Protocol for a systematic review of prognosis after mild traumatic brain injury: an update of the WHO Collaborating Centre Task Force findings.
Mild traumatic brain injury (MTBI) is a major public-health concern and represents 70-90% of all treated traumatic brain injuries. The last best-evidence synthesis, conducted by the WHO Collaborating Centre for Neurotrauma, Prevention, Management and Rehabilitation in 2002, found few quality studies on prognosis. The objective of this review is to update these findings. Specifically, we aim to describe the course, identify modifiable prognostic factors, determine long-term sequelae, and identify effects of interventions for MTBI. Finally, we will identify gaps in the literature, and make recommendations for future research. The databases MEDLINE, PsychINFO, Embase, CINAHL and SPORTDiscus were systematically searched (2001 to date). The search terms included 'traumatic brain injury', 'craniocerebral trauma', 'prognosis', and 'recovery of function'. Reference lists of eligible papers were also searched. Studies were screened according to pre-defined inclusion and exclusion criteria. Inclusion criteria included original, published peer-reviewed research reports in English, French, Swedish, Norwegian, Danish and Spanish, and human participants of all ages with an accepted definition of MTBI. Exclusion criteria included publication types other than systematic reviews, meta-analyses, randomized controlled trials, cohort studies, and case-control studies; as well as cadaveric, biomechanical, and laboratory studies. All eligible papers were critically appraised using a modification of the Scottish Intercollegiate Guidelines Network (SIGN) criteria. Two reviewers performed independent, in-depth reviews of each eligible study, and a third reviewer was consulted for disagreements. Data from accepted papers were extracted into evidence tables, and the evidence was synthesized according to the modified SIGN criteria. The results of this study form the basis for a better understanding of recovery after MTBI, and will allow development of prediction tools and recommendation of interventions, as well as informing health policy and setting a future research agenda.


Use of sirolimus in liver transplant recipients with renal insufficiency: a systematic review and meta-analysis.
Sirolimus is used in patients with renal insufficiency after liver transplantation (LT) and especially in those with calcineurin inhibitor (CNI)-associated nephrotoxicity. We conducted a systematic review of all randomized controlled trials and observational studies to test the hypothesis that the use of sirolimus is associated with an improvement in renal function at 1 year in LT recipients with renal insufficiency [glomerular filtration rate (GFR) < 60 mL/minute or creatinine level ≥ 1.5 mg/dL]. We performed a search of all major databases, conference proceedings, and relevant journals through December 2009 and contacted content experts, corresponding authors, and the pharmaceutical manufacturer. A random effects model was used to determine the pooled estimate of the change in renal function and pooled risk estimates of adverse events that may be associated with sirolimus-based therapy at 1 year. Eleven studies (three randomized controlled trials and eight observational studies) met the final inclusion criteria. A nonsignificant improvement of 3.38 mL/minute [95% confidence interval (CI) = -2.93 to 9.69] was observed in methodologically sound observational studies and controlled trials reporting the primary outcome. In controlled trials, baseline GFR >50 mL/min sirolimus use was associated with an improvement of 10.35 mL/minute (95% CI = 3.98-16.77) in GFR or creatinine clearance. Sirolimus was not significantly associated with death [relative risk (RR) = 1.12, 95% CI = 0.66-1.88] or graft failure (RR = 0.80, 95% CI = 0.45-1.41), although reporting was incomplete. It was associated with a statistically significant risk of infection (RR = 2.47, 95% CI = 1.14-5.36), rash (RR = 7.57, 95% CI = 1.75-32.70), ulcers (RR = 7.44, 95% CI = 2.03-27.28), and discontinuation of therapy (RR = 3.61, 95% CI = 1.32-9.89). Conversion to sirolimus from CNIs is associated with a nonsignificant improvement in renal function in LT recipients with renal insufficiency, although the results are limited by heterogeneity, a risk of bias, and a lack of standardized reporting.


Efficient intratracheal delivery of airway epithelial cells in mice and pigs.
Cellular therapy via direct intratracheal delivery has gained interest as a novel therapeutic strategy for treating various pulmonary diseases including cystic fibrosis lung disease. However, concerns such as insufficient cell engraftment in lungs and lack of large animal model data remain to be resolved. This study aimed to establish a simple method for evaluating cell retention in lungs and to develop reproducible approaches for efficient cell delivery into mouse and pig lungs. Human lung epithelial cells including normal human bronchial/tracheal epithelial (NHBE) cells and human lung epithelial cell line A549 were infected with pSicoR-green fluorescent protein (GFP) lentivirus. GFP-labeled NHBE cells were delivered via a modified intratracheal cell instillation method into the lungs of C57BL/6J mice. Two days following cell delivery, GFP ELISA-based assay revealed a substantial cell-retention efficiency (10.48 ± 2.86%, n = 7) in mouse lungs preinjured with 2% polidocanol. When GFP-labeled A549 cells were transplanted into Yorkshire pig lungs with a tracheal intubation fiberscope, a robust initial cell attachment (22.32% efficiency) was observed at 24 h. In addition, a lentiviral vector was developed to induce the overexpression and apical localization of cystic fibrosis transmembrane conductance regulator (CFTR)-GFP fusion proteins in NHBE cells as a means of ex vivo CFTR gene transfer in nonprogenitor (relatively differentiated) lung epithelial cells. These results have demonstrated the convenience and efficiency of direct delivery of exogenous epithelial cells to lungs in mouse and pig models and provided important background for future preclinical evaluation of intratracheal cell transplantation to treat lung diseases.


A case for including spirituality in quality of life measurement in oncology.
Most of the commonly used quality of life (QOL) instruments in oncology do not include spirituality as a core domain. However, previous research suggests that spirituality might be an important aspect of QOL for cancer patients and that it may, in fact, be especially salient in the context of life-threatening illness. This study used a large (n=1610) and ethnically diverse sample to address three questions relevant to including spirituality in QOL measurement: (1) Does spirituality demonstrate a positive association with QOL?; (2) Is this association unique?; and (3) Is there clinical utility in including spirituality in QOL measurement? Spirituality, as measured by the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being (FACIT-Sp), was found to be associated with QOL to the same degree as physical well-being, a domain unquestioned in its importance to QOL. The significant association between spirituality and QOL was unique, remaining after controlling for core QOL domains as well as other possible confounding variables. Furthermore, spiritual well-being was found to be related to the ability to enjoy life even in the midst of symptoms, making this domain a potentially important clinical target. It is concluded that these results support the move to the biopsychosocialspiritual model for QOL measurement in oncology.


"All boys and men can play football": a qualitative investigation of recreational football in prostate cancer patients.
Evidence is accumulating that exercise-based rehabilitation improves physical capacity and quality of life in cancer survivors. However, recruitment and persistence of male cancer patients in rehabilitation and physical activity are low and novel health promotion strategies are warranted. The purpose of this study was to gain an understanding of the meaning of recreational football as a team and interaction-oriented health-promoting activity in men with prostate cancer (n = 26). Qualitative data were collected through six focus group interviews (n = 4-6) and 20 h of participant observations. The two data sets were analyzed using framework analysis. The analysis produced 11 subthemes that were structured into three overarching themes: (a) motivational drivers; (b) united in sport; and (c) confirmation of own capacity. The findings indicated that participants regarded football as a welcome opportunity to regain control and acquire a sense of responsibility for own health without assuming the patient role, and football training legitimized and promoted mutual caring behavior in a male-oriented context. In conclusion, the study suggests that football, due to its cultural representation of masculine ideals, may be a potent and unique strategy for increasing recruitment and adherence to physical activity in prostate cancer patients.


Dimensionality reduction for visualizing single-cell data using UMAP.
Advances in single-cell technologies have enabled high-resolution dissection of tissue composition. Several tools for dimensionality reduction are available to analyze the large number of parameters generated in single-cell studies. Recently, a nonlinear dimensionality-reduction technique, uniform manifold approximation and projection (UMAP), was developed for the analysis of any type of high-dimensional data. Here we apply it to biological data, using three well-characterized mass cytometry and single-cell RNA sequencing datasets. Comparing the performance of UMAP with five other tools, we find that UMAP provides the fastest run times, highest reproducibility and the most meaningful organization of cell clusters. The work highlights the use of UMAP for improved visualization and interpretation of single-cell data.


Melatonin inhibits the sphingosine kinase 1/sphingosine-1-phosphate signaling pathway in rabbits with fulminant hepatitis of viral origin.
The sphingosine kinase (SphK)1/sphingosine-1-phosphate (S1P) pathway is involved in multiple biological processes, including liver diseases. This study investigate whether modulation of the SphK1/S1P system associates to the beneficial effects of melatonin in an animal model of acute liver failure (ALF) induced by the rabbit hemorrhagic disease virus (RHDV). Rabbits were experimentally infected with 2 × 10(4) hemagglutination units of a RHDV isolate and received 20 mg/kg of melatonin at 0, 12, and 24 hr postinfection. Liver mRNA levels, protein concentration, and immunohistochemical labeling for SphK1 increased in RHDV-infected rabbits. S1P production and protein expression of the S1PR1 receptor were significantly elevated following RHDV infection. These effects were significantly reduced by melatonin. Rabbits also exhibited increased expression of toll-like receptor (TLR)4, tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, nuclear factor-kappa B (NF-κB) p50 and p65 subunits, and phosphorylated inhibitor of kappa B (IκB)α. Melatonin administration significantly inhibited those changes and induced a decreased immunoreactivity for RHDV viral VP60 antigen in the liver. Results obtained indicate that the SphK1/S1P system activates in parallel to viral replication and the inflammatory process induced by the virus. Inhibition of the lipid signaling pathway by the indole reveals novel molecular pathways that may account for the protective effect of melatonin in this animal model of ALF, and supports the potential of melatonin as an antiviral agent.


Targeted DNA demethylation and activation of endogenous genes using programmable TALE-TET1 fusion proteins.
Genome-wide studies have defined cell type-specific patterns of DNA methylation that are important for regulating gene expression in both normal development and disease. However, determining the functional significance of specific methylation events remains challenging, owing to the lack of methods for removing such modifications in a targeted manner. Here we describe an approach for efficient targeted demethylation of specific CpGs in human cells using fusions of engineered transcription activator-like effector (TALE) repeat arrays and the TET1 hydroxylase catalytic domain. Using these TALE-TET1 fusions, we demonstrate that modification of critical methylated promoter CpG positions can lead to substantial increases in the expression of endogenous human genes. Our results delineate a strategy for understanding the functional significance of specific CpG methylation marks in the context of endogenous gene loci and validate programmable DNA demethylation reagents with potential utility for research and therapeutic applications.


