further investigation. Responses among myelofibrosis patients were minor. Therefore, a combination treatment regimen including imatinib may be more effective.


The effectiveness of educational interventions to enhance the adoption of fee-based arsenic testing in Bangladesh: a cluster randomized controlled trial.
Arsenic (As) testing could help 22 million people, using drinking water sources that exceed the Bangladesh As standard, to identify safe sources. A cluster randomized controlled trial was conducted to evaluate the effectiveness of household education and local media in the increasing demand for fee-based As testing. Randomly selected households (N = 452) were divided into three interventions implemented by community workers: 1) fee-based As testing with household education (HE); 2) fee-based As testing with household education and a local media campaign (HELM); and 3) fee-based As testing alone (Control). The fee for the As test was US$ 0.28, higher than the cost of the test (US$ 0.16). Of households with untested wells, 93% in both intervention groups HE and HELM purchased an As test, whereas only 53% in the control group. In conclusion, fee-based As testing with household education is effective in the increasing demand for As testing in rural Bangladesh.


Population diversity and relatedness in Sugarbirds (Promeropidae: Promerops spp.).
Sugarbirds are a family of two socially-monogamous passerine species endemic to southern Africa. Cape and Gurney's Sugarbird (Promerops cafer and P. gurneyi) differ in abundance, dispersion across their range and in the degree of sexual dimorphism in tail length, factors that affect breeding systems and potentially genetic diversity. According to recent data, P. gurneyi are in decline and revision of the species' IUCN conservation status to a threatened category may be warranted. It is therefore necessary to understand genetic diversity and risk of inbreeding in this species. We used six polymorphic microsatellite markers and one mitochondrial gene (ND2) to compare genetic diversity in P. cafer from Helderberg Nature Reserve and P. gurneyi from Golden Gate Highlands National Park, sites at the core of each species distribution. We describe novel universal avian primers which amplify the entire ND2 coding sequence across a broad range of bird orders. We observed high mitochondrial and microsatellite diversity in both sugarbird populations, with no detectable inbreeding and large effective population sizes.


Medication adherence in patients with myotonic dystrophy and facioscapulohumeral muscular dystrophy.
Myotonic dystrophy (DM) and facioscapulohumeral muscular dystrophy (FSHD) are the two most common adult muscular dystrophies and have progressive and often disabling manifestations. Higher levels of medication adherence lead to better health outcomes, especially important to patients with DM and FSHD because of their multisystem manifestations and complexity of care. However, medication adherence has not previously been studied in a large cohort of DM type 1 (DM1), DM type 2 (DM2), and FSHD patients. The purpose of our study was to survey medication adherence and disease manifestations in patients enrolled in the NIH-supported National DM and FSHD Registry. The study was completed by 110 DM1, 49 DM2, and 193 FSHD patients. Notable comorbidities were hypertension in FSHD (44 %) and DM2 (37 %), gastroesophageal reflux disease in DM1 (24 %) and DM2 (31 %) and arrhythmias (29 %) and thyroid disease (20 %) in DM1. Each group reported high levels of adherence based on regimen complexity, medication costs, health literacy, side effect profile, and their beliefs about treatment. Only dysphagia in DM1 was reported to significantly impact medication adherence. Approximately 35 % of study patients reported polypharmacy (taking 6 or more medications). Of the patients with polypharmacy, the DM1 cohort was significantly younger (mean 55.0 years) compared to DM2 (59.0 years) and FSHD (63.2 years), and had shorter disease duration (mean 26 years) compared to FSHD (26.8 years) and DM2 (34.8 years). Future research is needed to assess techniques to ease pill swallowing in DM1 and to monitor polypharmacy and potential drug interactions in DM and FSHD.


Correlations between photoactivable porphyrins' fluorescence, erythema and the pain induced by PDT on normal skin using ALA-derivatives.
Photodynamic therapy (PDT) with precursors of photoactivable porphyrins is a well-established treatment modality for skin pathologies as well as hair removal. Pain is a major side effect thereof, and it affects the treatment compliance and acceptance. Five male subjects underwent a PDT procedure on normal skin, either with a diode laser (635 nm) or a lamp (405 nm), 3 or 6h after application of various precursors of photoactivable porphyrins (ALA 1M; Metvix(®) 1M; ALA-DGME 1M; ALA-DGME 3.66 M). Light doses ranged from 30 to 150 J/cm(2) and irradiances were 100 or 180 mW/cm(2). Fluorescence measurements were performed just before PDT, pain was quantified during PDT, and erythema was determined 24h afterwards. Because precursor ALA-DGME was very selective for the pilosebaceous apparatus vs. the epidermis, we solely carried out the PDTs using this precursor. In the absence of light, no pain was reported. An increase in pain was observed when increasing the irradiance. A correlation was observed between the follicular fluorescence and the maximal pain score during PDT. A correlation was observed between follicular fluorescence and skin erythema, and between pain score and skin erythema. With our well-controlled PDT parameters and homogenous subjects' conditions, we showed that pain could be reduced by reducing irradiance during PDT procedures. With the various correlations observed, we conclude that both pain and PaP fluorescence are useful tools to predict the post-PDT tissue effects (side effects and outcome). We suggest that A∂ nerve fibres would be the best candidate as first generators of PDT-induced pain.


How to effectively manage myopia.
Myopia has become epidemic in the world. Without effective control, the progression may lead to excessive myopia with severe complications affecting vision and ocular alignment. The genetic factors and environmental factors of myopia are closely interrelated to each other. Asian ethnicity and parental myopia, among other genetic factors, influence the refractive outcome dramatically when environmental risk factors such as hours of near work and reading distance are analyzed. Outdoor activities are protective measures that retard myopia progression. Total time under the sun and not the specific outdoor activities are contributing factors. Current effective treatments for myopia include atropine of high, moderate, and low doses, relative peripheral myopia-inducing devices, and bifocal spectacles including prism bifocal spectacle lenses. Although atropine is considered highly effective in randomized controlled trials, it is not well tolerated in a clinical setting, especially in high dosage. Since the severity of rebound effect of atropine after cessation of usage and the side effects are directly related to the concentration of the medication, it is recommended that low-dose atropine is used in the initial attempt. Higher concentration for better control can be considered when compliance is observed. Devices that induce relative peripheral myopia such as orthokeratology are moderately effective interventions that are well accepted by children who wish to be spectacle free. Bifocal spectacles generally have low effect in myopia control. Prism bifocal spectacle lenses may have a special niche in myopia retardation for patients with low lags of accommodation.


Cross-utilization of the beta sliding clamp by replicative polymerases of evolutionary divergent organisms.
Chromosomal replicases are multiprotein machines comprised of a DNA polymerase, a sliding clamp, and a clamp loader. This study examines replicase components for their ability to be switched between Gram-positive and Gram-negative organisms. These two cell types diverged over 1 billion years ago, and their sequences have diverged widely. Yet the Escherichia coli beta clamp binds directly to Staphylococcus aureus PolC and makes it highly processive, confirming and extending earlier results (Low, R. L., Rashbaum, S. A. , and Cozzarelli, N. R. (1976) J. Biol. Chem. 251, 1311-1325). We have also examined the S. aureus beta clamp. The results show that it functions with S. aureus PolC, but not with E. coli polymerase III core. PolC is a rather potent polymerase by itself and can extend a primer with an intrinsic speed of 80-120 nucleotides per s. Both E. coli beta and S. aureus beta converted PolC to a highly processive polymerase, but surprisingly, beta also increased the intrinsic rate of DNA synthesis to 240-580 nucleotides per s. This finding expands the scope of beta function beyond a simple mechanical tether for processivity to include that of an effector that increases the intrinsic rate of nucleotide incorporation by the polymerase.


