Role of ghrelin in drug abuse and reward-relevant behaviors: a burgeoning field and gaps in the literature.
Ghrelin is a gut-brain hormone that regulates energy balance through food consumption. While ghrelin is well known for its role in hypothalamic activation and homeostatic feeding, more recent evidence suggests that ghrelin also is involved in hedonic feeding through the dopaminergic reward pathway. This paper investigated how ghrelin administration (intraperitoneal, intracerebroventricular, or directly into dopaminergic reward-relevant brain regions) activates the dopaminergic reward pathway and associated reward-relevant behavioral responses in rodents. A total of 19 empirical publications that examined one or more of these variables were included in this review. Overall, ghrelin administration increases dopamine levels in the nucleus accumbens, as well as reward-relevant behaviors such as food (both standard chow and palatable foods) and alcohol consumption. Ghrelin administration also increases operant responding for sucrose, and conditioned place preference. Following a review of the small body of literature examining the effects of ghrelin administration on the dopamine reward pathway, we present a model of the relationship between ghrelin and dopaminergic reward activation. Specifically, ghrelin acts on ghrelin receptors (GHS-R1A) in the ventral tegmental area (VTA) and lateral dorsal tegmental nucleus (LDTg) to stimulate the mesolimbic dopamine reward pathway, which results in increased rewarding behaviors in rodents. Results from this review suggest that selective antagonism of the ghrelin system may serve as potential treatment for addictive drug use. This review highlights gaps in the literature, including a lack of examination of sex- or age-related differences in the effects of ghrelin on dopamine reward processes. In light of vulnerability to drug abuse among female and adolescent populations, future studies should target these individual difference factors.


Contemporary approaches to the rapid molecular diagnosis of sepsis.
Although the administration of appropriate antimicrobials within the very first hour remains the mainstay of sepsis management, the correct selection of antimicrobials is hampered by the delay of conventional microbiology providing results after at least 48 hours. Methods of rapid detection of pathogens are an approach to overcome these difficulties. Areas covered: This review analyzes the advantages and the disadvantages of these approaches with major emphasis on technologies based on multiplex PCR for the rapid detection of pathogens using whole blood. The most broadly studied platform is SeptFast. Sensitivity ranges between 42% and 73% and specificity between 50% and 97%. The main disadvantages are high cost, the risk of contamination and the lack of information for the presence of resistance genes. A brief review of the use of PCR techniques for the diagnosis of endocarditis and of the recognition of the bacterial proteome for the rapid identification of grown colonies (MALDI-TOF) is also provided. Expert commentary: More randomized clinical trials are necessary to validate the use of molecular techniques for decision-making for patients' outcomes, taking into consideration the cost-benefit for the patient.


Field fluxes and speciation of arsines emanating from soils.
The biogeochemical cycle of arsenic (As) has been extensively studied over the past decades because As is an environmentally ubiquitous, nonthreshold carcinogen, which is often elevated in drinking water and food. It has been known for over a century that micro-organisms can volatilize inorganic As salts to arsines (arsine AsH(3), mono-, di-, and trimethylarsines, MeAsH(2), Me(2)AsH, and TMAs, respectively), but this part of the As cycle, with the exception of geothermal environs, has been almost entirely neglected because of a lack of suited field measurement approaches. Here, a validated, robust, and low-level field-deployable method employing arsine chemotrapping was used to quantify and qualify arsines emanating from soil surfaces in the field. Up to 240 mg/ha/y arsines was released from low-level polluted paddy soils (11.3 ± 0.9 mg/kg As), primarily as TMAs, whereas arsine flux below method detection limit was measured from a highly contaminated mine spoil (1359 ± 212 mg/kg As), indicating that soil chemistry is vital in understanding this phenomenon. In microcosm studies, we could show that under reducing conditions, induced by organic matter (OM) amendment, a range of soils varied in their properties, from natural upland peats to highly impacted mine-spoils, could all volatilize arsines. Volatilization rates from 0.5 to 70 μg/kg/y were measured, and AsH(3), MeAsH(2), Me(2)AsH, and TMAs were all identified. Addition of methylated oxidated pentavalent As, namely monomethylarsonic acid (MMAA) and dimethylarsinic acid (DMAA), to soil resulted in elevated yearly rates of volatilization with up to 3.5% of the total As volatilized, suggesting that the initial conversion of inorganic As to MMAA limits the rate of arsine and methylarsines production by soils. The nature of OM amendment altered volatilization quantitatively and qualitatively, and total arsines release from soil showed correlation between the quantity of As and the concentration of dissolved organic carbon (DOC) in the soil porewater. The global flux of arsines emanating from soils was estimated and placed in the context of As atmospheric inputs, with arsines contributing from 0.9 to 2.6% of the global budget.


Crystal structure and function of a DARPin neutralizing inhibitor of lactococcal phage TP901-1: comparison of DARPin and camelid VHH binding mode.
Combinatorial libraries of designed ankyrin repeat proteins (DARPins) have been proven to be a valuable source of specific binding proteins, as they can be expressed at very high levels and are very stable. We report here the selection of DARPins directed against a macromolecular multiprotein complex, the baseplate BppUxBppL complex of the lactococcal phage TP901-1. Using ribosome display, we selected several DARPins that bound specifically to the tip of the receptor-binding protein (RBP, the BppL trimer). The three selected DARPins display high specificity and affinity in the low nanomolar range and bind with a stoichiometry of one DARPin per BppL trimer. The crystal structure of a DARPin complexed with the RBP was solved at 2.1 A resolution. The DARPinxRBP interface is of the concave (DARPin)-convex (RBP) type, typical of other DARPin protein complexes and different from what is observed with a camelid VHH domain, which penetrates the phage p2 RBP inter-monomer interface. Finally, phage infection assays demonstrated that TP901-1 infection of Lactococcus lactis cells was inhibited by each of the three selected DARPins. This study provides proof of concept for the possible use of DARPins to circumvent viral infection. It also provides support for the use of DARPins in co-crystallization, due to their rigidity and their ability to provide multiple crystal contacts.


Increased risk of acute myocardial infarction after acute episode of schizophrenia: 6 year follow-up study.
The aim of the present study was to estimate the risk of acute myocardial infarction (AMI) among patients who received a first hospital diagnosis of schizophrenia during a 6 year follow-up period. Data from the Taiwan National Health Insurance Research Database were used. The study cohort consisted of 7353 patients who were hospitalized with a principal diagnosis of schizophrenia in 2000. The comparison cohort were 22 059 enrollees randomly selected matched with the study group in terms of gender and age. Each patient was tracked from their index hospitalization in 2000 until the end of 2006 to identify whether or not an AMI had occurred during the follow-up period. Cox proportional hazard regressions were performed to compute the adjusted 6 year survival rate, following adjustment for possible confounding variables. A total of 130 patients suffered AMI during the 6 year follow-up period, including 30 from the study cohort (0.41% of the schizophrenia patients), and 100 (0.45%) from the comparison cohort. But after censoring those patients who died from non-AMI causes and adjusting for potential confounding factors, the risk of AMI occurrence during the 6 year follow-up period was 1.83-fold greater for schizophrenia patients (95% confidence interval 5 1.62-2.05) than for patients in the comparison cohort. Schizophrenia patients had a higher risk of AMI compared to patients in the comparison cohort. The present study draws attention to the need for clinicians to more actively monitor and treat schizophrenia patients with well-recognized risk factors associated with AMI.


Informing radiotherapy decisions in stage I/IIa Hodgkin lymphoma: modeling life expectancy using radiation dosimetry.
In recent randomized trials, omitting consolidative radiotherapy (RT) in early-stage Hodgkin lymphoma (ESHL) increased relapses. However, decades of follow-up are required to observe whether lower initial disease control is compensated by reduced risk of late effects. Extrapolation beyond trial follow-up is therefore necessary to inform current treatment decisions. To this end, we developed a microsimulation model to estimate lifetime quality-adjusted life years (QALYs) after combined modality treatment (CMT) or chemotherapy-alone for stage I/IIa ESHL. For CMT, the model included risks of breast and lung cancer, coronary heart disease, and ischemic stroke. Comparative outcomes were assessed for a clinically relevant range of example patients differing by age, sex, smoking status, and representative organs at risk (OAR) radiation doses informed by the RAPID trial. Analysis was performed with and without a 3.5% discount rate on future health. Smoking status had a large effect on optimal treatment choice. CMT was superior for nearly all never smoker example patients regardless of age, sex, and OAR doses. At a maximum, CMT produced a 1.095 (95% CI: 1.054-1.137) gain in undiscounted QALYs for a 20-year-old male never smoker with unilateral neck disease. In contrast, current smokers could substantially gain from chemotherapy-alone treatment. Again at a maximum, a 20-year-old male current smoker with bilateral neck and whole mediastinum involvement gained 3.500 (95% CI: 3.400 to 3.600) undiscounted QALYs with chemotherapy-alone treatment. Overall, CMT was more favorable the younger the patient, when future health discounting was included, and in never smokers.


Novel porcine-like human G26P[19] rotavirus identified in hospitalized paediatric diarrhoea patients in Ho Chi Minh City, Vietnam.
During a hospital-based diarrhoeal disease study conducted in Ho Chi Minh City, Vietnam from 2009 to 2010, we identified four symptomatic children infected with G26P[19] rotavirus (RV)--an atypical variant that has not previously been reported in human gastroenteritis. To determine the genetic structure and investigate the origin of this G26P[19] strain, the whole genome of a representative example was characterized, revealing a novel genome constellation: G26-P[19]-I5-R1-C1-M1-A8-N1-T1-E1-H1. The genome segments were most closely related to porcine (VP7, VP4, VP6 and NSP1) and Wa-like porcine RVs (VP1-3 and NSP2-5). We proposed that this G26P[19] strain was the product of zoonotic transmission coupled with one or more reassortment events occurring in human and/or animal reservoirs. The identification of such strains has potential implications for vaccine efficacy in south-east Asia, and outlines the utility of whole-genome sequencing for studying RV diversity and zoonotic potential during disease surveillance.