Pressure pain thresholds increase after preconditioning 1 Hz repetitive transcranial magnetic stimulation with transcranial direct current stimulation.
The primary motor cortex (M1) is an effective target of non-invasive cortical stimulation (NICS) for pain threshold modulation. It has been suggested that the initial level of cortical excitability of M1 plays a key role in the plastic effects of NICS. Here we investigate whether transcranial direct current stimulation (tDCS) primed 1 Hz repetitive transcranial magnetic stimulation (rTMS) modulates experimental pressure pain thresholds and if this is related to observed alterations in cortical excitability. 15 healthy, male participants received 10 min 1 mA anodal, cathodal and sham tDCS to the left M1 before 15 min 1 Hz rTMS in separate sessions over a period of 3 weeks. Motor cortical excitability was recorded at baseline, post-tDCS priming and post-rTMS through recording motor evoked potentials (MEPs) from right FDI muscle. Pressure pain thresholds were determined by quantitative sensory testing (QST) through a computerized algometer, on the palmar thenar of the right hand pre- and post-stimulation. Cathodal tDCS-primed 1 Hz-rTMS was found to reverse the expected suppressive effect of 1 Hz rTMS on cortical excitability; leading to an overall increase in activity (p<0.001) with a parallel increase in pressure pain thresholds (p<0.01). In contrast, anodal tDCS-primed 1 Hz-rTMS resulted in a corresponding decrease in cortical excitability (p<0.05), with no significant effect on pressure pain. This study demonstrates that priming the M1 before stimulation of 1 Hz-rTMS modulates experimental pressure pain thresholds in a safe and controlled manner, producing a form of analgesia.


Risk factors for lethal arrhythmic events in children and adolescents with hypertrophic cardiomyopathy and an implantable defibrillator: An international multicenter study.
Predictors of risk of lethal arrhythmic events (LAE) is poorly understood and may differ from adults in children with hypertrophic cardiomyopathy (HCM). The purpose of this study was to determine predictors of LAE in children with HCM. A retrospective data collection was performed on 446 children and teenagers 20 years and younger (290 [65%] male; mean age 10.1 ± 5.7 years) with idiopathic HCM from 35 centers. Patients were classified as group 1 (HCM with LAE) if having a secondary prevention implantable cardioverter-defibrillator (ICD) or primary prevention ICD with appropriate interventions or group 2 (HCM without LAE) if having a primary prevention ICD without appropriate interventions. There were 152 children (34%) in group 1 and 294 (66%) in group 2. Risk factors for group 1 by univariate analysis were septal thickness, posterior left ventricular (LV) wall thickness, lower LV outflow gradient, and Q wave > 3 mm in inferior electrocardiographic leads. Factors not associated with LAE were family history of SCD, abnormal blood pressure response to exercise, and ventricular tachycardia on ambulatory electrocardiographic monitoring. Risk factors for SCD by multivariate analysis were age at ICD placement (hazard ratio [HR] 0.9; P = .0025), LV posterior wall thickness z score (HR 1.02; P < .005), and LV outflow gradient < 30 mm Hg (HR 2.0; P < .006). LV posterior wall thickness z score ≥ 5 was associated with LAE. Risk factors for LAE appear different in children compared to adults. Conventional adult risk factors were not significant in children. Further prospective studies are needed to improve risk stratification for LAE in children with HCM.


Endotracheal tube as a factor in measurement of respiratory mechanics.
The measurement of respiratory mechanics is frequently performed on intubated patients. This study shows the effect which the turbulent and inertial characteristics of an endotracheal tube have on the accuracy of the measurement. Two techniques are examined utilizing a mechanical model: the least-squares and the phasor technique. It is concluded that both techniques will give erroneous results if the characteristics of the tube are not accounted for. The error is markedly reduced if the turbulent and inertial terms are accounted for in the analysis.


Modeling convergent scale-by-scale skin color patterning in multiple species of lizards.
Skin color patterning in vertebrates emerges at the macroscale from microscopic cell-cell interactions among chromatophores. Taking advantage of the convergent scale-by-scale skin color patterning dynamics in five divergent species of lizards, we quantify the respective efficiencies of stochastic (Lenz-Ising and cellular automata, sCA) and deterministic reaction-diffusion (RD) models to predict individual patterns and their statistical attributes. First, we show that all models capture the underlying microscopic system well enough to predict, with similar efficiencies, neighborhood statistics of adult patterns. Second, we show that RD robustly generates, in all species, a substantial gain in scale-by-scale predictability of individual adult patterns without the need to parametrize the system down to its many cellular and molecular variables. Third, using 3D numerical simulations and Lyapunov spectrum analyses, we quantitatively demonstrate that, given the non-linearity of the dynamical system, uncertainties in color measurements at the juvenile stage and in skin geometry variation explain most, if not all, of the residual unpredictability of adult individual scale-by-scale patterns. We suggest that the efficiency of RD is due to its intrinsic ability to exploit mesoscopic information such as continuous scale colors and the relations among growth, scales geometries, and the pattern length scale. Our results indicate that convergent evolution of CA patterning dynamics, leading to dissimilar macroscopic patterns in different species, is facilitated by their spontaneous emergence under a large range of RD parameters, as long as a Turing instability occurs in a skin domain with periodic thickness. VIDEO ABSTRACT.


Identification of a myocyte nuclear factor that binds to the muscle-specific enhancer of the mouse muscle creatine kinase gene.
The muscle creatine kinase (MCK) gene is transcriptionally induced when skeletal muscle myoblasts differentiate into myocytes. The gene contains two muscle-specific enhancer elements, one located 1,100 nucleotides (nt)5' of the transcriptional start site and one located in the first intron. We have used gel mobility shift assays to characterize the trans-acting factors that interact with a region of the MCK gene containing the 5' enhancer. MM14 and C2C12 myocyte nuclear extracts contain a sequence-specific DNA-binding factor which recognizes a site within a 110-nt fragment of the MCK enhancer region shown to be sufficient for enhancer function. Preparative mobility shift gels were combined with DNase I footprinting to determine the site of binding within the 110-nt fragment. Site-directed mutagenesis within the footprinted region produced a 110-nt fragment which did not bind the myocyte factor in vitro. The mutant fragment had about 25-fold-less activity as a transcriptional enhancer in myocytes than did the wild-type fragment. Complementary oligomers containing 21 base pairs spanning the region protected from DNase degradation were also specifically bound by MM14 and C2C12 myocyte nuclear factors. The oligomer-binding activity was not found in nuclear extracts from the corresponding myoblasts, in nuclear extracts from a variety of nonmuscle cell types (including differentiation-defective MM14-DD1 cells and 10T1/2 mesodermal stem cells), or in cytoplasmic extracts. Both the 5' and intron 1 enhancer-containing fragments competed for factors that bind the oligomer probe, while total mouse genomic DNA and several DNA fragments containing viral and cellular enhancers did not. Interestingly, a 5' MCK proximal promoter fragment that also contains muscle-specific positive regulatory elements did not compete for factor binding to the oligomer. We have designated the factor which interacts with the two MCK enhancers myocyte-specific enhancer-binding nuclear factor 1 (MEF 1). A consensus for binding sites in muscle-specific regulatory regions is proposed.


High Burden of Burnout on Rheumatology Practitioners.
Burnout among physicians is common and has important implications. We assessed the extent of burnout among rheumatology practitioners and its associations. One hundred twenty-eight attendees at the 2019 Rheumatology Winter Clinical Symposium were surveyed using the Maslach Burnout Index (MBI) and a demographics questionnaire. Scores for emotional exhaustion (EE) ≥ 27, depersonalization (DP) ≥ 10, and personal accomplishment (PA) ≤ 33 were considered positive for burnout. Data regarding practitioner characteristics including age, sex, years in practice, and other demographics of interest were also collected. These data were used to determine prevalence and interactions of interest between practitioner characteristics and the risk of burnout. Of the 128 respondents, 50.8% demonstrated burnout in at least 1 MBI domain. Dissatisfaction with electronic health records was associated with a 2.86-times increased likelihood of burnout (OR 2.86, 95% CI 1.23-6.65, P = 0.015). Similar results were found for lack of exercise (OR 5.00, 95% CI 1.3-18.5, P = 0.016) and work hours > 60 per week (OR 2.6, 95% CI 1.16-5.6, P = 0.019). Practitioners in group practice were 57% less likely to burn out (OR 0.43, 95% CI 0.20-0.92, P = 0.029), as were those who spend > 20% of their time in personally satisfying work (OR 0.32, 95% CI 0.15-0.71, P = 0.005). In what we believe to be one of the largest studies regarding burnout among rheumatology practitioners, we found a substantial prevalence of burnout, with 51% of all respondents meeting criteria in at least 1 domain defined by the MBI and 54% of physicians meeting these same criteria.


Process evaluation of a bio-behavioural HIV research combined with prevention among GBMSM in 13 European countries.
Comparative European data using Second Generation Surveillance System (SGSS) are scarce among gay, bisexual and other men who have sex with men. This study evaluated the implementation of Sialon II, a bio-behavioural HIV research combined with targeted HIV prevention in 13 European cities conducted in collaboration with community partners. A mixed-methods process evaluation assessed the project's coverage, outputs, quality, challenges and opportunities for improvement. Data collected through structured questionnaire from 71 data collectors from community-based organisations and semi-structured interviews with 17 managers of participating gay venues were analysed. Overall implementation was successful, achieving 4901 valid behavioural questionnaires and obtaining 4716 biological samples. Challenges in conducting bio-behavioural research in gay venues related to strict research protocols and unfavourable characteristics of venues. Formative research, collaboration with community gay venues, and offering HIV prevention emerged as facilitators. Community researchers' training was crucial for fidelity to research protocols, increased trust amongst communities and enabled data collectors to effectively address practical problems in the field. Scientifically sound SGSS with community participation is feasible and allows for including 'hard-to-reach' populations. Prevention benefits include awareness raising, capacity building and sexual health promotion in gay venues. The findings are beneficial for epidemiological research among other HIV key populations.


