A genome wide search for alcoholism susceptibility genes.
Alcoholism is currently one of the most serious public health problems in the US. Lifetime prevalence rates are relatively high with one in five men and one in 12 women meeting criteria for this condition. Identification of genetic loci conferring an increased susceptibility to developing alcohol dependence could strengthen prevention efforts by informing individuals of their risk before abusive drinking ensues. Families identified through a double proband methodology have provided an exceptional opportunity for gene-finding because of the increased recurrence risks seen in these sibships. A total of 360 markers for 22 autosomes were spaced at an average distance of 9.4 cM and genotyping performed for 330 members of these multiplex families. Extensive clinical data, personality variation, and event-related potential characteristics were available for reducing heterogeneity and detecting robust linkage signals. Multipoint linkage analysis using different analytic strategies give strong support for loci on chromosomes 1, 2, 6, 7, 10, 12, 14, 16, and 17.


Airborne spread of foot-and-mouth disease--model intercomparison.
Foot-and-mouth disease virus (FMDV) spreads by direct contact between animals, by animal products (milk, meat and semen), by mechanical transfer on people or fomites and by the airborne route, with the relative importance of each mechanism depending on the particular outbreak characteristics. Atmospheric dispersion models have been developed to assess airborne spread of FMDV in a number of countries, including the UK, Denmark, Australia, New Zealand, USA and Canada. These models were compared at a Workshop hosted by the Institute for Animal Health/Met Office in 2008. Each modeller was provided with data relating to the 1967 outbreak of FMD in Hampshire, UK, and asked to predict the spread of FMDV by the airborne route. A number of key issues emerged from the Workshop and subsequent modelling work: (1) in general all models predicted similar directions for livestock at risk, with much of the remaining differences strongly related to differences in the meteorological data used; (2) determination of an accurate sequence of events on the infected premises is highly important, especially if the meteorological conditions vary substantially during the virus emission period; (3) differences in assumptions made about virus release, environmental fate and susceptibility to airborne infection can substantially modify the size and location of the downwind risk area. All of the atmospheric dispersion models compared at the Workshop can be used to assess windborne spread of FMDV and provide scientific advice to those responsible for making control and eradication decisions in the event of an outbreak of disease.


Cholera toxin B-HRP and wheat germ agglutinin-HRP tracing of tensor tympani muscle motoneurons and processes in rabbits.
The brain stem position, organization and number of motoneurons innervating the rabbit tensor tympani muscle (TTM) were determined by retrograde axonal transport of cholera toxin B/horseradish peroxidase conjugate (CTB-HRP) and wheat germ agglutinin HRP conjugate (WGA-HRP) tracers. The synaptic input to the TTM motoneurons was examined with WGA-HRP. The results show the motoneurons of the TTM to be localized in a cluster ventro-lateral to the outer margin of the ipsilateral trigeminal motor nucleus (VMN) and dorso-lateral to the superior olive. The number of labeled cells was greater in the combined CTB-HRP/WGA-HRP injected cases. The TTM motoneurons were triangular and elongated in shape and smaller than those of the VMN. An extensive network of dendritic branches was present ventro-laterally in the vicinity of the superior olive. Similar, but less extensive collections of dendritic processes were observed to course dorso-medially, rostrally and caudally. Axons were observed to project first dorsally or laterally, towards the trigeminal motor root, then after a sharp turn coursed ventrally within the trigeminal motor root (VMR). Transneuronal transport of the WGA-HRP was not accomplished in any preparation, suggesting among other things, system or species differences in the effectiveness of the WGA-HRP conjugate as a transynaptic tracer. It is concluded that the TTM acoustic reflex in rabbits and other mammals, its threshold, prolonged contraction capacity, and its influence on middle ear sound transmission may be related to its demonstrated extensive synaptic field in the reflex chain, particularly in the area of the superior olive, while its many other physiological functions may be made possible by the number, location, and multi-dimensional orientation of its motoneurons and dendrites.


Do Words Matter? Detecting Social Isolation and Loneliness in Older Adults Using Natural Language Processing.
Introduction: Social isolation and loneliness (SI/L) are growing problems with serious health implications for older adults, especially in light of the COVID-19 pandemic. We examined transcripts from semi-structured interviews with 97 older adults (mean age 83 years) to identify linguistic features of SI/L. Methods: Natural Language Processing (NLP) methods were used to identify relevant interview segments (responses to specific questions), extract the type and number of social contacts and linguistic features such as sentiment, parts-of-speech, and syntactic complexity. We examined: (1) associations of NLP-derived assessments of social relationships and linguistic features with validated self-report assessments of social support and loneliness; and (2) important linguistic features for detecting individuals with higher level of SI/L by using machine learning (ML) models. Results: NLP-derived assessments of social relationships were associated with self-reported assessments of social support and loneliness, though these associations were stronger in women than in men. Usage of first-person plural pronouns was negatively associated with loneliness in women and positively associated with emotional support in men. ML analysis using leave-one-out methodology showed good performance (F1 = 0.73, AUC = 0.75, specificity = 0.76, and sensitivity = 0.69) of the binary classification models in detecting individuals with higher level of SI/L. Comparable performance were also observed when classifying social and emotional support measures. Using ML models, we identified several linguistic features (including use of first-person plural pronouns, sentiment, sentence complexity, and sentence similarity) that most strongly predicted scores on scales for loneliness and social support. Discussion: Linguistic data can provide unique insights into SI/L among older adults beyond scale-based assessments, though there are consistent gender differences. Future research studies that incorporate diverse linguistic features as well as other behavioral data-streams may be better able to capture the complexity of social functioning in older adults and identification of target subpopulations for future interventions. Given the novelty, use of NLP should include prospective consideration of bias, fairness, accountability, and related ethical and social implications.


A Review on MR Image Intensity Inhomogeneity Correction.
Intensity inhomogeneity (IIH) is often encountered in MR imaging, and a number of techniques have been devised to correct this artifact. This paper attempts to review some of the recent developments in the mathematical modeling of IIH field. Low-frequency models are widely used, but they tend to corrupt the low-frequency components of the tissue. Hypersurface models and statistical models can be adaptive to the image and generally more stable, but they are also generally more complex and consume more computer memory and CPU time. They are often formulated together with image segmentation within one framework and the overall performance is highly dependent on the segmentation process. Beside these three popular models, this paper also summarizes other techniques based on different principles. In addition, the issue of quantitative evaluation and comparative study are discussed.