Reduced uptake of [¹⁸F]FDOPA PET in asymptomatic welders with occupational manganese exposure.
Welding exposes workers to manganese (Mn) fumes, but it is unclear if this exposure damages dopaminergic neurons in the basal ganglia and predisposes individuals to develop parkinsonism. PET imaging with 6-[(18)F]fluoro-l-dopa (FDOPA) is a noninvasive measure of nigrostriatal dopaminergic neuron integrity. The purpose of this study is to determine whether welding exposure is associated with damage to nigrostriatal neurons in asymptomatic workers. We imaged 20 asymptomatic welders exposed to Mn fumes, 20 subjects with idiopathic Parkinson disease (IPD), and 20 normal controls using FDOPA PET. All subjects were examined by a movement disorders specialist. Basal ganglia volumes of interest were identified for each subject. The specific uptake of FDOPA, K(i), was generated for each region using graphical analysis method. Repeated measures general linear model (GLM) analysis demonstrated a strong interaction between diagnostic group and region (F(4,112) = 15.36, p < 0.001). Caudate K(i)s were lower in asymptomatic welders (0.0098 + 0.0013 minutes(-1)) compared to control subjects (0.0111 + 0.0012 minutes(-1), p = 0.002). The regional pattern of uptake in welders was most affected in the caudate > anterior putamen > posterior putamen. This uptake pattern was anatomically reversed from the pattern found in subjects with IPD. Active, asymptomatic welders with Mn exposure demonstrate reduced FDOPA PET uptake indicating dysfunction in the nigrostriatal dopamine system. The caudate K(i) reduction in welders may represent an early (asymptomatic) marker of Mn neurotoxicity and appears to be distinct from the pattern of dysfunction found in symptomatic IPD.


PARTIALLY CONSTRAINED SEX ALLOCATION AND THE INDIRECT EFFECTS OF ASSISTED REPRODUCTIVE TECHNOLOGIES ON THE HUMAN SEX RATIO.
Infertility affects around 15% of human couples and in many countries approximately 1-4% of babies are born following Assisted Reproductive Technologies (ART). Several ART techniques are used and these differentially affect the sex ratio of offspring successfully produced. These direct effects on sex ratio also have the potential to influence, indirectly, the sex ratios of offspring born to untreated couples. This is of concern because human sex ratio bias may adversely affect public health. Here the extent of indirect effects of ART that could operate, via Fisherian frequency-dependent natural selection, on the progeny sex ratio of unassisted members of a population is heuristically modelled. Given the degrees to which ART techniques bias sex ratios directly, it is predicted that well over 20% of couples would have to reproduce via ART for there to be any discernible effect on the sex ratios produced, in response, by the remainder of the population. This value is greater than the estimated prevalence of infertility problems among human couples. It is concluded that providing ART to couples with fertility problems does not currently generate significant ethical issues or public health concern in terms of indirect effects on the offspring sex ratios of untreated couples.


MS in South Asians in England: early disease onset and novel pattern of myelin autoimmunity.
Epidemiological studies describe a latitude gradient for increased MS prevalence and a preponderance of disease in Caucasian individuals. However, individuals from other ethnic backgrounds and low-risk regions can acquire a raised risk through migration. Nearly a fifth of the London population is of Asian/Asian-British origin and a significant proportion of referrals are from this group. We investigated whether there were differences in timing, presentation, severity, and immunology of disease (with respect to CD4 myelin epitope recognition) between individuals in London with MS who were either of S. Asian or Caucasian origin. Individuals of S. Asian origin with MS were compared with healthy S. Asian controls, individuals with MS and of Caucasian origin and Caucasian controls. Age at MS onset is significantly lower in the S. Asian group, attributable to earlier onset specifically in UK-born individuals, though clinical presentation is similar. Analysis of CD4 autoimmunity to myelin antigens shows disease in S. Asian individuals to encompass recognition of novel epitopes; immunity to MBP116-130 in S. Asian individuals was highly disease-specific. These findings emphasize the need to define disease profiles across ethnicities and identify environmental triggers conferring acquired risk. Such findings must inform choices for immunotherapeutic interventions suitable for all, across ethnicities.


Mechanical complications in adult spinal deformity and the effect of restoring the spinal shapes according to the Roussouly classification: a multicentric study.
To evaluate the incidence of mechanical complications in patients with adult spine deformity (ASD) treated by restoring the normal shape according to the Roussouly classification. This is a retrospective multicentric study with a minimum follow-up of 2 years. Patients operated on with fusion for ASD (minimum performed fusion: L2 to sacrum) were included. Patients with a history of previous spinal fusion of more than three levels were excluded. Spinal and pelvic parameters were measured on the preoperative and the immediate postoperative follow-up. All mechanical complications were recorded. A total of 290 patients met the criteria of inclusion with a minimum follow-up of 2 years. Mechanical complications occurred in 30.4% of the cohort. The most common complication was PJK with an incidence of 18% while nonunion or instrumentation failure (rod breakage, implant failure) occurred in 12.4%. 66% of the patients were restored to the normal shape according to the Roussouly classification based on their PI and had a mechanical complication rate of 22.5%, whereas the remaining 34% of patients had a complication rate of 46.8% (p < 0.001). The relative risk for developing a mechanical complication if the algorithm was not met was 3 (CI 1.5-4.3; p < 0.001) CONCLUSION: In the recent literature, there are no clear guidelines for ASD correction. Restoring the sagittal spinal contour to the normal shapes of Roussouly according to the PI could serve as a guideline for ASD treatment. Ignoring this algorithm has a threefold risk of increased mechanical complications. We recommend this algorithm for treatment of ASD. IV cross-sectional observational study. These slides can be retrieved under Electronic Supplementary Material.


Pain trajectory defines knee osteoarthritis subgroups: a prospective observational study.
Knee osteoarthritis (OA) is a heterogeneous disease, and identification of its subgroups/phenotypes can improve patient treatment and drug development. We aimed to identify homogeneous OA subgroups/phenotypes using pain development over time; to understand the interplay between pain and functional limitation in time course; and to investigate subgroups' responses to available pharmacological and surgical treatments. We used group-based trajectory modelling to identify pain trajectories in the phase-3 VIDEO trial (n = 474, 3-year follow-up) and also in the Osteoarthritis Initiative cohort study (n = 4796, 9-year follow-up). We extended trajectory models by (1) fitting dual trajectories to investigate the interplay between pain and functional limitation over time, and (2) including analgesic use as a time-varying covariate. Also, we investigated the relationship between trajectory groups and knee replacement in regression models. We identified 4 pain trajectory groups in the trial and 6 in the cohort. These overlapped and led us to define 4 OA phenotypes: low-fluctuating, mild-increasing, moderate-treatment-sensitive, and severe-treatment-insensitive pain. Over time, functional knee limitation followed the same trajectory as pain with almost complete concordance (94.3%) between pain and functional limitation trajectory groups. Notably, we identified a phenotype with severe pain that did not benefit from available treatments, and another one most likely to benefit from knee replacement. Thus, knee OA subgroups/phenotypes can be identified based on patients' pain experiences in studies with long and regular follow-up. We provided a robust approach, reproducible between different study designs, which informs clinicians about symptom development and delivery of treatment options and opens a new avenue toward personalized medicine in OA.