Increased plasma XOR activity induced by NAFLD/NASH and its possible involvement in vascular neointimal proliferation.
Xanthine oxidoreductase (XOR) is an enzyme that catalyzes hypoxanthine to xanthine and xanthine to uric acid, respectively. However, the underlying mechanisms of increased plasma XOR and its pathological roles in systemic diseases, such as atherosclerosis, are not fully understood. In this study, we found that changes in plasma XOR activity after bariatric surgery closely associated with those in liver enzymes, but not with those in BMI. In a mouse model of nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), plasma XOR activity markedly increased. Besides, purine catabolism was accelerated in the plasma per se of NASH mice and human patients with high XOR activity. In our NASH mice, we observed an increased vascular neointima formation consisting of dedifferentiated vascular smooth muscle cells (SMCs), which was significantly attenuated by topiroxostat, a selective XOR inhibitor. In vitro, human liver S9-derived XOR promoted proliferation of SMCs with phenotypic modulation and induced ROS production by catabolizing hypoxanthine released from human endothelial cells. Collectively, the results from human and mouse models suggest that increased plasma XOR activity, mainly explained by excess hepatic leakage, was involved in the pathogenesis of vascular injury, especially in NAFLD/NASH conditions.


Effectiveness of step-down versus outpatient dialectical behaviour therapy for patients with severe levels of borderline personality disorder: a pragmatic randomized controlled trial.
Step-down dialectical behaviour therapy (DBT) is a treatment consisting of 3 months of residential DBT plus 6 months of outpatient DBT. The program was specifically developed for people suffering from severe borderline personality disorder (BPD). The present study examines the effectiveness and cost-effectiveness of step-down DBT compared to 12 months of regular, outpatient DBT. Eighty-four participants reporting high levels of BPD-symptoms (mean age 26 years, 95% female) were randomly assigned to step-down versus standard DBT. Measurements were conducted at baseline and after 3, 6, 9 and 12 months. The Lifetime Parasuicide Count and BPD Severity Index (BPDSI) were used to assess suicidal behaviour, non-suicidal self-injury (NSSI) and borderline severity. Costs per Quality Adjusted Life Year (QALY) were calculated using data from the EQ-5D-3L and the Treatment Inventory Cost in Psychiatric Patients (TIC-P). In step-down DBT, 95% of patients started the program, compared to 45% of patients in outpatient DBT. The probability of suicidal behaviour did not change significantly over 12 months. The probability of NSSI decreased significantly in step-down DBT, but not in outpatient DBT. BPDSI decreased significantly in both groups, with the improvement leveling off at the end of treatment. While step-down DBT was more effective in increasing quality of life, it also cost significantly more. The extra costs per gained QALY exceeded the €80,000 threshold that is considered acceptable for severely ill patients in the Netherlands. A pragmatic randomized controlled trial in the Netherlands showed that 9 months of step-down DBT is an effective treatment for people suffering from severe levels of BPD. However, step-down DBT is not more effective than 12 months of outpatient DBT, nor is it more cost-effective. These findings should be considered tentative because of high noncompliance with the treatment assignment in outpatient DBT. Furthermore, the long-term effectiveness of step-down DBT, and moderators of treatment response, remain to be evaluated. www.clinicaltrials.govNCT01904227. Registered 22 July 2013 (retrospectively registered).


Twist effect on spectral properties of two-mode fiber acousto-optic filters.
The splitting and the shift of resonance peaks in the output spectrum of two-mode fiber acousto-optic devices caused by twist perturbation are described. An elliptical-core two-mode fiber and a two-mode photonic-crystal fiber are used for the analysis. The splitting of the resonance peaks are found to be almost linearly proportional to the twist angle of the fiber with the slopes of about 0.58 nm/(rad/m) for the elliptical-core fiber and about 0.29 nm/(rad/m) for the photonic crystal fiber. The experimental results compare well with the theoretical predictions.


Influence of nanobody binding on fluorescence emission, mobility, and organization of GFP-tagged proteins.
Advanced fluorescence microscopy studies require specific and monovalent molecular labeling with bright and photostable fluorophores. This necessity led to the widespread use of fluorescently labeled nanobodies against commonly employed fluorescent proteins (FPs). However, very little is known how these nanobodies influence their target molecules. Here, we tested commercially available nanobodies and observed clear changes of the fluorescence properties, mobility and organization of green fluorescent protein (GFP) tagged proteins after labeling with the anti-GFP nanobody. Intriguingly, we did not observe any co-diffusion of fluorescently labeled nanobodies with the GFP-labeled proteins. Our results suggest significant binding of the nanobodies to a non-emissive, likely oligomerized, form of the FPs, promoting disassembly into monomeric form after binding. Our findings have significant implications on the application of nanobodies and GFP labeling for studying dynamic and quantitative protein organization in the plasma membrane of living cells using advanced imaging techniques.


Maturation of limbic corticostriatal activation and connectivity associated with developmental changes in temporal discounting.
Temporal discounting (TD) matures with age, alongside other markers of increased impulse control, and coherent, self-regulated behaviour. Discounting paradigms quantify the ability to refrain from preference of immediate rewards, in favour of delayed, larger rewards. As such, they measure temporal foresight and the ability to delay gratification, functions that develop slowly into adulthood. We investigated the neural maturation that accompanies the previously observed age-related behavioural changes in discounting, from early adolescence into mid-adulthood. We used functional magnetic resonance imaging of a hypothetical discounting task with monetary rewards delayed in the week to year range. We show that age-related reductions in choice impulsivity were associated with changes in activation in ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), ventral striatum (VS), insula, inferior temporal gyrus, and posterior parietal cortex. Limbic frontostriatal activation changes were specifically associated with age-dependent reductions in impulsive choice, as part of a more extensive network of brain areas showing age-related changes in activation, including dorsolateral PFC, inferior parietal cortex, and subcortical areas. The maturational pattern of functional connectivity included strengthening in activation coupling between ventromedial and dorsolateral PFC, parietal and insular cortices during selection of delayed alternatives, and between vmPFC and VS during selection of immediate alternatives. We conclude that maturational mechanisms within limbic frontostriatal circuitry underlie the observed post-pubertal reductions in impulsive choice with increasing age, and that this effect is dependent on increased activation coherence within a network of areas associated with discounting behaviour and inter-temporal decision-making.


Treatment-related damage in elderly-onset ANCA-associated vasculitis: safety outcome analysis of two nationwide prospective cohort studies.
It is not elucidated that there is treatment-related damage in elderly patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Elderly (≥ 75 years of age) patients were enrolled from two nationwide prospective inception cohort studies. The primary outcome was 12-month treatment-related Vasculitis Damage Index (VDI) score. Secondary outcomes included serious infections within 6 months, total VDI score, remission, and relapse. Patient characteristics and outcomes were compared across three different initial glucocorticoid (GC) dose groups: high-dose, prednisolone (PSL) ≥ 0.8 mg/kg/day; medium-dose, 0.6 ≤ PSL < 0.8 mg/kg/day; and low-dose, PSL < 0.6 mg/kg/day. Of the 179 eligible patients, the mean age was 80.0 years; 111 (62%) were female. The mean Birmingham Vasculitis Activity Score was 16.1. Myeloperoxidase-ANCA findings were positive in 168 (94%) patients, while proteinase 3-ANCA findings were positive in 11 (6%). The low-dose group was older and had higher serum creatinine levels than the other groups. There were no statistically significant intergroup differences in remission or relapse, whereas serious infection developed more frequently in the high-dose (29 patients [43%]) than the low-dose (13 patients [22%]) or medium-dose (10 patients [19%]) groups (p = 0.0007). Frequent VDI items at 12 months included hypertension (19%), diabetes (13%), atrophy and weakness (13%), osteoporosis (8%), and cataracts (8%). Logistic regression analysis revealed that GC dose at 12 months (odds ratio, 1.14; 95% confidence interval, 1.00-1.35) was a predictor for diabetes. A reduced initial GC dose with rapid reduction might be required to ensure the safe treatment of elderly AAV patients.


Mesenchymal stem cells and osteoarthritis: remedy or accomplice?
Multipotent mesenchymal stromal or stem cells (MSCs) are likely to be agents of connective tissue homeostasis and repair. Because the hallmark of osteoarthritis (OA) is degeneration and failure to repair connective tissues it is compelling to think that these cells have a role to play in OA. Indeed, MSCs have been implicated in the pathogenesis of OA and, in turn, progression of the disease has been shown to be therapeutically modulated by MSCs. This review discusses current knowledge on the potential of both marrow- and local joint-derived MSCs in OA, the mode of action of the cells, and possible effects of the osteoarthritic niche on the function of MSCs. The use of stem cells for repair of isolated cartilage lesions and strategies for modulation of OA using local cell delivery are discussed as well as therapeutic options for the future to recruit and appropriately activate endogenous progenitors and/or locally systemically administered MSCs in the early stages of the disease. The use of gene therapy protocols, particularly as they pertain to modulation of inflammation associated with the osteoarthritic niche, offer an additional option in the treatment of this chronic disease. In summary, elucidation of the etiology of OA and development of technologies to detect early disease, allied to an increased understanding of the role MSCs in aging and OA, should lead to more targeted and efficacious treatments for this debilitating chronic disease in the future.


Functional Interchangeability of Nucleotide Sugar Transporters URGT1 and URGT2 Reveals That urgt1 and urgt2 Cell Wall Chemotypes Depend on Their Spatio-Temporal Expression.
Nucleotide sugar transporters (NSTs) are Golgi-localized proteins that play a role in polysaccharide biosynthesis by transporting substrates (nucleotide sugars) from the cytosol into the Golgi apparatus. In Arabidopsis, there is an NST subfamily of six members, called URGTs, which transport UDP-rhamnose and UDP-galactose in vitro. URGTs are very similar in protein sequences, and among them, URGT1 and URGT2 are highly conserved in protein sequence and also showed very similar kinetic parameters toward UDP-rhamnose and UDP-galactose in vitro. Despite the similarity in sequence and in vitro function, mutants in urgt1 led to a specific reduction in galactose in rosette leaves. In contrast, mutants in urgt2 showed a decrease in rhamnose content in soluble mucilage from seeds. Given these specific and quite different chemotypes, we wonder whether the differences in gene expression could explain the observed differences between the mutants. Toward that end, we analyzed whether URGT2 could rescue the urgt1 phenotype and vice versa by performing a promoter swapping experiment. We analyzed whether the expression of the URGT2 coding sequence, controlled by the URGT1 promoter, could rescue the urgt1 rosette phenotype. A similar strategy was used to determine whether URGT1 could rescue the urgt2 mucilage phenotype. Expression analysis of the swapped genes, using qRT-PCR, was similar to the native URGT1 and URGT2 genes in wild-type plants. To monitor the protein expression of the swapped genes, both URGTs were tagged with green fluorescent protein (GFP). Confocal microscopy analyses of the swapped lines containing URGT2-GFP showed fluorescence in motile dot-like structures in rosette leaves. Swapped lines containing URGT1-GFP showed fluorescence in dot-like structures in the seed coat. Finally, the expression of URGT2 in urgt1 mutants rescued galactose reduction in rosette leaves. In the same manner, the expression of URGT1 in urgt2 mutants recovered the content of rhamnose in soluble mucilage. Hence, our results showed that their expression in different organs modulates the role in vivo of URGT1 and URGT2. Likely, this is due to their presence in different cellular contexts, where other proteins, acting in partnership, may drive their functions toward different pathways.