Understanding How the Diagnostic Delay of Spondyloarthritis Differs Between Women and Men: A Systematic Review and Metaanalysis.
To identify empirical evidence of diagnostic delay in spondyloarthritis (SpA), determine whether sex-related differences persist, and conduct an analysis from that perspective of the possible causes, including the influence of quality research, in this group of inflammatory rheumatic diseases. A systematic review was done of delay in diagnosis of SpA in MEDLINE and EMBASE and other sources. Study quality was determined in line with the Strengthening The Reporting of OBservational studies in Epidemiology (STROBE) statement. A metaanalysis of 13 papers reporting sex-disaggregated data was performed to evaluate sex-related differences in diagnostic delay. The global effect of diagnostic delay by sex was calculated using means difference (D) through a fixed effects model. The review included 23,883 patients (32.3% women) from 42 papers. No significant differences between the sexes were detected for symptoms at disease onset or during evolution. However, the mean for delay in diagnosis of SpA showed sex-related differences, being 8.8 years (7.4-10.1) for women and 6.5 (5.6-7.4) for men (p = 0.01). Only 40% of papers had high quality. A metaanalysis included 12,073 participants (31.2% women). The mean global effect was D = 0.6 years (0.31-0.89), indicating that men were diagnosed 0.6 year (7 months) before women. Delay in diagnosis of SpA persists, and is longer in women than in men. There are no significant sex-related differences in symptoms that could explain sex-related differences in diagnostic delay. Methodological and possible publication bias could result in sex-biased medical practice.


Multimodal manual therapy vs. pharmacological care for management of tension type headache: A meta-analysis of randomized trials.
Manual therapies are generally requested by patients with tension type headache. To compare the efficacy of multimodal manual therapy vs. pharmacological care for the management of tension type headache pain by conducting a meta-analysis of randomized controlled trials. PubMed, MEDLINE, EMBASE, AMED, CINAHL, EBSCO, Cochrane Database of Systematic Reviews, Cochrane Collaboration Trials Register, PEDro and SCOPUS were searched from their inception until June 2014. All randomized controlled trials comparing any manual therapy vs. medication care for treating tension type headache adults were included. Data were extracted and methodological quality assessed independently by two reviewers. We pooled headache frequency as the main outcome and also intensity and duration. The weighted mean difference between manual therapy and pharmacological care was used to determine effect sizes. Five randomized controlled trials met our inclusion criteria and were included in the meta-analysis. Pooled analyses found that manual therapies were more effective than pharmacological care in reducing frequency (weighted mean difference -0.8036, 95% confidence interval -1.66 to -0.44; three trials), intensity (weighted mean difference -0.5974, 95% confidence interval -0.8875 to -0.3073; five trials) and duration (weighted mean difference -0.5558, 95% confidence interval -0.9124 to -0.1992; three trials) of the headache immediately after treatment. No differences were found at longer follow-up for headache intensity (weighted mean difference -0.3498, 95% confidence interval -1.106 to 0.407; three trials). Manual therapies were associated with moderate effectiveness at short term, but similar effectiveness at longer follow-up for reducing headache frequency, intensity and duration in tension type headache than pharmacological medical drug care. However, due to the heterogeneity of the interventions, these results should be considered with caution at this stage.


Risk of Anticoagulant Rodenticide Exposure for Mammals and Birds in Parc National des Pyrénées, France.
The extensive use of anticoagulant rodenticides (ARs) to control rodent populations poses intoxication risks for wildlife: persistence of ARs in rodents can cause secondary exposure and poisoning of predators or scavengers. We investigated risk factors for wildlife exposure to ARs in the Parc National des Pyrénées (PNP), France, using a multivariable logistic regression analysis. A total of 157 liver samples were collected from carcasses of 10 mammal and three bird species found in the PNP between 2010 and 2018 and screened for presence of AR residues. First- and second-generation ARs were detected in more than 60% of red fox (Vulpes vulpes) and stone marten (Martes foina) samples and in around 40% of wild cat (Felis silvestris), European pine marten (Martes martes), American mink (Neovison vison), and Eurasian Buzzard (Buteo buteo) samples. Wildlife exposure to ARs was significantly associated with species having a regular consumption of small mammals (odds ratio [OR]: 2.5, 95% confidence interval [CI]: 1.1-5.8) being collected in the Ossau valley (OR: 2.5, 95% CI: 1.1-6.1) and between 2013 and 2015 (OR: 4.8, 95% CI: 2.0-11.7). We identified wild species that could be targeted for risk-based surveillance program for AR secondary exposure and determined high risk areas in which alternative measures should be applied for rodent control.


Histopathology of root surface caries.
The histopathology of active and arrested human root caries was examined in extracted teeth by different optical methods. Significant differences were observed between the mechanisms operating on the various dental structures. Three different patterns of initial cementum and dentin lesions could be distinguished, depending on the severity of the cariogenic attack, the degree of sclerosis of the peripheral dentin, and the presence of calculus. Advanced lesions were characterized by various patterns of demineralization. In particular, a massive lateral spread of bacteria into intertubular dentin was observed. Consequently, unaffected dentinal areas became continuously undermined. In arrested lesions, either a partial or complete mineralization of the intertubular dentin was apparent. Dentinal tubules were sclerosed passively by re- or precipitation of Ca and PO4 ions. In contrast, tubules filled with ghosts of bacteria appeared mineralized by fine-granular crystals. Our observations indicate that both the arrestment and the remineralization of active lesions depend on (1) the degree of active sclerosis of dentinal tubules in areas underlying the lesion, (2) the degree of the bacterial infection of the dentin, (3) the degree of progression of the lesions, and (4) the location of the lesions at the various root surfaces. It is suggested that remineralization of active lesions can occur. This supports the concept of non-invasive treatment of root caries lesions without cavitation.


Phenotypic plasticity in genitalia: baculum shape responds to sperm competition risk in house mice.
Males are known to adjust their expenditure on testes growth and sperm production in response to sperm competition risk. Genital morphology can also contribute to competitive fertilization success but whether male genital morphology can respond plastically to the sperm competition environment has received little attention. Here, we exposed male house mice to two different sperm competition environments during their sexual development and quantified phenotypic plasticity in baculum morphology. The sperm competition environment generated plasticity in body growth. Males maturing under sperm competition risk were larger and heavier than males maturing under no sperm competition risk. We used a landmark-based geometric morphometric approach to measure baculum size and shape. Independent of variation in body size, males maintained under risk of sperm competition had a relatively thicker and more distally extended baculum bulb compared with males maintained under no sperm competition risk. Plasticity in baculum shape paralleled evolutionary responses to selection from sperm competition reported in previous studies of house mice. Our findings provide experimental evidence of socially mediated phenotypic plasticity in male genitalia.