Target regulation of PI3K/Akt/mTOR pathway by cannabidiol in treatment of experimental multiple sclerosis.
This study was aimed to investigate whether treatment with purified cannabidiol (CBD) may counteract the development of experimental multiple sclerosis (MS), by targeting the PI3K/Akt/mTOR pathway. Although the PI3K/Akt/mTOR pathway was found to be activated by cannabinoids in several immune and non-immune cells, currently, there is no data about the effects of CBD in the PI3K/Akt/mTOR activity in MS. Experimental Autoimmune Encephalomyelitis (EAE), the most common model of MS, was induced in C57BL/6 mice by immunization with myelin oligodendroglial glycoprotein peptide (MOG)35-55. After EAE onset, which occurs approximately 14days after disease induction, mice were daily intraperitoneally treated with CBD (10mg/kg mouse) and observed for clinical signs of EAE. At 28days from EAE-induction, mice were euthanized and spinal cord tissues were sampled to perform immunohistochemical evaluations and western blot analysis. Our results showed a clear downregulation of the PI3K/Akt/mTOR pathway following EAE induction. CBD treatment was able to restore it, increasing significantly the phosphorylation of PI3K, Akt and mTOR. Also, an increased level of BNDF in CBD-treated mice seems to be involved in the activation of PI3K/Akt/mTOR pathway. In addition, our data demonstrated that therapeutic efficacy of CBD treatment is due to reduction of pro-inflammatory cytokines, like IFN-γ and IL-17 together with an up-regulation of PPARγ. Finally, CBD was found to promote neuronal survival by inhibiting JNK and p38 MAP kinases. These results provide an interesting discovery about the regulation of the PI3K/Akt/mTOR pathway by cannabidiol administration, that could be a new potential therapeutic target for MS management.


The Human RNA-Binding Proteome and Its Dynamics during Translational Arrest.
Proteins and RNA functionally and physically intersect in multiple biological processes, however, currently no universal method is available to purify protein-RNA complexes. Here, we introduce XRNAX, a method for the generic purification of protein-crosslinked RNA, and demonstrate its versatility to study the composition and dynamics of protein-RNA interactions by various transcriptomic and proteomic approaches. We show that XRNAX captures all RNA biotypes and use this to characterize the sub-proteomes that interact with coding and non-coding RNAs (ncRNAs) and to identify hundreds of protein-RNA interfaces. Exploiting the quantitative nature of XRNAX, we observe drastic remodeling of the RNA-bound proteome during arsenite-induced stress, distinct from autophagy-related changes in the total proteome. In addition, we combine XRNAX with crosslinking immunoprecipitation sequencing (CLIP-seq) to validate the interaction of ncRNA with lamin B1 and EXOSC2. Thus, XRNAX is a resourceful approach to study structural and compositional aspects of protein-RNA interactions to address fundamental questions in RNA-biology.


Oxidation of tartrazine with ultraviolet light emitting diodes: pH and duty cycles effects.
The presence of tartrazine (TAR) in the water cycle poses serious threats to human health. This study investigated the used of light emitting diodes (LEDs) in the advanced oxidation of TAR under different pH and duty cycle (DC) conditions. The first order reaction rate constant for TAR oxidation was positively correlated with DC, negatively correlated with pH, and typically greatest at pH 6. Chemical byproduct analysis indicated that OH addition, H abstraction, and electron transfer without molecule transfer were among the relevant reaction mechanisms for TAR degradation. Six byproducts were identified, four were reported for the first time, and two demonstrated that TAR rings were cleaved. This research is the first to determine the optimal pH for UVLED-driven oxidation of TAR and the first to identify new TAR-related byproducts from UVLED-based water treatment.


The long-term outcomes of interventions for the management of attention-deficit hyperactivity disorder in children and adolescents: a systematic review of randomized controlled trials.
To systematically identify and review the currently available evidence on the long-term outcomes of recommended attention-deficit hyperactivity disorder (ADHD) interventions following randomized controlled trials with children and young people. A systematic search was conducted to identify trials >1 year in length using the following databases: CINAHL (January 1982- July 2012), MEDLINE (Ovid and Cambridge Scientific Abstracts [CSA]), Psych info, Science Direct (Elsevier), and Cochrane Library. Hand searches of key journals in the subject, book chapters, and conference proceedings were also carried out. Relevant papers were critically appraised using the Cochrane risk of bias tool. Eight controlled trials were identified as being relevant, of duration ranging from 1 year to 8 years (at follow up). The total number of participants in the studies was 1,057, of whom 579 (54.7%) were from one cohort and included 26 different outcome measures. Results suggest there is moderate-to-high-level evidence that combined pharmacological and behavioral interventions, and pharmacological interventions alone can be effective in managing the core ADHD symptoms and academic performance at 14 months. However, the effect size may decrease beyond this period. This review has highlighted the paucity and limitations of the evidence investigating the long-term outcomes of recommended interventions for managing ADHD symptoms. There is little evidence to suggest that the effects observed over the relatively short term are maintained throughout longer periods of impairment. Furthermore, much of the existing evidence examining effectiveness beyond 12 months does not include newer medications currently available or consider significant contextual and cultural differences, such as UK/European and Asian populations. Longitudinal studies are required to examine the long-term outcomes for children and young people with ADHD managed with currently recommended service interventions. They should also include the whole spectrum of ADHD, with its full range of coexisting conditions, and cultural and contextual diversity.


The international suicide prevention trial (interSePT): rationale and design of a trial comparing the relative ability of clozapine and olanzapine to reduce suicidal behavior in schizophrenia and schizoaffective patients.
Suicidal behavior in patients with psychotic disorders represents a seriously undertreated life-threatening condition. The International Suicide Prevention Trial (InterSePT) is the first large-scale, prospective study designed to evaluate the potential of antipsychotic medications to reduce suicidal behaviors in patients with schizophrenia or schizoaffective disorder who are known to be at high risk for suicide. The unique challenges to study design and the solutions identified for the InterSePT study are described. These challenges included defining suicidal behavior in patients with psychosis, endpoint selection, determination of analytic strategy, and development of scales to assess suicidal behavior. Given the life-threatening nature of suicidal behavior, ethical considerations required that the design minimize suicide attempts and deaths. While the study focused primarily on treatment of suicide, opportunities were used to collect data in related areas of interest, including suicide risk factors, other efficacy measures (e.g., Positive and Negative Syndrome Scale, Covi Anxiety Scale, Calgary Depression Scale), adverse events, pharmacoeconomics, and pharmacogenetics. Because of the complexity of the design issues, a steering committee, suicide monitoring board, and publication committee were established to assist with their management.


