Exploring the response shift effect on the quality of life of patients with schizophrenia: an application of the random forest method.
Interpretation of quality of life (QoL) scores over time can be difficult because of possible changes in internal standards, values, and conceptualization of QoL by individuals. This effect is called a response shift (RS). The purpose of this study was to examine whether an RS effect occurred over a 24-mo period in patients who were suffering from schizophrenia. The random forest method was applied to detect any RS reprioritization in a multicenter cohort study. QoL was recorded using a generic questionnaire (SF36) at baseline (T0), 12 mo (T12), and 24 mo (T24). Patients were categorized into 3 groups based on psychotic symptoms and relapse (stable, improved, and worsened groups) from their clinical profiles. The random forest method was performed to predict the General Health score of the SF36 from the other QoL domain scores of the SF36. We estimated the average variable importance of the QoL domain for each of the 3 groups. A total of 124 (53.2%) patients were defined as stable, 59 (25.3%) as improved, and 50 (21.5%) as worsened. Among the stable group, the Social Functioning domain became more important over time. Of those classified as improved, the Mental Health domain became more important over time, while the Vitality domain became less important. Among those in the group who worsened, the Mental Health domain became less important while the Vitality and Bodily Pain domains became more important. Our study identified differential RS reprioritization among patients with different clinical profiles. Further work is needed to determine whether RS should be interpreted as a measurement bias or as an effect integrated in a true change.


Fatty acid composition at the base of aquatic food webs is influenced by habitat type and watershed land use.
Spatial variation in food resources strongly influences many aspects of aquatic consumer ecology. Although large-scale controls over spatial variation in many aspects of food resources are well known, others have received little study. Here we investigated variation in the fatty acid (FA) composition of seston and primary consumers within (i.e., among habitats) and among tributary systems of Lake Michigan, USA. FA composition of food is important because all metazoans require certain FAs for proper growth and development that cannot be produced de novo, including many polyunsaturated fatty acids (PUFAs). Here we sampled three habitat types (river, rivermouth and nearshore zone) in 11 tributaries of Lake Michigan to assess the amount of FA in seston and primary consumers of seston. We hypothesize that among-system and among-habitat variation in FAs at the base of food webs would be related to algal production, which in turn is influenced by three land cover characteristics: 1) combined agriculture and urban lands (an indication of anthropogenic nutrient inputs that fuel algal production), 2) the proportion of surface waters (an indication of water residence times that allow algal producers to accumulate) and 3) the extent of riparian forested buffers (an indication of stream shading that reduces algal production). Of these three land cover characteristics, only intense land use appeared to strongly related to seston and consumer FA and this effect was only strong in rivermouth and nearshore lake sites. River seston and consumer FA composition was highly variable, but that variation does not appear to be driven by the watershed land cover characteristics investigated here. Whether the spatial variation in FA content at the base of these food webs significantly influences the production of economically important species higher in the food web should be a focus of future research.


CO2 enrichment and soil type additively regulate grassland productivity.
Atmospheric CO2 enrichment usually increases the aboveground net primary productivity (ANPP) of grassland vegetation, but the magnitude of the ANPP-CO2 response differs among ecosystems. Soil properties affect ANPP via multiple mechanisms and vary over topographic to geographic gradients, but have received little attention as potential modifiers of the ANPP-CO2 response. We assessed the effects of three soil types, sandy loam, silty clay and clay, on the ANPP response of perennial C3 /C4 grassland communities to a subambient to elevated CO2 gradient over 10 yr in Texas, USA. We predicted an interactive, rather than additive, effect of CO2 and soil type on ANPP. Contrary to prediction, CO2 and soil additively influenced grassland ANPP. Increasing CO2 by 250 μl l-1 increased ANPP by 170 g m-2 across soil types. Increased clay content from 10% to 50% among soils reduced ANPP by 50 g m-2 . CO2 enrichment increased ANPP via a predominant direct effect, accompanied by a smaller indirect effect mediated by a successional shift to increased dominance of the C4 tallgrass Sorghastrum nutans. Our results indicate a large, positive influence of CO2 enrichment on grassland productivity that resulted from the direct physiological benefits of CO2 augmented by species succession, and was expressed similarly across soils of differing physical properties.


Biological Profiling of Coleoptericins and Coleoptericin-Like Antimicrobial Peptides from the Invasive Harlequin Ladybird Harmonia axyridis.
The spread of antibiotic-resistant human pathogens and the declining number of novel antibiotics in the development pipeline is a global challenge that has fueled the demand for alternative options. The search for novel drug candidates has expanded to include not only antibiotics but also adjuvants capable of restoring antibiotic susceptibility in multidrug-resistant (MDR) pathogens. Insect-derived antimicrobial peptides (AMPs) can potentially fulfil both of these functions. We tested two coleoptericins and one coleoptericin-like peptides from the invasive harlequin ladybird Harmonia axyridis against a panel of human pathogens. The AMPs displayed little or no activity when tested alone but were active even against clinical MDR isolates of the Gram-negative ESKAPE strains when tested in combination with polymyxin derivatives, such as the reserve antibiotic colistin, at levels below the minimal inhibitory concentration. Assuming intracellular targets of the AMPs, our data indicate that colistin potentiates the activity of the AMPs. All three AMPs achieved good in vitro therapeutic indices and high intrahepatic stability but low plasma stability, suggesting they could be developed as adjuvants for topical delivery or administration by inhalation for anti-infective therapy to reduce the necessary dose of colistin (and thus its side effects) or to prevent development of colistin resistance in MDR pathogens.


Immunodetection and quantification of airborne (1-3)-β-D-glucan-carrying particles with the halogen immunoassay.
Fungal cell wall components, such as (1-3)-β-D-glucan, are known to be capable of activating the innate immune system and pose a respiratory health risk in different environments. Mass-based non-viable techniques commonly used for assessment of fungal exposures could be β-D-glucan-specific, but are limited to analysis of liquid extracts. The variable solubility of different β-D-glucans may underestimate β-D-glucan exposure and long sampling times required for mass-based methods make assessing short-term exposures difficult. In this study, we evaluated the utility of the halogen immunoassay (HIA), an immunoblotting technique previously used for allergens, to immunodetect and quantify β-D-glucan-carrying particles (BGCPs). The HIA was able to detect BGCPs without background staining when β-D-glucan standards and air samples collected at a poultry house during short sampling periods were evaluated. The image analysis protocol previously developed by our group for mouse allergen allowed simultaneous immunodetection and quantification of β-D-glucan-containing particles. Our results suggest that the HIA holds promise for quantifying β-D-glucan exposures. To our knowledge, this is the first time in which the HIA was used for non-allergenic compounds of microbial or fungal origins.


Impact of a Lung Cancer Screening Information Film on Informed Decision-making: A Randomized Trial.
Rationale: Lung cancer screening has the potential to save lives, but it also carries a risk of potential harms. Explaining the benefits and harms of screening in a way that is balanced and comprehensible to individuals with various levels of education is essential. Although a shared decision-making approach is mandated by the Centers for Medicare & Medicaid Services, there have been no randomized studies to evaluate the impact of different forms of lung screening information. Objectives: To evaluate the impact of a novel information film on informed decision-making in individuals considering participating in lung cancer screening. Methods: A subset of participants from LSUT (Lung Screen Uptake Trial) were randomly allocated either to view the information film and receive a written information booklet or to receive the booklet alone. The primary outcome was the objective knowledge score after intervention. Secondary outcomes included subjective knowledge, decisional conflict, final screening participation, and acceptability of the materials. Univariate and multivariate analyses were performed to determine differences in pre- and postintervention knowledge scores in both groups and between groups for the primary and secondary outcomes. Results: In the final analysis of 229 participants, both groups showed significantly improved subjective and objective knowledge scores after intervention. This improvement was greatest in the film + booklet group, where mean objective knowledge improved by 2.16 points (standard deviation [SD] 1.8) compared with 1.84 points (SD 1.9) in the booklet-alone group (β coefficient 0.62; confidence interval, 0.17-1.08; P = 0.007 in the multivariable analysis). Mean subjective knowledge increased by 0.92 points (SD 1.0) in the film + booklet group and 0.55 points (SD 1.1) in the booklet-alone group (β coefficient 0.32; CI, 0.05-0.58; P = 0.02 in the multivariable analysis). Decisional certainty was higher in the film + booklet (mean 8.5/9 points [SD 1.3], group than in the booklet-alone group (mean 8.2/9 points [SD 1.5]). Both information materials were well accepted, and there were no differences in final screening participation rates between groups. Conclusions: The information film improved knowledge and reduced decisional conflict without affecting lung-screening uptake. Clinical trial registered with clinicaltrials.gov (NCT02558101).


Physicochemical characterization of human intestinal lactase.
Human lactase was isolated from solubilized small-intestinal brush-border membranes by a combination of chromatography on concanavalin A-Sepharose, Bio-Gel 1.5m and chromatofocusing, with a yield of approx. 1% and a 750-fold purification. The enzyme appeared to be homogeneous on SDS/polyacrylamide-gel electrophoresis under both reduced and non-reduced conditions, with an apparent Mr of approx. 170,000. On gel filtration, however, it displayed an apparent Mr of approx. 380,000. The protein had a pI of 4.8, as judged by the chromatofocusing experiment, and had a lactase activity whose optimum is at pH 6.0. In addition to the beta-galactosidase activity, the protein also hydrolysed to various extents cellobiose, phlorizin, p-nitrophenyl beta-D-galactoside, p-nitrophenyl beta-D-glucoside, o-nitrophenyl beta-D-galactoside and o-nitrophenyl beta-D-fucoside. Antisera had been raised against the purified enzyme in two rabbits. One of the antibody populations could inhibit the enzyme in a concentration-dependent manner. This antibody population was used to set up an antibody-bound Sepharose column for the use in an immunoaffinity purification of lactase from crude intestinal homogenate. A partially purified preparation of lactase could thus be obtained. The antibody population was also used to set up a radioimmunoassay for quantifying the enzyme. The competition assay could detect about 0.5 micrograms of lactase protein/ml.