Fruitless isoforms and target genes specify the sexually dimorphic nervous system underlying Drosophila reproductive behavior.
Courtship is pivotal to successful reproduction throughout the animal kingdom. Sexual differences in the nervous system are thought to underlie courtship behavior. Male courtship behavior in Drosophila is in large part regulated by the gene fruitless (fru). fru has been reported to encode at least three putative BTB-zinc-finger transcription factors predicted to have different DNA-binding specificities. Although a large number of previous studies have demonstrated that fru plays essential roles in male courtship behavior, we know little about the function of Fru isoforms at the molecular level. Our recent study revealed that male-specific Fru isoforms are expressed in highly overlapping subsets of neurons in the male brain and ventral nerve cord. Fru isoforms play both distinct and redundant roles in male courtship behavior. Importantly, we have identified for the first time, by means of the DamID technique, direct Fru transcriptional target genes. Fru target genes overwhelmingly represent genes previously reported to be involved in the nervous system development, such as CadN, lola and pdm2. Our study provides important insight into how the sexually dimorphic neural circuits underlying reproductive behavior are established.


Scaling of geochemical reaction rates via advective solute transport.
Transport in porous media is quite complex, and still yields occasional surprises. In geological porous media, the rate at which chemical reactions (e.g., weathering and dissolution) occur is found to diminish by orders of magnitude with increasing time or distance. The temporal rates of laboratory experiments and field observations differ, and extrapolating from laboratory experiments (in months) to field rates (in millions of years) can lead to order-of-magnitude errors. The reactions are transport-limited, but characterizing them using standard solute transport expressions can yield results in agreement with experiment only if spurious assumptions and parameters are introduced. We previously developed a theory of non-reactive solute transport based on applying critical path analysis to the cluster statistics of percolation. The fractal structure of the clusters can be used to generate solute distributions in both time and space. Solute velocities calculated from the temporal evolution of that distribution have the same time dependence as reaction-rate scaling in a wide range of field studies and laboratory experiments, covering some 10 decades in time. The present theory thus both explains a wide range of experiments, and also predicts changes in the scaling behavior in individual systems with increasing time and/or length scales. No other theory captures these variations in scaling by invoking a single physical mechanism. Because the successfully predicted chemical reactions include known results for silicate weathering rates, our theory provides a framework for understanding changes in the global carbon cycle, including its effects on extinctions, climate change, soil production, and denudation rates. It further provides a basis for understanding the fundamental time scales of hydrology and shallow geochemistry, as well as the basis of industrial agriculture.


Brazilian medicinal plants to treat upper respiratory tract and bronchial illness: systematic review and meta-analyses-study protocol.
Respiratory illness, often associated with cough and sputum, is frequent. In Brazil, herbal medicines are often recommended as a first-line treatment for respiratory illness. There exists uncertainty regarding the effectiveness of these treatments. No systematic review has evaluated Brazilian medicinal plants (BMP) to treat upper respiratory tract and bronchial illness (URTI). We will conduct a systematic review and, if appropriate, a series of meta-analyses evaluating the safety and effectiveness of BMP for URTI. Eligible randomised controlled trials and observational studies will enrol adult or paediatric patients presenting with URTI treated by BMP approved by the Brazilian Health Surveillance Agency compared with placebo, no treatment or an alternative therapy. Our search will include the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Illness Group's Specialized Register; MEDLINE; EMBASE; CINAHL (Cumulative Index to Nursing and Allied Health Literature); Web of Science; AMED; LILACS; CAB abstracts; clinical trial.gov; the WHO Trial Register and the Brazilian thesis database (CAPES) without any language restrictions. Outcomes of interest are time to resolution of clinical symptoms and/or signs (cough, sputum production or activity limitations), severity of symptoms prior to resolution and major/minor adverse events. Teams of reviewers will, independently and in duplicate, screen titles and abstracts and the complete full text to determine eligibility. For eligible studies, reviewers will perform data abstraction and assess risk of bias of eligible trials. When appropriate, we will conduct meta-analyses. We will also assess the quality of body of evidence (confidence in estimates of effect) for each of the outcomes using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The systematic review will be published in a peer-reviewed journal. Brief reports of review findings will be disseminated directly to appropriate audiences via email and other modes of communication. The review will guide healthcare practice and policy in Brazil. Prospero CRD42014007057.


Side-chain cysteine-functionalized poly(2-oxazoline)s for multiple peptide conjugation by native chemical ligation.
We prepared statistical copolymers composed of 2-methyl-2-oxazoline (MeOx) in combination with 2-butenyl-2-oxazoline (BuOx) or 2-decenyl-2-oxazoline (DecOx) as a basis for polymer analogous introduction of 1,2-aminothiol moieties at the side chain. MeOx provides hydrophilicity as well as cyto- and hemocompatibility, whereas the alkene groups of BuOx and DecOx serve for functionalization with a thiofunctional thiazolidine by UV-mediated thiol-ene reaction. After deprotection the cysteine content in functionalized poly(2-oxazoline) (POx) is quantified by NMR and a modified trinitrobenzenesulfonic acid assay. The luminescent cell viability assay shows no negative influence of cysteine-functionalized POx (cys-POx) concerning cell viability and cell number. cys-POx was used for multiple chemically orthogonal couplings with thioester-terminated peptides through native chemical ligation (NCL), which was performed and confirmed by NMR and MALDI-ToF measurements.


Identification of stage-regulated and differentiation-enriched transcripts during transformation of the African trypanosome from its bloodstream to procyclic form.
Trypanosoma brucei undergoes dramatic stage-specific changes in surface antigen expression, metabolic development, cellular morphogenesis and cell-cycle control. These events can be studied in detail during the transition between the bloodstream stumpy stage and the tsetse fly midgut procyclic form. This differentiation can be induced in vitro, is synchronous in the population and there are abundant markers for stage-regulated and differentiation events. We have used this differentiation system to investigate the role of de novo transcription during different phases of this well-characterised cellular transformation. Our experiments implicate early transcriptional involvement in shedding of the variable surface glycoprotein coat, cell restructuring and cell-cycle re-entry. The synchrony of differentiation has also been exploited to identify transcripts which define distinct regulated processes during this differentiation. The transcripts identified provide good coverage of the different molecular regulation events that accompany this life-cycle transformation. These included a surface antigen gene (encoding procyclin/PARP), a cell cycle regulated component (encoding histone H2B), a homologue of the Leishmania activated protein kinase C receptor (LACK) and a putative gene for sub unit VI of cytochrome c oxidase.


Irregular treatment of hypertension in the former Soviet Union.
The USSR failed to establish a modern pharmaceutical industry and lacked the capacity for reliable distribution of drugs. Patients were required to pay for outpatient drugs and the successor states have inherited this legacy, so that those requiring long-term treatment face considerable barriers in receiving it. It was hypothesised that citizens of former Soviet republics requiring treatment for hypertension may not be receiving regular treatment. To describe the regularity of treatment among those diagnosed with hypertension and prescribed treatment in eight countries of the former Soviet Union, and explore which factors are associated with not taking medication regularly. Using data from over 18 000 respondents from eight former Soviet countries, individuals who had been told that they had hypertension by a health professional and prescribed treatment were identified. By means of multivariate logistic analysis the characteristics of those taking treatment daily and less than daily were compared. Only 26% of those prescribed treatment took it daily. The probability of doing so varied among countries and was highest in Russia, Belarus and Georgia, and lowest in Armenia (although Georgia's apparent advantage may reflect low rates of diagnosis). Women, older people, those living in urban areas, and non-smokers and non-drinkers were more likely to take treatment daily. A high proportion of those who have been identified by health professionals as requiring hypertension treatment are not taking it daily. These findings suggest that irregular hypertension treatment is a major problem in this region and will require an urgent response.


[The history of home hemodialysis and its likely revival].
The home extracorporeal hemodialysis, which aroused a great interest in the past, has not kept its promises due to the complexity and expectations for family involvement in treatment management. In the United States NxStage One portable system was proposed and designed for home use. In this work we describe, starting from the history of home hemodialysis, the method with NxStage system by comparing it with the conventional HD in 5 patients. The dialysis efficiency was similar between the two treatments, even if home hemodialysis showed a reduction in serum urea, creatinine and phosphorus. At the same time phosphate binders use decreased with an increase in serum calcium while hemoglobin increased reducing doses of erythropoietin. The method was successful in the training of the patients and their partners during hospital training and at home. Patients have shown great enthusiasm at the beginning and during the therapy, which is developed around the users personal needs, being able to decide at its own times during 24 hours according to personal needs, in addition to faster recovery after the dialysis. This method certainly improved the patients' wellness and increased their autonomy.


Development and characterization of a scintillating cell imaging dish for radioluminescence microscopy.
Radioluminescence microscopy is an emerging modality that can be used to image radionuclide probes with micron-scale resolution. This technique is particularly useful as a way to probe the metabolic behavior of single cells and to screen and characterize radiopharmaceuticals, but the quality of the images is critically dependent on the scintillator material used to image the cells. In this paper, we detail the development of a microscopy dish made of a thin-film scintillating material, Lu2O3:Eu, that could be used as the blueprint for a future consumable product. After developing a simple quality control method based on long-lived alpha and beta sources, we characterize the radioluminescence properties of various thin-film scintillator samples. We find consistent performance for most samples, but also identify a few samples that do not meet the specifications, thus stressing the need for routine quality control prior to biological experiments. In addition, we test and quantify the transparency of the material, and demonstrate that transparency correlates with thickness. Finally, we evaluate the biocompatibility of the material and show that the microscopy dish can produce radioluminescent images of live single cells.