Determining the intrinsic dimension of a hyperspectral image using random matrix theory.
Determining the intrinsic dimension of a hyperspectral image is an important step in the spectral unmixing process and under- or overestimation of this number may lead to incorrect unmixing in unsupervised methods. In this paper, we discuss a new method for determining the intrinsic dimension using recent advances in random matrix theory. This method is entirely unsupervised, free from any user-determined parameters and allows spectrally correlated noise in the data. Robustness tests are run on synthetic data, to determine how the results were affected by noise levels, noise variability, noise approximation, and spectral characteristics of the endmembers. Success rates are determined for many different synthetic images, and the method is tested on two pairs of real images, namely a Cuprite scene taken from Airborne Visible InfraRed Imaging Spectrometer (AVIRIS) and SpecTIR sensors, and a Lunar Lakes scene taken from AVIRIS and Hyperion, with good results.


Photonic de Haas-van Alphen effect.
Based on the recently proposed concept of effective gauge potential and magnetic field for photons, we numerically demonstrate a photonic de Haas-van Alphen effect. We show that in a dynamically modulated photonic resonator lattice exhibiting an effect magnetic field, the trajectories of the light beam at a given frequency have the same shape as the constant energy contour for the photonic band structure of the lattice in the absence of the effective magnetic field.


Depression and anxiety in patients repeatedly referred to secondary care with medically unexplained symptoms: a case-control study.
One third of referrals from primary to secondary care are for medically unexplained symptoms (MUS). We aimed to determine the association of depression and anxiety disorders with high use of specialist services by patients with MUS. We did this by comparing their prevalence in patients who had been repeatedly referred with symptoms for which they had received repeated specialist diagnoses of MUS with that in two control groups. We also determined the adequacy of treatment received. A case-control study in five general practices in Edinburgh, UK. Data collection was by case note review and questionnaire. Cases were 193 adults with three or more referrals over 5 years, at least two of which resulted in a diagnosis of MUS. Controls were: (a) patients referred only once over 5 years (n=152); (b) patients with three or more referrals for symptoms always diagnosed as medically explained (n=162). In total, 93 (48%) of the cases met our criteria for current depression, anxiety or panic disorders. This compared with 38 (25%) and 52 (35.2%) of the control groups; odds ratios (95% confidence intervals) of 2.6 (1.6-4.1) and 1.6 (1.01-2.4), respectively. Almost half (44%) of the cases with current depression or anxiety had not received recent minimum effective therapy. Depression, anxiety and panic disorders are common in patients repeatedly referred to hospital with MUS. Improving the recognition and treatment of these disorders in these patients has the potential to provide better, more appropriate and more cost-effective medical care.


The role of haemoglobin mass on VO(2)max following normobaric 'live high-train low' in endurance-trained athletes.
It remains unclear by which mechanism 'live high-train low' (LHTL) altitude training increases exercise performance. Haematological and skeletal muscle adaptations have both been proposed. To test the hypotheses that (i) LHTL improves maximal oxygen uptake (VO(2)max) and (ii) this improvement is related to hypoxia-induced increases in total haemoglobin mass (Hb(mass)) and not to improved maximal oxidative capacity of skeletal muscle, we determined VO(2)max before LHTL and after LHTL, before and after the altitude-induced increases in Hb(mass) (measured by carbon-monoxide rebreathing) had been abolished by isovolumic haemodilution. We obtained skeletal muscle biopsies to quantify mitochondrial oxidative capacity and efficiency. Sixteen endurance-trained athletes were assigned (double-blinded, placebo controlled) to ≥16 h/day over 4 weeks to normoxia (placebo, n=6) or normobaric hypoxia equivalent to 3000 m altitude (LHTL, n=10). Four-week LHTL did not increase VO(2)max, irrespective of treatment (LHTL: 1.5%; placebo: 2.0%). Hb(mass) was slightly increased (4.6%) in 5 (of 10) LHTL subjects but this was not accompanied by a concurrent increase in VO(2)max. In the subjects demonstrating an increase in Hb(mass), isovolumic haemodilution elicited a 5.8% decrease in VO(2)max. Cycling efficiency was altered neither with time nor by LHTL. Neither maximal capacity of oxidative phosphorylation nor mitochondrial efficiency was modified by time or LHTL. The present results suggest that LHTL has no positive effect on VO(2)max in endurance-trained athletes because (i) muscle maximal oxidative capacity is not improved following LHTL and (ii) erythrocyte volume expansion after LHTL, if any, is too small to alter O(2) transport.


Fibrinogen and the albumin-globulin ratio in recurrent stroke.
In following patients initially recruited for a cross-sectional study of blood viscosity in ischemic cerebrovascular disease, it was noted that those having a low albumin-globulin ratio appeared to experience the majority of subsequent vascular events. Accordingly, a prospective study in which subjects were assigned to a high or low albumin-globulin cohort was undertaken to examine the relation between a low albumin-globulin ratio, the presence of clinical risk factors for stroke, and the occurrence of subsequent stroke, myocardial infarction, or vascular death. Three groups of subjects were followed for an average of 1.5 +/- 0.8 years to ascertain vascular end points. Group 1 consisted of 126 patients with acute ischemic stroke; group 2 included 109 subjects matched with group 1 for age, medications, and recognized clinical risk factors for stroke; and group 3 was composed of 84 healthy volunteers, matched for age with groups 1 and 2. The median albumin-globulin ratio for group 1 at enrollment, 1.45, was used to dichotomize patients into two cohorts: all subjects with an albumin-globulin ratio of 1.45 or less were assigned to the "low" albumin-globulin cohort; those whose ratio was greater than 1.45 were assigned to the "high" albumin-globulin cohort. The occurrence of vascular end points was verified during subsequent hospitalizations and outpatient clinic visits and by telephone interviews of patients and providers. A total of 51 vascular events occurred, including 39 in group 1, 8 in group 2, and 4 in group 3. Subjects in either group 1 or 2 who were in the low albumin-globulin cohort had at least double the risk for a subsequent vascular event compared with their counterparts in the high albumin-globulin cohort (P < .01 and P < .03, respectively). In comparison with the high albumin-globulin cohort, significantly more patients in the low albumin-globulin cohort in group 1 had a history of prior stroke (P < .03). When groups 1 and 2 were combined, both a low albumin-globulin ratio and diabetes had a significant independent association with increased risk for subsequent vascular events in a Cox proportional-hazards model (P < .01 and P < .03, respectively). The results of this study indicate that significantly increased risk for subsequent vascular events in stroke patients and in subjects with clinical risk factors for stroke is associated with a shift in the concentrations of blood proteins to a prothrombotic environment characterized by lower levels of albumin and an increased concentration of globulins and fibrinogen.


Effective grating theory for resonance domain surface-relief diffraction gratings.
An effective grating model, which generalizes effective-medium theory to the case of resonance domain surface-relief gratings, is presented. In addition to the zero order, it takes into account the first diffraction order, which obeys the Bragg condition. Modeling the surface-relief grating as an effective grating with two diffraction orders provides closed-form analytical relationships between efficiency and grating parameters. The aspect ratio, the grating period, and the required incidence angle that would lead to high diffraction efficiencies are predicted for TE and TM polarization and verified by rigorous numerical calculations.