Estrogen receptor alpha as a key target of red wine polyphenols action on the endothelium.
A greater reduction in cardiovascular risk and vascular protection associated with diet rich in polyphenols are generally accepted; however, the molecular targets for polyphenols effects remain unknown. Meanwhile evidences in the literature have enlightened, not only structural similarities between estrogens and polyphenols known as phytoestrogens, but also in their vascular effects. We hypothesized that alpha isoform of estrogen receptor (ERalpha) could be involved in the transduction of the vascular benefits of polyphenols. Here, we used ERalpha deficient mice to show that endothelium-dependent vasorelaxation induced either by red wine polyphenol extract, Provinols, or delphinidin, an anthocyanin that possesses similar pharmacological profile, is mediated by ERalpha. Indeed, Provinols, delphinidin and ERalpha agonists, 17-beta-estradiol and PPT, are able to induce endothelial vasodilatation in aorta from ERalpha Wild-Type but not from Knock-Out mice, by activation of nitric oxide (NO) pathway in endothelial cells. Besides, silencing the effects of ERalpha completely prevented the effects of Provinols and delphinidin to activate NO pathway (Src, ERK 1/2, eNOS, caveolin-1) leading to NO production. Furthermore, direct interaction between delphinidin and ERalpha activator site is demonstrated using both binding assay and docking. Most interestingly, the ability of short term oral administration of Provinols to decrease response to serotonin and to enhance sensitivity of the endothelium-dependent relaxation to acetylcholine, associated with concomitant increased NO production and decreased superoxide anions, was completely blunted in ERalpha deficient mice. This study provides evidence that red wine polyphenols, especially delphinidin, exert their endothelial benefits via ERalpha activation. It is a major breakthrough bringing new insights of the potential therapeutic of polyphenols against cardiovascular pathologies.


Anxiety Disorders and the Brain's Resting State Networks: From Altered Spatiotemporal Synchronization to Psychopathological Symptoms.
Anxiety disorders include a variety of different disorders including panic disorder (PD), social anxiety disorder (SAD), generalized anxiety disorder (GAD), and phobias. We here focus our review on GAD, SAD, and PD and put a specific emphasis on resting state networks and the coupling between the brain and the heart as all anxiety disorders exhibit abnormal perception of their own heartbeat in some way or the other. Resting state functional connectivity (rsFC) studies demonstrate abnormalities in default-mode network (DMN) in all anxiety disorders, e.g., mostly decreases in rsFC of DMN. In contrast, resting state fMRI shows increased rsFC in salience network (SN) (SAD, GAD) and/or somato-motor/sensory network (SMN) (PD). Since rsFC is coherence- or phase-based operating in the infraslow frequency domain (0.01-0.1 Hz), these data suggest spatiotemporal hypo- or hyper-synchronization in DMN and SMN/SN, respectively. These abnormalities in the neural network's spatiotemporal synchronization may, in turn, impact phase-based temporal synchronization of neural and cardiac activities resulting in decreased (DMN) or increased (SMN/SN) neuro-cardiac coupling in anxiety disorders. That, in turn, may be related to the various psychopathological symptoms like unstable sense of self (as based on unstable DMN showing spatiotemporal hypo-synchronization), increased emotions and specifically anxiety (as related to increased SN showing spatiotemporal hyper-synchronization), and increased bodily awareness (mediated by increased SMN with spatiotemporal hyper-synchronization) in anxiety disorders. Taken together, we here suggest altered spatiotemporal synchronization of neural and cardiac activity within the brain's resting state to underlie various psychopathological symptoms in anxiety disorders. Such spatiotemporal basis of psychopathological symptoms is well compatible with the recently suggested "Spatiotemporal Psychopathology."


Bacterial resistance: origins, epidemiology, and impact.
The basic mechanisms of antibacterial resistance are well known, but critical new aspects continue to be discovered. Recently discovered factors with major implications for the emergence, dissemination, and maintenance of resistance include multidrug efflux, hypermutability, integrons, and plasmid addiction. Some resistances are widespread and others local, with prevalence rates often worst in newly prosperous countries and in those specialist units where antibacterial use is heaviest. Multidrug-resistant epidemic strains are critical to the total accumulation of resistance (e.g., among Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, Klebsiella pneumoniae), but it remains unclear why some bacterial lineages achieve epidemic spread whereas others that are equally resistant do not. The correlation between in vitro resistance and treatment failure is imperfect, but resistance undoubtedly increases mortality, morbidity, and costs in many settings. Recent concern has led to a plethora of governmental and agency reports advocating less antibacterial use, better antibacterial use, better infection control, and the development of new antibacterials. The evidence that better prescribing can reduce resistance rates is mixed, and although changes to hospital regimens may reduce one resistance problem, other opportunistic bacteria may fill the vacant niche. Overall, the best that can reasonably be anticipated is an improved balance between the accumulation of resistance and new antibacterial development.


Muscular anatomy and aspects of the structure of the antennae of Anthosoma crassum (Dichelesthiidae: Siphonostomatoidae: Copepoda).
The muscular anatomy and fine structure of the antennae of adult Anthosoma crassum are described from specimens collected from jaws of shortfin makos. Casual observations of live parasites showed that embedded adult A. crassum can move toward or away from the host by shortening or lengthening the antennae, respectively. These movements were controlled by antennal retractor muscles. Microprotuberances located on the distal antennal segments may increase friction between these copepods and their hosts, thus strengthening parasite attachment.


Outcome in schizoaffective, psychotic, and nonpsychotic depression. Course during a six- to 24-month follow-up.
In the National Institute of Mental Health Collaborative Study of the Psychobiology of Depression, six-month follow-up evaluations are available for 24 patients with schizoaffective disorder (depressed type), 56 with psychotic depression, and 274 with nonpsychotic major depression. Outcome for patients with schizoaffective depression was significantly worse than for patients with nonpsychotic depression. The psychotic depression group held an intermediate position on most outcome measures and on psychosocial measures had outcomes significantly worse than those of the nonpsychotic group. Recovery rates assumed a very similar pattern in another cohort admitted more than 40 years ago and followed up without somatic treatment. Follow-ups of 12, 18, and 24 months are available for proportions of each diagnostic group. Survival curves suggest similar outcomes in psychotic depression and nonpsychotic depression, whereas outcomes in schizoaffective depression remain disparate. These trends together with family history studies suggest that a small proportion of patients with schizoaffective disorder, depressed type, will have a long-term course consistent with schizophrenia. Moreover, these data show that outcome studies of schizoaffective disorder must control for follow-up length and the effects of psychosis per se.


The Medical Library Association's professional development program: a look back at the way ahead.
Reflecting patterns evident in past Janet Doe Lectures, the 2005 address reviews the Medical Library Association's (MLA's) professional development activities from their beginnings after World War II. A group of related but separate activities is traced through the establishment of an integrated professional development program. A further objective is to introduce newer members of MLA to their heritage and to remind others how the association has reached this point in its history. The lecture provides an overview of the evolution of MLA's professional development program-with emphasis on certification and continuing education in the early years. It further reflects briefly on some of the more recent MLA activities that have greatly impacted professional development and underscores some new initiatives. The efforts of a virtual who's who of MLA's membership have been responsible for the convergence of the association's efforts over more than half a century to provide a comprehensive professional development program. As a participant in MLA's professional development activities for more than forty years, the 2005 lecturer provides a personal view of the growth and expansion of the program. Professional development has been a hallmark of MLA for many years. The association's challenge is to continue to develop creative and innovative programs, to continuously review and revise existing programs, and to have the vision and vitality to maintain a viable program that will provide the membership with the knowledge and skills needed to function effectively now and in the future.


Picosecond-resolved fluorescence studies of substrate and cofactor-binding domain mutants in a thermophilic alcohol dehydrogenase uncover an extended network of communication.
Time-resolved fluorescence dynamics are investigated in two mutants of a thermophilic alcohol dehydrogenase (ht-ADH): Y25A (at the dimer interface) and V260A (at the cofactor-binding domain). These residues, ca. 32 Å apart, are shown to exhibit opposing low-temperature effects on the hydride tunneling step. Using single-tryptophan constructs at the active site (Trp87) and a remote, surface-exposed site (Trp167), time-dependent Stokes shifts and collisional quenching data allow an analysis of intra-protein dynamical communication. A double mutant, Y25A:V260A, was also inserted into each single-Trp construct and analyzed accordingly. None of the mutations affect fluorescence lifetimes, Stokes shift relaxation rates, and quenching data for the surface-exposed Trp167 to an appreciable extent. By contrast, fluorescent probes of the active-site tryptophan 87 reveal distinctive forms of dynamical communication. Stokes shifts show that the distal Y25A increases active-site flexibility, V260A introduces a temperature-dependent equilibration process not previously reported by such measurements, and the double mutant (Y25A:V260A) eliminates the temperature-dependent transition sensed by the active-site tryptophan in the presence of V260A. Collisional quenching data at Trp87 further show a structural change in the active-site environment/solvation for V260A. In the aggregate, the temperature dependencies of the fluorescence data are distinct from the breaks in behavior previously reported for catalysis and hydrogen/deuterium exchange, attributed to time scales for the interconversion of protein conformational substates that are slower and more global than the local motions monitored within. An extended network of dynamical communication between the protein dimer surface and substrate- and cofactor-binding domains emerges from the flourescent data.


Housing need, housing assistance, and connection to HIV medical care.
HIV infection has become a chronic condition that for most persons can be effectively managed with regular monitoring and appropriate medical care. However, many HIV positive persons remain unconnected to medical care or have less optimal patterns of health care utilization than recommended by good clinical practice standards. This paper investigates housing status as a contextual factor affecting access and maintenance in appropriate HIV medical care. Data provided from 5,881 interviews conducted from 1994 to 2006 with a representative sample of 1,661 persons living with HIV/AIDS in New York City demonstrated a strong and consistent relationship between housing need and remaining outside of or marginal to HIV medical care. In contrast, housing assistance increased access and retention in medical care and appropriate treatment. The relationship between housing and medical care outcomes remain controlling for client demographics, health status, insurance coverage, co-occurring mental illness, and problem drug use and the receipt of supportive services to address co-occurring conditions. Findings provide strong evidence that housing needs are a significant barrier to consistent, appropriate HIV medical care, and that receipt of housing assistance has an independent, direct impact on improved medical care outcomes.