Horizontal Gene Transfer and Tandem Duplication Shape the Unique CAZyme Complement of the Mycoparasitic Oomycetes Pythium oligandrum and Pythium periplocum.
Crop protection strategies that are effective but that reduce our reliance on chemical pesticides are urgently needed to meet the UN sustainable development goals for global food security. Mycoparasitic oomycetes such as Pythium oligandrum and Pythium periplocum, have potential for the biological control of plant diseases that threaten crops and have attracted much attention due to their abilities to antagonize plant pathogens and modulate plant immunity. Studies of the molecular and genetic determinants of mycoparasitism in these species have been less well developed than those of their fungal counterparts. Carbohydrate-active enzymes (CAZymes) from P. oligandrum and P. periplocum are predicted to be important components of mycoparasitism, being involved in the degradation of the cell wall of their oomycete and fungal prey species. To explore the evolution of CAZymes of these species we performed an in silico identification and comparison of the full CAZyme complement (CAZyome) of the two mycoparasitic Pythium species (P. oligandrum and P. periplocum), with seven other Pythium species, and four Phytophthora species. Twenty CAZy gene families involved in the degradation of cellulose, hemicellulose, glucan, and chitin were expanded in, or unique to, mycoparasitic Pythium species and several of these genes were expressed during mycoparasitic interactions with either oomycete or fungal prey, as revealed by RNA sequencing and quantitative qRT-PCR. Genes from three of the cellulose and chitin degrading CAZy families (namely AA9, GH5_14, and GH19) were expanded via tandem duplication and predominantly located in gene sparse regions of the genome, suggesting these enzymes are putative pathogenicity factors able to undergo rapid evolution. In addition, five of the CAZy gene families were likely to have been obtained from other microbes by horizontal gene transfer events. The mycoparasitic species are able to utilize complex carbohydrates present in fungal cell walls, namely chitin and N-acetylglucosamine for growth, in contrast to their phytopathogenic counterparts. Nonetheless, a preference for the utilization of simple sugars for growth appears to be a common trait within the oomycete lineage.


Axillary lymph node metastasis: CA-15-3 and carcinoembryonic antigen concentrations in fine-needle aspirates for preoperative diagnosis in patients with breast cancer.
To assess whether concentrations of the tumor markers breast cancer antigen 15-3 (CA-15-3) and carcinoembryonic antigen (CEA) in fine-needle aspirates (FNAs) differ between benign and malignant lymph nodes and whether FNA concentrations of the tumor markers can improve the sensitivity of axillary lymph node (ALN) FNA in patients with breast cancer. An Institutional Review Board approved this study. All subjects gave written informed consent. Ultrasonographically (US)-guided FNA was performed for 134 ALNs in 134 women (mean age, 49.6 years; range, 28-92 years) with breast cancer. Immediately after obtaining an FNA cytology specimen, the needle was rinsed with 1 mL of normal saline solution. CEA and CA-15-3 concentrations were measured in the washout. Of the 134 ALNs, 86 were malignant and 48 were benign. Sensitivity of FNA cytology alone was compared with the sensitivity of FNA cytology and CEA and CA-15-3 FNA concentrations. Patients with a positive metastatic diagnosis had significantly higher FNA concentrations of CEA and CA-15-3 than did those with a negative diagnosis (both P = .02). FNA cytology sensitivity was 87.2%, and the combined sensitivity of FNA cytology and FNA tumor marker concentrations was 96.5% (P = .01). Evaluation of CEA and CA-15-3 concentrations in FNA could be helpful for the preoperative diagnosis of ALN metastasis in patients with breast cancer. (c) RSNA, 2010.


Morphology of the corpus callosum at different stages of schizophrenia: cross-sectional study in first-episode and chronic illness.
The shape of the corpus callosum may differ in schizophrenia, although no study has compared first-episode with established illness. To investigate the size and shape of the corpus callosum in a large sample of people with first-episode and established schizophrenia. Callosal size and shape were determined using high-resolution magnetic resonance imaging on 76 patients with first-episode schizophrenia-spectrum disorders, 86 patients with established schizophrenia and 55 healthy participants. There were no significant differences in total area across groups. Reductions in callosal width were seen in the region of the anterior genu in first-episode disorder (P<0.005). Similar reductions were seen in the chronic schizophrenia group in the anterior genu, but also in the posterior genu and isthmus (P=0.0005). Reductions in anterior callosal regions connecting frontal cortex are present at the onset of schizophrenia, and in established illness are accompanied by changes in other regions of the callosum connecting cingulate, temporal and parietal cortices.


N-Docosahexaenoylethanolamide promotes development of hippocampal neurons.
DHA (docosahexaenoic acid, C22:6,n-3) has been shown to promote neurite growth and synaptogenesis in embryonic hippocampal neurons, supporting the importance of DHA known for hippocampus-related learning and memory function. In the present study, we demonstrate that DHA metabolism to DEA (N-docosahexaenoylethanolamide) is a significant mechanism for hippocampal neuronal development, contributing to synaptic function. We found that a fatty acid amide hydrolase inhibitor URB597 potentiates DHA-induced neurite growth, synaptogenesis and synaptic protein expression. Active metabolism of DHA to DEA was observed in embryonic day 18 hippocampal neuronal cultures, which was increased further by URB597. Synthetic DEA promoted hippocampal neurite growth and synaptogenesis at substantially lower concentrations in comparison with DHA. DEA-treated neurons increased the expression of synapsins and glutamate receptor subunits and exhibited enhanced glutamatergic synaptic activity, as was the case for DHA. The DEA level in mouse fetal hippocampi was altered according to the maternal dietary supply of n-3 fatty acids, suggesting that DEA formation is a relevant in vivo process responding to the DHA status. In conclusion, DHA metabolism to DEA is a significant biochemical mechanism for neurite growth, synaptogenesis and synaptic protein expression, leading to enhanced glutamatergic synaptic function. The novel DEA-dependent mechanism offers a new molecular insight into hippocampal neurodevelopment and function.


Activator protein 2alpha suppresses intestinal tumorigenesis in the Apc(min) mouse.
Activator protein 2alpha (AP-2alpha) is a putative tumor suppressor, and various reports have described the loss or reduction of AP-2alpha expression in cutaneous malignant melanomas, as well as in cancers of the prostate, breast and colon. Previously, AP-2alpha was shown to attenuate beta-catenin/T-cell factor-4 (TCF-4) nuclear interactions and beta-catenin/TCF-4-dependent transcriptional activity in human colorectal cancer cells [Q. Li, R.H. Dashwood, Activator protein 2alpha associates with adenomatous polyposis coli/beta-catenin and Inhibits beta-catenin/T-cell factor transcriptional activity in colorectal cancer cells, J. Biol. Chem. 279 (2004) 45669-45675]. Here, we show that in vivo gene delivery of AP-2alpha suppressed intestinal polyp formation in the Apc(min) mouse, and protected against the development of anemia and splenomegaly. Immunoblot analyses and immunohistochemistry following gene delivery revealed an increase in AP-2alpha expression in the mouse intestinal mucosa and liver. Co-immunoprecipitation experiments provided evidence for interactions between AP-2alpha, beta-catenin, and adenomatous polyposis coli (APC) proteins in mouse intestinal mucosa, as well as in a primary human colorectal cancer. Collectively, these studies support a tumor suppressor role for AP-2alpha in the gastrointestinal tract, and suggest that AP-2alpha represents a novel target for therapeutic intervention in human cancers characterized by dysregulated Wnt signaling.


Immunosuppressive effect of restraint stress on the initiation of allergic rhinitis in mice.
Exposure to acute stressors modulates both innate and acquired immune function. However, little is known about whether stress has the potential to modulate the pathogenesis of allergic rhinitis. To determine the effects of acute restraint stress on the initiation of allergic rhinitis in a murine model. CBA/J mice were repeatedly intranasally sensitized with phospholipase A2 (PLA2) from honeybee venom without adjuvant. Restraint stress was applied using uniform cylinders once a week for a continuous 8-hour period, on five occasions in total. Production of PLA2-specific antibodies and degree of nasal and blood eosinophilia were compared between stressed and control mice. Repeated intranasal sensitization with PLA2 induced PLA2-specific IgE and marked eosinophilia in both the nose and blood in CBA/J mice. Exposure to restraint stress significantly inhibited production of PLA2-specific IgE, IgG1 and IgG2a. Conversely, the stress exerted no significant effect on eosinophilia. Exposure to acute restraint stress inhibits antigen-specific antibody production, but not local or systemic eosinophilia. The results of this study suggest that acute stress has the potential to modulate the initiation of allergic rhinitis.


Genetic and therapeutic targeting of properdin in mice prevents complement-mediated tissue injury.
The alternative pathway (AP) of complement activation is constitutively active and must be regulated by host proteins to prevent autologous tissue injury. Dysfunction of AP regulatory proteins has been linked to several human inflammatory disorders. Properdin is a positive regulator of AP complement activation that has been shown to extend the half-life of cell surface–bound C3 convertase C3bBb; it may also initiate AP complement activation. Here, we demonstrate a critical role for properdin in autologous tissue injury mediated by AP complement activation. We identified myeloid lineage cells as the principal source of plasma properdin by generating mice with global and tissue-specific knockout of Cfp (which encodes properdin) and by generating BM chimeric mice. Properdin deficiency rescued mice from AP complement–mediated embryonic lethality caused by deficiency of the membrane complement regulator Crry and markedly reduced disease severity in the K/BxN model of arthritis. Ab neutralization of properdin in WT mice similarly ameliorated arthritis development, whereas reconstitution of properdin-null mice with exogenous properdin restored arthritis sensitivity. These data implicate systemic properdin as a key contributor to AP complement–mediated injury and support its therapeutic targeting in complement-dependent human diseases.