Multi-omics Signature of Candida auris, an Emerging and Multidrug-Resistant Pathogen.
Candida auris is a recently described pathogenic fungus that is causing invasive outbreaks on all continents. The fungus is of high concern given the numbers of multidrug-resistant strains that have been isolated in distinct sites across the globe. The fact that its diagnosis is still problematic suggests that the spreading of the pathogen remains underestimated. Notably, the molecular mechanisms of virulence and antifungal resistance employed by this new species are largely unknown. In the present work, we compared two clinical isolates of C. auris with distinct drug susceptibility profiles and a Candida albicans reference strain using a multi-omics approach. Our results show that, despite the distinct drug resistance profile, both C. auris isolates appear to be very similar, albeit with a few notable differences. However, compared to C. albicans both C. auris isolates have major differences regarding their carbon utilization and downstream lipid and protein content, suggesting a multifactorial mechanism of drug resistance. The molecular profile displayed by C. auris helps to explain the antifungal resistance and virulence phenotypes of this new emerging pathogen.IMPORTANCE Candida auris was first described in Japan in 2009 and has now been the cause of significant outbreaks across the globe. The high number of isolates that are resistant to one or more antifungals, as well as the high mortality rates from patients with bloodstream infections, has attracted the attention of the medical mycology, infectious disease, and public health communities to this pathogenic fungus. In the current work, we performed a broad multi-omics approach on two clinical isolates isolated in New York, the most affected area in the United States and found that the omic profile of C. auris differs significantly from C. albicans In addition to our insights into C. auris carbon utilization and lipid and protein content, we believe that the availability of these data will enhance our ability to combat this rapidly emerging pathogenic yeast.


Genital HIV-1 RNA predicts risk of heterosexual HIV-1 transmission.
High plasma HIV-1 RNA concentrations are associated with an increased risk of HIV-1 transmission. Although plasma and genital HIV-1 RNA concentrations are correlated, no study has evaluated the relationship between genital HIV-1 RNA and the risk of heterosexual HIV-1 transmission. In a prospective study of 2521 African HIV-1 serodiscordant couples, we assessed genital HIV-1 RNA quantity and HIV-1 transmission risk. HIV-1 transmission linkage was established within the partnership by viral sequence analysis. We tested endocervical samples from 1805 women, including 46 who transmitted HIV-1 to their partner, and semen samples from 716 men, including 32 who transmitted HIV-1 to their partner. There was a correlation between genital and plasma HIV-1 RNA concentrations: For endocervical swabs, Spearman's rank correlation coefficient ρ was 0.56, and for semen, ρ was 0.55. Each 1.0 log(10) increase in genital HIV-1 RNA was associated with a 2.20-fold (for endocervical swabs: 95% confidence interval, 1.60 to 3.04) and a 1.79-fold (for semen: 95% confidence interval, 1.30 to 2.47) increased risk of HIV-1 transmission. Genital HIV-1 RNA independently predicted HIV-1 transmission risk after adjusting for plasma HIV-1 quantity (hazard ratio, 1.67 for endocervical swabs and 1.68 for semen). Seven female-to-male and four male-to-female HIV-1 transmissions (incidence <1% per year) occurred from persons with undetectable genital HIV-1 RNA, but in all 11 cases, plasma HIV-1 RNA was detected. Thus, higher genital HIV-1 RNA concentrations are associated with greater risk of heterosexual HIV-1 transmission, and this effect was independent of plasma HIV-1 concentrations. These data suggest that HIV-1 RNA in genital secretions could be used as a marker of HIV-1 sexual transmission risk.


Dietary omega-3 fatty acid deficiency and high fructose intake in the development of metabolic syndrome, brain metabolic abnormalities, and non-alcoholic fatty liver disease.
Western diets are characterized by both dietary omega-3 fatty acid deficiency and increased fructose intake. The latter found in high amounts in added sugars such as sucrose and high fructose corn syrup (HFCS). Both a low intake of omega-3 fatty acids or a high fructose intake contribute to metabolic syndrome, liver steatosis or non-alcoholic fatty liver disease (NAFLD), promote brain insulin resistance, and increase the vulnerability to cognitive dysfunction. Insulin resistance is the core perturbation of metabolic syndrome. Multiple cognitive domains are affected by metabolic syndrome in adults and in obese adolescents, with volume losses in the hippocampus and frontal lobe, affecting executive function. Fish oil supplementation maintains proper insulin signaling in the brain, ameliorates NAFLD and decreases the risk to metabolic syndrome suggesting that adequate levels of omega-3 fatty acids in the diet can cope with the metabolic challenges imposed by high fructose intake in Western diets which is of major public health importance. This review presents the current status of the mechanisms involved in the development of the metabolic syndrome, brain insulin resistance, and NAFLD a most promising area of research in Nutrition for the prevention of these conditions, chronic diseases, and improvement of Public Health.


Use of low molecular mass heparin (enoxaparin) in newborn infants: a prospective cohort study of 62 patients.
To detail low molecular mass heparin (enoxaparin) use in the first few months of life. Prospective, consecutive cohort of unselected newborn infants. Newborn infants were divided into groups by gestational age, underlying condition, hepatic and renal function, thrombocytopenia, and prothrombin time (PT/INR). Groups were analysed with respect to many aspects of enoxaparin treatment using multivariate methods. Sixty two newborn infants received enoxaparin representing 5.39 treatment years. Thromboembolic events (TEs) occurred predominantly in the lower and upper venous system in the presence of indwelling catheters (69%). Preterm infants required longer than full term infants to achieve an anti-(factor Xa) level in the target range (six versus two days). Preterm infants required higher doses of enoxaparin than full term infants to maintain anti-(factor Xa) levels in the target range (2.1 v 1.7 mg/kg/12 h). Infants with congenital heart disease (CHD) required less enoxaparin than those without CHD to maintain an anti-(factor Xa) level in the target range (1.7 v 2.1 mg/kg/12 h). Impaired renal and liver function influenced the number of dose changes needed (three versus one a month). Complete or partial resolution of TE was accomplished in 59% of newborn infants. Four infants developed major bleeds (1.2% per patient year). Recurrent TE and clot extension occurred in three infants (0.9% per patient year). Preterm infants are more difficult to treat with enoxaparin than full term infants. Enoxaparin appears to be an alternative to treatment with standard heparin or no treatment.


Pegfilgrastim reduces the length of hospitalization and the time to engraftment in multiple myeloma patients treated with melphalan 200 and auto-SCT compared with filgrastim.
To reduce the duration of neutropenia after conditioning chemotherapy and autologous peripheral blood stem cell transplantation (APBSCT), granulocyte-colony stimulating factors (G-CSF) are commonly administered. We retrospectively evaluated the impact of pegfilgrastim compared to filgrastim on neutrophil engraftment, hospital stay, and supportive measures in patients with multiple myeloma after conditioning with Melphalan 200 (Mel200) followed by APBSCT. Ninety-two APBSCT after Mel200 treatment were performed in 72 patients between January 2006 and December 2009 at our institution. Patients received either single-dose pegfilgrastim (n = 46; 50%), or daily filgrastim (n = 46; 50%) after APBSCT (median duration of filgrastim use, 9 days; range, 3-14 days). Duration of neutropenia grade IV was shorter with pegfilgrastim compared with filgrastim (median, 5 days (range, 3-14 days) versus 6 days (range, 3-9 days), p = 0.0079). The length of hospitalization differed significantly (pegfilgrastim (median, 14.5 days; range, 11-47 days) versus filgrastim (median, 15.5 days; range, 12-64 days), p = 0.024). Pegfilgrastim-treated patients had less red blood cell transfusions (median, 0 transfusions (range, 0-10) versus 0.5 transfusions (range, 0-9), p = 0.00065). Pegfilgrastim was associated with reduced cost of the treatment procedure compared with filgrastim (p = 0.031). Pegfilgrastim appears to be at least equivalent to filgrastim without additional expenditure in myeloma patients treated with Mel200 and APBSCT.


Effects of the Mendelsohn maneuver on extent of hyoid movement and UES opening post-stroke.
The Mendelsohn maneuver, voluntary prolongation of laryngeal elevation during the swallow, has been widely used as a compensatory strategy to improve upper esophageal sphincter (UES) opening and bolus flow. Recent research suggests that when used as a rehabilitative exercise, it significantly improves duration of hyoid movement and positively impacts duration of UES opening (DOUESO). The data presented here were derived from that same prospective crossover study of 18 participants with dysphagia post-stroke evaluated with videofluoroscopy after treatment using the Mendelsohn maneuver versus no treatment. Results demonstrate gains in the extent of hyoid movement and UES opening and improvements in coordination of structural movements with each other as well as with bolus flow.


Postprandial Peaking and Plateauing of Triglycerides and VLDL in Patients with Underlying Cardiovascular Diseases Despite Treatment.
Dyslipidemia is associated with cardiovascular morbidities and mortality. Currently, fasting lipid profile determination is used to monitor treatment response. Recently, postprandial lipemia is of increasing interest because of its atherogenic and thrombogenic potential and also was found to be more predictive for cardiovascular diseases. To demonstrate postprandial lipemia among patients with cardiovascular diseases despite low fat diet, normal fasting lipid profile and even statin regimen. Patients aged 40-80 years old with cardiovascular diseases (i.e. coronary artery disease and cerebrovascular disease) more than 6 months, on statin treatment for more than 6 months and normal fasting lipid profile (according to NCEP ATP III guidelines) were included. Study exclusion criteria were pregnancy, acute cardiovascular events < 6 months, hepatic or renal failure. Finally, twelve patients were included. The triglyceride level showed a significant rise from fasting to 2 hours after breakfast with a mean difference of 23.86 mg/dL (P =0.012). The level peaked at 4 hours after breakfast with a mean difference (MD) of 72.02 mg/dL (P =0.002). Subsequent triglyceride levels plateaued and were significantly higher than the baseline (P <0.05) until the 12th hour of observation. VLDL levels showed a similar pattern. Levels increased significantly from fasting to 2h after breakfast (mean difference: 4.49 mg/dL, P = 0.007), then plateaued and further increased 4 hours after breakfast (MD: 14.01 mg/dL, P = 0.002). VLDL levels were significantly higher than fasting (P < 0.05) and did not return to baseline until the 12th hour of observation. In contrast, the levels of total cholesterol, HDL and LDL decreased postprandially. Triglyceride and VLDL peaking and plateauing were observed in patients with cardiovascular diseases despite low fat diet, normal fasting lipid profile and statin regimen. These findings may raise more attentions in monitoring and management of dyslipidemia in patients with cardiovascular and cerebrovascular events.