Empowering the crowd: feasible strategies for epidemic management in high-density informal settlements. The case of COVID-19 in Northwest Syria.
More than 1 billion people live in informal settlements worldwide, where precarious living conditions pose unique challenges to managing a COVID-19 outbreak. Taking Northwest Syria as a case study, we simulated an outbreak in high-density informal Internally Displaced Persons (IDP) camps using a stochastic Susceptible-Exposed-Infectious-Recovered model. Expanding on previous studies, taking social conditions and population health/structure into account, we modelled several interventions feasible in these settings: moderate self-distancing, self-isolation of symptomatic cases and protection of the most vulnerable in 'safety zones'. We considered complementary measures to these interventions that can be implemented autonomously by these communities, such as buffer zones, health checks and carers for isolated individuals, quantifying their impact on the micro-dynamics of disease transmission. All interventions significantly reduce outbreak probability and some of them reduce mortality when an outbreak does occur. Self-distancing reduces mortality by up to 35% if contacts are reduced by 50%. A reduction in mortality by up to 18% can be achieved by providing one self-isolation tent per eight people. Protecting the most vulnerable in a safety zone reduces the outbreak probability in the vulnerable population and has synergistic effects with the other interventions. Our model predicts that a combination of all simulated interventions may reduce mortality by more than 90% and delay an outbreak's peak by almost 2 months. Our results highlight the potential for non-medical interventions to mitigate the effects of the pandemic. Similar measures may be applicable to controlling COVID-19 in other informal settlements, particularly IDP camps in conflict regions, around the world.


Inflammatory bowel disease: An Indian perspective.
Inflammatory bowel disease (IBD) in recent times is causing a significant healthcare burden as both ulcerative colitis and Crohn's disease (CD) require lifelong therapy and constant monitoring. The current review highlights the concerns in a country like India with special reference to the changing trends of IBD, risk attribution and the financial issues. Indian immigrants behave like residential Indians, whereas their children show IBD prevalence similar to the West, highlighting the role of environmental triggers. However, the environmental and genetic factors in Indians with IBD are not well understood. Men appear to be more frequently affected than women in India. The disease severity is milder in the patients, both males and females, but the risk for colorectal cancer (CRC) is similar to the West. The incidence of paediatric IBD is on the rise. The major burden of IBD in the Indian subcontinent at present is in children, adolescents and teens. Cost towards the management of complications, non-adherence to treatment, differentiating tuberculosis from CD and finally screening for CRC in patients with IBD are the points to ponder in the Indian scenario.


A time-course comparative clinical and immune response evaluation study between the human pathogenic Orientia tsutsugamushi strains: Karp and Gilliam in a rhesus macaque (Macaca mulatta) model.
Scrub typhus is a vector-borne febrile illness caused by Orientia tsutsugamushi transmitted by the bite of Trombiculid mites. O. tsutsugamushi has a high genetic diversity and is increasingly recognized to have a wider global distribution than previously assumed. We evaluated the clinical outcomes and host immune responses of the two most relevant human pathogenic strains of O. tsutsugamushi; Karp (n = 4) and Gilliam (n = 4) in a time-course study over 80 days post infection (dpi) in a standardized scrub typhus non-human primate rhesus macaque model. We observed distinct features in clinical progression and immune response between the two strains; Gilliam-infected macaques developed more pronounced systemic infection characterized by an earlier onset of bacteremia, lymph node enlargement, eschar lesions and higher inflammatory markers during the acute phase of infection, when compared to the Karp strain. C-reactive protein (CRP) plasma levels, interferon gamma (IFN-γ, interleukin-1 receptor antagonist (IL-1ra), IL-15 serum concentrations, CRP/IL10- and IFN-γ/IL-10 ratios correlated positively with bacterial load in blood, implying activation of the innate immune response and preferential development of a T helper-type 1 immune response. The O. tsutsugamushi-specific immune memory responses in cells isolated from skin and lymph nodes at 80 dpi were more markedly elevated in the Gilliam-infected macaques than in the Karp-infected group. The comparative cytokine response dynamics of both strains revealed significant up-regulation of IFN-γ, tumor necrosis factor (TNF), IL-15, IL-6, IL-18, regulatory IL-1ra, IL-10, IL-8 and granulocyte-colony-stimulating factor (G-CSF). These data suggest that the clinical outcomes and host immune responses to scrub typhus could be associated with counter balancing effects of pro- and anti-inflammatory cytokine-mediated responses. Currently, no data on characterized time-course comparisons of O. tsutsugamushi strains regarding measures of disease severity and immune response is available. Our study provides evidence for the strain-specificity of host responses in scrub typhus, which supports our understanding of processes at the initial inoculation site (eschar), systemic disease progression, protective and/or pathogenic host immune mechanisms and cellular immune memory function. This study characterised an improved intradermal rhesus macaque challenge model for scrub typhus, whereby the Gilliam strain infection associated with higher disease severity in the rhesus macaque model than the previous Karp strain infection. Difficulties associated with inoculum quantitation for obligate-intracellular bacteria were overcome by using functional inoculum titrations in outbred mice. The Gilliam-based rhesus macaque model provides improved endpoint measurements and contributes towards the identification of correlates of protection for future vaccine development.


Microbial communities display alternative stable states in a fluctuating environment.
The effect of environmental fluctuations is a major question in ecology. While it is widely accepted that fluctuations and other types of disturbances can increase biodiversity, there are fewer examples of other types of outcomes in a fluctuating environment. Here we explore this question with laboratory microcosms, using cocultures of two bacterial species, P. putida and P. veronii. At low dilution rates we observe competitive exclusion of P. veronii, whereas at high dilution rates we observe competitive exclusion of P. putida. When the dilution rate alternates between high and low, we do not observe coexistence between the species, but rather alternative stable states, in which only one species survives and initial species' fractions determine the identity of the surviving species. The Lotka-Volterra model with a fluctuating mortality rate predicts that this outcome is independent of the timing of the fluctuations, and that the time-averaged mortality would also lead to alternative stable states, a prediction that we confirm experimentally. Other pairs of species can coexist in a fluctuating environment, and again consistent with the model we observe coexistence in the time-averaged dilution rate. We find a similar time-averaging result holds in a three-species community, highlighting that simple linear models can in some cases provide powerful insight into how communities will respond to environmental fluctuations.


Effect of saline water and sludge addition on biodegradation of municipal solid waste in bioreactor landfills.
Bioreactor landfills require sufficient moisture to optimize the biodegradation processes and methane generation. In arid regions, this is problematic given the lack of fresh water supplies. Saline water can be used but may inhibit the biodegradation of the municipal solid waste (MSW) in landfills. Sludge may be used to enhance the biodegradation of MSW under saline conditions. For this study, two groups of laboratory-scale bioreactor cells were used to study the impact of saline water and sludge addition on the biodegradation of MSW in bioreactor landfills. The first group (four bioreactors) operated without sludge addition. The second group (four bioreactors) operated with the addition of sludge. The salt concentrations in the two groups were 0, 0.5, 1 and 3% (w/v), respectively. All bioreactors were operated at neutral pH levels with leachate recycling. The methane yield was 70.6, 61.7 and 47.5 L kg(-1) dry waste for bioreactors R1, R2 and R4, respectively; and 84.7, 78.7, 72.6 and 59 L kg(-1) dry waste for bioreactors R5, R6, R7 and R8, respectively. The high salt content (3%) inhibited the MSW biodegradation as evidenced by the methane yield, the percentage reduction in leachate concentration and the settlement that occurred during the study. Sludge addition was able to improve the methane yield at all salt concentrations.