Osteoblast Differentiation at a Glance.
Ossification is a tightly regulated process, performed by specialized cells called osteoblasts. Dysregulation of this process may cause inadequate or excessive mineralization of bones or ectopic calcification, all of which have grave consequences for human health. Understanding osteoblast biology may help to treat diseases such as osteogenesis imperfecta, calcific heart valve disease, osteoporosis, and many others. Osteoblasts are bone-building cells of mesenchymal origin; they differentiate from mesenchymal progenitors, either directly or via an osteochondroprogenitor. The direct pathway is typical for intramembranous ossification of the skull and clavicles, while the latter is a hallmark of endochondral ossification of the axial skeleton and limbs. The pathways merge at the level of preosteoblasts, which progress through 3 stages: proliferation, matrix maturation, and mineralization. Osteoblasts can also differentiate into osteocytes, which are stellate cells populating narrow interconnecting passages within the bone matrix. The key molecular switch in the commitment of mesenchymal progenitors to osteoblast lineage is the transcription factor cbfa/runx2, which has multiple upstream regulators and a wide variety of targets. Upstream is the Wnt/Notch system, Sox9, Msx2, and hedgehog signaling. Cofactors of Runx2 include Osx, Atf4, and others. A few paracrine and endocrine factors serve as coactivators, in particular, bone morphogenetic proteins and parathyroid hormone. The process is further fine-tuned by vitamin D and histone deacetylases. Osteoblast differentiation is subject to regulation by physical stimuli to ensure the formation of bone adequate for structural and dynamic support of the body. Here, we provide a brief description of the various stimuli that influence osteogenesis: shear stress, compression, stretch, micro- and macrogravity, and ultrasound. A complex understanding of factors necessary for osteoblast differentiation paves a way to introduction of artificial bone matrices.


The clinical spectrum of idiopathic hyperuricosuria in children: isolated and associated with hypercalciuria/hyperoxaluria.
The clinical manifestations of hyperuricosuria (HU) are usually underestimated by the clinician. The aim of this study was to review the clinical spectrum of symptomatology of HU and to evaluate the presence of associated hypercalciuria (HC) and hyperoxaluria (HX). A retrospective review was done on 64 children with HU seen between January 2004 and December 2008. The patients were divided into HU 19, HU + HC 4, HU + HX 21 and HU + HC + HX 20. The mean age at diagnosis was 80 months (range six to 156 months). Duration of follow-up ranged was from six to 66 months. There were 228 symptomatic episodes for 64 patients (males 31, females 33). The relationship of symptomatology to age and gender were not significant. The most common symptoms were abdominal pain 67.2% (in 7/44 it was localized to the right lower quadrant, mimicking appendicitis), flank pain 59.4%, increased urinary frequency 43.4%, urgency 39%, enuresis 31.25%, oliguria 29.7%, dysuria 25%, red urine 20.35%, vaginal itching 15.21%, dribbling 14.06%, orange urine 12.5%, hesitancy 12.5% and penile pain 7.81%. To our knowledge, the vaginal itching and penile pain were not previously described. Family history was positive for stones and/or gout in 62.5%. The presence of a positive family history and red urine were significant (P-value <0.05) for the presence of an underlying HU. In the presence of recurrent abdominal/flank pain, hematuria without proteinuria or edema and urological symptomatology, especially in the presence of red urine, and a positive family history of gout or stones, a search for HU is in order. This will avoid unnecessary and invasive investigations.


The use of milrinone in neonates with persistent pulmonary hypertension of the newborn - a randomised controlled trial pilot study (MINT 1): study protocol and review of literature.
Persistent pulmonary hypertension of the newborn (PPHN) is a relatively common condition which results in a mortality of up to 33%. Up to 40% of infants treated with nitric oxide (iNO) either have a transient response or fail to demonstrate an improvement in oxygenation. Milrinone, a selective phosphodiesterase 3 (PDE3) inhibitor with inotropic and lusitropic properties may have potential benefit in PPHN. This pilot study was developed to assess the impact of milrinone administration on time spent on iNO in infants with PPHN. This is a multicentre, randomized, double-blind, two arm pilot study, with a balanced (1:1) allocation of 20 infants. In this pilot study, we hypothesise that infants ≥34 weeks gestation and ≥ 2000 g with a clinical and echocardiography diagnosis of PPHN, intravenous milrinone used in conjunction with iNO will result in a reduction in the time spent on iNO. In addition, we hypothesise that milrinone treatment will lead to an improvement in myocardial performance and global hemodynamics when compared to iNO alone. We will also compare the rate of adverse events associated with the milrinone, and the pre-discharge outcomes of both groups. The purpose of this pilot study is to assess the feasibility of performing the trial and to obtain preliminary data to calculate a sample size for a definitive multi-centre trial of milrinone therapy in PPHN. Trial registration: www.isrctn.com; ISRCTN:12949496; EudraCT Number:2014-002988-16.


Prevention. How much harm? How much benefit? 4. The ethics of informed consent for preventive screening programs.
Preventive interventions may have few or unproven benefits, or they may even be harmful. Since three of the fundamental precepts of Western biomedical ethics are beneficence, non-maleficence and respect for individual autonomy, failure to obtain truly informed consent for many current preventive interventions may be unethical. However, there are many impediments to obtaining such consent. Physicians need to be aware of an immense amount of up-to-date, complex information. It may be difficult for patients to assimilate this information, and there is rarely time for physicians to become informed and to inform their patients. Clinical practice guidelines may be helpful, but not all are based on evidence, and recommendations are often conflicting. Medical institutions, as well as individual clinicians, can help solve these dilemmas. Authors and journal editors can make a commitment to report and publish well-referenced evidence-based guidelines. Organizations such as the Canadian Task Force on the Periodic Health Examination and the US Preventive Services Task Force can develop balanced, evidence-based patient-information material. Faculty at all levels of medical education can increase their emphasis on the ethics of prevention. Individual clinicians should avoid making clinical decisions on the basis of relative reductions of morbidity or mortality, should use evidence-based clinical practice guidelines rather than those based on authority whenever possible, should make use of patient-information material and, most important, should have a consistent policy of obtaining informed consent from patients before they participate in potentially harmful preventive programs.


Acute decompensated heart failure is routinely treated as a cardiopulmonary syndrome.
Heart failure as recognized and treated in typical practice may represent a complex condition that defies discrete categorizations. To illuminate this complexity, we examined treatment strategies for patients hospitalized and treated for decompensated heart failure. We focused on the receipt of medications appropriate for other acute conditions associated with shortness of breath including acute asthma, pneumonia, and exacerbated chronic obstructive pulmonary disease. Using Premier Perspective(®), we studied adults hospitalized with a principal discharge diagnosis of heart failure and evidence of acute heart failure treatment from 2009-2010 at 370 US hospitals. We determined treatment with acute respiratory therapies during the initial 2 days of hospitalization and daily during hospital days 3-5. We also calculated adjusted odds of in-hospital death, admission to the intensive care unit, and late intubation (intubation after hospital day 2). Among 164,494 heart failure hospitalizations, 53% received acute respiratory therapies during the first 2 hospital days: 37% received short-acting inhaled bronchodilators, 33% received antibiotics, and 10% received high-dose corticosteroids. Of these 87,319 hospitalizations, over 60% continued receiving respiratory therapies after hospital day 2. Respiratory treatment was more frequent among the 60,690 hospitalizations with chronic lung disease. Treatment with acute respiratory therapy during the first 2 hospital days was associated with higher adjusted odds of all adverse outcomes. Acute respiratory therapy is administered to more than half of patients hospitalized with and treated for decompensated heart failure. Heart failure is therefore regularly treated as a broader cardiopulmonary syndrome rather than as a singular cardiac condition.


Learning to read vertical text in peripheral vision.
English-language text is almost always written horizontally. Text can be formatted to run vertically, but this is seldom used. Several studies have found that horizontal text can be read faster than vertical text in the central visual field. No studies have investigated the peripheral visual field. Studies have also concluded that training can improve reading speed in the peripheral visual field for horizontal text. We aimed to establish whether the horizontal vertical differences are maintained and if training can improve vertical reading in the peripheral visual field. Eight normally sighted young adults participated in the first study. Rapid serial visual presentation (RSVP) reading speed was measured for horizontal and vertical text in the central visual field and at 10 degrees eccentricity in the upper or lower (horizontal text) and right or left (vertical text) visual fields. Twenty-one normally sighted young adults split equally between two training groups and one control group participated in the second study. Training consisted of RSVP reading using either vertical text in the left visual field or horizontal text in the inferior visual field. Subjects trained daily over 4 days. Pre- and post- horizontal and vertical RSVP reading speeds were carried out for all groups. For the training groups, these measurements were repeated 1 week and 1 month posttraining. Before training, RSVP reading speeds were faster for horizontal text in the central and peripheral visual fields when compared with vertical text. Training vertical reading improved vertical reading speeds by an average factor of 2.8. There was partial transfer of training to the opposite (right) hemifield. The training effects were retained for up to a month. Rapid serial visual presentation training can improve RSVP vertical text reading in peripheral vision. These findings may have implications for patients with macular degeneration or hemianopic field loss.


Comparison of high purity factor IX concentrates and a prothrombin complex concentrate in a canine model of thrombogenicity.
A non-stasis canine model of thrombogenicity has been used to evaluate batches of high purity factor IX concentrates from 4 manufacturers and a conventional prothrombin complex concentrate (PCC). Platelets, activated partial thromboplastin time (APTT), fibrinogen, fibrin(ogen) degradation products and fibrinopeptide A (FPA) were monitored before and after infusion of concentrate. Changes in FPA were found to be the most sensitive and reproducible indicator of thrombogenicity after infusion of batches of the PCC at doses of between 60 and 180 IU/kg, with a dose related delayed increase in FPA occurring. Total FPA generated after 100-120 IU/kg of 3 batches of PCC over the 3 h time course was 9-12 times that generated after albumin infusion. In contrast the amounts of FPA generated after 200 IU/kg of the 4 high purity factor IX products were in all cases similar to albumin infusion. It was noted that some batches of high purity concentrates had short NAPTTs indicating that current in vitro tests for potential thrombogenicity may be misleading in predicting the effects of these concentrates in vivo.