Risk Factors for Proximal Junctional Fracture Following Fusion Surgery for Osteoporotic Vertebral Collapse with Delayed Neurological Deficits: A Retrospective Cohort Study of 403 Patients.
Approximately 3% of osteoporotic vertebral fractures develop osteoporotic vertebral collapse (OVC) with neurological deficits, and such patients are recommended to be treated surgically. However, a proximal junctional fracture (PJFr) following surgery for OVC can be a serious concern. Therefore, the aim of this study is to identify the incidence and risk factors of PJFr following fusion surgery for OVC. This study retrospectively analyzed registry data collected from facilities belonging to the Japan Association of Spine Surgeons with Ambition (JASA) in 2016. We retrospectively analyzed 403 patients who suffered neurological deficits due to OVC below T10 and underwent corrective surgery; only those followed up for ≥2 years were included. Potential risk factors related to the PJFr and their cut-off values were calculated using multivariate logistic regression analysis and receiver operating characteristic (ROC) analysis. Sixty-three patients (15.6%) suffered PJFr during the follow-up (mean 45.7 months). In multivariate analysis, the grade of osteoporosis (grade 2, 3: adjusted odds ratio (aOR) 2.92; p=0.001) and lower instrumented vertebra (LIV) level (sacrum: aOR 6.75; p=0.003) were independent factors. ROC analysis demonstrated that lumbar bone mineral density (BMD) was a predictive factor (area under curve: 0.72, p=0.035) with optimal cut-off value of 0.61 g/cm2 (sensitivity, 76.5%; specificity, 58.3%), but that of the hip was not (p=0.228). PJFr was found in 16% cases within 4 years after surgery; independent risk factors were severe osteoporosis and extended fusion to the sacrum. The lumbar BMD with cut-off value 0.61 g/cm2 may potentially predict PJFr. Our findings can help surgeons select perioperative adjuvant therapy, as well as a surgical strategy to prevent PJFr following surgery.


How females of Achtheinus spp. (Pandaridae: Siphonostomatoida) attach to their elasmobranch hosts with notes on their effects on the hosts' fins.
Copepods of the genus Achtheinus Wilson, 1908 (Pandaridae) are parasites of elasmobranchs that attach to their fins, gill slits and around the nostrils. Specimens of Achtheinus pinguis Wilson, 1912 were collected and examined using histology and scanning electron microscopy to determine their way of attachment to the host and the possible effect on the host. They insert their antennae deep into the dermis of the shark's skin, which causes the most damage due to possible tissue compression and/or fibrosis as well as rupture of the connective tissue. Additionally, the presence of the copepod on the skin causes cell erosion of the epidermal cells and thus reduces the number of epidermal layers. The maxillipeds are used to attach to the placoid scales that cover the shark's skin and probably serve to keep the copepod and inserted antennae in position. This is accomplished by the insertion of the placoid scales into the flaccid corpus of the maxillipeds. Observed damage seems to be negligible to the shark apart from the possibility of secondary infection.


Novel mouse monoclonal antibodies specifically recognizing β-(1→3)-D-glucan antigen.
β-(1→3)-D-Glucan is an essential component of the fungal cell wall. Mouse monoclonal antibodies (mAbs) against synthetic nona-β-(1→3)-D-glucoside conjugated with bovine serum albumin (BSA) were generated using hybridoma technology. The affinity constants of two selected mAbs, 3G11 and 5H5, measured by a surface plasmon resonance biosensor assay using biotinylated nona-β-(1→3)-D-glucan as the ligand, were approximately 11 nM and 1.9 nM, respectively. The glycoarray, which included a series of synthetic oligosaccharide derivatives representing β-glucans with different lengths of oligo-β-(1→3)-D-glucoside chains, demonstrated that linear tri-, penta- and nonaglucoside, as well as a β-(1→6)-branched octasaccharide, were recognized by mAb 5H5. By contrast, only linear oligo-β-(1→3)-D-glucoside chains that were not shorter than pentaglucosides (but not the branched octaglucoside) were ligands for mAb 3G11. Immunolabelling indicated that 3G11 and 5H5 interact with both yeasts and filamentous fungi, including species from Aspergillus, Candida, Penicillium genera and Saccharomyces cerevisiae, but not bacteria. Both mAbs could inhibit the germination of Aspergillus fumigatus conidia during the initial hours and demonstrated synergy with the antifungal fluconazole in killing C. albicans in vitro. In addition, mAbs 3G11 and 5H5 demonstrated protective activity in in vivo experiments, suggesting that these β-glucan-specific mAbs could be useful in combinatorial antifungal therapy.


Nosocomial outbreak of carbapenem-resistant Acinetobacter baumannii in intensive care units and successful outbreak control program.
Acinetobacter baumannii has been increasingly reported as a significant causative organism of various nosocomial infections. Here we describe an outbreak of carbapenem-resistant A. baumannii (CRAB) in the ICUs of a Korean university hospital, along with a successful outbreak control program. From October 2007 through July 2008, CRAB was isolated from 57 ICU patients. Nineteen patients were diagnosed as being truly infected with CRAB, four of whom were presumed to have died due to CRAB infection, producing a case-fatality rate of 21.1%. In surveillance of the environment and the healthcare workers (HCWs), CRAB was isolated from 24 (17.9%) of 135 environmental samples and seven (10.9%) of 65 HCWs. The pulsed field gel electrophoresis patterns showed that the isolates from patients, HCWs, and the environment were genetically related. Control of the outbreak was achieved by enforcing contact precautions, reducing environmental contamination through massive cleaning, and use of a closed-suctioning system. By August 2008 there were no new cases of CRAB in the ICUs. This study shows that the extensive spread of CRAB can happen through HCWs and the environmental contamination, and that proper strategies including strict contact precautions, massive environmental decontamination, and a closed-suctioning system can be effective for controlling CRAB outbreaks.


Genetic components of variations of red cell glycolytic intermediates at two altitudes among the South American Aymara.
Red cell haemoglobin (Hb), haematocrit (Ht), 2,3-diphosphoglycerate (DPG), and adenosine triphosphate (ATP) levels were measured in 876 individuals from six villages at two altitude levels (altiplano and coast) of the Departmento de Arica of Northern Chile. Of these, data on 761 individuals are subjected to analysis to search for the evidence of genetic adaptation to a hypoxic environment at a high altitude. Total phenotypic variance for each of the variables is higher at the altiplano as compared to their counterparts at the coastal level. Data on 1127 pairs of relatives of six degrees of relationships are used to determine the genetic component of variation in each of these four traits. To a certain extent the larger familial correlations as well as higher variances at altiplano are explained by the apparent assortative mating (which may again be due to their restricted population size) at the higher elevation. Yet, at least in three variables (Hb, Ht, and DPG) no reduction in the additive genetic component of variation is noticed at the higher altitude. ATP seems to have the highest degree of genetic component of variance, particularly at the coastal level. Some implications of these results are discussed in the light of their roles in the glycolytic pathway.


KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS.
The mechanism by which the wild-type KRAS allele imparts a growth inhibitory effect to oncogenic KRAS in various cancers, including lung adenocarcinoma (LUAD), is poorly understood. Here, using a genetically inducible model of KRAS loss of heterozygosity (LOH), we show that KRAS dimerization mediates wild-type KRAS-dependent fitness of human and murine KRAS mutant LUAD tumor cells and underlies resistance to MEK inhibition. These effects are abrogated when wild-type KRAS is replaced by KRASD154Q, a mutant that disrupts dimerization at the α4-α5 KRAS dimer interface without changing other fundamental biochemical properties of KRAS, both in vitro and in vivo. Moreover, dimerization has a critical role in the oncogenic activity of mutant KRAS. Our studies provide mechanistic and biological insights into the role of KRAS dimerization and highlight a role for disruption of dimerization as a therapeutic strategy for KRAS mutant cancers.


Sterol carrier protein-2 directly interacts with caveolin-1 in vitro and in vivo.
HDL-mediated reverse-cholesterol transport as well as phosphoinositide signaling are mediated through plasma membrane microdomains termed caveolae/lipid rafts. However, relatively little is known regarding mechanism(s) whereby these lipids traffic to or are targeted to caveolae/lipid rafts. Since sterol carrier protein-2 (SCP-2) binds both cholesterol and phosphatidylinositol, the possibility that SCP-2 might interact with caveolin-1 and caveolae was examined. Double immunolabeling and laser scanning fluorescence microscopy showed that a small but significant portion of SCP-2 colocalized with caveolin-1 primarily at the plasma membrane of L-cells and more so within intracellular punctuate structures in hepatoma cells. In SCP-2 overexpressing L-cells, SCP-2 was detected in close proximity to caveolin, 48 +/- 4 A, as determined by fluorescence resonance energy transfer (FRET) and immunogold electron microscopy. Cell fractionation of SCP-2 overexpressing L-cells and Western blotting detected SCP-2 in purified plasma membranes, especially in caveolae/ lipid rafts as compared to the nonraft fraction. SCP-2 and caveolin-1 were coimmunoprecipitated from cell lysates by anti-caveolin-1 and anti-SCP-2. Finally, a yeast two-hybrid assay demonstrated that SCP-2 directly interacts with caveolin-1 in vivo. These interactions of SCP-2 with caveolin-1 were specific since a functionally related protein, phosphatidyinositol transfer protein (PITP), colocalized much less well with caveolin-1, was not in close proximity to caveolin-1 (i.e., >120 A), and was not coimmunoprecipitated by anti-caveolin-1 from cell lysates. In summary, it was shown for the first time that SCP-2 (but not PITP) selectively interacted with caveolin-1, both within the cytoplasm and at the plasma membrane. These data contribute significantly to our understanding of the role of SCP-2 in cholesterol and phosphatidylinositol targeted from intracellular sites of synthesis in the endoplasmic reticulum to caveolae/lipid rafts at the cell surface plasma membrane.


Unlike dietary restriction, rapamycin fails to extend lifespan and reduce transcription stress in progeroid DNA repair-deficient mice.
Dietary restriction (DR) and rapamycin extend healthspan and life span across multiple species. We have recently shown that DR in progeroid DNA repair-deficient mice dramatically extended healthspan and trippled life span. Here, we show that rapamycin, while significantly lowering mTOR signaling, failed to improve life span nor healthspan of DNA repair-deficient Ercc1∆/- mice, contrary to DR tested in parallel. Rapamycin interventions focusing on dosage, gender, and timing all were unable to alter life span. Even genetically modifying mTOR signaling failed to increase life span of DNA repair-deficient mice. The absence of effects by rapamycin on P53 in brain and transcription stress in liver is in sharp contrast with results obtained by DR, and appoints reducing DNA damage and transcription stress as an important mode of action of DR, lacking by rapamycin. Together, this indicates that mTOR inhibition does not mediate the beneficial effects of DR in progeroid mice, revealing that DR and rapamycin strongly differ in their modes of action.