Characterization of a P2X-purinoceptor in cultured neurones of the rat dorsal root ganglia.
1. The electrophysiological actions of the P2-purinoceptor agonists, adenosine 5'-triphosphate (ATP), 2-methylthio ATP (2-meSATP) and alpha, beta-methyleneATP (alpha, beta-meATP) and of uridine 5'-triphosphate (UTP) were studied under concentration and voltage-clamp conditions in dissociated neurones of 1-6 day old rat dorsal root ganglia. 2. ATP (10 nM-100 microM) applied rapidly via a U-tube perfusion system (equilibration time < 10 ms) activated concentration-dependent inward currents with a latency to onset of a few ms, an EC50 of 719 nM and a Hill slope of 1.47. 3. 2-meSATP (10 nM- 100 microM) and alpha, beta-meATP (100 nM - 100 microM) also evoked transient inward currents. The EC50 and Hill slopes were 450 nM and 1.58 for 2-meSATP and 1.95 microM and 1.53 for alpha, beta-meATP respectively. There was no significant difference between the maximum currents evoked by the three agonists. 4. As the concentration of ATP increased so the rate of rise and decay of the currents also increased. At 100 and 300 nM ATP the decay of the current was best fitted by a single exponential, but at 1 microM and above two exponentials were required. Log-log plots of the rise time or time constants of decay versus concentration were linear. Currents evoked by 2-meSATP and alpha, beta-meATP showed a similar concentration-dependence in their kinetics. 5. Inward currents evoked by ATP, 2-meSATP and alpha, beta-meATP (300 nM) were abolished by the P2-purinoceptor antagonist, suramin (100 microM). 6. UTP (10 microM) evoked similar transient inward currents, which were sensitive to suramin (100 microM). ATP (10 microM), applied 2 min beforehand, reduced the response to UTP (10 microM) by 80 +/- 10%. 7. This study shows that ATP, 2-meSATP and alpha, beta-meATP act via a suramin-sensitive P2x-purinoceptor to evoke rapid, transient inward currents in dissociated neurones of rat dorsal root ganglia. The pyrimidine nucleotide, UTP, was also active. It is likely that the agonists were acting at the P2x3-subtype to produce these effects.


Efficacy of quinine against ichthyophthiriasis in common carp Cyprinus carpio.
Ichthyophthiriasis, caused by Ichthyophthirius multifiliis, is an economically important worldwide parasitic disease that infects all freshwater fish. Since the banning of malachite green for use in food fish, there has been a great need for alternative therapeutants. The goal of this study was to investigate the efficacy of quinine against I. multifiliis. Parasite developmental stages from our laboratory-established life cycle in rainbow trout Oncorhynchus mykiss were exposed to quinine in vitro, and a dual fluorescent staining technique was used to allow a clear distinction between viable and damaged parasites. Furthermore, the effect of quinine was assessed in vivo by oral administration and intraperitoneal injections in common carp Cyprinus carpio. The results of the in vitro experiments proved quinine to be effective against the parasite. Quinine injected at a dosage of 60 mg kg(-1) body weight resulted in a significantly lower number of trophonts. In contrast, in-feed trials did not show a significant reduction of trophonts after treatment commencing 1 d after infection with concentrations of up to 20 g quinine kg(-1) feed for 3 d. After a 14-d treatment at concentrations of up to 10 g quinine kg(-1) feed prior to theront exposure, there was also no significant difference in parasite numbers between treated and control groups. The results of oral versus parenteral application of quinine indicate that the substance is not completely absorbed from the intestinal tract of common carp. However, medicated feed containing higher concentrations of quinine was less readily accepted by the fish, presumably due to the bitter taste.


Refining the measurement of physician job satisfaction: results from the Physician Worklife Survey. SGIM Career Satisfaction Study Group. Society of General Internal Medicine.
Physician job satisfaction has been linked to various patient care and health system outcomes. A survey instrument that concisely measures physicians' satisfaction with various job facets can help diverse stake-holders to better understand and manage these outcomes. To document the development and validation of a multidimensional physician job satisfaction measure and separate global satisfaction measures. Self-administered questionnaire: Physician Worklife Survey (PWS). A pilot study employed a national American Medical Association Masterfile sample of US primary care physicians and random samples from four states. Responses (n = 835; 55% return rate) were randomly assigned to developmental (n = 560) or cross-validation (n = 275) samples. A national sample (n = 2,325; 52% response rate) of physicians was used in a subsequent validation study. A 38-item, 10-facet satisfaction measure resulting from factor and reliability analyses of 70 pilot items was further reduced to 36 items. Reliabilities of the 10 facets ranged from .65 to .77. Three scales measuring global job, career, and specialty satisfaction were also constructed with reliabilities from .84 to .88. Results supported face, content, convergent, and discriminant validity of the measures. Physician job satisfaction is a complex phenomenon that can be measured using the PWS.


Accounting for Uncertainty in Gene Tree Estimation: Summary-Coalescent Species Tree Inference in a Challenging Radiation of Australian Lizards.
Accurate gene tree inference is an important aspect of species tree estimation in a summary-coalescent framework. Yet, in empirical studies, inferred gene trees differ in accuracy due to stochastic variation in phylogenetic signal between targeted loci. Empiricists should, therefore, examine the consistency of species tree inference, while accounting for the observed heterogeneity in gene tree resolution of phylogenomic data sets. Here, we assess the impact of gene tree estimation error on summary-coalescent species tree inference by screening ${\sim}2000$ exonic loci based on gene tree resolution prior to phylogenetic inference. We focus on a phylogenetically challenging radiation of Australian lizards (genus Cryptoblepharus, Scincidae) and explore effects on topology and support. We identify a well-supported topology based on all loci and find that a relatively small number of high-resolution gene trees can be sufficient to converge on the same topology. Adding gene trees with decreasing resolution produced a generally consistent topology, and increased confidence for specific bipartitions that were poorly supported when using a small number of informative loci. This corroborates coalescent-based simulation studies that have highlighted the need for a large number of loci to confidently resolve challenging relationships and refutes the notion that low-resolution gene trees introduce phylogenetic noise. Further, our study also highlights the value of quantifying changes in nodal support across locus subsets of increasing size (but decreasing gene tree resolution). Such detailed analyses can reveal anomalous fluctuations in support at some nodes, suggesting the possibility of model violation. By characterizing the heterogeneity in phylogenetic signal among loci, we can account for uncertainty in gene tree estimation and assess its effect on the consistency of the species tree estimate. We suggest that the evaluation of gene tree resolution should be incorporated in the analysis of empirical phylogenomic data sets. This will ultimately increase our confidence in species tree estimation using summary-coalescent methods and enable us to exploit genomic data for phylogenetic inference. [Coalescence; concatenation; Cryptoblepharus; exon capture; gene tree; phylogenomics; species tree.].


Subdural empyema, brain abscess, and superior sagittal sinus venous thrombosis secondary to Streptococcus anginosus.
Streptococcus anginosus can be frequently isolated from brain abscesses, but is a rare cause of the liver, lung, and deep tissue abscesses. In this report, we present a patient with subdural empyema, brain abscess, and superior sagittal cerebral venous thrombosis as complications of rhinosinusitis whose purulent empyema sample yielded S. anginosus. A 13-year-old female patient was referred to our pediatric intensive care unit with altered mental status, aphasia, and behavioral change. On a brain computed tomography scan, subdural empyema extending from the left frontal sinus to the frontal interhemispheric area and left hemispheric dura was detected. Intravenous ceftriaxone, vancomycin, and metronidazole treatments were started. Subdural empyema was surgically drained. Postoperative brain magnetic resonance venography imaging showed superior sagittal sinus thrombosis. Cultures obtained from purulent empyema sample revealed S. anginosus. On the third day of hospitalization, a brain computed tomography scan showed brain edema, especially in the left hemisphere and significantly increased subdural empyema that had been previously drained. She was reoperated and decompressive craniectomy was performed. On the fifth day, partial epileptic seizures occurred. Brain magnetic resonance imaging showed a brain abscess on the interhemispheric area. The magnetic resonance imaging findings of abscess formation improved on 30th day and she was discharged on the 45th day after the completion of antibiotic therapy.


How does private finance affect public health care systems? Marshaling the evidence from OECD nations.
The impact of private finance on publicly funded health care systems depends on how the relationship between public and private finance is structured. This essay first reviews the experience in five nations that exemplify different ways of drawing the public/private boundary to address the particular questions raised by each model. This review is then used to interpret aggregate empirical analyses of the dynamic effects between public and private finance in OECD nations over time. Our findings suggest that while increases in the private share of health spending substitute in part for public finance (and vice versa), this is the result of a complex mix of factors having as much to do with cross-sectoral shifts as with deliberate policy decisions within sectors and that these effects are mediated by the different dynamics of distinctive national models. On balance, we argue that a resort to private finance is more likely to harm than to help publicly financed systems, although the effects will vary depending on the form of private finance.


The power of the liver transplant waiting list: a case presentation.
End-stage liver disease (ESLD), the final stage of chronic liver disease, is treated with liver transplant. Many patients have serious ESLD-related complications and are admitted to the intensive care unit for treatment. Such patients are temporarily unsuitable to undergo transplant surgery and are placed into a temporarily inactive category, "status 7," on the transplant waiting list. Status 7 patients account for about 15% of all patients on the list. To describe the experience of a status 7 patient on the liver transplant waiting list from the perspectives of family members, 38 hours of bedside observation of participants, 9 semistructured interviews with 6 family members, and 9 semistructured interviews with 8 health care professionals from nursing, medicine, and other health care disciplines were done. Data were analyzed via conventional content analysis. Family members' perspectives fit into 3 phases that correspond to the progression of the patient's clinical condition: dealing with crisis, confusion and frustration, and back on the road to transplant. All 3 phases related to 1 goal: getting the patient's status reactivated on the liver transplant waiting list. This case exposes the struggles that patients with ESLD and their families may go through during the status 7 period and could serve as a starting point for further examination of this period.


Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males.
Four agents--acarbose (ACA), 17-α-estradiol (EST), nordihydroguaiaretic acid (NDGA), and methylene blue (MB)--were evaluated for lifespan effects in genetically heterogeneous mice tested at three sites. Acarbose increased male median lifespan by 22% (P < 0.0001), but increased female median lifespan by only 5% (P = 0.01). This sexual dimorphism in ACA lifespan effect could not be explained by differences in effects on weight. Maximum lifespan (90th percentile) increased 11% (P < 0.001) in males and 9% (P = 0.001) in females. EST increased male median lifespan by 12% (P = 0.002), but did not lead to a significant effect on maximum lifespan. The benefits of EST were much stronger at one test site than at the other two and were not explained by effects on body weight. EST did not alter female lifespan. NDGA increased male median lifespan by 8-10% at three different doses, with P-values ranging from 0.04 to 0.005. Females did not show a lifespan benefit from NDGA, even at a dose that produced blood levels similar to those in males, which did show a strong lifespan benefit. MB did not alter median lifespan of males or females, but did produce a small, statistically significant (6%, P = 0.004) increase in female maximum lifespan. These results provide new pharmacological models for exploring processes that regulate the timing of aging and late-life diseases, and in particular for testing hypotheses about sexual dimorphism in aging and health.


Rapid Repression of ADP Transport by Palmitoyl-CoA Is Attenuated by Exercise Training in Humans: A Potential Mechanism to Decrease Oxidative Stress and Improve Skeletal Muscle Insulin Signaling.
Mitochondrial ADP transport may represent a convergence point unifying two prominent working models for the development of insulin resistance, as reactive lipids (specifically palmitoyl-CoA [P-CoA]) can inhibit ADP transport and subsequently increase mitochondrial reactive oxygen species emissions. In the current study, we aimed to determine if exercise training in humans diminished P-CoA attenuation of mitochondrial ADP respiratory sensitivity. Six weeks of exercise training increased whole-body glucose homeostasis and skeletal muscle Akt signaling and reduced markers of oxidative stress without reducing maximal mitochondrial H2O2 emissions. To ascertain if enhanced mitochondrial ADP transport contributed to the improvement in the in vivo oxidative state, we determined mitochondrial ADP sensitivity in the presence and absence of P-CoA. In the absence of P-CoA, exercise training reduced mitochondrial ADP sensitivity. In contrast, exercise training increased mitochondrial ADP sensitivity with P-CoA present. We further show that P-CoA noncompetitively inhibits mitochondrial ADP transport and the ability of ADP to attenuate mitochondrial H2O2 emission. Altogether, the current data provide a potential mechanism for how P-CoA contributes to insulin resistance and highlight the ability of exercise training to diminish P-CoA attenuation in mitochondrial ADP transport.


Bacillus velezensis DP-2 isolated from Douchi and its application in soybean meal fermentation.
Soybean meal (SBM) is the most common protein source used in the poultry and livestock industries. It has high-quality protein, an excellent amino acid (AA) profile, and positive isoflavone properties. However, the antigen proteins in SBM are unsuitable for young animals. The objective of this study was to identify a Bacillus strain that can degrade soybean antigen proteins, and to evaluate the feasibility of its application in SBM fermentation. Bacillus velezensis DP-2 was isolated from Douchi, a fermented Chinese food. It degraded 96.14% and 66.51% of glycinin and β-conglycinin, and increased the trichloroacetic acid-soluble protein (TCAN) content by 5.46 times in the SBM medium. DP-2 could secrete alkaline protease and neutral protease, with productivities of 5.85 and 5.99 U mL-1 . It had broad-spectrum, antibacterial activities against Rhizopus nigricans HR, Fusarium oxysporum ACCC37404, Penicillium digitatum SQ2, Aspergillus flavus C1, Aspergillus niger ACCC30005, Trichoderma viride YZ1, Candida tropicalis CICC1630, and Salmonella sp. ZY. For SBM fermentation, the optimal inoculum rate, temperature, and fermentation time of DP-2 were 2.21 × 107 CFU g-1 , 37 °C, and 48 h, respectively. The fermented soybean meal (FSBM) was cream-colored and glutinous. Its crude protein (CP), soluble protein, and TCA-N content were improved by 13.45%, 12.53%, and 6.37 times, respectively. The glycinin and β-conglycinin content were reduced by 78.00% and 43.07%, respectively, compared with raw SBM. Bacillus velezensis DP-2 has potential as a starter culture for SBM fermentation. © 2020 Society of Chemical Industry.


Three dimensional imaging with randomly distributed sensors.
As a promising three dimensional passive imaging modality, Integral Imaging (II) has been investigated widely within the research community. In virtually all of such investigations, there is an implicit assumption that the collection of elemental images lie on a simple geometric surface (e.g. flat, concave, etc), also known as pickup surface. In this paper, we present a generalized framework for 3D II with arbitrary pickup surface geometry and randomly distributed sensor configuration. In particular, we will study the case of Synthetic Aperture Integral Imaging (SAII) with random location of cameras in space, while all cameras have parallel optical axes but different distances from the 3D scene. We assume that the sensors are randomly distributed in 3D volume of pick up space. For 3D reconstruction, a finite number of sensors with known coordinates are randomly selected from within this volume. The mathematical framework for 3D scene reconstruction is developed based on an affine transform representation of imaging under geometrical optics regime. We demonstrate the feasibility of the methods proposed here by experimental results. To the best of our knowledge, this is the first report on 3D imaging using randomly distributed sensors.


Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. The National Epidemiology of Mycosis Survey.
To assess risk factors for development of candidal blood stream infections (CBSIs), a prospective cohort study was performed at 6 sites that involved all patients admitted to the surgical intensive care unit (SICU) for >48 h over a 2-year period. Among 4276 such patients, 42 CBSIs occurred (9.82 CBSIs per 1000 admissions). The overall incidence was 0.98 CBSIs per 1000 patient days and 1.42 per 1000 SICU days with a central venous catheter in place. In multivariate analysis, factors independently associated with increased risk of CBSI included prior surgery (relative risk [RR], 7.3), acute renal failure (RR, 4.2), receipt of parenteral nutrition (RR, 3.6), and, for patients who had undergone surgery, presence of a triple lumen catheter (RR, 5.4). Receipt of an antifungal agent was associated with decreased risk (RR, 0.3). Prospective clinical studies are needed to identify which antifungal agents are most protective and which high-risk patients will benefit from antifungal prophylaxis.


Consumer-resource coupling in wet-dry tropical rivers.
1. Despite implications for top-down and bottom-up control and the stability of food webs, understanding the links between consumers and their diets remains difficult, particularly in remote tropical locations where food resources are usually abundant and variable and seasonal hydrology produces alternating patterns of connectivity and isolation. 2. We used a large scale survey of freshwater biota from 67 sites in three catchments (Daly River, Northern Territory; Fitzroy River, Western Australia; and the Mitchell River, Queensland) in Australia's wet-dry tropics and analysed stable isotopes of carbon (δ(13) C) to search for broad patterns in resource use by consumers in conjunction with known and measured indices of connectivity, the duration of floodplain inundation, and dietary choices (i.e. stomach contents of fish). 3. Regression analysis of biofilm δ(13) C against consumer δ(13) C, as an indicator of reliance on local food sources (periphyton and detritus), varied depending on taxa and catchment. 4. The carbon isotope ratios of benthic invertebrates were tightly coupled to those of biofilm in all three catchments, suggesting assimilation of local resources by these largely nonmobile taxa. 5. Stable C isotope ratios of fish, however, were less well-linked to those of biofilm and varied by catchment according to hydrological connectivity; the perennially flowing Daly River with a long duration of floodplain inundation showed the least degree of coupling, the seasonally flowing Fitzroy River with an extremely short flood period showed the strongest coupling, and the Mitchell River was intermediate in connectivity, flood duration and consumer-resource coupling. 6. These findings highlight the high mobility of the fish community in these rivers, and how hydrological connectivity between habitats drives patterns of consumer-resource coupling.


Activity performance problems of patients with cardiac diseases and their impact on quality of life.
[Purpose] To describe the functional consequences of patients with cardiac diseases and analyze associations between activity limitations and quality of life. [Subjects and Methods] Seventy subjects (mean age: 60.1±12.0 years) were being treated by Physical Medicine and Rehabilitation and Cardiology Departments were included in the study. Activity limitations and participation restrictions as perceived by the individual were measured by the Canadian Occupational Performance Measure (COPM). The Nottingham Extended Activities of Daily Living (NEADL) Scale was used to describe limitations in daily living activities. To detect the impact of activity limitations on quality of life the Nottingham Health Profile (NHP) was used. [Results] The subjects described 46 different types of problematic activities. The five most identified problems were walking (45.7%), climbing up the stairs (41.4%), bathing (30%), dressing (28.6%) and outings (27.1%). The associations between COPM performance score with all subgroups of NEADL and NHP; total, energy, physical abilities subgroups, were statistically significant. [Conclusion] Our results showed that patients with cardiac diseases reported problems with a wide range of activities, and that also quality of life may be affected by activities of daily living. COPM can be provided as a patient-focused outcome measure, and it may be a useful tool for identifying those problems.


Ecological network analysis of an urban metabolic system based on input-output tables: model development and case study for Beijing.
If cities are considered as "superorganisms", then disorders of their metabolic processes cause something analogous to an "urban disease". It is therefore helpful to identify the causes of such disorders by analyzing the inner mechanisms that control urban metabolic processes. Combining input-output analysis with ecological network analysis lets researchers study the functional relationships and hierarchy of the urban metabolic processes, thereby providing direct support for the analysis of urban disease. In this paper, using Beijing as an example, we develop a model of an urban metabolic system that accounts for the intensity of the embodied ecological elements using monetary input-output tables from 1997, 2000, 2002, 2005, and 2007, and use this data to compile the corresponding physical input-output tables. This approach described the various flows of ecological elements through urban metabolic processes and let us build an ecological network model with 32 components. Then, using two methods from ecological network analysis (flow analysis and utility analysis), we quantitatively analyzed the physical input-output relationships among urban components, determined the ecological hierarchy of the components of the metabolic system, and determined the distribution of advantage-dominated and disadvantage-dominated relationships, thereby providing scientific support to guide restructuring of the urban metabolic system in an effort to prevent or cure urban "diseases".