Analysis of Emergency Department Length of Stay for Mental Health Patients at Ten Massachusetts Emergency Departments.
Prolonged boarding times in the emergency department (ED) disproportionately affect mental health patients, resulting in patient and provider dissatisfaction and increased patient morbidity and mortality. Our objective is to quantify the burden of mental health boarding and to elucidate the effect of insurance together with demographic, social, and comorbid factors on length of stay. We conducted a cross-sectional observational study of 871 consecutive patients requiring an ED mental health evaluation at one of 10 unaffiliated Massachusetts hospitals. Demographics; insurance; length of stay; medical, psychiatric, and social history; and disposition data were collected. We evaluated the effect of these characteristics on boarding time. ED median length of stay varied greatly by disposition, driven primarily by ED boarding time. Admitted and transferred patients had longer delays than discharged patients (5.63, 9.32, and 1.23 hours, respectively). Medical clearance time (1.40 hours) composed only 10.5% of total ED length of stay and varied little by insurance. In our multivariate analyses, patients with Medicaid and the uninsured had significantly longer total lengths of stay and were more than twice as likely to remain in the ED for 24 hours or greater compared with privately insured patients. Mental health patients in Massachusetts have lengthy ED visits, particularly those requiring inpatient admission. Boarding time accounts for the majority of total ED length of stay and varies by insurance, even when other factors known to affect ED length of stay are controlled. Efforts to improve timeliness of care for mental health emergencies should focus on reducing ED boarding and eliminating disparities in care by insurance status.


Supervised Learning and Mass Spectrometry Predicts the in Vivo Fate of Nanomaterials.
The surface of nanoparticles changes immediately after intravenous injection because blood proteins adsorb on the surface. How this interface changes during circulation and its impact on nanoparticle distribution within the body is not understood. Here, we developed a workflow to show that the evolution of proteins on nanoparticle surfaces predicts the biological fate of nanoparticles in vivo. This workflow involves extracting nanoparticles at multiple time points from circulation, isolating the proteins off the surface and performing proteomic mass spectrometry. The mass spectrometry protein library served as inputs, while blood clearance and organ accumulation were used as outputs to train a supervised deep neural network that predicts nanoparticle biological fate. In a double-blinded study, we tested the network by predicting nanoparticle spleen and liver accumulation with upward of 94% accuracy. Our neural network discovered that the mechanism of liver and spleen uptake is due to patterns of a multitude of nanoparticle surface adsorbed proteins. There are too many combinations to change these proteins manually using chemical or biological inhibitors to alter clearance. Therefore, we developed a technique that uses the host to act as a bioreactor to prepare nanoparticles with predictable clearance patterns that reduce liver and spleen uptake by 50% and 70%, respectively. These techniques provide opportunities to both predict nanoparticle behavior and also to engineer surface chemistries that are specifically designed by the body.


Feasibility of Implementing an Exercise Program in a Geriatric Assessment Unit: the SPRINT Program.
An exercise program involving patients, caregivers, and professionals, entitled SPecific Retraining in INTerdisciplinarity (SPRINT), has been developed to prevent functional decline during hospitalization of older patients. Assess the feasibility of implementing SPRINT in the context of a Geriatric Assessment Unit (GAU). GAU's health-care professionals were instructed with the SPRINT. All new patients were evaluated by a physiotherapist shortly after admission to validate the eligibility criteria and allocation category of exercises. Questionnaires on physical activities were filled out by professionals, patients, and caregivers at baseline and after intervention. Quantitative and qualitative information was collected on adherence to the program. SPRINT was applied to 19 of the 50 patients admitted during the three-month pilot study. A daily average of one exercise session per patient was performed, most frequently with a nurse (37%), physician (20%), care attendant (13%) or by the patient alone (22%). The caregivers participated only 4% of the time. Barriers and facilitators in applying SPRINT have been identified. SPRINT appears relevant and applicable within GAUs. Future studies should be conducted to assess its safety and effectiveness in preventing hospital-related functional decline.


Amisulpride for very late-onset schizophrenia-like psychosis: the ATLAS three-arm RCT.
Very late-onset (aged ≥ 60 years) schizophrenia-like psychosis (VLOSLP) occurs frequently but no placebo-controlled, randomised trials have assessed the efficacy or risks of antipsychotic treatment. Most patients are not prescribed treatment. The study investigated whether or not low-dose amisulpride is superior to placebo in reducing psychosis symptoms over 12 weeks and if any benefit is maintained by continuing treatment thereafter. Treatment safety and cost-effectiveness were also investigated. Three-arm, parallel-group, placebo-controlled, double-blind, randomised controlled trial. Participants who received at least one dose of study treatment were included in the intention-to-treat analyses. Secondary care specialist old age psychiatry services in 25 NHS mental health trusts in England and Scotland. Patients meeting diagnostic criteria for VLOSLP and scoring > 30 points on the Brief Psychiatric Rating Scale (BPRS). Participants were randomly assigned to three arms in a two-stage trial: (1) 100 mg of amisulpride in both stages, (2) amisulpride then placebo and (3) placebo then amisulpride. Treatment duration was 12 weeks in stage 1 and 24 weeks (later reduced to 12) in stage 2. Participants, investigators and outcome assessors were blind to treatment allocation. Primary outcomes were psychosis symptoms assessed by the BPRS and trial treatment discontinuation for non-efficacy. Secondary outcomes were extrapyramidal symptoms measured with the Simpson-Angus Scale, quality of life measured with the World Health Organization's quality-of-life scale, and cost-effectiveness measured with NHS, social care and carer work loss costs and EuroQol-5 Dimensions. A total of 101 participants were randomised. Ninety-two (91%) participants took the trial medication, 59 (64%) completed stage 1 and 33 (56%) completed stage 2 treatment. Despite suboptimal compliance, improvements in BPRS scores at 12 weeks were 7.7 points (95% CI 3.8 to 11.5 points) greater with amisulpride than with placebo (11.9 vs. 4.2 points; p = 0.0002). In stage 2, BPRS scores improved by 1.1 point in those who continued with amisulpride but deteriorated by 5.2 points in those who switched from amisulpride to placebo, a difference of 6.3 points (95% CI 0.9 to 11.7 points; p = 0.024). Fewer participants allocated to the amisulpride group stopped treatment because of non-efficacy in stages 1 (p = 0.01) and 2 (p = 0.031). The number of patients stopping because of extrapyramidal symptoms and other side effects did not differ significantly between groups. Amisulpride treatment in the base-case analyses was associated with non-significant reductions in combined NHS, social care and unpaid carer costs and non-significant reductions in quality-adjusted life-years (QALYs) in both stages. Including patients who were intensive users of inpatient services in sensitivity analyses did not change the QALY result but resulted in placebo dominance in stage 1 and significant reductions in NHS/social care (95% CI -£8923 to -£122) and societal costs (95% CI -£8985 to -£153) for those continuing with amisulpride. The original recruitment target of 300 participants was not achieved and compliance with trial medication was highly variable. Low-dose amisulpride is effective and well tolerated as a treatment for VLOSLP, with benefits maintained by prolonging treatment. Potential adverse events include clinically significant extrapyramidal symptoms and falls. Trials should examine the longer-term effectiveness and safety of antipsychotic treatment in this patient group, and assess interventions to improve their appreciation of potential benefits of antipsychotic treatment and compliance with prescribed medication. Current Controlled Trials ISRCTN45593573 and EudraCT2010-022184-35. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 67. See the NIHR Journals Library website for further project information.


A total crapshoot? Evaluating bioinformatic decisions in animal diet metabarcoding analyses.
Metabarcoding studies provide a powerful approach to estimate the diversity and abundance of organisms in mixed communities in nature. While strategies exist for optimizing sample and sequence library preparation, best practices for bioinformatic processing of amplicon sequence data are lacking in animal diet studies. Here we evaluate how decisions made in core bioinformatic processes, including sequence filtering, database design, and classification, can influence animal metabarcoding results. We show that denoising methods have lower error rates compared to traditional clustering methods, although these differences are largely mitigated by removing low-abundance sequence variants. We also found that available reference datasets from GenBank and BOLD for the animal marker gene cytochrome oxidase I (COI) can be complementary, and we discuss methods to improve existing databases to include versioned releases. Taxonomic classification methods can dramatically affect results. For example, the commonly used Barcode of Life Database (BOLD) Classification API assigned fewer names to samples from order through species levels using both a mock community and bat guano samples compared to all other classifiers (vsearch-SINTAX and q2-feature-classifier's BLAST + LCA, VSEARCH + LCA, and Naive Bayes classifiers). The lack of consensus on bioinformatics best practices limits comparisons among studies and may introduce biases. Our work suggests that biological mock communities offer a useful standard to evaluate the myriad computational decisions impacting animal metabarcoding accuracy. Further, these comparisons highlight the need for continual evaluations as new tools are adopted to ensure that the inferences drawn reflect meaningful biology instead of digital artifacts.


Transcriptome analysis reveals tissue-specific responses of Mytilus unguiculatus to Vibrio alginolyticus infection.
Mytilus unguiculatus is an important economic bivalve species with wide consumption and aquaculture value. Disease is one of the primary limiting factors in mussel aquaculture, thus understanding the response of different tissues of M. unguiculatus to pathogens is crucial for disease prevention and control. In this study, we investigated the physiological and transcriptomic responses of the gills, adductor muscle, and mantle of M. unguiculatus infected with Vibrio alginolyticus. The results showed that V. alginolyticus infection caused inflammation and tissue structure changes in the gill, adductor muscle and mantle of M. unguiculatus. Meanwhile, the activities of superoxide dismutase and catalase in the three tissues increased, while the total antioxidant capacity decreased, suggesting that M. unguiculatus have an activated defense mechanism against infection-induced oxidative stress, despite a compromised total antioxidant capacity. Transcriptomic studies reveal that infected M. unguiculatus exhibits upregulation of endocytosis, lysosome activity, cellular apoptosis, and immune-related signaling pathways, indicating that M. unguiculatus responds to pathogen invasion by upregulating efferocytosis. Compared with the gill and adductor muscle, the mantle had a higher level of mytimycin, mytilin and myticin, and the three tissues also increased the expression of mytimycin to cope with the invasion of pathogens. In addition, the analysis of genes related to taste transduction pathways and muscle contraction and relaxation found that after infection with V. alginolyticus, M. unguiculatus may reduce appetite by inhibiting taste transduction in the gill, while improving muscle contraction of the adductor muscle and keeping the shell closed, to resist further invasion of pathogens and reduce the risk of pathogen transmission in the population.