Effects of visual and non-visual mechanisms on the vestibulo-ocular reflex during pseudo-random head movements in man.
1. The behaviour of the vestibulo-ocular reflex (VOR) in man was examined using pseudo-random and sinusoidal whole-body angular-motion stimuli applied about the yaw axis by a servo-controlled turn-table. 2. The VOR response was assessed in four conditions; during fixation on a head-fixed target (HFT); during attempted fixation in the dark of an imagined head-fixed (IHFT) or earth-fixed target (IEFT) and in darkness (DRK) whilst performing an auditory discrimination task. 3. When the pseudo-random stimulus was composed of four sinusoids, the three lowest frequencies (0.11, 0.24 and 0.37 Hz) were maintained constant whilst the highest frequency (F4) was varied from 0.39 to 2.08 Hz. In darkness (DRK condition) and when imagining a head-fixed target (IHFT condition) the gain of slow-phase eye velocity was not significantly affected by the frequency of the highest-frequency component, although there were significant changes in the phase for the IHFT condition. 4. During fixation of a real head-fixed target (HFT condition), both the gain and phase of eye velocity were significantly modified by the frequency (F4) of the highest-frequency component. When F4 was 0.39 Hz, all frequency components had a low gain (mean 0.05), but as F4 was increased there was a significant (P less than 0.001) increase in gain for all three low-frequency components which reached a maximum (mean 0.17) when F4 was 2.08 Hz. However, the gain for the highest frequency component always remained comparable to that obtained in response to a single discrete sinusoid of the same frequency. 5. When the stimulus was composed of only two sinusoids a similar increase in gain of the lower-frequency (0.22 Hz) component was observed in the head-fixed target condition as the frequency of the higher-frequency component was increased from 0.39 to 2.78 Hz. However, VOR gain was not significantly modified by the frequency of the higher-frequency component when subjects imagined a head-fixed or earth-fixed target in darkness. 6. The findings indicate that high levels of VOR suppression can be achieved in the head-fixed target condition with pseudo-random stimuli when all frequency components are below 0.4 Hz. But if the highest-frequency component rises above 0.8 Hz, optimum suppression is confined to the highest-frequency component, whilst suppression of the low-frequency components is significantly reduced.(ABSTRACT TRUNCATED AT 400 WORDS)


A genetically-encoded chloride and pH sensor for dissociating ion dynamics in the nervous system.
Within the nervous system, intracellular Cl(-) and pH regulate fundamental processes including cell proliferation, metabolism, synaptic transmission, and network excitability. Cl(-) and pH are often co-regulated, and network activity results in the movement of both Cl(-) and H(+). Tools to accurately measure these ions are crucial for understanding their role under physiological and pathological conditions. Although genetically-encoded Cl(-) and pH sensors have been described previously, these either lack ion specificity or are unsuitable for neuronal use. Here we present ClopHensorN-a new genetically-encoded ratiometric Cl(-) and pH sensor that is optimized for the nervous system. We demonstrate the ability of ClopHensorN to dissociate and simultaneously quantify Cl(-) and H(+) concentrations under a variety of conditions. In addition, we establish the sensor's utility by characterizing activity-dependent ion dynamics in hippocampal neurons.


beta-lactamase gene promoters of 71 clinical strains of Klebsiella oxytoca.
beta-Lactamase gene promoters of 45 clinical Klebsiella oxytoca isolates resistant to beta-lactams and exhibiting beta-lactamase hyperproduction differed from those in 26 susceptible strains. Direct sequencing revealed one mutation in either the -10 or -35 conserved sequences: a G-to-A transition of the fifth base (67%) or a G-to-T transversion of the first base of the -10 sequence (27%) or a T-to-A transversion in the fourth base in the -35 sequence (4%). One strain carried both the -10 transition and the -35 transversion.


Serum retinol and retinol-binding protein levels do not predict subsequent lung cancer.
Retinol and retinol-binding protein levels were measured in sera previously obtained, and stored in the frozen state, at multiphasic health checkups from 151 persons subsequently found to have lung cancer (cases) and 302 persons who remained free of cancer (controls). Two controls were matched to each case for sex, skin color, age, date of multiphasic health checkup, and aspects of the smoking habit. Mean levels in cases and controls were, respectively, retinol: 82.17 and 82.37 micrograms/dl (p = 0.93), and retinol-binding protein: 6.04 and 6.00 mg/dl (p = 0.81). Mean differences between cases and controls were, retinol: 0.195 micrograms/dl with 95% confidence limits, -3.91 and 4.30 micrograms/dl; retinol-binding protein: -0.033 mg/dl with 95% confidence limits, -0.31 and 0.24 mg/dl. No significant trend in relative risk of lung cancer was observed when the retinol or retinol-binding protein distribution was divided into quintiles. No significant associations were observed in subgroups based on age, sex, histologic type of cancer, cigarette consumption, or interval between blood drawing and cancer diagnosis. In this large study, retinol and retinol-binding protein levels were not useful in predicting the subsequent development of lung cancer.


Methods of patient warming during abdominal surgery.
Keeping abdominal surgery patients warm is common and warming methods are needed in power outages during natural disasters. We aimed to evaluate the efficacy of low-cost, low-power warming methods for maintaining normothermia in abdominal surgery patients. Patients (n = 160) scheduled for elective abdominal surgery were included in this prospective clinical study. Five warming methods were applied: heated blood transfusion/fluid infusion vs. unheated; wrapping patients vs. not wrapping; applying moist dressings, heated or not; surgical field rinse heated or not; and applying heating blankets or not. Patients' nasopharyngeal and rectal temperatures were recorded to evaluate warming efficacy. Significant differences were found in mean temperatures of warmed patients compared to those not warmed. When we compared temperatures of abdominal surgery patient groups receiving three specific warming methods with temperatures of control groups not receiving these methods, significant differences were revealed in temperatures maintained during the surgeries between the warmed groups and controls. The value of maintaining normothermia in patients undergoing abdominal surgery under general anesthesia is accepted. Three effective economical and practically applicable warming methods are combined body wrapping and heating blanket; combined body wrapping, heated moist dressings, and heating blanket; combined body wrapping, heated moist dressings, and warmed surgical rinse fluid, with or without heating blanket. These methods are practically applicable when low-cost method is indeed needed.