A Rare Case of Rib Fractures During Centrifuge Training.
There are several injuries potentially related to high-G exposure, including neck and back pain, spinal fractures, and pneumomediastinum. We present a young military pilot diagnosed with isolated fractures of the right 9th and 10th ribs via X-ray after high-G exposure (maximum G level: 9G). This patient presented with progressive and localized pain in the right anterior chest and flank region. After conservative treatment with rest and pain management, he recovered from the rib fractures and completed all profile challenges in the advanced high-G training program. A review of the annual health examination of the pilot did not show any rib lesions or other related illnesses. He was qualified for flying class II and considered fit for flight training. His medication history was unremarkable, and he did not have a family history of malignancy, osteoporosis, or osteopenia. He also denied having previously experienced trauma of the rib cage or participated in any strenuous military training program or exercise before centrifuge training. The potential explanations for the multiple rib fractures are repetitive stress from the anti-G straining maneuver and anti-G suit compression of the abdominal bladder. To our knowledge, consecutive rib fractures related to high-G exposure have never been documented. This report may increase the awareness of flight surgeons and training units regarding the risk of chest wall injuries during high-G exposure and encourage them to use multiple diagnostic tools to determine the correct diagnosis.


[Thyroid and lipidic dysfunction associated with bexarotene in cutaneous T-cell lymphoma].
Bexarotene is a synthetic selective X receptor rexinoide approved for the systemic treatment of cutaneous T-cell lymphoma. During treatment is very frequent the occurrence of hypothyroidism and severe mixed hyperlipidemia, both are reversibles and dose-dependent adverse events. Increase of triglycerides and LDL-cholesterol level (up to even higher levels have been associated with pancreatitis in some cases) is widely described (as is the case with other retinoids) but decrease in HDL-cholesterol is poored know. We review our experience with the use of bexarotene. We present a serie of 3 clinical report of patients treated with bexarotene in whose, in addition to these well-known adverse event, a serious lowering of HDL-cholesterol was observed. The 3 patients studied had metabolic complications like central hypothyroidism and severe mixed hyperlipidemia; with special emphasis on the sharp fall (mean decrease>83%) in the HDL-cholesterol level. Cholesterol lowering medication and substitutive hormonal replacement with levotiroxine resulted in an improvement of the biochimical parameters without reaching the correct goals. Bexarotene produce as predictable side effects severe mixed hyperlipidemia with marked decrease in HDL-cholesterol levels and central hypothyroidism, being the both reversible and dose-dependent. A reflection on the possible aetiological mechanisms and implications of this phenomenon are included.


A retrospective study of the MRI findings in 18 dogs with stifle injuries.
To make an objective assessment of the usefulness of magnetic resonance imaging in the diagnosis of meniscal damage and cranial cruciate ligament disease in the canine stifle by comparing magnetic resonance imaging findings with surgical findings. Magnetic resonance images of 18 stifles from 18 dogs which had undergone magnetic resonance imaging for the investigation of stifle disease were reviewed. For every stifle, the menisci and cranial cruciate ligaments were assessed according to predetermined criteria. The magnetic resonance imaging findings were compared with the reported surgical findings and the sensitivity, specificity, positive and negative predictive values (PPV and NPV) were calculated using the surgical findings as the gold standard. Kappa analysis was used as an objective measure of agreement between surgical and magnetic resonance imaging findings. For 11 stifles, meniscal evaluation by three different observers was used to measure interobserver agreement using Kappa analysis. Magnetic resonance imaging was demonstrated to be an accurate technique in the detection of meniscal injury (k=0.86), with excellent interobserver agreement (k=0.89 to 1.0). Disruption of cranial cruciate ligament continuity and an increase in ligament intensity were found to be useful criteria in the diagnosis of cranial cruciate ligament rupture. Magnetic resonance imaging offers a non-invasive alternative to exploratory surgery in the evaluation of cranial cruciate ligament and meniscal disease.


Nutrient sensing, growth and senescence.
Cell growth is dictated by a wide range of mitogenic signals, the amplitude and relative contribution of which vary throughout development, differentiation and in a tissue-specific manner. The ability to sense and appropriately respond to changes in mitogens is fundamental to control cell growth, and reduced responsiveness of nutrient sensing pathways is widely associated with human disease and ageing. Cellular senescence is an important tumour suppressor mechanism that is characterised by an irreversible exit from the cell cycle in response to replicative exhaustion or excessive DNA damage. Despite the fact that senescent cells can no longer divide, they remain metabolically active and display a range of pro-growth phenotypes that are supported in part by the mTORC1-autophagy signalling axis. As our understanding of the basic mechanisms of controlling mTORC1-autophagy activity and cell growth continues to expand, we are able to explore how changes in nutrient sensing contribute to the acquisition and maintenance of cellular senescence. Furthermore, while the protective effect of senescence to limit cellular transformation is clear, more recently, the age-related accumulation of these pro-inflammatory senescent cells has been shown to contribute to a decline in organismal fitness. We will further discuss whether dysregulation of nutrient sensing pathways can be targeted to promote senescent cell death which would have important implications for healthy ageing.


Life in the fast lane? Towards a sociology of technology and time.
Assumptions about the pace of life speeding up abound in contemporary social theory. While many factors are contributing to this phenomenon, information and communication technologies are seen as the main drivers. This article considers the way social theorists analyse the concepts of time and speed and then examines how these claims might be assessed in the light of empirical research. Such research shows that time compression has multiple dimensions, and that the effect of digital devices like the mobile phone is not simply one of acceleration. In particular, I suggest that the social studies of technology offers a richer analysis of the reciprocal relationship between technological innovation and changing time practices. My argument is that while the hitherto neglected temporal dimension in sociological theory is now being addressed, there is an urgent need for increased dialogue to connect social theory with detailed empirical studies. Without this, we will continue to have difficulty distinguishing social science from science fiction.


Androgen receptor-dependent and -independent mechanisms driving prostate cancer progression: Opportunities for therapeutic targeting from multiple angles.
Despite aggressive treatment for localized cancer, prostate cancer (PC) remains a leading cause of cancer-related death for American men due to a subset of patients progressing to lethal and incurable metastatic castrate-resistant prostate cancer (CRPC). Organ-confined PC is treated by surgery or radiation with or without androgen deprivation therapy (ADT), while options for locally advanced and disseminated PC include radiation combined with ADT, or systemic treatments including chemotherapy. Progression to CRPC results from failure of ADT, which targets the androgen receptor (AR) signaling axis and inhibits AR-driven proliferation and survival pathways. The exact mechanisms underlying the transition from androgen-dependent PC to CRPC remain incompletely understood. Reactivation of AR has been shown to occur in CRPC despite depletion of circulating androgens by ADT. At the same time, the presence of AR-negative cell populations in CRPC has also been identified. While AR signaling has been proposed as the primary driver of CRPC, AR-independent signaling pathways may represent additional mechanisms underlying CRPC progression. Identification of new therapeutic strategies to target both AR-positive and AR-negative PC cell populations and, thereby, AR-driven as well as non-AR-driven PC cell growth and survival mechanisms would provide a two-pronged approach to eliminate CRPC cells with potential for synthetic lethality. In this review, we provide an overview of AR-dependent and AR-independent molecular mechanisms which drive CRPC, with special emphasis on the role of the Jak2-Stat5a/b signaling pathway in promoting castrate-resistant growth of PC through both AR-dependent and AR-independent mechanisms.


Patients' Experiences After Attempted Suicide: A Literature Review.
The aim of this study has been to synthesize research on suicidal patients' experiences of the suicide process. A literature search was performed in CINAHL, PubMed, and PsycINFO, and the analysis of the 15 articles covered was based on meta-synthesis. Patients experience a wide variety of feelings regarding their situation during the suicide process, and these exist on two levels: they relate to the different aspects of care that the patients receive and the patients' need to communicate with others and regain hope. The patients in this study described the struggle to maintain hope when life became too difficult and their suffering despite a sense of security, and they sought to achieve emotional balance. A good understanding of how suicidal individuals live with and manage suicidal ideation, while maintaining hope is important for planning effective nursing care. Further research from the patient perspective is needed to further develop psychiatric care for people at risk of suicide.


The nature, frequency and course of psychiatric disorders in the first year after traumatic brain injury: a prospective study.
Psychiatric disorders are common following traumatic brain injury (TBI). However, few studies have examined the course of disorder development and the influence of pre-injury psychiatric history. The present study aimed to examine the frequency of, and association between, psychiatric disorders occurring pre- and post-injury, and to examine the post-injury course of disorders. Participants were 102 adults (75.5% male) with predominantly moderate-severe TBI. Participants were initially assessed for pre-injury and current disorders, and reassessed at 3, 6 and 12 months post-injury using the Structured Clinical Interview for DSM-IV Disorders (SCID). Over half of the participants had a pre-injury psychiatric disorder; predominantly substance use, mood, and anxiety disorders. In the first year post-injury, 60.8% of participants had a psychiatric disorder, commonly anxiety and mood disorders. Post-injury disorders were associated with the presence of a pre-injury history (p<0.01), with 74.5% of participants with a pre-injury psychiatric history experiencing a post-injury disorder, which commonly presented at initial assessment or in the first 6 months. However, 45.8% of participants without a pre-injury history developed a novel post-injury disorder, which was less likely to emerge at the initial assessment and generally developed later in the year. Despite evidence that most post-injury psychiatric disorders represent the continuation of pre-existing disorders, a significant number of participants developed novel psychiatric disorders. This study demonstrates that the timing of onset may differ according to pre-injury history. There seem to be different trajectories for anxiety and depressive disorders. This research has important implications for identifying the time individuals are most at risk of psychiatric disorders post-injury.