Permo-Triassic Boundary Superanoxia and Stratified Superocean: Records from Lost Deep Sea
Pelagic cherts of Japan and British Columbia, Canada, recorded a long-term and worldwide deep-sea anoxic (oxygen-depleted) event across the Permo-Triassic (or Paleozoic and Mesozoic) boundary (251 ± 2 million years ago). The symmetry in lithostratigraphy and redox condition of the boundary sections suggest that the superocean Panthalassa became totally stratified for nearly 20 million years across the boundary. The timing of onset, climax, and termination of the oceanic stratification correspond to global biotic events including the end-Guadalupian decline, the end-Permian extinction, and mid-Triassic recovery.


Prediction and characterization of MXene nanosheet anodes for non-lithium-ion batteries.
Rechargeable non-lithium-ion (Na(+), K(+), Mg(2+), Ca(2+), and Al(3+)) batteries have attracted great attention as emerging low-cost and high energy-density technologies for large-scale renewable energy storage applications. However, the development of these batteries is hindered by the limited choice of high-performance electrode materials. In this work, MXene nanosheets, a class of two-dimensional transition-metal carbides, are predicted to serve as high-performing anodes for non-lithium-ion batteries by combined first-principles simulations and experimental measurements. Both O-terminated and bare MXenes are shown to be promising anode materials with high capacities and good rate capabilities, while bare MXenes show better performance. Our experiments clearly demonstrate the feasibility of Na- and K-ion intercalation into terminated MXenes. Moreover, stable multilayer adsorption is predicted for Mg and Al, which significantly increases their theoretical capacities. We also show that O-terminated MXenes can decompose into bare MXenes and metal oxides when in contact with Mg, Ca, or Al. Our results provide insight into metal ion storage mechanisms on two-dimensional materials and suggest a route to preparing bare MXene nanosheets.


Senescing human bone-marrow-derived clonal mesenchymal stem cells have altered lysophospholipid composition and functionality.
Mesenchymal stem cells (MSCs) have been used in a wide range of research and clinical studies because MSCs do not have any ethical issues and have the advantage of low carcinogenicity due to their limited proliferation. However, because only a small number of MSCs can be obtained from the bone marrow, ex vivo amplification is inevitably required. For that reason, this study was conducted to acquire the metabolic information to examine and control the changes in the activities and differentiation potency of MSCs during the ex vivo culture process. Endogenous metabolites of human bone-marrow-derived clonal MSCs (hcMSCs) during cellular senescence were profiled by ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/QTOFMS). To select significant metabolites, we used the linear mixed effects model having fixed effects for batch and time (passage) and random effects for metabolites, determining the mean using a t test and the standard deviation using an F test. We used structural analysis with representative standards and spectrum patterns with different collision energies to distinctly identify eight metabolites with altered expression during senescence as types of lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), such as LPC 16:0 and LPE 22:4. The present study revealed changes in endogenous metabolites and mechanisms due to senescence.


Maternal hypoxia and caffeine exposure depress fetal cardiovascular function during primary organogenesis.
Hypoxia is known to influence cardiovascular (CV) function, in part, through adenosine receptor activation. We have shown in a mouse model that during primary cardiac morphogenesis, acute maternal hypoxia negatively affects fetal heart rate, and recurrent maternal caffeine exposure reduces fetal cardiac output (CO) and downregulates fetal adenosine A(2A) receptor gene expression. In the present study, we investigated whether maternal caffeine dosing exacerbates the fetal CV response to acute maternal hypoxia during the primary morphogenesis period. Gestational-day-11.5 pregnant mice were exposed to hypoxia (45 s duration followed by 10 min of recovery and repeated 3 times) while simultaneously monitoring maternal and fetal CO using high-resolution echocardiography. Following maternal hypoxia exposure, maternal CO transiently decreased and then returned to pre-hypoxia baseline values. In contrast to a uniform maternal cardiac response to each exposure to hypoxia, the fetal CO recovery time to the baseline decreased, and CO rebounded above baseline following the second and third episodes of maternal hypoxia. Maternal caffeine treatment inhibited the fetal CO recovery to maternal hypoxia by lengthening the time to CO recovery and eliminating the CO rebound post-recovery. Selective treatment with an adenosine A(2A) receptor antagonist, but not an adenosine A(1) receptor antagonist, reproduced the altered fetal CO response to maternal hypoxia created by caffeine exposure. Results suggest an additive negative effect of maternal caffeine on the fetal CV response to acute maternal hypoxia, potentially mediated via adenosine A(2A) receptor inhibition during primary cardiovascular morphogenesis.


Efficacy and tolerability of a low-dose mefloquine-sulfadoxine-pyrimethamine combination compared with chloroquine in the treatment of acute malaria infection in a population with multiple drug-resistant Plasmodium falciparum.
The efficacy and tolerability of single, low-dose mefloquine, sulfadoxine-pyrimethamine (MSP) combination was compared with chloroquine (CQ) for malaria treatment in a malaria-endemic area of Nigeria with multiple drug-resistant Plasmodium falciparum. The two drug regimens (MSP and CQ) were tested in a 12-month prospective population study. The patients were divided into two groups. Group 1 patients were treated presumptively, based on malaria symptoms. Group 2 patients were treated based on a parasitologic diagnosis using the World Health Organization seven-day in vivo test and extended to a 28-day follow-up period. Tolerability was assessed by the incidence and intensity of adverse events. One thousand nine hundred thirty-five patients visiting 10 health facilities, including the University of Calabar Teaching Hospital, were enrolled. The study showed that the low-dose MSP was efficacious, with day 7 response rates of 95% and 91% for (presumptive) Group 1 and (in vivo) Group 2, respectively, while CQ had day 7 response rates of 82% and 66% in Groups 1 and 2, respectively. The low-dose MSP was significantly (P < 0.0001) more efficacious, with faster fever and parasite clearance times than CQ in this area of CQ-resistant P. falciparum malaria. Eight patients treated with CQ, including seven severe cases (RII-RIII) were successfully re-treated with MSP. Adverse events were generally more common among those treated with MSP (29%) than those treated with CQ (17%). However, the adverse events caused by both drugs were mild to moderate and self-limited. The MSP combination appears to be a good substitute for CQ, in view of multiple drug resistance, especially in areas with severe (RII-RIII) malaria.