Dysfunctional astrocytic and synaptic regulation of hypothalamic glutamatergic transmission in a mouse model of early-life adversity: relevance to neurosteroids and programming of the stress response.
Adverse early-life experiences, such as poor maternal care, program an abnormal stress response that may involve an altered balance between excitatory and inhibitory signals. Here, we explored how early-life stress (ELS) affects excitatory and inhibitory transmission in corticotrophin-releasing factor (CRF)-expressing dorsal-medial (mpd) neurons of the neonatal mouse hypothalamus. We report that ELS associates with enhanced excitatory glutamatergic transmission that is manifested as an increased frequency of synaptic events and increased extrasynaptic conductance, with the latter associated with dysfunctional astrocytic regulation of glutamate levels. The neurosteroid 5α-pregnan-3α-ol-20-one (5α3α-THPROG) is an endogenous, positive modulator of GABAA receptors (GABAARs) that is abundant during brain development and rises rapidly during acute stress, thereby enhancing inhibition to curtail stress-induced activation of the hypothalamic-pituitary-adrenocortical axis. In control mpd neurons, 5α3α-THPROG potently suppressed neuronal discharge, but this action was greatly compromised by prior ELS exposure. This neurosteroid insensitivity did not primarily result from perturbations of GABAergic inhibition, but rather arose functionally from the increased excitatory drive onto mpd neurons. Previous reports indicated that mice (dams) lacking the GABAAR δ subunit (δ(0/0)) exhibit altered maternal behavior. Intriguingly, δ(0/0) offspring showed some hallmarks of abnormal maternal care that were further exacerbated by ELS. Moreover, in common with ELS, mpd neurons of δ(0/0) pups exhibited increased synaptic and extrasynaptic glutamatergic transmission and consequently a blunted neurosteroid suppression of neuronal firing. This study reveals that increased synaptic and tonic glutamatergic transmission may be a common maladaptation to ELS, leading to enhanced excitation of CRF-releasing neurons, and identifies neurosteroids as putative early regulators of the stress neurocircuitry.


Model-based cardiac diagnosis of pulmonary embolism.
A minimal cardiac model has been shown to accurately capture a wide range of cardiovascular system dynamics commonly seen in the intensive care unit (ICU). However, standard parameter identification methods for this model are highly non-linear and non-convex, hindering real-time clinical application. An integral-based identification method that transforms the problem into a linear, convex problem, has been previously developed, but was only applied on continuous simulated data with random noise. This paper extends the method to handle discrete sets of clinical data, unmodelled dynamics, a significantly reduced data set theta requires only the minimum and maximum values of the pressure in the aorta, pulmonary artery and the volumes in the ventricles. The importance of integrals in the formulation for noise reduction is illustrated by demonstrating instability in the identification using simple derivative-based approaches. The cardiovascular system (CVS) model and parameter identification method are then clinically validated on porcine data for pulmonary embolism. Errors for the identified model are within 10% when re-simulated and compared to clinical data. All identified parameter trends match clinically expected changes. This work represents the first clinical validation of these models, methods and approach to cardiovascular diagnosis in critical care.


Laboratory study of nitrate photolysis in Antarctic snow. II. Isotopic effects and wavelength dependence.
Atmospheric nitrate is preserved in Antarctic snow firn and ice. However, at low snow accumulation sites, post-depositional processes induced by sunlight obscure its interpretation. The goal of these studies (see also Paper I by Meusinger et al. ["Laboratory study of nitrate photolysis in Antarctic snow. I. Observed quantum yield, domain of photolysis, and secondary chemistry," J. Chem. Phys. 140, 244305 (2014)]) is to characterize nitrate photochemistry and improve the interpretation of the nitrate ice core record. Naturally occurring stable isotopes in nitrate ((15)N, (17)O, and (18)O) provide additional information concerning post-depositional processes. Here, we present results from studies of the wavelength-dependent isotope effects from photolysis of nitrate in a matrix of natural snow. Snow from Dome C, Antarctica was irradiated in selected wavelength regions using a Xe UV lamp and filters. The irradiated snow was sampled and analyzed for nitrate concentration and isotopic composition (δ(15)N, δ(18)O, and Δ(17)O). From these measurements an average photolytic isotopic fractionation of (15)ɛ = (-15 ± 1.2)‰ was found for broadband Xe lamp photolysis. These results are due in part to excitation of the intense absorption band of nitrate around 200 nm in addition to the weaker band centered at 305 nm followed by photodissociation. An experiment with a filter blocking wavelengths shorter than 320 nm, approximating the actinic flux spectrum at Dome C, yielded a photolytic isotopic fractionation of (15)ɛ = (-47.9 ± 6.8)‰, in good agreement with fractionations determined by previous studies for the East Antarctic Plateau which range from -40 to -74.3‰. We describe a new semi-empirical zero point energy shift model used to derive the absorption cross sections of (14)NO3 (-) and (15)NO3 (-) in snow at a chosen temperature. The nitrogen isotopic fractionations obtained by applying this model under the experimental temperature as well as considering the shift in width and center well reproduced the values obtained in the laboratory study. These cross sections can be used in isotopic models to reproduce the stable isotopic composition of nitrate found in Antarctic snow profiles.


Molecular recognition with nanostructures fabricated by photopolymerization within metallic subwavelength apertures.
The first demonstration of fabrication of submicron lateral resolution molecularly imprinted polymer (MIP) patterns by photoinduced local polymerization within metal subwavelength apertures is reported. The size of the photopolymerized MIP features is finely tuned by the dose of 532 nm radiation. Rhodamine 123 (R123) has been selected as a fluorescent model template to prove the recognition capability of the MIP nanostructures, which has been evaluated by fluorescence lifetime imaging microscopy (FLIM) with single photon timing measurements. The binding selectivity provided by the imprinting effect has been confirmed in the presence of compounds structurally related to R123. These results pave the way to the development of nanomaterial architectures with biomimetic artificial recognition properties for environmental, clinical and food testing.


Specific amino acid substitutions in β strand S2 of FtsZ cause spiraling septation and impair assembly cooperativity in Streptomyces spp.
Bacterial cell division is orchestrated by the Z ring, which is formed by single-stranded treadmilling protofilaments of FtsZ. In Streptomyces, during sporulation, multiple Z rings are assembled and lead to formation of septa that divide a filamentous hyphal cell into tens of prespore compartments. We describe here mutant alleles of ftsZ in Streptomyces coelicolor and Streptomyces venezuelae that perturb cell division in such a way that constriction is initiated along irregular spiral-shaped paths rather than as regular septa perpendicular to the cell length axis. This conspicuous phenotype is caused by amino acid substitutions F37I and F37R in β strand S2 of FtsZ. The F37I mutation leads, instead of regular Z rings, to formation of relatively stable spiral-shaped FtsZ structures that are capable of initiating cell constriction. Further, we show that the F37 mutations affect the polymerization properties and impair the cooperativity of FtsZ assembly in vitro. The results suggest that specific residues in β strand S2 of FtsZ affect the conformational switch in FtsZ that underlies assembly cooperativity and enable treadmilling of protofilaments, and that these features are required for formation of regular Z rings. However, the data also indicate FtsZ-directed cell constriction is not dependent on assembly cooperativity.


Preventing loss of independence through exercise (PLIÉ): a pilot clinical trial in older adults with dementia.
Current dementia medications have small effect sizes, many adverse effects and do not change the disease course. Therefore, it is critically important to study alternative treatment strategies. The goal of this study was to pilot-test a novel, integrative group exercise program for individuals with mild-to-moderate dementia called Preventing Loss of Independence through Exercise (PLIÉ), which focuses on training procedural memory for basic functional movements (e.g., sit-to-stand) while increasing mindful body awareness and facilitating social connection. We performed a 36-week cross-over pilot clinical trial to compare PLIÉ with usual care (UC) at an adult day program for individuals with dementia in San Francisco, CA. Assessments of physical performance, cognitive function, physical function, dementia-related behaviors, quality of life and caregiver burden were performed by blinded assessors at baseline, 18 weeks (cross-over) and 36 weeks. Our primary outcomes were effect sizes based on between-group comparisons of change from baseline to 18 weeks; secondary outcomes were within-group comparisons of change before and after cross-over. Twelve individuals enrolled (7 PLIÉ, 5 UC) and 2 withdrew (1 PLIÉ, 18 weeks; 1 UC, 36 weeks). Participants were 82% women (mean age, 84 ± 4 years); caregivers were 82% daughters (mean age, 56 ± 13 years). Effect sizes were not statistically significant but suggested potentially clinically meaningful (≥ 0.25 SDs) improvement with PLIÉ versus UC for physical performance (Cohen's D: 0.34 SDs), cognitive function (0.76 SDs) and quality of life (0.83 SDs) as well as for caregiver measures of participant's quality of life (0.33 SDs) and caregiver burden (0.49 SDs). Results were similar when within-group comparisons were made before and after cross-over. PLIÉ is a novel, integrative exercise program that shows promise for improving physical function, cognitive function, quality of life and caregiver burden in individuals with mild-to-moderate dementia. Larger randomized, controlled trials are warranted. ClinicalTrials.gov NCT01371214.


Brain and muscle Arnt-like 1 promotes skeletal muscle regeneration through satellite cell expansion.
Circadian clock is an evolutionarily conserved timing mechanism governing diverse biological processes and the skeletal muscle possesses intrinsic functional clocks. Interestingly, although the essential clock transcription activator, Brain and muscle Arnt-like 1 (Bmal1), participates in maintenance of muscle mass, little is known regarding its role in muscle growth and repair. In this report, we investigate the in vivo function of Bmal1 in skeletal muscle regeneration using two muscle injury models. Bmal1 is highly up-regulated by cardiotoxin injury, and its genetic ablation significantly impairs regeneration with markedly suppressed new myofiber formation and attenuated myogenic induction. A similarly defective regenerative response is observed in Bmal1-null mice as compared to wild-type controls upon freeze injury. Lack of satellite cell expansion accounts for the regeneration defect, as Bmal1(-/-) mice display significantly lower satellite cell number with nearly abolished induction of the satellite cell marker, Pax7. Furthermore, satellite cell-derived primary myoblasts devoid of Bmal1 display reduced growth and proliferation ex vivo. Collectively, our results demonstrate, for the first time, that Bmal1 is an integral component of the pro-myogenic response that is required for muscle repair. This mechanism may underlie its role in preserving adult muscle mass and could be targeted therapeutically to prevent muscle-wasting diseases.