Urban cholera transmission hotspots and their implications for reactive vaccination: evidence from Bissau city, Guinea bissau.
Use of cholera vaccines in response to epidemics (reactive vaccination) may provide an effective supplement to traditional control measures. In Haiti, reactive vaccination was considered but, until recently, rejected in part due to limited global supply of vaccine. Using Bissau City, Guinea-Bissau as a case study, we explore neighborhood-level transmission dynamics to understand if, with limited vaccine and likely delays, reactive vaccination can significantly change the course of a cholera epidemic. We fit a spatially explicit meta-population model of cholera transmission within Bissau City to data from 7,551 suspected cholera cases from a 2008 epidemic. We estimated the effect reactive vaccination campaigns would have had on the epidemic under different levels of vaccine coverage and campaign start dates. We compared highly focused and diffuse strategies for distributing vaccine throughout the city. We found wide variation in the efficiency of cholera transmission both within and between areas of the city. "Hotspots", where transmission was most efficient, appear to drive the epidemic. In particular one area, Bandim, was a necessary driver of the 2008 epidemic in Bissau City. If vaccine supply were limited but could have been distributed within the first 80 days of the epidemic, targeting vaccination at Bandim would have averted the most cases both within this area and throughout the city. Regardless of the distribution strategy used, timely distribution of vaccine in response to an ongoing cholera epidemic can prevent cases and save lives. Reactive vaccination can be a useful tool for controlling cholera epidemics, especially in urban areas like Bissau City. Particular neighborhoods may be responsible for driving a city's cholera epidemic; timely and targeted reactive vaccination at such neighborhoods may be the most effective way to prevent cholera cases both within that neighborhood and throughout the city.


Search for Higgs Boson Decays into a Z Boson and a Light Hadronically Decaying Resonance Using 13 TeV pp Collision Data from the ATLAS Detector.
A search for Higgs boson decays into a Z boson and a light resonance in two-lepton plus jet events is performed, using a pp collision dataset with an integrated luminosity of 139 fb^{-1} collected at sqrt[s]=13 TeV by the ATLAS experiment at the CERN LHC. The resonance considered is a light boson with a mass below 4 GeV from a possible extended scalar sector or a charmonium state. Multivariate discriminants are used for the event selection and for evaluating the mass of the light resonance. No excess of events above the expected background is found. Observed (expected) 95% confidence-level upper limits are set on the Higgs boson production cross section times branching fraction to a Z boson and the signal resonance, with values in the range 17-340 pb (16_{-5}^{+6}-320_{-90}^{+130} pb) for the different light spin-0 boson mass and branching fraction hypotheses, and with values of 110 and 100 pb (100_{-30}^{+40} and 100_{-30}^{+40} pb) for the η_{c} and J/ψ hypotheses, respectively.


Patterns and predictors of formal and informal care among elderly persons living in board and care homes.
The purpose of this study was to investigate the patterns and predictors of formal and informal help among a sample of older persons living in board and care homes (N = 617). Formal helpers such as facility staff, service agencies, and community organizations were the most common providers of assistance, particularly for activities of daily living (ADLs; e.g., bathing, dressing, toileting) that required close and continual proximity. Informal helpers such as family members, friends, and other residents were most likely to assist with instrumental ADL (IADL) tasks such as shopping and getting around outside. The need for assistance with ADLs predicted the amount of formal ADL help received by residents, whereas both ADL need and the presence of mental illness predicted the amount of IADL help received from formal sources. In contrast, demographic factors such as gender and race, as well as the frequency of family contact, predicted the amount of informal help with IADL tasks. White residents, women, and those with frequent family contact were among those most likely to receive assistance from informal helpers. The results suggest the need to encourage the provision of informal assistance as well as the need to ensure the availability of sufficient staff and other formal helpers are available to provide formal care in these settings.


Effects of acute hypergravity exposure and parity on maternal behavior in CD-1 mice.
We assessed the behavioral response to acute hypergravity exposure in lactating mother mice, Mus musculus of the outbred CD-1 strain. Primiparous or terziparous dams were exposed with their litters to a centrifugal force equivalent to 2G hypergravity for 1 h daily from postnatal day 2 (P2) to P9. We made detailed behavioral observations before, during and after the rotation on selected days to identify elements of the maternal behavioral repertoire vulnerable to 2G challenge. Licking and nest building were reduced during rotation while mothers sniffed and snouted their pups more. Nursing and total time in physical contact with pups were relatively stable. The effects of rotation were most pronounced on P2, dams appearing to habituate to the treatment with repeated exposure. Dam parity had a limited effect on the behavioral response to rotation, primiparous mothers tending to spend longer nursing their pups during the rotation and showing a greater tendency to lick and nest-build in post-rotation. Differences between parity groups diminished over days. Body weight was decreased in rotated primiparous dams and their pups gained less weight than stationary controls. Ultrasonic vocalization (USV) rates recorded on P2, P5 and P9 seemed to indicate delayed behavioral development in rotated pups.


A framework to develop semiautomated surveillance of surgical site infections: An international multicenter study.
Automated surveillance of healthcare-associated infections reduces workload and improves standardization, but it has not yet been adopted widely. In this study, we assessed the performance and feasibility of an easy implementable framework to develop algorithms for semiautomated surveillance of deep incisional and organ-space surgical site infections (SSIs) after orthopedic, cardiac, and colon surgeries. Retrospective cohort study in multiple countries. European hospitals were recruited and selected based on the availability of manual SSI surveillance data from 2012 onward (reference standard) and on the ability to extract relevant data from electronic health records. A questionnaire on local manual surveillance and clinical practices was administered to participating hospitals, and the information collected was used to pre-emptively design semiautomated surveillance algorithms standardized for multiple hospitals and for center-specific application. Algorithm sensitivity, positive predictive value, and reduction of manual charts requiring review were calculated. Reasons for misclassification were explored using discrepancy analyses. The study included 3 hospitals, in the Netherlands, France, and Spain. Classification algorithms were developed to indicate procedures with a high probability of SSI. Components concerned microbiology, prolonged length of stay or readmission, and reinterventions. Antibiotics and radiology ordering were optional. In total, 4,770 orthopedic procedures, 5,047 cardiac procedures, and 3,906 colon procedures were analyzed. Across hospitals, standardized algorithm sensitivity ranged between 82% and 100% for orthopedic surgery, between 67% and 100% for cardiac surgery, and between 84% and 100% for colon surgery, with 72%-98% workload reduction. Center-specific algorithms had lower sensitivity. Using this framework, algorithms for semiautomated surveillance of SSI can be successfully developed. The high performance of standardized algorithms holds promise for large-scale standardization.


Design and calibration of a digital Fourier holographic microscope for particle sizing via goniometry and optical scatter imaging in transmission.
Goniometry and optical scatter imaging have been used for optical determination of particle size based upon optical scattering. Polystyrene microspheres in suspension serve as a standard for system validation purposes. The design and calibration of a digital Fourier holographic microscope (DFHM) are reported. Of crucial importance is the appropriate scaling of scattering angle space in the conjugate Fourier plane. A detailed description of this calibration process is described. Spatial filtering of the acquired digital hologram to use photons scattered within a restricted angular range produces an image. A pair of images, one using photons narrowly scattered within 8 - 15° (LNA), and one using photons broadly scattered within 8 - 39° (HNA), are produced. An image based on the ratio of these two images, OSIR = HNA/LNA, following Boustany et al. (2002), yields a 2D Optical Scatter Image (OSI) whose contrast is based on the angular dependence of photon scattering and is sensitive to the microsphere size, especially in the 0.5-1.0µm range. Goniometric results are also given for polystyrene microspheres in suspension as additional proof of principle for particle sizing via the DFHM.


Genetic variation in BEACON influences quantitative variation in metabolic syndrome-related phenotypes.
The BEACON gene (also known as UBL5) was identified as differentially expressed between lean and obese Psammomys obesus, a polygenic animal model of obesity, type 2 diabetes, and dyslipidemia. The human homologue of BEACON is located on chromosome 19p, a region likely to contain genes affecting metabolic syndrome-related quantitative traits as established by linkage studies. To assess whether the human BEACON gene may be involved in influencing these traits, we exhaustively analyzed the complete gene for genetic variation in 40 unrelated individuals and identified four variants (three novel). The two more common variants were tested for association with a number of quantitative metabolic syndrome-related traits in two large cohorts of unrelated individuals. Significant associations were found between these variants and fat mass (P = 0.026), percentage of fat (P = 0.001), and waist-to-hip ratio (P = 0.031). The same variants were also associated with total cholesterol (P = 0.024), LDL cholesterol (P = 0.019), triglycerides (P = 0.006), and postglucose load insulin levels (P = 0.018). Multivariate analysis of these correlated phenotypes also yielded a highly significant association (P = 0.0004), suggesting that BEACON may influence phenotypic variation in metabolic syndrome-related traits.


Conditioned response suppression in the IntelliCage: assessment of mouse strain differences and effects of hippocampal and striatal lesions on acquisition and retention of memory.
The IntelliCage allows fully automated continuous testing of various behaviours in the home cage environment without handling the mice. Here we tested whether conditioned avoidance is retained after a time period delay spent outside the IntelliCage. During the training, nosepokes in one of the four learning corners were punished with an air-puff. After 24h of training, the mice were placed in regular cages for 24h. During the last 18h of this interval, the mice were water deprived and then returned to the IntelliCage for a probe trial where drinking was allowed in all corners. The C57BL/6 mice developed a significant suppression of nosepoking in the punished corner during training, and the avoidance was carried over to the following probe trial. Repetition of the experiment by delivering punishment in a different corner assigned to individual mice revealed a similar performance pattern. Comparison between the different strains revealed a reduced nosepoke suppression in DBA/2 and B6D2F1 mice as compared to C57BL/6 mice in the probe trial, despite similar error rates during the training with short (1-s) air-puffs. However, the performance of the three strains in the probe trial were equalised when the air-puffs were prolonged until the end of the corner visit. Significant extinction of the nosepoke suppression occurred after 6 days. A prolonged interval (7 days) between the training and the probe trial resulted in a loss of suppression in DBA/2 mice, but not in C57BL/6 and B6D2F1 mice. Additional experiments revealed that performance in the probe trial was dependent on a complex set of intramaze cues. Testing of mice with bilateral excitotoxic lesions of the hippocampus or dorso-lateral striatum revealed that learning this task was dependent on an intact hippocampus, but not on an intact striatum. In summary, the conditioned nosepoke suppression test presented here is sensitive to both genetic differences and hippocampal lesions. This test could be applied to the screening of mutant mice with impaired hippocampal functions more efficiently than those of the standard memory tests.