Hand rehabilitation using MIDI keyboard playing in adolescents with brain damage: a preliminary study.
As a sequential, programmed movement of fingers, keyboard playing is a promising technique for inducing execution and a high level of coordination during finger movements. Also, keyboard playing can be physically and emotionally rewarding for adolescents in rehabilitation settings and thereby motivate continued involvement in treatment. The purpose of this study is to evaluate the effects of keyboard playing using Musical Instrument Digital Interface (MIDI) on finger movement for adolescents with brain damage. Eight adolescents with brain damage, ages 9 to 18 years (M = 13 years, SD = 2.78), in physical rehabilitation settings participated in this study. Measurements included MIDI keyboard playing for pressing force of the fingers and hand function tests (Grip and Pinch Power Test, Box and Block Test of Manual Dexterity [BBT], and the Jebsen Taylor Hand Function Test). Results showed increased velocity of all fingers on the MIDI-based test, and statistical significance was found in the velocity of F2 (index finger), F3 (middle finger), and F5 (little finger) between pre- and post-training tests. Correlation analysis between the pressing force of the finger and hand function tests showed a strong positive correlation between the measure of grip power and the pressing force of F2 and F5 on the Grip and Pinch Strength Test. All fingers showed strong correlation between MIDI results and BBT. For the Jebsen Taylor Hand Function Test, only the moving light objects task at post-training yielded strong correlation with MIDI results of all fingers. The results support using keyboard playing for hand rehabilitation, especially in the pressing force of individual finger sequential movements. Further investigation is needed to define the feasibility of the MIDI program for valid hand rehabilitation for people with brain damage.


Monitoring and talking to the room: autochthonous coordination patterns in team interaction and performance.
This paper builds on and extends theory on team functioning in high-risk environments. We examined 2 implicit coordination behaviors that tend to emerge autochthonously within high-risk teams: team member monitoring and talking to the room. Focusing on nonrandom patterns of behavior, we examined sequential patterns of team member monitoring and talking to the room in higher- and lower-performing action teams working in a high-risk health care environment. Using behavior observation methods, we coded verbal and nonverbal behaviors of 27 anesthesia teams performing an induction of general anesthesia in a natural setting and assessed team performance with a Delphi-validated checklist-based performance measure. Lag sequential analyses revealed that higher-performing teams were characterized by patterns in which team member monitoring was followed by speaking up, providing assistance, and giving instructions and by patterns in which talking to the room was followed by further talking to the room and not followed by instructions. Higher- and lower-performing teams did not differ with respect to the frequency of team member monitoring and talking to the room occurrence. The results illustrate the importance of patterns of autochthonous coordination behaviors and demonstrate that the interaction patterns, as opposed to the behavior frequencies, discriminated higher- from lower-performing teams. Implications for future research and for team training are included. (PsycINFO Database Record (c) 2014 APA, all rights reserved).


HEMATOLOGY, PLASMA BIOCHEMISTRY, AND URINALYSIS OF FREE-RANGING GREY-HEADED FLYING FOXES ( PTEROPUS POLIOCEPHALUS) IN AUSTRALIA.
The grey-headed flying fox ( Pteropus poliocephalus) is a species endemic to coastal eastern Australia. This study presents a comprehensive set of biochemistry, hematology, and urinalysis biomarkers from which reference values were derived. Blood samples collected from free-ranging P. poliocephalus were submitted for hematology ( n = 140) and plasma biochemistry ( n = 161) and urine for urinalysis ( n = 95). The values for P. poliocephalus were broadly consistent with those values published for other Australian Pteropus species. Statistically significant within-species age and sex effects were observed: adult P. poliocephalus had higher mean corpuscular volume, mean corpuscular hemoglobin, urea, creatinine, bilirubin, alanine transferase (ALT), protein, globulin, urinary specific gravity, and urinary ketones, whereas subadults had higher mean red blood cell, white blood cell (WBC), lymphocyte, and monocyte counts, and juveniles had higher mean neutrophil count and alkaline phosphatase; male P. poliocephalus had higher mean reticulocyte count, alanine transferase, glucose, and urinary ketones, whereas females had higher mean WBC, lymphocyte, and monocyte counts. The findings inform both clinical and research scenarios for P. poliocephalus in captivity or rehabilitation and for health assessments of free-living populations.


AACAP 2001 research forum: challenges and recommendations regarding recruitment and retention of participants in research investigations.
Clinical research depends on the participation of representative samples. At the 2001 Annual Meeting of the American Academy of Child and Adolescent Psychiatry, the Workgroup on Research conducted a research forum with the purpose of improving recruitment and retention of children and adolescents in research protocols. An interdisciplinary group of participants focused on (1) consumers and families, (2) communities, (3) professionals and health care delivery systems, (4) regulatory bodies, and (5) alternative research designs. Obstacles and challenges were identified and solutions were discussed. Key recommendations include the following: Investigators must become involved with community stakeholders and more explicitly communicate with families about research procedures, risks, and benefits; budgets should include explicit items for case management and referrals to families who do not meet entry criteria; the culture of clinical settings must incorporate research conducted by clinicians; regulatory bodies must streamline and coordinate protocols and procedures; designs emphasizing flexible treatment strategies and adaptive treatments should be encouraged; and health care systems should consider changing incentives for research participation, including the radical notion that reimbursement be made in terms of improvement rather than service units. An integrated approach is recommended, requiring direct involvement of investigators in communities where research is to be conducted.


Growth hormone and Klotho.
Acromegaly is characterized by excessively high GH and IGF1 levels. Recent data suggest that soluble Klotho (sKlotho) is also elevated in patients with active acromegaly. sKlotho decreases towards normal following removal of the GH-producing pituitary adenoma. The Klotho gene was identified in mice following its accidental disruption by ectopic DNA. It is an ageing suppressor gene of restricted expression (mainly in kidneys, brain, and parathyroid and pituitary glands) encoding a transmembrane protein, mKlotho. mKlotho serves as a co-receptor in fibroblast growth factor 23 (FGF23) signalling. FGF23 promotes urinary phosphate excretion and inhibits the synthesis of calcitriol. The ectodomain of mKlotho is enzymatically released to result in a humoral factor, sKlotho, which exerts systemic effects (on ion channels and signalling pathways), possibly by working as an enzyme that modifies glycans of cell surface glycoproteins. GH enhances renal phosphate reabsorption and calcitriol production, i.e. exerts effects in the proximal tubule opposing those attributed to mKlotho, and attenuates calciuria in the distal tubule similar to sKlotho. sKlotho can be measured in extracellular fluids (serum, urine and cerebrospinal fluid (CSF)) by an ELISA. In line with predominant expression of Klotho in kidneys and choroid plexus, concentrations of sKlotho are particularly high in urine and CSF. Determination of sKlotho in serum and urine (both presumably reflecting GH action on the kidneys) could be used as a supplementary tool in the diagnosis and follow-up of patients with acromegaly. The question arises whether GH exerts selected actions via modifying activities of Klotho.


Socioeconomic disparities and risk of hypertension among older Americans: the Health and Retirement Study.
Reducing hypertension represents a critical point of intervention to lower the burden of cardiovascular disease worldwide. Although the relationship between lower socioeconomic status and higher rates of hypertension is well documented, most of the evidence comes from prevalence studies involving young adult population. To investigate the independent association of wealth, education and income with incident hypertension among older adults living in the United States. This cohort study included 16 587 individuals aged 50 years and older, free of hypertension and cardiovascular disease at baseline from the Health and Retirement Study over the period 1992-2014. We used Cox proportional hazards models to examine longitudinal associations between wealth, education, and income at baseline and self-reported diagnosis of incident hypertension. During a median follow-up of 7.8 years, 6817 participants declared an occurrence of hypertension (incidence rate: 45.3 [95% confidence interval (CI) = 44.2-46.4] per 1000 person-years). Overall, those in low as compared with high socioeconomic status groups had a higher risk of developing hypertension in late life. In particular, adjusted hazard ratios [95% CI] across decreasing wealth quartiles were 1.0 (reference), 0.97 [0.88-1.08], 1.17 [1.05-1.30], and 1.20 [1.07-1.35] in men, and 1.0 (reference), 1.28 [1.17-1.41], 1.21 [1.09-1.33], and 1.28 [1.16-1.42] in women. In multivariate analyses, wealth remained strongly associated with incident hypertension among women after accounting for other socioeconomic, behavioral and anthropometric risk factors. Socioeconomic status, especially wealth, is a strong independent predictor of incident hypertension in older adults. Our findings support population-based interventions tailored to those in disadvantaged socioeconomic groups to reduce the risk of hypertension.