The neurodevelopmental model of schizophrenia: update 2005.
Neurodevelopmental models of schizophrenia that identify longitudinal precursors of illness have been of great heuristic importance focusing most etiologic research over the past two decades. These models have varied considerably with respect to specificity and timing of hypothesized genetic and environmental 'hits', but have largely focused on insults to prenatal brain development. With heritability around 80%, nongenetic factors impairing development must also be part of the model, and any model must also account for the wide range of age of onset. In recent years, longitudinal brain imaging studies of both early and adult (to distinguish from late ie elderly) onset populations indicate that progressive brain changes are more dynamic than previously thought, with gray matter volume loss particularly striking in adolescence and appearing to be an exaggeration of the normal developmental pattern. This supports an extended time period of abnormal neurodevelopment in schizophrenia in addition to earlier 'lesions'. Many subtle cognitive, motor, and behavioral deviations are seen years before illness onset, and these are more prominent in early onset cases. Moreover, schizophrenia susceptibility genes and chromosomal abnormalities, particularly as examined for early onset populations (ie GAD1, 22q11DS), are associated with premorbid neurodevelopmental abnormalities. Several candidate genes for schizophrenia (eg dysbindin) are associated with lower cognitive abilities in both schizophrenic and other pediatric populations more generally. Postmortem human brain and developmental animal studies document multiple and diverse effects of developmental genes (including schizophrenia susceptibility genes), at sequential stages of brain development. These may underlie the broad array of premorbid cognitive and behavioral abnormalities seen in schizophrenia, and neurodevelopmental disorders more generally. Increased specificity for the most relevant environmental risk factors such as exposure to prenatal infection, and their interaction with susceptibility genes and/or action through phase-specific altered gene expression now both strengthen and modify the neurodevelopmental theory of schizophrenia.


Global outbreak of severe Mycobacterium chimaera disease after cardiac surgery: a molecular epidemiological study.
Since 2013, over 100 cases of Mycobacterium chimaera prosthetic valve endocarditis and disseminated disease were notified in Europe and the USA, linked to contaminated heater-cooler units (HCUs) used during cardiac surgery. We did a molecular epidemiological investigation to establish the source of these patients' disease. We included 24 M chimaera isolates from 21 cardiac surgery-related patients in Switzerland, Germany, the Netherlands, and the UK, 218 M chimaera isolates from various types of HCUs in hospitals, from LivaNova (formerly Sorin; London, UK) and Maquet (Rastatt, Germany) brand HCU production sites, and unrelated environmental sources and patients, as well as eight Mycobacterium intracellulare isolates. Isolates were analysed by next-generation whole-genome sequencing using Illumina and Pacific Biosciences technologies, and compared with published M chimaera genomes. Phylogenetic analysis based on whole-genome sequencing of 250 isolates revealed two major M chimaera groups. Cardiac surgery-related patient isolates were all classified into group 1, in which all, except one, formed a distinct subgroup. This subgroup also comprised isolates from 11 cardiac surgery-related patients reported from the USA, most isolates from LivaNova HCUs, and one from their production site. Isolates from other HCUs and unrelated patients were more widely distributed in the phylogenetic tree. HCU contamination with M chimaera at the LivaNova factory seems a likely source for cardiothoracic surgery-related severe M chimaera infections diagnosed in Switzerland, Germany, the Netherlands, the UK, the USA, and Australia. Protective measures and heightened clinician awareness are essential to guarantee patient safety. Partly funded by the EU Horizon 2020 programme, its FP7 programme, the German Center for Infection Research (DZIF), the Swiss National Science Foundation, the Swiss Federal Office of Public Health, and National Institute of Health Research Oxford Health Protection Research Units on Healthcare Associated Infection and Antimicrobial Resistance.


Multimodal recording of brain activity in term newborns during photic stimulation by near-infrared spectroscopy and electroencephalography.
In this study 14 healthy term newborns (postnatal mean age 2.1 days) underwent photic stimulation during sleep on two different days. Near-infrared spectroscopy (NIRS) and electroencephalography (EEG) was acquired simultaneously. The aims of the study were: to determine (i) the sensitivity and (ii) the repeatability of NIRS to detect the hemodynamic response, (iii) the sensitivity and (iv) the repeatability of EEG to detect a visual evoked potential (VEP), (v) to analyze optical data for the optical neuronal signal, and (vi) to test whether inadequate stimulation could be reason for absent hemodynamic responses. The results of the study were as follows. (i) Sensitivity of NIRS was 61.5% to detect hemodynamic responses; (ii) their reproducibility was 41.7%. A VEP was detected (iii) in 96.3% of all subjects with (iv) a reproducibility of 92.3%. (v) In two measurements data met the criteria for an optical neuronal signal. The noise level was 9.6·10-5% change in optical density. (vi) Insufficient stimulation was excluded as reason for absent hemodynamic responses. We conclude that NIRS is an promising tool to study cognitive activation and development of the brain. For clinical application, however, the sensitivity and reproducibility on an individual level needs to be improved.


Medication Adherence and Technology-Based Interventions for Adolescents With Chronic Health Conditions: A Few Key Considerations.
The number of children and adolescents with chronic health conditions (CHCs) has doubled over the past two decades. Medication adherence is a key component of disease management within these groups. Low adherence to prescribed medications is a known problem in adolescents with CHCs and is related to health outcomes, including quality of life, disease complications, and mortality. Adolescence is a critical time to create routines and health behaviors that optimize disease self-management and transition to adult care. The mounting interest in the development and use of mobile health tools provides novel opportunities to connect patients, particularly adolescents, with their providers outside of the clinic and to improve health outcomes. There is growing evidence to support the efficacy of technology-based approaches, in particular text-messaging and mobile apps, to improve adherence behavior in adolescents, although cost-effectiveness and long-term health benefits remain unclear. In this short viewpoint article, we review some important considerations for promoting medication adherence in adolescents with CHCs using technology-based approaches.


Spatially explicit paleogenomic simulations support cohabitation with limited admixture between Bronze Age Central European populations.
The Bronze Age is a complex period of social, cultural and economic changes. Recent paleogenomic studies have documented a large and rapid genetic change in early Bronze Age populations from Central Europe. However, the detailed demographic and genetic processes involved in this change are still debated. Here we have used spatially explicit simulations of genomic components to better characterize the demographic and migratory conditions that may have led to this change. We investigated various scenarios representing the expansion of pastoralists from the Pontic steppe, potentially linked to the Yamnaya cultural complex, and their interactions with local populations in Central Europe, considering various eco-evolutionary factors, such as population admixture, competition and long-distance dispersal. Our results do not support direct competition but rather the cohabitation of pastoralists and farmers in Central Europe, with limited gene flow between populations. They also suggest occasional long-distance migrations accompanying the expansion of pastoralists and a demographic decline in both populations following their initial contact. These results link recent archaeological and paleogenomic observations and move further the debate of genomic changes during the early Bronze Age.


The nature and prevalence of partner psychological abuse in a national sample of adults.
A detailed analysis of the occurrence of serious psychological abuse (PSYAB) in one's "worst relationship" was solicited from a nationwide sample of adults in the United States. To designate that they experienced any of the psychologically abusive behaviors, respondents had to have perceived malignant intent by the perpetrator. Respondents reported significant rates of the presence and frequency for 14 specified categories of serious PSYAB as well as for the 42 individual behaviors constituting these categories (i.e., 3 per category). The 3 behaviors within each category frequently co-occurred even though they represented distinct manifestations and increasing levels of severity for that type of PSYAB. Only some of the behaviors demonstrated a relationship between frequency of that behavior in a relationship and subsequent emotional and behavioral impact. Neither demographics nor social desirability were strongly related to report of partner PSYAB.