Importance of the Candida albicans cell wall during commensalism and infection.
An imbalance of the normal microbial flora, breakage of epithelial barriers or dysfunction of the immune system favour the transition of the human pathogenic yeast Candida albicans from a commensal to a pathogen. C. albicans has evolved to be adapted as a commensal on mucosal surfaces. As a commensal it has also acquired attributes, which are necessary to avoid or overcome the host defence mechanisms. The human host has also co-evolved to recognize and eliminate potential fungal invaders. Many of the fungal genes that have been the focus of this co-evolutionary process encode cell wall components. In this review, we will discuss the transition from commensalism to pathogenesis, the key players of the fungal cell surface that are important for this transition, the role of the morphology and the mechanisms of host recognition and response.


Insights into evolution of multicellular fungi from the assembled chromosomes of the mushroom Coprinopsis cinerea (Coprinus cinereus).
The mushroom Coprinopsis cinerea is a classic experimental model for multicellular development in fungi because it grows on defined media, completes its life cycle in 2 weeks, produces some 10(8) synchronized meiocytes, and can be manipulated at all stages in development by mutation and transformation. The 37-megabase genome of C. cinerea was sequenced and assembled into 13 chromosomes. Meiotic recombination rates vary greatly along the chromosomes, and retrotransposons are absent in large regions of the genome with low levels of meiotic recombination. Single-copy genes with identifiable orthologs in other basidiomycetes are predominant in low-recombination regions of the chromosome. In contrast, paralogous multicopy genes are found in the highly recombining regions, including a large family of protein kinases (FunK1) unique to multicellular fungi. Analyses of P450 and hydrophobin gene families confirmed that local gene duplications drive the expansions of paralogous copies and the expansions occur in independent lineages of Agaricomycotina fungi. Gene-expression patterns from microarrays were used to dissect the transcriptional program of dikaryon formation (mating). Several members of the FunK1 kinase family are differentially regulated during sexual morphogenesis, and coordinate regulation of adjacent duplications is rare. The genomes of C. cinerea and Laccaria bicolor, a symbiotic basidiomycete, share extensive regions of synteny. The largest syntenic blocks occur in regions with low meiotic recombination rates, no transposable elements, and tight gene spacing, where orthologous single-copy genes are overrepresented. The chromosome assembly of C. cinerea is an essential resource in understanding the evolution of multicellularity in the fungi.


Mean-Field Phase Transitions in Tensorial Group Field Theory Quantum Gravity.
Controlling the continuum limit and extracting effective gravitational physics are shared challenges for quantum gravity approaches based on quantum discrete structures. The description of quantum gravity in terms of tensorial group field theory (TGFT) has recently led to much progress in its application to phenomenology, in particular, cosmology. This application relies on the assumption of a phase transition to a nontrivial vacuum (condensate) state describable by mean-field theory, an assumption that is difficult to corroborate by a full RG flow analysis due to the complexity of the relevant TGFT models. Here, we demonstrate that this assumption is justified due to the specific ingredients of realistic quantum geometric TGFT models: combinatorially nonlocal interactions, matter degrees of freedom, and Lorentz group data, together with the encoding of microcausality. This greatly strengthens the evidence for the existence of a meaningful continuum gravitational regime in group-field and spin-foam quantum gravity, the phenomenology of which is amenable to explicit computations in a mean-field approximation.


[Behavioral auditory processing evaluation in individuals with stuttering].
the behavioral auditory processing (AP) evaluation allows the investigation of neuroaudiological processes involved in speech fluency processing. the purpose of this study was to describe the results obtained in the AP evaluation in stutterers, comparing the type of AP disorder with the severity of stuttering. 56 subjects, 49 male and 7 female, ranging in age from 4 to 34 years, were referred from the speech-language clinic of UNIFESP to the AP evaluation. All patients were submitted to the following evaluations: audiological, speech and language. Disfluency was classified according to the protocol proposed by Riley (1994) which includes the following stuttering severity levels: very mild, mild, moderate, severe and very severe. Behavioral AP tests were selected and analyzed according to the patient's age and to the proposal of Pereira & Schochat (1997). subjects with ages between 4 to 7 years and between 12 to 34 years presented mostly mild stuttering, subjects between 8 to 11 years presented mostly moderate stuttering. From the total of 56 individuals who were evaluated, 92.85% presented AP disorders. The most common auditory processing disorders were supra-segmental and decoding. No statistical differences were found considering the results of the AP evaluation and the severity of stuttering for none of the age groups. the AP evaluation indicated deficits for most of the participants of all age groups, however no correlations were observed with the severity of stuttering.


The effectiveness of the Bobath concept in stroke rehabilitation: what is the evidence?
In the Western world, the Bobath Concept or neurodevelopmental treatment is the most popular treatment approach used in stroke rehabilitation, yet the superiority of the Bobath Concept as the optimal type of treatment has not been established. This systematic review of randomized, controlled trials aimed to evaluate the available evidence for the effectiveness of the Bobath Concept in stroke rehabilitation. Method- A systematic literature search was conducted in the bibliographic databases MEDLINE and CENTRAL (March 2008) and by screening the references of selected publications (including reviews). Studies in which the effects of the Bobath Concept were investigated were classified into the following domains: sensorimotor control of upper and lower limb; sitting and standing, balance control, and dexterity; mobility; activities of daily living; health-related quality of life; and cost-effectiveness. Due to methodological heterogeneity within the selected studies, statistical pooling was not considered. Two independent researchers rated all retrieved literature according to the Physiotherapy Evidence Database (PEDro) scale from which a best evidence synthesis was derived to determine the strength of the evidence for both effectiveness of the Bobath Concept and for its superiority over other approaches. The search strategy initially identified 2263 studies. After selection based on predetermined criteria, finally, 16 studies involving 813 patients with stroke were included for further analysis. There was no evidence of superiority of Bobath on sensorimotor control of upper and lower limb, dexterity, mobility, activities of daily living, health-related quality of life, and cost-effectiveness. Only limited evidence was found for balance control in favor of Bobath. Because of the limited evidence available, no best evidence synthesis was applied for the health-related quality-of-life domain and cost-effectiveness. This systematic review confirms that overall the Bobath Concept is not superior to other approaches. Based on best evidence synthesis, no evidence is available for the superiority of any approach. This review has highlighted many methodological shortcomings in the studies reviewed; further high-quality trials need to be published. Evidence-based guidelines rather than therapist preference should serve as a framework from which therapists should derive the most effective treatment.


Oxidative stress mediated mitochondrial and vascular lesions as markers in the pathogenesis of Alzheimer disease.
Mitochondrial dysfunction plausibly underlies the aging-associated brain degeneration. Mitochondria play a pivotal role in cellular bioenergetics and cell-survival. Oxidative stress consequent to chronic hypoperfusion induces mitochondrial damage, which is implicated as the primary cause of cerebrovascular accidents (CVA) mediated Alzheimer's disease (AD). The mitochondrial function deteriorates with aging, and the mitochondrial damage correlates with increased intracellular production of oxidants and pro-oxidants. The prolonged oxidative stress and the resultant hypoperfusion in the brain tissues stimulate the expression of nitric oxide synthase (NOS) enzymes, which further drives the formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The ROS and RNS collectively contributes to the dysfunction of the blood-brain barrier (BBB) and damage to the brain parenchymal cells. Delineating the molecular mechanisms of these processes may provide clues for the novel therapeutic targets for CVA and AD patients.


MicroRNA-31 inhibits lung adenocarcinoma stem-like cells via down-regulation of MET-PI3K-Akt signaling pathway.
Accumulated evidences suggested that microRNAs (miRs) play an important role in non-small cell lung cancer (NSCLC). However, how miRs perform their functions in lung adenocarcinoma cancer stem cells (CSCs) remains unknown. Notably, most studies pay more attention to the effects of miRNAs on the metastasis traits whereas the growth activities of CSCs are rather undervalued. In our report, using A549CD133+cells, we examined the inhibitory effects and the underlying mechanisms of microRNA-31 (miR-31) on the growth of lung adenocarcinoma CSC-like cells. Initially, we determined the level of miR-31 in A549 and A549CD133+ cells. Over-expression of miR-31 was found in A549CD133+ cells by microarray and real-time quantitative PCR (RTqPCR) assays. Experiments in multiple NSCLC cell lines in vitro and A549CD133+ cells xenograft models in vivo confirmed that down regulation of miR-31 resulted in increase of A549CD133+ cells growth, whereas overexpression of miR-31 led to the inhibition of adenocarcinoma cell proliferation. Also, MET proto-oncogene has been determined to be a direct target of miR-31 by dual luciferase report, RT-qPCR and western blot analysis. Down regulation of MET inhibited viability of A549CD133+ cells. The levels of PI3Kinase, Akt and p-Akt as well as downstream proteins were consequently decreased. These results suggest that miR-31 might inhibit the growth of lung adenocarcinoma cancer stem-like cells via down regulation of the MET-PI3K-Akt signaling pathway.


Mathematical modelling long-term effects of replacing Prevnar7 with Prevnar13 on invasive pneumococcal diseases in England and Wales.
England and Wales recently replaced the 7-valent pneumococcal conjugate vaccine (PCV7) with its 13-valent equivalent (PCV13), partly based on projections from mathematical models of the long-term impact of such a switch compared to ceasing pneumococcal conjugate vaccination altogether. A compartmental deterministic model was used to estimate parameters governing transmission of infection and competition between different groups of pneumococcal serotypes prior to the introduction of PCV13. The best-fitting parameters were used in an individual based model to describe pneumococcal transmission dynamics and effects of various options for the vaccination programme change in England and Wales. A number of scenarios were conducted using (i) different assumptions about the number of invasive pneumococcal disease cases adjusted for the increasing trend in disease incidence prior to PCV7 introduction in England and Wales, and (ii) a range of values representing serotype replacement induced by vaccination of the additional six serotypes in PCV13. Most of the scenarios considered suggest that ceasing pneumococcal conjugate vaccine use would cause an increase in invasive pneumococcal disease incidence, while replacing PCV7 with PCV13 would cause an overall decrease. However, the size of this reduction largely depends on the level of competition induced by the additional serotypes in PCV13. The model estimates that over 20 years of PCV13 vaccination, around 5000-62000 IPD cases could be prevented compared to stopping pneumococcal conjugate vaccination altogether. Despite inevitable uncertainty around serotype replacement effects following introduction of PCV13, the model suggests a reduction in overall invasive pneumococcal disease incidence in all cases. Our results provide useful evidence on the benefits of PCV13 to countries replacing or considering replacing PCV7 with PCV13, as well as data that can be used to evaluate the cost-effectiveness of such a switch.