[Relationship between autoantibodies and HLA-DQ genotypes in patients with type 1 diabetes mellitus].
To explore the relationship between the 3 islet autoantibodies, i.e., glutamic acid decarboxylase antibody (GADA), protein-tyrosine-phosphatase-2 autoantibody (IA-2A), and insulin autoantibody (IAA), and human leukocyte HLA-DQ genotypes in the patients with type 1 diabetes mellitus (T1DM). Peripheral blood samples were collected from 495 T1DM patients and 376 healthy controls. Radioligand assay was used to detect the levels of GADA and IA-2A. Seventy-one of the 495 T1DM patients with insulin treatment less than 14 days underwent radioligand assay to measure the IAA level. 338 TIDM patients, including 187 antibodies-positive and 151 antibodies-negative patients, and 278 healthy controls underwent PCR and sequencing so as to examine the genetic polymorphism of HLA-DQ. (1) The frequencies of DQA1*03-DQB1 *0303, DQA1*05-DQB1*0201, and DQA1*03-DQB1*0401 haplotypes in the T1DM patients were 32.6%, 14.1% and 10.2% respectively, all significantly higher than those in the controls (21.9%, 3.5%, and 2.9% respectively, all P < 0.01), however, the frequency of DQA1*0102-DQB1*0602 haplotype in the T1DM patients was 1.7%, significantly lower than that in the controls (5.3%, P < 0.05). (2) The GADA positive rates of in the T;DM patients with DQA1*05-DQB1*0201 or DQA1*03-DQB1*0401 haplotype were 55.8% and 65.5% respectively, both significantly higher than those of the T1DM patients without DQA1*05-DQB1*0201 or DQA1*03-DQB1*0401 haplotype (41.0% and 40.3%, respectively P < 0.05 or P < 0.01), and the IA-2A positive rate of the T1DM patients with DQA1*03-DQB1*0303 haplotype was 27.0%, significantly higher than that of the T1DM patients without DQA1*03-DQB1*0303 haplotype (7.9%, P < 0.01), there were no significant differences in GADA and IA-2A positivity between the T1DM patients with and without DQA1*03-DQB1*0302 haplotype (48.5% vs 43.9% and 24.2% vs 15.4%, both P > 0.05). The GADA positivity rate of the T1DM patients with DQA1*0102-DQB1 *0602 haplotype was 16.7%, significantly lower than those patients without DQA1*0102-DQB1 *0602 haplotype (45.9%, P < 0.05). There was no significant difference in IAA level between those patients with and without susceptible DQ alleles and haplotypes (P > 0.05). GADA is associated with HLA-DQA1*05-DQB1*0201 and DQA1*03-DQB1*0401 haplotypes, and IA-2A is associated with DQA1*03-DQB1 *0303 haplotype.


[Social participation in health in rural northeastern Brazil].
To analyze the social participation taking place through Municipal Health Councils (MHC) in two small towns in northeastern Brazil. A qualitative, exploratory, multicase study focused on the MHCs of Lafayete Coutinho (state of Bahia) and Groaíras (state of Ceará) was conducted. Data were gathered from February-April 2005 through analysis of documents, direct observation of MHC meetings, and semistructured interviews. Documents analyzed included decrees, laws, and municipal regulations; city health department annual management reports; municipal health plans; and reports of municipal health conferences. MHC meeting minutes for the period between inception of these councils and 2004 were also reviewed. Interviews of 17 council members took place, eight of whom were from Lafayete Coutinho and nine from Groaíras. Both councils had irregular practices regarding membership structure and nomination of members, such as frequent changes in appointed members and continuous "reshuffling" of council structure. In addition, new council members were appointed each time a new mayor took charge. Sporadic frequency of meetings was also observed. In Lafayete Coutinho, of 96 meetings planned, just 37 took place; in Groaíras, of 186 meetings planned, 93 took place. Analysis of MHC efforts to formulate and control municipal health policies revealed three themes: health status of the population and public policies; organization and functioning of health services; and financial management and accounting. The interviews showed that council members were dissatisfied with the practices of the MHCs and revealed a lack of confidence in how truly representative the councils are and how much power they have. Social participation strategies in Brazil must be reconsidered with an angle toward promoting political responsibility and raising awareness among citizens.


DARPP-32, a dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. III. Immunocytochemical localization.
Immunocytochemical studies have been carried out to determine the regional and cellular distribution of DARPP-32, a protein the phosphorylation of which can be regulated by dopamine and cAMP in intact cells. These immunocytochemical studies indicate tha DARPP-32 is localized primarily in those brain regions enriched in dopaminergic nerve terminals. Moreover, the staining pattern supports the conclusion that the DARPP-32 is present in dopaminoceptive neurons, i.e., neurons that receive a dopamine input, and that it is absent from the dopaminergic neurons themselves. Within the caudatoputamen, nucleus accumbens, olfactory tubercle, bed nucleus of the stria terminalis, and portions of the amygdaloid complex, all of which receive a strong dopamine input, DARPP-32 immunoreactivity is present in neuronal cell bodies and dendrites. In brain regions that are known to receive projections from these nuclei, puncta (presumed nerve terminals) are strongly immunoreactive for DARPP-32 but indigenous cell bodies and dendrites are not immunoreactive. These target areas include the globus pallidus, ventral pallidum, entopeduncular nucleus, and the pars reticulata of the substantia nigra. No immunoreactivity is detected in neuronal cell bodies or dendrites in any of the dopaminergic nuclei. Furthermore, nerve terminals immunoreactive for DARPP-32 do not resemble dopaminergic varicosities in either their morphology or their pattern of distribution. Many neurons are weakly immunoreactive for DARPP-32 and some of these are found in areas that apparently lack a dopaminergic input: weakly labeled neuronal cell bodies and dendrites were found throughout the neocortex, primarily in layer VI, and in the Purkinje neurons of the cerebellum. DARPP-32 immunoreactivity is also present in certain glial cells, especially in the median eminence, arcuate nucleus, and medial habenula. The present immunocytochemical studies, taken together with biochemical studies (Hemmings, H.C., Jr., A.C. Nairn, D.W. Aswad, and P. Greengard (1984) J. Neurosci. 4: 99-110; Walaas, S.I., and P. Greengard (1984) J. Neurosci. 4: 84-98) on DARPP-32, indicate that DARPP-32, is present in the subclass of dopaminoceptive neurons containing D-1 receptors (dopamine receptors coupled to adenylate cyclase). DARPP-32 may be an effective marker for certain of the actions of dopamine that are mediated through cAMP and its associated protein kinase.