Reduced hepatocyte proliferation is the basis of retarded liver tumor progression and liver regeneration in mice lacking N-acetylglucosaminyltransferase III.
Mice lacking N-acetylglucosaminyltransferase III (GlcNAc-TIII) exhibit slightly but significantly retarded liver tumor progression after a single injection of 10 micro g/g diethylnitrosamine (DEN) and continued administration of phenobarbital (PB) in drinking water. A key question is whether the absence of GlcNAc-TIII inhibits cell proliferation or induces apoptosis. Because PB aids tumor progression, we tested whether it diminished the difference in tumor progression between Mgat3(+/+) and Mgat3(Delta/Delta) mice. Here, we show that in the absence of PB, control males developed about twice as many liver tumor nodules as males lacking GlcNAc-TIII. Both the size of liver tumors and liver weights were significantly greater in DEN-treated wild-type or heterozygous mice. Apoptosis assays performed monthly after DEN treatment showed no differences between mutant and wild-type. However, there was a marked retardation in liver regeneration after partial (70%) hepatectomy (PH). Wild-type mice incorporated bromodeoxyuridine in approximately 15% of hepatocyte nuclei at 48 h after PH, whereas mice lacking GlcNAc-TIII had only approximately 5% positive nuclei. This was not because of enhanced apoptosis in mutant mice after PH. Expression of the Mgat3 gene remained undetectable in wild-type liver by Northern analysis after tumor induction or after PH. In addition, transgenic overexpression of GlcNAc-TIII in hepatocytes did not enhance tumor progression in Mgat3(Delta/Delta) mice, and there were no differences in tumor progression or liver regeneration after PH between control and transgenic mice overexpressing GlcNAc-TIII in liver. Therefore, the nonhepatic action of GlcNAc-TIII promotes hepatocyte proliferation after PH, as well as the progression of DEN-induced tumors, providing evidence for a functional role of the bisecting GlcNAc on circulating glycoprotein growth factor(s) that stimulate hepatocyte proliferation.


Sleep quality and morningness-eveningness of shift nurses.
The aim of the study was to analyse, while controlling for identified covariates, the effects of morningness-eveningness on sleep quality for shift nurses. Shift nurses had greater difficulty falling asleep or staying asleep, thus resulting in higher rates of retiring from hospital. Existing research has addressed the effects of manpower demand and personal preferences on shift assignment; however, the concept of endogenous rhythms is rarely considered. This analysis included 137 nurses between the ages of 21-58. Nurses completed the Horne and Ostberg questionnaire to assess morningness-eveningness and the Pittsburgh Sleep Quality Index (PSQI) questionnaire to measure self-reported sleep quality over the last month. The 18-point Chinese version had a Cronbach's reliability coefficient of 0.79 overall and 0.86 respectively. This study analysed correlates of sleep quality by comparing the groups with better or worse sleep quality according to the median of PSQI. Univariate and multivariate analyses were used for the risk factors of worse sleep quality. The result showed that the strongest predictor of sleep quality was morningness-eveningness not the shift schedule or shift pattern for nurses under controlling the variable of age. Greater age and longer years employed in nursing significantly decreased the risk of worse sleep quality. The confounding age factor was properly controlled; evening types working on changing shifts had higher risk of poor sleep quality compared to morning types. Morningness-eveningness was the strongest predictor of sleep quality under controlling the variable of age in shift nurses. Our results suggested that determining if nurses were attributed to morning or evening types is an important sleep issue before deciding the shift assignment.


Tumour angiogenesis: the gap between theory and experiments.
A common experimental technique for viewing in vivo angiogenesis utilises tumours implanted into a test animal cornea. The cornea is avascular but the tumour promotes vascularisation from the limbus and the new blood vessels can be readily observed through the transparent cornea. Many of the early mathematical models for tumour angiogenesis used this scenario as their experimental template and as such assumed that there is a large gap, of the order of 2mm, between the tumour and neighbouring vasculature at the onset of angiogenesis. In this work we consider whether the assumption that there is a significant gap between the tumour and neighbouring vasculature is unique to intra-cornea tumour implants, or whether this characterises avascular tumour growth more generally. To do this we utilise a simple scaling argument, derive a multi-compartment model for tumour growth, and consider in vivo images. This analysis demonstrates that the corneal implant experiments and the corresponding mathematical models cannot generally be applied to a clinical setting.


Stenting of atherosclerotic stenoses of the extracranial carotid artery.
Percutaneous transluminal angioplasty (PTA) and stenting seems to be, at present, the treatment of choice for early restenosis after endarterectomy and for atherosclerotic stenoses of supra-aortic trunks near or at the ostium. In contrast, the role of PTA and stenting for treatment of symptomatic and asymptomatic atherosclerotic stenosis of carotid bifurcation is still debated. The present study comprises 27 consecutive cases of atherosclerotic lesions of the carotid bifurcation treated with PTA and stenting. All patients were symptomatic, except for 2 suffering from asymptomatic stenosis with contralateral carotid occlusion. There were 23 stenoses occluding 70% or more of the lumen according to the NASCET criteria and 4 mild stenoses (50-60% of the lumen) with large type C ulcers. Criteria for exclusion from surgery in these cases were aged >79 years, previous neck surgery for laryngeal cancer, carotid bifurcation at C2, association with intracranial aneurysms, occlusion of the contralateral carotid artery, and heart, lung and kidney diseases. All procedures were performed under local anaesthesia associated with mild sedation in a few cases. In all cases, self-expandable stents (Wallstent) were used. Follow-up ranged from 6 to 37 months. Transient neurological deficit occurred in 3 cases (11%). One case (3.7%) experienced a minor stroke at three months. Asymptomatic tight restenosis due to intimal hyperplasia occurred in one case (3.7%). In 8 cases (40%) of complex stenosis involving common and internal carotid arteries there was some loss of contact of the stent with the wall of the common carotid artery in the late follow-up. One case (3.7%) experienced severe and prolonged hypotension and bradycardia during the release of the stent. From literature data and our results it emerges that periprocedural catastrophic embolism is unlikely to occur. The best results are undoubtedly obtained when treating stenosis limited to the internal carotid artery. Nevertheless, the ideal stent to treat vessels of different calibre, as occurs at the carotid bifurcation, is not yet available. The problem of periprocedural cerebral protection has not been resolved. Reported series are heterogeneous and retrospective, and an adequate follow-up of cases is still lacking.