Identification of a novel 82 kDa proMMP-9 species associated with the surface of leukaemic cells: (auto-)catalytic activation and resistance to inhibition by TIMP-1.
MMP-9 (matrix metalloproteinase 9) plays a critical role in tumour progression. Although the biochemical properties of the secreted form of proMMP-9 are well characterized, little is known about the function and activity of cell surface-associated proMMP-9. We purified a novel 82 kDa species of proMMP-9 from the plasma membrane of THP-1 leukaemic cells, which has substantial differences from the secreted 94 kDa proMMP-9. The 82 kDa form was not detected in the medium even upon stimulation with a phorbol ester. It is truncated by nine amino acid residues at its N-terminus, lacks O-linked oligosaccharides present in the 94 kDa proMMP-9, but retains N-linked carbohydrates. Incubation of 94 kDa proMMP-9 with MMP-3 generated the well-known 82 kDa active form, but the 82 kDa proMMP-9 was converted into an active species of 35 kDa, which was also produced by autocatalytic processing in the absence of activating enzymes. The activated 35 kDa MMP-9 efficiently degraded gelatins, native collagen type IV and fibronectin. The enzyme was less sensitive to TIMP-1 (tissue inhibitor of metalloproteinase 1) inhibition with IC50 values of 82 nM compared with 1 nM for the 82 kDa active MMP-9. The synthetic MMP inhibitor GM6001 blocked the activity of both enzymes, with similar IC50 values below 1 nM. The 82 kDa proMMP-9 is also produced in HL-60 and NB4 leukaemic cell lines as well as ex vivo leukaemic blast cells. It is, however, absent from neutrophils and mononuclear cells isolated from peripheral blood of healthy individuals. Thus, the 82 kDa proMMP-9 expressed on the surface of malignant cells may escape inhibition by natural TIMP-1, thereby facilitating cellular invasion in vivo.


Pharmacokinetic-pharmacodynamic analysis of antipsychotics-induced extrapyramidal symptoms based on receptor occupancy theory incorporating endogenous dopamine release.
We aimed to analyze the risks of extrapyramidal symptoms (EPS) induced by typical and atypical antipsychotic drugs using a common pharmacokinetic-pharmacodynamic (PK-PD) model based on the receptor occupancy. We collected the data for EPS induced by atypical antipsychotics, risperidone, olanzapine and quetiapine, and a typical antipsychotic, haloperidol from literature and analyzed the following five indices of EPS, the ratio of patients obliged to take anticholinergic medication, the occurrence rates of plural extrapyramidal symptoms (more than one of tremor, dystonia, hypokinesia, akathisia, extrapyramidal syndrome, etc.), parkinsonism, akathisia, and extrapyramidal syndrome. We tested two models, i.e., a model incorporating endogenous dopamine release owing to 5-HT2A receptor inhibition and a model not considering the endogenous dopamine release, and used them to examine the relationship between the D2 receptor occupancy of endogenous dopamine and the extent of drug-induced EPS. The model incorporating endogenous dopamine release better described the relationship between the mean D2 receptor occupancy of endogenous dopamine and the extent of EPS than the other model, as assessed by the final sum of squares of residuals (final SS) and Akaike's Information Criteria (AIC). Furthermore, the former model could appropriately predict the risks of EPS induced by two other atypical antipsychotics, clozapine and ziprasidone, which were not incorporated into the model development. The developed model incorporating endogenous dopamine release owing to 5-HT2A receptor inhibition may be useful for the prediction of antipsychotics-induced EPS.


Consumer understanding and use of health claims: the case of functional foods.
As widely acknowledged functional foods (FFs) may contribute to improve human health due to the presence of specific components useful for their protective action against several diseases. However it is essential that consumers are able to comprehend and assess the properties of FFs health claims play a central role in helping consumers to select among food alternatives, beyond providing protection against unsupported or misleading statements about foods properties. At the same time health claims are the main marketing tool that the food industry could use to differentiate FFs from other products. Clearly, massive investments in research and development are necessary to enter the FF market segment, together with the possibility to protect innovation through patents. Current paper aims to examine factors influencing consumer understanding and use of food health claims on FFs, as well as providing several indications for developers, marketers and policy makers. After a brief review of the literature the results of a quantitative survey conducted online on 650 Italian consumers are presented. Results show that consumer use and understanding of health claims on FFs depend on different variables such as socio-demographic characteristics, knowledge and confidence with nutrition information but also wording and variables related specifically to the product. Furthermore, different segments with a diverse degree of use and understanding of health claims have been identified. Therefore, to boost market growth, more efforts are needed by policy makers and marketers to provide better information on nutrition and health aspects of FF using an approach capable to ensure truthful, significant and clear information. Finally some recent patents related to the FFs market with specific regard to components and/or functionality investigated in the current paper are reviewed.


Female Salix viminalis are more severely infected by Melampsora spp. but neither sex experiences associational effects.
Associational effects of plant genotype or species on plant biotic interactions are common, not least for disease spread, but associational effects of plant sex on interactions have largely been ignored. Sex in dioecious plants can affect biotic interactions with herbivores and pollinators; however, its effects on plant-pathogen interactions are understudied and associational effects are unknown. In a replicated field experiment, we assessed Melampsora spp. leaf rust infection in monosexual and mixed sex plots of dioecious Salix viminalis L. to determine whether plant sex has either direct or associational effects on infection severity. We found no differences in Melampsora spp. infection severity among sexual monocultures and mixtures in our field experiment. However, female plants were overall more severely infected. In addition, we surveyed previous studies of infection in S. viminalis clones and reevaluated the studies after we assigned sex to the clones. We found that females were generally more severely infected, as in our field study. Similarly, in a survey of studies on sex-biased infection in dioecious plants, we found more female-biased infections in plant-pathogen pairs. We conclude that there was no evidence for associational plant sex effects of neighboring conspecifics for either females or males on infection severity. Instead, plant sex effects on infection act at an individual plant level. Our findings also suggest that female plants may in general be more severely affected by fungal pathogens than males.


Topology and interactions in a frustrated slab: tuning from Weyl semimetals to C>1 fractional Chern insulators.
We show that, quite generically, a [111] slab of spin-orbit coupled pyrochlore lattice exhibits surface states whose constant energy curves take the shape of Fermi arcs, localized to different surfaces depending on their quasimomentum. Remarkably, these persist independently of the existence of Weyl points in the bulk. Considering interacting electrons in slabs of finite thickness, we find a plethora of known fractional Chern insulating phases, to which we add the discovery of a new higher Chern number state which is likely a generalization of the Moore-Read fermionic fractional quantum Hall state. By contrast, in the three-dimensional limit, we argue for the absence of gapped states of the flat surface band due to a topologically protected coupling of the surface to gapless states in the bulk. We comment on generalizations as well as experimental perspectives in thin slabs of pyrochlore iridates.


Antigen delivery to dendritic cells by poly(propylene sulfide) nanoparticles with disulfide conjugated peptides: Cross-presentation and T cell activation.
Vaccines aiming to activate cytotoxic T cells require cross-presentation of exogenous antigen by antigen-presenting cells (APCs). We recently developed a synthetic nanoparticle vaccine platform that targets lymph node-resident dendritic cells (DCs), capable of mounting an immune response to conjugated antigen. Here, we explore routes of processing and the efficiency of MHC I cross-presentation of OVA peptides conjugated using both reducible and non-reducible linkages, exploring the hypothesis that reduction-sensitive conjugation will lead to better antigen cross-presentation. Both clathrin and macropinocytic pathways were implicated in nanoparticle uptake by colocalization and inhibitor studies. Cross-presentation by DCs was demonstrated by direct antibody staining and in vitro stimulation of CD8(+) T cells from OT-I mice and was indeed most efficient with the reduction-sensitive conjugation. Similarly, we observed IFN-γ production by CD4(+) T cells from OT-II mice. Finally, immunization with the OVA peptide-bearing nanoparticles resulted in in vivo proliferation and IFN-γ production by adoptively transferred CD8(+) OT-I T cells and was also most efficient with reduction-sensitive linking of the peptide antigen. These results demonstrate the relevance of the poly(propylene sulfide) nanoparticle vaccine platform and antigen conjugation scheme for activating both cytotoxic and helper T cell responses.


Major structural differences and novel potential virulence mechanisms from the genomes of multiple campylobacter species.
Sequencing and comparative genome analysis of four strains of Campylobacter including C. lari RM2100, C. upsaliensis RM3195, and C. coli RM2228 has revealed major structural differences that are associated with the insertion of phage- and plasmid-like genomic islands, as well as major variations in the lipooligosaccharide complex. Poly G tracts are longer, are greater in number, and show greater variability in C. upsaliensis than in the other species. Many genes involved in host colonization, including racR/S, cadF, cdt, ciaB, and flagellin genes, are conserved across the species, but variations that appear to be species specific are evident for a lipooligosaccharide locus, a capsular (extracellular) polysaccharide locus, and a novel Campylobacter putative licABCD virulence locus. The strains also vary in their metabolic profiles, as well as their resistance profiles to a range of antibiotics. It is evident that the newly identified hypothetical and conserved hypothetical proteins, as well as uncharacterized two-component regulatory systems and membrane proteins, may hold additional significant information on the major differences in virulence among the species, as well as the specificity of the strains for particular hosts.


Impact of urinary incontinence on medical rehabilitation inpatients.
To determine the prevalence of urinary incontinence (UI) and its association with rehabilitation outcomes in patients receiving inpatient medical rehabilitation in the United States. A retrospective, cohort study of 425,547 Medicare patients discharged from inpatient rehabilitation facilities (IRFs) in 2005. We examined prevalence of UI at admission and discharge for 5 impairment groups. We examined the impact of demographics, health, and functional status on the primary outcome, change in continence status, and secondary outcomes of discharge location and 6-month mortality. Approximately one-quarter (26.6%) of men were incontinent at admission compared to 22.2% of women. In all diagnostic groups, continence status remains largely unchanged from admission to discharge. Patients who are older, have cognitive difficulties, less functional improvement, and longer lengths of stay (LOS), are more likely to remain incontinent, compared to those who improved, after controlling for patient factors and clinical variables. UI was significantly associated with discharge to another post-acute setting (PAC). For orthopedic patients, UI was associated with a 71% increase in the likelihood of discharge to an institutional setting after controlling for patient factors and clinical variables. UI was not associated with death at 6 months post-discharge. UI is highly prevalent in IRF patients and is associated with increased likelihood of discharge to institutional care, particularly for orthopedic patients. Greater attention to identifying and treating UI in IRF patients may reduce medical expenditures and improve other outcomes. Neurourol. Urodynam. 36:176-183, 2017. © 2015 Wiley Periodicals, Inc.