Why American Sign Language Gloss Must Matter.
Responding to an article by Grushkin on how deaf children best learn to read, published, along with the present article, in an American Annals of the Deaf special issue, the authors review American Sign Language gloss. Topics include how ASL gloss enables deaf children to learn to read in their own language and simultaneously experience a transition to written English, and what gloss looks like and how it underlines deaf children's learning and mastery of English literacy through ASL. Rebuttal of Grushkin's argument includes data describing a deaf child's engagement in reading aloud (entirely in ASL) with a gloss text, which occurred without the breakdown implied by Grushkin. The authors characterize Grushkin's argument that deaf children need to learn to read through a conventional ASL writing system as limiting, asserting that ASL gloss contributes more by providing a path for learning and mastering English literacy.


Urea uptake and carbon fixation by marine pelagic bacteria and archaea during the Arctic summer and winter seasons.
How Arctic climate change might translate into alterations of biogeochemical cycles of carbon (C) and nitrogen (N) with respect to inorganic and organic N utilization is not well understood. This study combined 15N uptake rate measurements for ammonium, nitrate, and urea with 15N- and 13C-based DNA stable-isotope probing (SIP). The objective was to identify active bacterial and archeal plankton and their role in N and C uptake during the Arctic summer and winter seasons. We hypothesized that bacteria and archaea would successfully compete for nitrate and urea during the Arctic winter but not during the summer, when phytoplankton dominate the uptake of these nitrogen sources. Samples were collected at a coastal station near Barrow, AK, during August and January. During both seasons, ammonium uptake rates were greater than those for nitrate or urea, and nitrate uptake rates remained lower than those for ammonium or urea. SIP experiments indicated a strong seasonal shift of bacterial and archaeal N utilization from ammonium during the summer to urea during the winter but did not support a similar seasonal pattern of nitrate utilization. Analysis of 16S rRNA gene sequences obtained from each SIP fraction implicated marine group I Crenarchaeota (MGIC) as well as Betaproteobacteria, Firmicutes, SAR11, and SAR324 in N uptake from urea during the winter. Similarly, 13C SIP data suggested dark carbon fixation for MGIC, as well as for several proteobacterial lineages and the Firmicutes. These data are consistent with urea-fueled nitrification by polar archaea and bacteria, which may be advantageous under dark conditions.


Correlation between cytosolic free calcium, contracture, ATP, and irreversible ischemic injury in perfused rat heart.
The relations between ATP depletion, increased cytosolic free calcium concentration [( Cai]), contracture development, and lethal myocardial ischemic injury, as evaluated by enzyme release, were examined using 19F nuclear magnetic resonance to measure [Cai] in 1,2-bis(2-amino-5-fluorophenoxy)ethane-N,N,N',N'-tetraacetic acid (5F-BAPTA)-loaded perfused rat hearts. Total ischemia at 37 degrees C was induced in beating hearts, potassium-arrested hearts, magnesium-arrested hearts, and hearts pretreated with 0.9 microM diltiazem to reduce but not abolish contractility. In the beating hearts, time-averaged [Cai], which is intermediate between the systolic and the basal [Cai], was 544 +/- 74 nM. In contrast, in the potassium- and magnesium-arrested hearts, the time-averaged values are lower than in beating hearts (352 +/- 88 nM for potassium arrest, 143 +/- 22 nM for magnesium arrest). During ischemia, ATP depletion, contracture, and a rise in [Cai] are delayed by cardiac arrest, but all occur more rapidly in the potassium-arrested hearts than in the magnesium-arrested hearts. The diltiazem-treated hearts were generally similar to the magnesium-arrested hearts in their response to ischemia. Under all conditions, contracture development was initiated after tissue ATP had fallen to less than 50% of control; invariably, there was a progressive rise in [Cai] during and following contracture development. Reperfusion with oxygenated perfusate shortly after peak contracture development resulted in a return of [Cai] to its preischemic level, resynthesis of creatine phosphate, no significant enzyme release, and no substantial loss of 5F-BAPTA from the heart. The data demonstrate that an increase in [Cai] precedes lethal myocardial ischemic injury. This rise in [Cai] may accelerate the depletion of cellular ATP and may directly contribute to the development of lethal ischemic cell injury.


Ultrasmall black phosphorus quantum dots: synthesis, characterization, and application in cancer treatment.
Black phosphorus quantum dots (BPQDs) are gaining popularity for applications in various fields because of their unique advantages. For biomedical applications, good biosafety is a prerequisite for the use of BPQDs in vivo. However, currently, little information is available about their basic properties and biocompatibility, which are of great importance for potential biomedical applications. In this work, we prepared BPQDs by an improved solvothermal method and evaluated their fluorescence, biocompatibility, and photothermal therapy (PTT) effectiveness. First, the structures and functions of the BPQDs were investigated at the cellular and molecular levels. It was found that the fluorescence of the BPQDs is wavelength-dependent and that they absorb in the UV-vis range; also, their quantum yield reached 10.2%. In particular, we considered the morphology and lysis of human red blood cells, in vivo blood coagulation, and plasma recalcification profiles. We found that the BPQDs have excellent biocompatibility and hemocompatibility with blood components. Overall, concentrations of the BPQDs ≤0.5 mg mL-1 had few adverse effects on blood components. The resulting BPQDs can efficiently convert near-infrared (NIR) light into heat; thus, they are suitable as a novel nanotheranostic agent for PTT of cancer. Meanwhile, the results of serum biochemistry tests revealed that the indicators were at similar levels for mice exposed to BPQDs and for control mice. Furthermore, from biodistribution analysis of the BPQDs, no apparent pathological damage was observed in any organs, especially in the spleen and kidneys, during the 30 day period. Our research indicates that the BPQDs have bio-imaging capability and biocompatibility and highlights their great potential in the therapy of cancer.


Simple generation of human induced pluripotent stem cells using poly-beta-amino esters as the non-viral gene delivery system.
Reprogramming of somatic cells to induced pluripotent stem (iPS) cells can be achieved by the delivery of a combination of transcription factors, including Oct4, Sox2, Klf4, and c-Myc. Retroviral and lentiviral vectors are commonly used to express these four reprogramming factors separately and obtain reprogrammed iPS cells. Although efficient and reproducible, these approaches involve the time-consuming and labor-intensive production of retroviral or lentiviral particles together with a high risk of working with potentially harmful viruses overexpressing potent oncogenes, such as c-Myc. Here, we describe a simple method to produce bona fide iPS cells from human fibroblasts using poly-β-amino esters as the transfection reagent for the delivery of a single CAG-driven polycistronic plasmid expressing Oct4, Sox2, Klf4, c-Myc, and a GFP reporter gene (OSKMG). We demonstrate for the first time that poly-β-amino esters can be used to deliver a single polycistronic reprogramming vector into human fibroblasts, achieving significantly higher transfection efficiency than with conventional transfection reagents. After a protocol of serial transfections using poly-β-amino esters, we report a simple methodology to generate human iPS cells from human fibroblasts avoiding the use of viral vectors.