Selective impairment of platelet activation to collagen in the absence of GATA1.
Defects in the X-linked DNA-binding megakaryocyte transcription factor GATA1 cause thrombocytopenia and abnormal platelet function. However, detailed studies of GATA1 function in platelet activation are lacking. Here, we studied platelets from GATA1-deficient mice and from a male patient (S14) with a bleeding diathesis attributed to a single amino acid substitution (R216Q) in the N-terminal GATA1 zinc finger that alters binding to DNA. In both cases there was inhibition of aggregation to collagen and decreased tyrosine phosphorylation of glycoprotein VI (GPVI)-signaling proteins. This effect was more marked in GATA1-deficient murine platelets, where it was associated with a significant reduction in surface GPVI expression. Moreover, both human and murine GATA1-mutant platelets showed reduced adhesion and aggregate formation on a collagen matrix at an intermediate rate of shear, although this could not be accounted solely by the thrombocytopenia and altered GPVI expression, indicating that GATA1 regulates additional factors important for platelet activation under shear. In contrast, there was no inhibition of responses to G protein-coupled receptor agonists in GATA1-perturbed platelets. Our results are consistent with GATA1 regulating some but not all pathways of platelet activation, leading to an impairment of aggregate formation under flow, which cannot be attributed solely to the thrombocytopenia.


Retrobulbar structure visualization with enhanced depth imaging optical coherence tomography.
To assess enhanced depth imaging optical coherence tomography (EDI-OCT) visualization of deep posterior pole structures and retrobulbar tissues in myopic eyes and evaluate ocular structural elements that influence this capability. Thirty consecutive myopic eyes (>-6 diopters) from 21 patients were enrolled. Exclusion criteria included any pathological condition affecting the posterior pole. Patients underwent biometry to assess axial length, and irises were classified as darkly or lightly pigmented. EDI-OCT scans were obtained by spectral-domain OCT to image posterior pole and retrobulbar structures. Choroidal thickness was measured manually, and for eyes in which the sclera was fully visible, scleral thickness was also measured manually. The influence of central retinal thickness, axial length, refractive error, mean choroidal thickness, mean scleral thickness, and iris pigmentation on EDI-OCT visualization of structures beyond the choroid was tested. Choroidal thickness was measurable in all eyes. In 11 of 30 eyes, the sclera was not completely visible (group 1). In 19 eyes, the full scleral thickness was measurable (group 2). In seven of the group 2 eyes, the full sclera was the deepest structure detected. In the remaining 11 eyes, deeper structures were visible. Choroidal thickness was the only parameter that correlated with the ability to visualize the full sclera (P < 0.001) and deeper structures (P = 0.044). The full thickness of the choroid was visualized by EDI-OCT in all eyes. Full thicknesses of the sclera and retrobulbar structures were not always visible. Choroidal thickness was the only parameter that significantly correlated with EDI-OCT visualization of deeper structures.


Intermittent marijuana use is associated with improved retention in naltrexone treatment for opiate-dependence.
Naltrexone is a theoretically promising alternative to agonist substitution treatment for opioid dependence, but its effectiveness has been severely limited by poor adherence. This study examined, in an independent sample, a previously observed association between moderate cannabis use and improved retention in naltrexone treatment. Opioid dependent patients (N = 63), admitted for inpatient detoxification and induction onto oral naltrexone, and randomized into a six-month trial of intensive behavioral therapy (Behavioral Naltrexone Therapy) versus a control behavioral therapy (Compliance Enhancement), were classified into three levels of cannabis use during treatment based on biweekly urine toxicology: abstinent (0% cannabis positive urine samples); intermittent use (1% to 79% cannabis positive samples); and consistent use (80% or greater cannabis positive samples). Intermittent cannabis users showed superior retention in naltrexone treatment (median days retained = 133; mean = 112.8, SE = 17.5), compared to abstinent (median = 35; mean = 47.3, SE = 9.2) or consistent users (median = 35; mean = 68.3, SE = 14.1) (log rank = 12.2, df = 2, p = .002). The effect remained significant in a Cox model after adjustment for baseline level of heroin use and during treatment level of cocaine use. Intermittent cannabis use was also associated with greater adherence to naltrexone pill-taking. Treatment interacted with cannabis use level, such that intensive behavioral therapy appeared to moderate the adverse prognosis in the consistent cannabis use group. The association between moderate cannabis use and improved retention on naltrexone treatment was replicated. Experimental studies are needed to directly test the hypothesis that cannabinoid agonists exert a beneficial pharmacological effect on naltrexone maintenance and to understand the mechanism.


Compression stockings in the management of fractures of the ankle: a randomised controlled trial.
In this randomised controlled trial, we evaluated the role of elastic compression using ankle injury stockings (AIS) in the management of fractures of the ankle. A total of 90 patients with a mean age of 47 years (16 to 79) were treated within 72 hours of presentation with a fracture of the ankle, 31 of whom were treated operatively and 59 conservatively, were randomised to be treated either with compression by AIS plus an Aircast boot or Tubigrip plus an Aircast boot. Male to female ratio was 36:54. The primary outcome measure was the functional Olerud-Molander ankle score (OMAS). The secondary outcome measures were; the American Orthopaedic Foot and Ankle Society score (AOFAS); the Short Form (SF)-12v2 Quality of Life score; and the frequency of deep vein thrombosis (DVT). Compression using AIS reduced swelling of the ankle at all time points and improved the mean OMAS score at six months to 98 (95% confidence interval (CI) 96 to 99) compared with a mean of 67 (95% CI 62 to 73) for the Tubigrip group (p < 0.001). The mean AOFAS and SF-12v2 scores at six months were also significantly improved by compression. Of 86 patients with duplex imaging at four weeks, five (12%) of 43 in the AIS group and ten (23%) of 43 in the Tubigrip group developed a DVT (p = 0.26). Compression improved functional outcome and quality of life following fracture of the ankle. DVTs were frequent, but a larger study would be needed to confirm that compression with AISs reduces the incidence of DVT.


The amino acid sequences of the myelin-associated glycoproteins: homology to the immunoglobulin gene superfamily.
The myelin associated glycoproteins (MAG) are integral plasma membrane proteins which are found in oligodendrocytes and Schwann cells and are believed to mediate the axonal-glial interactions of myelination. In this paper we demonstrate the existence in central nervous system myelin of two MAG polypeptides with Mrs of 67,000 and 72,000 that we have designated small MAG (S-MAG) and large MAG (L-MAG), respectively. The complete amino acid sequence of L-MAG and a partial amino acid sequence of S-MAG have been deduced from the nucleotide sequences of corresponding cDNA clones isolated from a lambda gt11 rat brain expression library. Based on their amino acid sequences, we predict that both proteins have an identical membrane spanning segment and a large extracellular domain. The putative extracellular region contains an Arg-Gly-Asp sequence that may be involved in the interaction of these proteins with the axon. The extracellular portion of L-MAG also contains five segments of internal homology that resemble immunoglobulin domains, and are strikingly homologous to similar domains of the neural cell adhesion molecule and other members of the immunoglobulin gene superfamily. In addition, the two MAG proteins differ in the extent of their cytoplasmically disposed segments and appear to be the products of alternatively spliced mRNAs. Of considerable interest is the finding that the cytoplasmic domain of L-MAG, but not of S-MAG, contains an amino acid sequence that resembles the autophosphorylation site of the epidermal growth factor receptor.