Classification and energetics of the base-phosphate interactions in RNA.
Structured RNA molecules form complex 3D architectures stabilized by multiple interactions involving the nucleotide base, sugar and phosphate moieties. A significant percentage of the bases in structured RNA molecules in the Protein Data Bank (PDB) hydrogen-bond with phosphates of other nucleotides. By extracting and superimposing base-phosphate (BPh) interactions from a reduced-redundancy subset of 3D structures from the PDB, we identified recurrent phosphate-binding sites on the RNA bases. Quantum chemical calculations were carried out on model systems representing each BPh interaction. The calculations show that the centers of each cluster obtained from the structure superpositions correspond to energy minima on the potential energy hypersurface. The calculations also show that the most stable phosphate-binding sites occur on the Watson-Crick edge of guanine and the Hoogsteen edge of cytosine. We modified the 'Find RNA 3D' (FR3D) software suite to automatically find and classify BPh interactions. Comparison of the 3D structures of the 16S and 23S rRNAs of Escherichia coli and Thermus thermophilus revealed that most BPh interactions are phylogenetically conserved and they occur primarily in hairpin, internal or junction loops or as part of tertiary interactions. Bases that form BPh interactions, which are conserved in the rRNA 3D structures are also conserved in homologous rRNA sequence alignments.


Highly sensitive colorimetric detection of allergies based on an immunoassay using peroxidase-mimicking nanozymes.
Nanomaterials that exhibit enzyme-like characteristics, which are called nanozymes, have recently attracted significant attention due to their potential to overcome the intrinsic limitations of natural enzymes, such as low stability and relatively high cost for preparation and purification. In this study, we report a highly efficient colorimetric allergy detection system based on an immunoassay utilizing the peroxidase-mimicking activity of hierarchically structured platinum nanoparticles (H-Pt NPs). The H-Pt NPs had a diameter of 30 nm, and were synthesized by a seed-mediated growth method, which led to a significant amount of peroxidase-like activity. This activity mainly occurs because of the high catalytic power of the Pt element, and the fact that the H-Pt NPs have a large surface area available for catalytic events. The H-Pt NPs were conjugated to an antibody for the detection of immunoglobulin E (IgE) in the analytes; IgE is a representative marker for the diagnosis of allergies. They were then successfully integrated into a conventionally used allergy diagnostic test, the ImmunoCAP diagnostic test, as a replacement for natural signaling enzymes. Using this strategy, total and specific IgE levels were detected within 5 min at room temperature, with high specificity and sensitivity. The practical utility of the immunoassay was also successfully verified by correctly determining the levels of both total and specific IgE in real human serum samples with high precision and reproducibility. The present H-Pt NP-based immunoassay system would serve as a platform for rapid, robust, and convenient analysis of IgE, and can be extended to the construction of diagnostic systems for a variety of clinically important target molecules.


Effects of Virtual Reality and Augmented Reality on Induced Anxiety.
To explore the effects of virtual reality (VR) and augmented reality (AR) in the treatment of claustrophobia, the potential effects of VR and AR on induced anxiety were investigated in this paper. During the experiment, 34 subjects were randomly selected and distributed in AR and VR scenes in a sequence. The skin conductance and heart rates of the subjects were measured throughout the entire process, and the anxiety scale was used to assess the subjective anxiety when the task in each scene was completed. The results showed the following: (1) AR and VR scenes led to feelings of discomfort, but the subjective anxiety scores obtained in the two scenes were not significantly different; (2) the skin conductance level of the subjects significantly increased from the baseline when the subjects entered the experimental scene but remained active in the two scenes without showing significant difference between the scenes; and (3) the heart rate index significantly increased from the baseline after the subjects entered the scene and then gradually decreased. The heart rates of the subjects significantly increased again when the anxiety-induced event was triggered. However, no significant difference was observed between AR and VR scenes. AR and VR have induced obvious anxiety, which was reflected in the subjective and objective physiological indicators. However, no significant difference was found in the effects of AR and VR on the induced anxiety. Considering the cost of building two scenes and other factors, AR was more suitable for the treatment of claustrophobia than VR.


Temporal aspects of increases in eye-neck activation levels during visually deficient near work.
In an experimental study two levels of oculomotor load were induced via optical trial lenses. Trapezius muscle activity was measured with bipolar surface electromyography and normalized to a submaximal contraction. Sixty-six subjects with a median age of 36 (range 19-47, std 8) viewed a black and white Gabor grating (5 c/deg) for two 7-min periods monocularly through a 0 D lens or binocularly through -3.5 D lenses. The effect of time was separately regressed to EMG in two different subgroups of responders: a High-Oculomotor-Load (HOL) and a Low-Oculomotor-Load (LOL) group. A linear regression model was fitted on group level with exposure time on the x-axis and normalized trapezius muscle EMG (%RVE) on the y-axis. The slope coefficient was significantly positive in the -D blur condition for only the HOL subgroup of responders: 0.926 + Time(min 1-7) × 0.088 (p = 0.002, r(2)=0.865). There was no obvious sign of this activity to level off or to stabilize. These results suggest that professional information technology users that are exposed to a high level of oculomotor load, during extended times, are at an increased risk of exhibiting an increased trap.m. activity.


Prospective study of sickle cell trait and venous thromboembolism incidence.
Sickle cell trait may increase risk of venous thromboembolism, but this is not fully established. We sought to determine the association of sickle cell trait with deep vein thrombosis and pulmonary embolism. Middle-aged African Americans participating in a prospective, population-based cohort investigation, the Atherosclerosis Risk in Communities Study, were followed from 1987 through 2011 for incident hospitalized pulmonary embolism (n = 111) or isolated deep vein thrombosis (n = 138), verified by physician review of medical records. Sickle cell trait (heterozygosity for hemoglobin S, n = 268) was compared with no sickle cell trait (n = 3748). Over a median of 22 years of follow-up, 249 participants had an incident venous thromboembolism. The hazard ratio of venous thromboembolism was 1.50 (95% confidence interval [CI] 0.96-2.36) for participants with vs. without sickle cell trait, after adjustment for age, sex, ancestry, hormone replacement therapy (women), body mass index, diabetes, and estimated glomerular filtration rate. This hazard ratio was 2.05 (95% CI 1.12-3.76) for pulmonary embolism and 1.15 (95% CI 0.58-2.27) for deep vein thrombosis without pulmonary embolism. Sickle cell trait in African Americans carries a 2-fold increased risk of pulmonary embolism but does not elevate deep vein thrombosis risk. Because neonatal screening for sickle hemoglobin is being conducted in the United States, consideration should be paid to the increased pulmonary embolism risk of individuals with sickle cell trait.


Prototype of a nanostructured sensing contact lens for noninvasive intraocular pressure monitoring.
To present the application of a new sensor based on a flexible, highly piezoresistive, nanocomposite, all-organic bilayer (BL) adapted to a contact lens (CL) for non-invasive monitoring intraocular pressure (IOP). A prototype of a sensing CL, adapted to a pig eyeball, was tested on different enucleated pig eyes. A rigid, gas-permeable CL was designed as a doughnut shape with a 3-mm hole, where the BL film-based sensor was incorporated. The sensor was a polycarbonate film coated with a polycrystalline layer of the highly piezoresistive molecular conductor β-(ET)₂I₃, which can detect deformations caused by pressure changes of 1 mm Hg. The pig eyeballs were subjected to controlled-pressure variations (low-pressure transducer) to register the electrical resistance response of the CL sensor to pressure changes. Similarly, a CL sensor was designed according to the anatomic characteristics of the eye of a volunteer on the research team. A good correlation (r² = 0.99) was demonstrated between the sensing CL electrical response, and IOP (mm Hg) changes in pig eyes, with a sensitivity of 0.4 Ω/mm Hg. A human eye test also showed the high potential of this new sensor (IOP variations caused by eye massage, blinking, and eye movements were registered). A new nanostructured sensing CL for continuous monitoring of IOP was validated in an in vitro model (porcine eyeball) and in a human eye. This prototype has adequate sensitivity to continuously monitor IOP. This device will be useful for glaucoma diagnosis and treatment.


IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats.
This study demonstrates that IL-23 stimulates the differentiation of human osteoclasts from peripheral blood mononuclear cells (PBMC). Furthermore, in vivo blockade of endogenous IL-23 activity by treatment with anti-IL-23 antibody attenuates collagen-induced arthritis in rats by preventing both inflammation and bone destruction. IL-23 induced human osteoclastogenesis in cultures of PBMC in the absence of osteoblasts or exogenous soluble-receptor activator of NF-kappaB ligand (RANKL). This IL-23-induced osteoclastogenesis was inhibited by osteoprotegerin, anti-IL-17 antibody, and etanercept, suggesting that RANKL, IL-17, and TNF-alpha are involved. In addition, we found the ratio of production levels of IL-17 to those of IFN-gamma from activated human T cells was elevated at 1 to 10 ng/ml IL-23. The inductive effect of IL-17 and the inhibitory effect of IFN-gamma on osteoclastogenesis indicate that the balance of these two cytokines is particularly important. We also demonstrated that IL-23 administered at a later stage significantly reduced paw volume in rats with collagen-induced arthritis, in a dose-dependent manner. Furthermore, anti-IL-23 antibody reduced synovial tissue inflammation and bone destruction in these rats. These findings suggest that IL-23 is important in human osteoclastogenesis and that neutralizing IL-23 after onset of collagen-induced arthritis has therapeutic potential. Thus, controlling IL-23 production and function could be a strategy for preventing inflammation and bone destruction in patients with rheumatoid arthritis.