Fast determination of thiacloprid by photoinduced chemiluminescence.
A new and sensitive application of chemiluminescence detection has been developed for the determination of the pesticide thiacloprid in water. It was based on the on-line photoreaction of thiacloprid in a basic medium, with quinine acting as the sensitizer of the chemiluminescent response; cerium (IV) in sulfuric acid medium was used as the oxidant. High degrees of automation and reproducibility were achieved using a flow-injection analysis (FIA) manifold. The validation of the method was performed in terms of selectivity, linearity, limit of detection (LOD), precision, and accuracy. Liquid chromatography with ultraviolet (UV) detection was used as reference for mineral, tap, ground, and spring water samples. The proposed method is fast (with a throughput of 130 h(-1)), sensitive (LOD of 0.8 ng mL(-1) without preconcentration steps and of 0.08 ng mL(-1) with solid-phase extraction [SPE]), low cost, and possible to couple with separation methods for the simultaneous determination of other pesticides. The enhanced chemiluminescence intensity was linear with the thiacloprid concentration above the 2-80 and 80-800 ng mL(-1) ranges. A possible reaction mechanism is also discussed.


Diagnosing syncope. Part 1: Value of history, physical examination, and electrocardiography. Clinical Efficacy Assessment Project of the American College of Physicians.
To review the literature on diagnostic testing in syncope and provide recommendations for a comprehensive, cost-effective approach to establishing its cause. Studies were identified through a MEDLINE search (1980 to present) and a manual review of bibliographies of identified articles. Papers were eligible if they addressed diagnostic testing in syncope or near syncope and reported results for at least 10 patients. The usefulness of tests was assessed by calculating diagnostic yield: the number of patients with diagnostically positive test results divided by the number of patients tested or, in the case of monitoring studies, the sum of true-positive and true-negative test results divided by the number of patients tested. Despite the absence of a diagnostic gold standard and the paucity of data from randomized trials, several points emerge. First, history, physical examination, and electrocardiography are the core of the syncope workup (combined diagnostic yield, 50%). Second, neurologic testing is rarely helpful unless additional neurologic signs or symptoms are present (diagnostic yield of electroencephalography, computed tomography, and Doppler ultrasonography, 2% to 6%). Third, patients in whom heart disease is known or suspected or those with exertional syncope are at higher risk for adverse outcomes and should have cardiac testing, including echocardiography, stress testing. Holter monitoring, or intracardiac electrophysiologic studies, alone or in combination (diagnostic yields, 5% to 35%). Fourth, syncope in the elderly often results from polypharmacy and abnormal physiologic responses to daily events. Fifth, long-term loop electrocardiography (diagnostic yield, 25% to 35%) and tilt testing (diagnostic yield < or = 60%) are most useful in patients with recurrent syncope in whom heart disease is not suspected. Sixth, psychiatric evaluation can detect mental disorders associated with syncope in up to 25% of cases. Seventh, hospitalization may be indicated for patients at high risk for cardiac syncope (those with an abnormal electrocardiogram, organic heart disease, chest pain, history of arrhythmia, age > 70 years) or with acute neurologic signs. Many tests for syncope have a low diagnostic yield. A careful history, physical examination, and electrocardiography will provide a diagnosis or determine whether diagnostic testing is necessary in most patients.


Assisted reproductive technologies in cattle: a review.
Over a period of approximately thirty years, commercial bovine embryo transfer has become a large international business. The technology is well established, and more than 500,000 embryos are produced annually from superovulated cows world wide. Since bovine embryos with intact zonae pellucidae can be specified pathogen-free through washing procedures, thousands of frozen embryos are routinely sold and transferred between countries. Throughout the world, approximately 15% of bovine embryos are produced by in vitro technology. Polymerase chain reaction technology is currently being used for sexing embryos on a small scale, and it is likely that this technology will be used for 'embryo diagnostics' in the future. Semen sexing is an established technology and is likely to be used on a small scale in the near future, especially in in vitro embryo production systems. The cloning of adult cattle through nuclear transfer and the production of cloned, transgenic cattle has been technically achieved. However, this is an expensive and inefficient technology, which is being used primarily by the pharmaceutical industry. Benefits in agriculture are likely to be minimal in the near future.


Similarity-based classifier using topomers to provide a knowledge base for hERG channel inhibition.
In a proof of principle study we show that the similarity property principle can be applied to predict ADMET properties, exemplified on the case of hERG K+ channel inhibition. Early prediction of a drug candidate's hERG channel activity is becoming increasingly important in the drug discovery process because blockade of the hERG channel may lead to life-threatening cardiac arrhythmias. Using the Tripos Topomer Search technology as compound similarity measure, we query molecules with unknown hERG activity for similar molecules in a set of compounds with known hERG activity. The hERG activity of the query molecule is then predicted based on the hERG activity of its Topomer Search neighbors and their distances to the query molecule. The similarity property principle can be applied with promising performance to predict hERG inhibition as long as there is a high structural overlap between the chemical spaces of the query compounds and the reference data set. We show that this is achievable for database sizes of about 10,000 structurally diverse molecules. In this case topoHERG is a similarity-based hERG classifier, which also acts as a knowledge base for hERG channel inhibition.


Neuropsychological function in Gulf War veterans: relationships to self-reported toxicant exposures.
The present study was aimed at (1) exploring evidence of central nervous system (CNS) dysfunction among Gulf War (GW) veterans on neuropsychological tests and (2) examining whether performance on neuropsychological tests was related to specific neurotoxicant exposures experienced in the Gulf. The GW-deployed groups were selected using stratified random sampling methods from two distinct cohorts of GW veterans. A comparison group that had been called up for GW service but deployed to Germany rather than the Gulf also was examined. Neuropsychological function was assessed using a pre-determined battery chosen to include tests known to be highly sensitive to the behavioral effects of the neurotoxicants thought to have been present in the Gulf. Self-reported exposures were related to neuropsychological test performance controlling for post-traumatic stress disorder, major depression, and other known covariates of neuropsychological test performance. Results showed that GW-deployed veterans performed more poorly than the Germany-deployed veterans on several specific neuropsychological tests, but after adjustment for multiple comparisons, only the differences in mood complaints remained significant. Within the GW-deployed group, self-reported exposure to chemical warfare agents was associated with poorer performance on cognitive tests involving specific functional domains. Results provide evidence that there are subtle differences in CNS function among GW-deployed veterans who report chemical warfare agent exposure while in the GW theater.


Pathology and pathogenesis of craniopharyngiomas.
Craniopharyngiomas are benign but locally invasive tumours of the sellar region that occur as two subtypes. The adamantinomatous type (aCP) occurs mainly during childhood while the papillary type (pCP) is found almost exclusively in adults. It is thought that aCPs arise from ectopic embryonic remnants of Rathke's pouch and these tumours share features with odontogenic tumours suggesting a common origin. The pathogenesis of pCPs is less understood but these tumours may arise from metaplastic transformation of anterior pituitary epithelial cells. Mutations in CTNNB1 that encodes β-catenin are found in around 70 % of aCPs. These mutations stabilise β-catenin, which evades destruction and accumulates in the nucleus and cytosol leading to constitutive activation of the Wnt signaling pathway. Expression of mutant β-catenin early in mouse pituitary development promotes the formation of tumours similar to aCPs. However, accumulation of β-catenin occurs only in small clusters of tumour cells even though the mutation is ubiquitous. These cell clusters are slow-growing and share some characteristics with pituitary stem cells. They are often present at the invading edge and express growth factors that may participate in paracrine signaling to surrounding cells. β-Catenin nuclear translocation may also occur in the absence of CTNNB1 mutations, suggesting that other genetic or epigenetic events can activate Wnt signaling in aCP. These mechanisms, as well as those underlying the molecular pathogenesis of pCPs remain to be identified.


[Pharmacological studies on small peptide fraction derived from soybean. The effects of small peptide fraction derived from soybean on fatigue, obesity and glycemia in mice].
The present research was an attempt to determine the pharmacological actions as for anti-fatigue, anti-obesity and hypoglycemia of small peptide isolated from soybean in mice. Small peptide administration prevented the decrease in sporting movement induced by concussion stress for 3 h in mice. In addition, it should be noted that the recovery rate of fatigue in 60 min after small peptide administration was over one hundred percentage in comparison with that after pretreatment, while the equivalent dose administration of amino acid mixture with the same small peptide amino acid composition did not prevent the decrease in sporting movement. In gold-thioglucose (500 mg/kg (i.p.))-induced obese mouse body weight gain, liver weight and body lipid level around uterine were significantly reduced by the chronic oral administration of small peptide (200, 1000 mg/kg). Administration in 1000 mg per kg of small peptide significantly lowered hyperglycemia in 30 and 120 min after glucose (3 g/kg (p.o.)) administration, whereas the equivalent amino acid mixture showed no effect. In conclusion, it suggested that small peptide isolated from soybean might have some pharmacological effects of anti-fatigue, anti-obesity, and hypoglycemia.


Visual speech contributes to phonetic learning in 6-month-old infants.
Previous research has shown that infants match vowel sounds to facial displays of vowel articulation [Kuhl, P. K., & Meltzoff, A. N. (1982). The bimodal perception of speech in infancy. Science, 218, 1138-1141; Patterson, M. L., & Werker, J. F. (1999). Matching phonetic information in lips and voice is robust in 4.5-month-old infants. Infant Behaviour & Development, 22, 237-247], and integrate seen and heard speech sounds [Rosenblum, L. D., Schmuckler, M. A., & Johnson, J. A. (1997). The McGurk effect in infants. Perception & Psychophysics, 59, 347-357; Burnham, D., & Dodd, B. (2004). Auditory-visual speech integration by prelinguistic infants: Perception of an emergent consonant in the McGurk effect. Developmental Psychobiology, 45, 204-220]. However, the role of visual speech in language development remains unknown. Our aim was to determine whether seen articulations enhance phoneme discrimination, thereby playing a role in phonetic category learning. We exposed 6-month-old infants to speech sounds from a restricted range of a continuum between /ba/ and /da/, following a unimodal frequency distribution. Synchronously with these speech sounds, one group of infants (the two-category group) saw a visual articulation of a canonical /ba/ or /da/, with the two alternative visual articulations, /ba/ and /da/, being presented according to whether the auditory token was on the /ba/ or /da/ side of the midpoint of the continuum. Infants in a second (one-category) group were presented with the same unimodal distribution of speech sounds, but every token for any particular infant was always paired with the same syllable, either a visual /ba/ or a visual /da/. A stimulus-alternation preference procedure following the exposure revealed that infants in the former, and not in the latter, group discriminated the /ba/-/da/ contrast. These results not only show that visual information about speech articulation enhances phoneme discrimination, but also that it may contribute to the learning of phoneme boundaries in infancy.