The age of the hominin fossils from Jebel Irhoud, Morocco, and the origins of the Middle Stone Age.
The timing and location of the emergence of our species and of associated behavioural changes are crucial for our understanding of human evolution. The earliest fossil attributed to a modern form of Homo sapiens comes from eastern Africa and is approximately 195 thousand years old, therefore the emergence of modern human biology is commonly placed at around 200 thousand years ago. The earliest Middle Stone Age assemblages come from eastern and southern Africa but date much earlier. Here we report the ages, determined by thermoluminescence dating, of fire-heated flint artefacts obtained from new excavations at the Middle Stone Age site of Jebel Irhoud, Morocco, which are directly associated with newly discovered remains of H. sapiens. A weighted average age places these Middle Stone Age artefacts and fossils at 315 ± 34 thousand years ago. Support is obtained through the recalculated uranium series with electron spin resonance date of 286 ± 32 thousand years ago for a tooth from the Irhoud 3 hominin mandible. These ages are also consistent with the faunal and microfaunal assemblages and almost double the previous age estimates for the lower part of the deposits. The north African site of Jebel Irhoud contains one of the earliest directly dated Middle Stone Age assemblages, and its associated human remains are the oldest reported for H. sapiens. The emergence of our species and of the Middle Stone Age appear to be close in time, and these data suggest a larger scale, potentially pan-African, origin for both.


ATM kinase enables the functional axis of YAP, PML and p53 to ameliorate loss of Werner protein-mediated oncogenic senescence.
Werner syndrome (WS) results from dysfunction of the WRN protein, and is associated with premature aging and early death. Here we report that loss of WRN function elicits accumulation of the Yes-associated protein (YAP protein), a major effector of the Hippo tumor suppressor pathway, both experimentally and in WS-derived fibroblasts. YAP upregulation correlates with slower cell proliferation and accelerated senescence, which are partially mediated by the formation of a complex between YAP and the PML protein, whose activity promotes p53 activation. The ATM kinase is necessary for YAP and PML accumulation in WRN-depleted cells. Notably, the depletion of either YAP or PML partially impairs the induction of senescence following WRN loss. Altogether, our findings reveal that loss of WRN activity triggers the activation of an ATM-YAP-PML-p53 axis, thereby accelerating cellular senescence. The latter has features of SASP (senescence-associated secretory phenotype), whose protumorigenic properties are potentiated by YAP, PML and p53 depletion.


The life history and shelter building behavior of Vettius coryna coryna Hewitson, 1866 in eastern Ecuador (Lepidoptera: Hesperiidae: Hesperiinae).
Abstract We describe all life-stages of Vettius coryna coryna Hewitson, 1866 in eastern Ecuador. The details of larval shelter structure and associated shelter building behavior are described and illustrated, as observed on two grass species (Poaceae). We provide brief observations on V. coryna adult behavior and a review of known life history information for other species of Vettius Godman, 1901.


Apoplexy of clinically silent pituitary adenoma during prostate cancer treatment with LHRH analog.
LHRH analogs have become a promising modality in prostate cancer therapy as an alternative to surgical castration, and the use of these agents is generally considered to be safe. Since now, only few cases of an apoplexy of previously undiagnosed pituitary adenoma (usually gonadotropinoma) at the beginning of therapy have been described in the medical literature. We present a case of a 74 year old patient who was diagnosed of prostate cancer at the age of 68. There was no evidence of metastatic disease. Radical prostatectomy was performed and LHRH analog gosereline (Zoladex 3.6 mg s.c.) was administered. During the first day after gosereline injection the patient developed headaches that became more severe over the next 3 days. Then the patient experienced nausea and vomiting, double vision and eyelid ptosis. On the 5th day the patient temporarily lost consciousness and was admitted to hospital. Imaging (computerized tomography, magnetic resonance imaging) revealed the presence of a pituitary tumor and hemorrhage within the gland. There was no evidence of pituitary dysfunction in hormonal studies. Neurosurgical intervention was postponed for 5 days after admission. Pathological mass with signs of recent hemorrhage was removed via transsphenoidal route. The tumor had negative immunohistochemical GH, ACTH and PRL staining. Neurological impairment resolved within 9 months after the operation. As a result the patient required adrenal and thyroid replacement. During 6 years of follow-up there was no evidence of prostate cancer recurrence.


Flow cytometric analysis and modeling of cell-cell adhesive interactions: the neutrophil as a model.
The immune function of granulocytes, monocytes, lymphocytes, and other specialized cells depends upon intercellular adhesion. In many cases the molecules mediating leukocyte cell adhesion belong to the Leu-CAM superfamily of adhesive molecules. To elucidate the events of homotypic aggregation in a quantitative fashion, we have examined the aggregation of neutrophils stimulated with formyl peptides, where aggregate formation is a transient reversible cell function. We have mathematically modeled the kinetics of aggregation using a linear model based on particle geometry and rates of aggregate formation and breakup. The time course was modeled as a three-phase process, each phase with distinct rate constants. Aggregate formation was measured on the flow cytometer; singlets and larger particles were distinguished using the intravital stain LDS-751. Aggregation proceeded rapidly after stimulation with formyl peptide (CHO-nle-leu-phe-nle-tyr-lys). The first phase lasted 30-60 s; this was modeled with the largest aggregation rate and smallest rate of disaggregation. Aggregate formation plateaued during the second phase which lasted up to 2.5 min. This phase was modeled with an aggregation rate nearly an order of magnitude less than that of the initial fast phase, whereas the disaggregation rate for this phase did not change significantly. A third phase where disaggregation predominated, lasted the remaining 2-3 min and was modeled with a four to fivefold increase of the disaggregation rate. The mechanism of cell-cell adhesion in the plateau phase was probed with the monoclonal antibody IB4 to the CD18 subunit of the adhesive receptor CR3. Based on these studies it appears that new aggregates do not form to a large degree after the first phase of aggregate formation is complete. However, new adhesive contact sites may form within the contact region of these adherent cells to keep the aggregates together.


Control of muscle glucose uptake: test of the rate-limiting step paradigm in conscious, unrestrained mice.
The aim of this study was to test whether in fact glucose transport is rate-limiting in control of muscle glucose uptake (MGU) under physiological hyperinsulinaemic conditions in the conscious, unrestrained mouse. C57Bl/6J mice overexpressing GLUT4 (GLUT4(Tg)), hexokinase II (HK(Tg)), or both (GLUT4(Tg) + HK(Tg)), were compared to wild-type (WT) littermates. Catheters were implanted into a carotid artery and jugular vein for sampling and infusions at 4 month of age. After a 5-day recovery period, conscious mice underwent one of two protocols (n = 8-14/group) after a 5-h fast. Saline or insulin (4 mU kg(-1) min(-1)) was infused for 120 min. All mice received a bolus of 2-deoxy[(3)H]glucose (2-(3)HDG) at 95 min. Glucose was clamped at approximately 165 mg dl(-1) during insulin infusion and insulin levels reached approximately 80 microU ml(-1). The rate of disappearance of 2-(3)HDG from the blood provided an index of whole body glucose clearance. Gastrocnemius, superficial vastus lateralis and soleus muscles were excised at 120 min to determine 2-(3)HDG-6-phosphate levels and calculate an index of MGU (R(g)). Results show that whole body and tissue-specific indices of glucose utilization were: (1) augmented by GLUT4 overexpression, but not HKII overexpression, in the basal state; (2) enhanced by HKII overexpression in the presence of physiological hyperinsulinaemia; and (3) largely unaffected by GLUT4 overexpression during insulin clamps whether alone or combined with HKII overexpression. Therefore, while glucose transport is the primary barrier to MGU under basal conditions, glucose phosphorylation becomes a more important barrier during physiological hyperinsulinaemia in all muscles. The control of MGU is distributed rather than confined to a single rate-limiting step such as glucose transport as glucose transport and phosphorylation can both become barriers to skeletal muscle glucose influx.


Characterizing Intervention Opportunities among Home-Delivered Meals Program Participants: Results from the 2017 National Survey of Older Americans Act Participants and a New York City Survey.
The Home Delivered Meals Program (HDMP) serves a vulnerable population of adults aged 60 and older who may benefit from technological services to improve health and social connectedness. The objectives of this study are (a) to better understand the needs of HDMP participants, and (b) to characterize the technology-readiness and the utility of delivering information via the computer. We analyzed data from the 2017 NSOAAP to assess the health and functional status and demographic characteristics of HDMP participants. We also conducted a telephone survey to assess technology use and educational interests among NYC HDMP participants. Functional measures of the national sample included comorbidities, recent hospitalizations, and ADL/IADL limitations. Participants from our local NYC sample completed a modified version of the validated Computer Proficiency Questionnaire. Technology readiness was assessed by levels of technology use, desired methods for receiving health information, and interest in learning more about virtual senior centers. About one-third (32.4%) of national survey HDMP participants (n=902) reported insufficient resources to buy food and 17.1% chose between food or medications. Within the NYC HDMP participant survey sample (n=33), over half reported having access to the internet (54.5%), 48.5% used a desktop or laptop, and 30.3% used a tablet, iPad, or smartphone. The HDMP provides an opportunity to reach vulnerable older adults and offer additional resources that can enhance social support and improve nutrition and health outcomes. Research is warranted to compare technological readiness of HDMP participants across urban and rural areas in the United States.


Brain structural substrates of cognitive procedural learning in alcoholic patients early in abstinence.
Procedural learning allows for the acquisition of new behavioral skills. Previous studies have shown that chronic alcoholism is characterized by impaired cognitive procedural learning and brain abnormalities affecting regions that are involved in the automation of new cognitive procedures in healthy individuals. The goal of the present study was to investigate the brain structural substrates of cognitive procedural learning in alcoholic patients (ALs) early in abstinence. Thirty-one ALs and 31 control participants (NCs) performed the Tower of Toronto task (4 daily learning sessions, each comprising 10 trials) to assess cognitive procedural learning. We also assessed episodic and working memory, executive functions, and visuospatial abilities. ALs underwent 1.5T structural magnetic resonance imaging. The initial cognitive phase was longer in the AL group than in the NC group, whereas the autonomous phase was shorter. In ALs, the longer cognitive phase was predicted by poorer planning and visuospatial working memory abilities, and by smaller gray matter (GM) volumes in the angular gyrus and caudate nucleus. ALs' planning abilities correlated with smaller GM volume in the angular gyrus. Cognitive procedural learning was impaired in ALs, with a delayed transition from the cognitive to the autonomous phase. This slowdown in the automation of the cognitive procedure was related to lower planning abilities, which may have hampered the initial generation of the procedure to be learned. In agreement with this neuropsychological finding, a persistent relationship was found between learning performance and the GM volumes of the angular gyrus and caudate nucleus, which are usually regarded as markers of planning and initial learning of the cognitive procedure.