Introducing New Antimalarial Analogues of Chloroquine and Amodiaquine: A Narrative Review.
Antimalarial drugs with the 4-aminoquinoline scaffold such as the important drugs, chloroquine (CQ) and amodiaquine (AQ), have been used to prevent and treat malaria for many years. The importance of these drugs is related to their simple usage, high efficacy, affordability, and cost-effectiveness of their synthesis. In recent years, with the spread of parasite resistance to CQ and cross-resistance to its other analogues have decreased their consumption in many geographical areas. On the other hand, AQ is an effective antimalarial drug which its usage has been restricted due to hepatic and hematological toxicities. The significance of the quinoline ring at quinoline-based antimalarial drugs has prompted research centers and pharmaceutical companies to focus on the design and synthesis of new analogues of these drugs, especially CQ and AQ analogues. Accordingly, various derivatives have been synthesized and evaluated in vitro and in vivo against the resistant strains of the malaria parasite to solve the problem of drug resistance. Also, the pharmacokinetic properties of these compounds have been evaluated to augment their efficacy and diminish their toxicity. Some of these analogues are currently in clinical and preclinical development. Consequently, the recent researches showed yet 4-aminoquinoline scaffold is active moiety in new compounds with antiplasmodial activity. Hence, the aim of this review article is to introduce of the novel synthetic analogues of CQ and AQ, which may constitute the next generation of antimalarial drugs with the 4-aminoquinoline scaffold.


Immune response against lymphocytic choriomeningitis virus infection in mice without CD8 expression.
The immune response against lymphocytic choriomeningitis virus (LCMV) was studied in a mutant mouse strain that does not possess CD8+ T lymphocytes. Virus-specific cytotoxic T cell activity was generated in spleens of wild-type mice in an acute LCMV infection but was not measurable in mutant mice. Injection of replicating LCMV into footpads of wild-type mice induced a CD8+ T cell-mediated swelling that peaked on day 8, followed by a CD4+ T cell-mediated swelling that peaked on day 11, whereas mutant mice exhibited only the CD4+ T cell-mediated swelling. After intracerebral inoculation with LCMV-Armstrong, all wild-type mice died of classical CD8+ T cell-dependent choriomeningitis in 8-10 days. Mutant mice showed symptoms of general malaise but most of them survived. Mutant mice depleted of CD4+ T cells by monoclonal antibody treatment showed no clinical signs of sickness. On day 9 after intravenous infection with LCMV-WE, virus was detected at high titers in spleens and livers of mutant mice but not in those of wild-type mice. On day 70 after injection of LCMV-WE into footpads, virus was not detected in wild-type mice and in one of the three mutant mice tested, but was still measurable in kidneys of the other two mutant mice. These results confirm in a new animal model that CD8+ T cell-mediated immunity is crucial in LCMV clearance and in the immunopathological disease during LCMV infection. In addition, our results demonstrated a less severe form of choriomeningitis mediated by CD4+ T cells and slow clearance of LCMV by alternative pathways independent of CD8+ T cells.


Hydration in the Pediatric Athlete - How to Guide Your Patients.
Hydration is arguably among the foremost priorities youth athletes, parents, and coaches habitually consider as vital for sports. Insufficient hydration and a resultant measurable sweat-induced body water deficit can negatively affect performance and, in some athletic scenarios, can be a danger to a young athlete's health and safety, especially during vigorous physical activity in a warm-to-hot environment. Accordingly, it is essential to be well hydrated prior to practice, training, and competition and minimize total body water deficits incurred while being mindful of the greater sweat losses and hydration needs/challenges that accompany physical growth and maturation. Informed clinicians can play a key role as trusted resources in providing the most effective guidelines and making the best overall individual recommendations regarding hydration for youth athletes.


Rhinosinusitis and aspirin-exacerbated respiratory disease.
Rhinosinusitis is a feature of aspirin-exacerbated respiratory disease (AERD), which in the initial phase is manifested as nasal congestion, mostly affecting females at the age of around 30 years on average. Subsequently, nasal inflammation progresses to chronic eosinophilic rhinosinusitis, asthma, nasal polyposis, and intolerance to aspirin and to other NSAIDs. While it has been long established that NSAIDs cause inhibition of cyclooxygenase-1 (COX-1), leading to excessive metabolism of arachidonic acid (AA) to cysteinyl-leukotrienes (cys-LTs), there is now evidence that both cytokines and staphylococcus superantigens amplify the inflammatory process exacerbating the disease. This paper gives a brief overview of the development of chronic rhinosinusitis (CRS) in sensitive patients, and we share our experience in the diagnosis and management of CRS in AERD.


Search for metastable heavy charged particles with large ionisation energy loss in pp collisions at [Formula: see text] TeV using the ATLAS experiment.
Many extensions of the Standard Model predict the existence of charged heavy long-lived particles, such as R-hadrons or charginos. These particles, if produced at the Large Hadron Collider, should be moving non-relativistically and are therefore identifiable through the measurement of an anomalously large specific energy loss in the ATLAS pixel detector. Measuring heavy long-lived particles through their track parameters in the vicinity of the interaction vertex provides sensitivity to metastable particles with lifetimes from 0.6 ns to 30 ns. A search for such particles with the ATLAS detector at the Large Hadron Collider is presented, based on a data sample corresponding to an integrated luminosity of [Formula: see text] fb[Formula: see text] of pp collisions at [Formula: see text] TeV. No significant deviation from the Standard Model background expectation is observed, and lifetime-dependent upper limits on R-hadrons and chargino production are set. Gluino R-hadrons with 10 ns lifetime and masses up to 1185 GeV are excluded at 95 [Formula: see text] confidence level, and so are charginos with 15 ns lifetime and masses up to 482 GeV.


Continence outcomes after bladder neck preservation during robot-assisted laparoscopic prostatectomy (RALP).
Urinary incontinence is one of the major prostate cancer treatment-related morbidities. We review our initial robot-assisted laparoscopic prostatectomy (RALP) experience, focusing on post-surgery continence rates. Two-hundred and thirty-three consecutive patients were identified from a prospectively maintained RALP database. A bladder neck sparing dissection was preferentially performed during transperitoneal RALP. On postoperative day 5 or 6 (clinic logistics), the urethral catheter was removed following a normal cystogram. Median operative time was 190 minutes and estimated blood loss was 75 mL. Three (1.3%) patients required bladder neck reconstruction, while 198 (85.0%) had bilateral, 20 (8.6%) had unilateral and 15 (6.4%) did not undergo nerve sparing prostatectomy. One-hundred and ninety-nine (85.4%) patients had negative surgical margins. Median hospitalization and urethral catheter duration were 1.0 and 5.0 days, respectively. At six weeks, a median 1.0 pad per day usage was reported and mean AUASS and QoL were significantly improved from baseline (p < 0.05). Of the 220 patients having a minimum three-month follow-up, 152 (69.1%) achieved urinary continence without pads. Age, AUASS, QoL, prostate volume and prior TUR surgery independently had significant impact on early continence rate (p < 0.05). A bladder neck sparing dissection allows for early return of urinary continence following RALP without compromising cancer control.


Laboratory layered latte.
Inducing thermal gradients in fluid systems with initial, well-defined density gradients results in the formation of distinct layered patterns, such as those observed in the ocean due to double-diffusive convection. In contrast, layered composite fluids are sometimes observed in confined systems of rather chaotic initial states, for example, lattes formed by pouring espresso into a glass of warm milk. Here, we report controlled experiments injecting a fluid into a miscible phase and show that, above a critical injection velocity, layering emerges over a time scale of minutes. We identify critical conditions to produce the layering, and relate the results quantitatively to double-diffusive convection. Based on this understanding, we show how to employ this single-step process to produce layered structures in soft materials, where the local elastic properties vary step-wise along the length of the material.


Can starling eggs be useful as a biomonitoring tool to study organohalogenated contaminants on a worldwide scale?
Large-scale international monitoring studies are important to assess emission patterns and environmental distributions of organohalogenated contaminants (OHCs) on a worldwide scale. In this study, the presence of OHCs was investigated on three continents (Europe, North America and Australasia), using eggs of starlings (Sturnus vulgaris and Sturnus unicolor) to assess their suitability for large-scale monitoring studies. To the best of our knowledge, this is the first study using bird eggs of the same species as a biomonitor for OHCs on an intercontinental scale. We found significant differences in OHC concentrations of the eggs among sampling locations, except for hexachlorocyclohexanes (HCHs). Mean concentrations of sum polychlorinated biphenyls (PCBs) in eggs ranged from 78±26 ng/glipid weight (lw) in Australia to 2900±1300 ng/g lw in the United States. The PCB profile was dominated by CB 153 and CB 138 in all locations, except for New Zealand, where the contribution of CB 95, CB 101 and CB 149 was also high. The highest mean sum polybrominated diphenyl ether (PBDE) concentrations were found in Canada (4400±830 ng/g lw), while the lowest mean PBDE concentrations were measured in Spain (3.7±0.1 ng/g lw). The PBDE profile in starling eggs was dominated by BDE 47 and BDE 99 in all countries, but in Belgium, the higher brominated PBDEs had a higher contribution compared to other countries. For the organochlorine pesticides (OCPs), dichlorodiphenyltrichloroethanes (DDTs) ranged from 110±16 ng/g lw in France to 17,000±3400 ng/g lw in New Zealand, while HCHs and hexachlorobenzene were generally in low concentrations in all sampling locations. Chlordanes were remarkably high in eggs from the United States (2500±1300 ng/g lw). The OCP profile in all countries was largely dominated by p,p'-DDE. In general, the worldwide trends we observed in starling eggs were in accordance with the literature on human and environmental OHC data, which suggests that there is potential for using starling eggs as a biomonitoring tool on a large geographical scale.