Dietary exposure to an environmental toxin triggers neurofibrillary tangles and amyloid deposits in the brain.
Neurofibrillary tangles (NFT) and β-amyloid plaques are the neurological hallmarks of both Alzheimer's disease and an unusual paralytic illness suffered by Chamorro villagers on the Pacific island of Guam. Many Chamorros with the disease suffer dementia, and in some villages one-quarter of the adults perished from the disease. Like Alzheimer's, the causal factors of Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) are poorly understood. In replicated experiments, we found that chronic dietary exposure to a cyanobacterial toxin present in the traditional Chamorro diet, β-N-methylamino-l-alanine (BMAA), triggers the formation of both NFT and β-amyloid deposits similar in structure and density to those found in brain tissues of Chamorros who died with ALS/PDC. Vervets (Chlorocebus sabaeus) fed for 140 days with BMAA-dosed fruit developed NFT and sparse β-amyloid deposits in the brain. Co-administration of the dietary amino acid l-serine with l-BMAA significantly reduced the density of NFT. These findings indicate that while chronic exposure to the environmental toxin BMAA can trigger neurodegeneration in vulnerable individuals, increasing the amount of l-serine in the diet can reduce the risk.


Global Matrix 3.0 physical activity report card for children and youth: a comparison across Europe.
The Global Matrix of report card grades on physical activity serves as a public health awareness tool by summarising the status of child and youth physical activity prevalence and action. The objectives were to: (1) provide a detailed examination of the evidence informing the 'School' and 'Community and Environment' indicators across all participating European Global Matrix 3.0 countries; (2) explore the comparability of the grades for these two indicators across Europe; (3) detail any limitations or issues with the methods used to assign grades; and (4) provide suggestions on how future grading of the indicators could be improved. A comparative review of published methods on the grading of Global Matrix 3.0 indicators across European countries. Key documents relating to the European countries involved in the 2018 Global Matrix 3.0 were collated and a template used to extract data for both the 'School' and 'Community and Environment' indicators. Seventeen of the 20 European Report Card countries (85%) had a grade for schools, and 15 countries (75%) had a grade for community and environment. All countries considered between one and five factors when assigning the grade for these indicators. There were wide disparities in the number and sources of evidence used to assign the grades for both indicators, limiting the comparability of the evidence between different countries. To enable comparability, the authors recommend moving towards an agreed standardised set of metrics for grading each indicator. Furthermore, it would be useful to develop and share common tools, methods and instruments to collect data in a uniform way across countries, where possible. Such action will ultimately make the Global Matrix a more robust and useful tool for the future.


Piperine inhibits proliferation of human osteosarcoma cells via G2/M phase arrest and metastasis by suppressing MMP-2/-9 expression.
The piperidine alkaloid piperine, a major ingredient in black pepper, inhibits the growth and metastasis of cancer cells both in vivo and in vitro, although its mechanism of action is unclear. Furthermore, its anticancer activity against osteosarcoma cells has not been reported. In this study, we show that piperine inhibited the growth of HOS and U2OS cells in dose- and time-dependent manners but had a weaker effect on the growth of normal hFOB cells. Piperine inhibited osteosarcoma cell proliferation by causing G2/M phase cell cycle arrest associated with decreased expression of cyclin B1 and increased phosphorylation of Cyclin-dependent kinase-1(CDK1) and checkpoint kinase 2 (Chk2). In addition, piperine treatment inhibited phosphorylation of Akt and activated phosphorylation of c-Jun N-terminal kinase (c-JNK) and p38 mitogen-activated protein kinase (MAPK) in HOS and U2OS cells. Piperine induced colony formation in these two cell types. We proved that piperine could suppress the metastasis of osteosarcoma cells using scratch migration assays and Transwell chamber tests. Moreover, gelatin zymography showed that piperine inhibited the activity of matrix metalloproteinase (MMP)-2/-9 and increased the expression of tissue inhibitor of metalloproteinase (TIMP)-1/-2. Taken together, our results indicate that piperine inhibits proliferation, by inducing G2/M cell cycle arrest, and the migration and invasion of HOS and U2OS cells, via increased expression of TIMP-1/-2 and down-regulation of MMP-2/-9. These findings support further study of piperine as a promising therapeutic agent in the treatment of osteosarcoma.


(1)H NMR-based metabolite profiling of planktonic and biofilm cells in Acinetobacter baumannii 1656-2.
Acinetobacter baumannii is an aerobic and gram-negative pathogenic bacterium that is resistant to most antibiotics. Recently, A. baumannii 1656-2 exhibited the ability to form biofilms under clinical conditions. In this study, global metabolite profiling of both planktonic and biofilm forms of A. baumannii 1656-2 was performed using high-resolution nuclear magnetic resonance (NMR) spectroscopy and multivariate statistical analysis to investigate the metabolic patterns leading to biofilm formation. Principal components analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) score plots showed a distinct separation between planktonic and biofilm cells. Metabolites including acetates, pyruvate, succinate, UDP-glucose, AMP, glutamate, and lysine were increasingly involved in the energy metabolism of biofilm formation. In particular, the ratio of N-acetyl-D-glucosamine (GlcNAc) to D-glucosamine (GlcNH2) was significantly higher during biofilm formation than under the planktonic condition. This study demonstrates that NMR-based global metabolite profiling of bacterial cells can provide valuable insight into the metabolic changes in multidrug resistant and biofilm-forming bacteria such as A. baumannii 1656-2.


Carbohydrate metabolism in insulin resistance: glucose uptake and lactate production by adipose and forearm tissues in vivo before and after a mixed meal.
1. To examine whether insulin resistance in vivo is manifest equally in both muscle and adipose tissues, we measured arteriovenous glucose and lactate fluxes across forearm (muscle) and abdominal subcutaneous (adipose) tissue in nine obese, glucose-intolerant subjects and 13 non-obese subjects of similar age and sex. 2. Compared with non-obese subjects, the forearm of the obese subjects was resistant to insulin stimulation of glucose uptake after a mixed meal. In contrast, adipose tissue showed little evidence of insulin stimulation of glucose uptake, and adipose tissue in subjects in both normal and obese groups behaved very similarly (assessed per 100 g of tissue). 3. For lactate flux, adipose tissue behaved very similarly (per 100 g of tissue) in obese and non-obese subjects, and was a consistent lactate exporter. 4. We conclude that insulin resistance of glucose uptake observed in the forearm of obese subjects is not evident in adipose tissue. Adipose tissue glucose uptake in obese, insulin-resistant subjects is similar to that in lean control subjects, although it occurs at elevated circulating insulin and glucose concentrations.


Sustained local drug delivery to the arterial wall via biodegradable microspheres.
This study was designed to evaluate the feasibility of applying locally delivered polylactic acid microspheres for drug delivery to the arterial wall. To study drug persistence, rhodamine-loaded microspheres were infused into one carotid artery of 14 rabbits and plain rhodamine solution into the other by using a porous balloon. To study tissue response, plain microspheres and dexamethasone-loaded microspheres were infused into the carotid arteries of another group of rabbits. To study the antiproliferative effects of locally delivered drug, 20 rabbits were subjected to overstretch balloon injury to both carotid arteries and divided into 4 groups: injury alone, plain microspheres, dexamethasone-loaded microspheres, and microspheres containing colchicine and dexamethasone. Fluorescent microspheres persisted in the vessel wall for 4 wk, whereas rhodamine without microspheres disappeared at 72 h. Histopathologic studies in arteries infused with unloaded microspheres showed inflammatory cell infiltrate with polymorphonuclear cells at 1 wk and macrophages and giant cells at 4 wk. Arteries infused with dexamethasone-loaded microspheres did not show any inflammatory cell infiltrate. Local delivery of dexamethasone or dexamethasone plus colchicine did not result in significant change in the intima-to-media ratio or in residual lumen following balloon injury. Polylactic acid microspheres may be used for prolonged delivery of drugs or other bioactive agents locally to the arterial wall. They induce an inflammatory reaction that is suppressable by dexamethasone in the microspheres. Dexamethasone or dexamethasone and colchicine delivered via this system, however, failed to reduce the degree of intimal hyperplasia after overstretch balloon injury to the rabbit carotid arteries.


Efficacy of a training program for long-term disease- free cancer survivors as health partners: a randomized controlled trial in Korea.
To determine whether the Health Partner Program is effective in training long-term cancer survivors to be health coaches. We randomly assigned cancer survivors who were selected through a rigorous screening process to either the Health Partner Program or the waiting-list control group. The program consisted of 8 weeks of training in health management, leadership, and coaching. At baseline, 8, and 16 weeks, we measured primary outcomes using the Seven Habit Profile (SHP), the Korean Leadership Coaching Competency Inventory (KCCI), Ed Diner's Satisfaction with Life Scale (SWLS), and the Posttraumatic Growth inventory (PTGI) and secondary outcomes using the Hospital Anxiety and Depression Scale (HADS), the Impact of Event Scale-Revised (IES-R), and the Medical Outcomes Study (MOS) short form 36-item questionnaire (SF- 36). We recruited 70 subjects and randomly assigned 34 to the intervention group. The Sharpen the Saw habit of the SHP increased significantly more in intervention group than in the control group (p = 0.049), as did most PTGI factors. The intervention group also showed a significantly greater enhancement of vitality (p = 0.015) and mental health (p = 0.049) SF-36 scores but no improvement in KCCI, SWLS, HADS, or IES-R scores. The intervention group also showed a greater clinically meaningful improvement in the "Think Win-Win" of SHP (p = 0.043) and in the personal strength score (p = 0.025) and total score (p = 0.015) of the PTGI. Long-term cancer survivors can benefit from the Health Partner Program to become health coaches.