Quantification of Drug-Induced Inhibition of Canalicular Cholyl-l-Lysyl-Fluorescein Excretion From Hepatocytes by High Content Cell Imaging.
We describe the use of a commercially available high content cell imaging algorithm (Cellomics Arrayscan Spot Detector) to quantify biliary excretion of the fluorescent probe substrate cholyl-l-lysyl-fluorescein (CLF) from rat hepatocytes cultured in collagen/matrigel sandwich configuration and to explore inhibition of this process by a variety of test compounds. The method provided robust, reproducible data. Twenty-nine pharmaceuticals inhibited biliary CLF efflux from hepatocytes and a broad range of potencies of inhibition were observed (IC50 values ranged between <1 and 794 µM). Thirteen drugs that inhibited CLF efflux also inhibited hepatocellular uptake of the probe substrate [(3)H]-taurocholate. Although no clear correlation between the potencies of inhibition of the 2 processes was evident, these data highlight the need to consider possible uptake transporter inhibition when interpreting hepatocyte CLF inhibition data. It has been reported that CLF is transported by MRP2. The CLF efflux inhibition data correlated closely with published data on inhibition by the drugs of the bile salt export pump (Bsep), which suggests that the tested drugs inhibit both Bsep and Mrp2. Calculation of the ratios between the maximum human plasma concentrations of the drugs and their CLF efflux inhibition IC50 values raised the possibility that for many, but not all, of them the in vitro effects may be functionally significant in vivo and that Mrp2 inhibition might be a drug-induced liver injury (DILI) risk factor. These data indicate that imaging hepatocyte CLF inhibition is a promising new method for quantification of biliary efflux inhibition by drugs, which could aid assessment of compound-related DILI risk.


Data-driven analysis of JAK2V617F kinetics during interferon-alpha2 treatment of patients with polycythemia vera and related neoplasms.
Treatment with PEGylated interferon-alpha2 (IFN) of patients with essential thrombocythemia and polycythemia vera induces major molecular remissions with a reduction in the JAK2V617F allele burden to undetectable levels in a subset of patients. A favorable response to IFN has been argued to depend upon the tumor burden, implying that institution of treatment with IFN should be as early as possible after the diagnosis. However, evidence for this statement is not available. We present a thorough analysis of unique serial JAK2V617F measurements in 66 IFN-treated patients and in 6 untreated patients. Without IFN treatment, the JAK2V617F allele burden increased exponentially with a period of doubling of 1.4 year. During monotherapy with IFN, the JAK2V617F allele burden decreased mono- or bi-exponentially for 33 responders of which 28 patients satisfied both descriptions. Bi-exponential description improved the fits in 19 cases being associated with late JAK2V617F responses. The decay of the JAK2V617F allele burden during IFN treatment was estimated to have half-lives of 1.6 year for the monoexponential response and 1.0 year in the long term for the bi-exponential response. In conclusion, through data-driven analysis of the JAK2V617F allele burden, we provide novel information regarding the JAK2V617F kinetics during IFN-treatment, arguing for early intervention.


A Continuing Mission to Optimize the Care of Older Women with Breast Cancer.
The majority of cases of breast cancer occur in the older population who are often un-represented in clinical trials. Given the growing ageing population globally, it becomes urgent and important to identify an optimal approach so that older women with breast cancer are neither under- or over-treated. An inter-disciplinary research program is ongoing to investigate differing tumor biology according to age, and the potential use of a geriatric assessment tool, aiming to help select older women with primary breast cancer for a personalized and optimal treatment. Full considerations of the biology of the patient's cancer and the geriatric domains of the patient must be taken into account when making treatment decisions.


Voyager: Exploratory Analysis via Faceted Browsing of Visualization Recommendations.
General visualization tools typically require manual specification of views: analysts must select data variables and then choose which transformations and visual encodings to apply. These decisions often involve both domain and visualization design expertise, and may impose a tedious specification process that impedes exploration. In this paper, we seek to complement manual chart construction with interactive navigation of a gallery of automatically-generated visualizations. We contribute Voyager, a mixed-initiative system that supports faceted browsing of recommended charts chosen according to statistical and perceptual measures. We describe Voyager's architecture, motivating design principles, and methods for generating and interacting with visualization recommendations. In a study comparing Voyager to a manual visualization specification tool, we find that Voyager facilitates exploration of previously unseen data and leads to increased data variable coverage. We then distill design implications for visualization tools, in particular the need to balance rapid exploration and targeted question-answering.


In vitro acetylcholinesterase inhibitory activity and the antioxidant properties of Aegle marmelos leaf extract: implications for the treatment of Alzheimer's disease.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder clinically characterized by loss of memory and cognition. The effective therapeutic options for AD are limited and thus there is a demand for new drugs. Aegle marmelos (Linn.) (A. marmelos) leaves have been used in traditional medicine to promote intellect and enhance memory. In this study, we evaluated A. marmelos for its acetylcholinesterase (AChE) inhibitory activity and antioxidant property in vitro in the treatment of AD. A crude methanol extract and four fractions (petroleum ether, chloroform, ethyl acetate and aqueous) were prepared from the leaves of A. marmelos. The preparations were assessed for AChE inhibitory activity by the Ellman method, and their antioxidant properties were assessed by several assays: reducing power, scavenging of 1,1-diphenyl-2-picrylhydrazyl free radical and hydroxyl radical, and inhibition of lipid peroxidation. Qualitative and quantitative analyses of endogenous substances in A. marmelos were performed by the standard phytochemical methods. Among the different extracts tested, the ethyl acetate fraction exhibited the highest inhibition of AChE activity. In the same way, ethyl acetate fraction showed the highest reducing activity and radical scavenging ability towards the 1,1-diphenyl-2-picrylhydrazyl (half maximal inhibitory concentration = 3.84 μg/mL) and hydroxyl free radicals (half maximal inhibitory concentration = 5.68 μg/mL). The antiradical activity of the ethyl acetate fraction appeared to be similar to that of the reference standard butylated hydroxytoluene and catechin used in this study. In addition, the ethyl acetate fraction displayed higher inhibition of brain lipid peroxidation. Phytochemical screening of different extractives of A. marmelos showed the presence of phenols and flavonoids, alkaloid, saponin, glycoside, tannin and steroids. Quantitative analysis revealed higher contents of phenolics (58.79-mg gallic acid equivalent/g dried extract) and flavonoids (375.73-mg gallic acid equivalent/g dried extract) in the ethyl acetate fraction. The results suggest that the ethyl acetate fraction of A. marmelos is a significant source of polyphenolic compounds with potential AChE inhibitory property and antioxidant activity and, thus, may be useful in the treatment of AD.


Photocatalytic reduction of CO2 based on a CeO2 photocatalyst loaded with imidazole fabricated N-doped graphene and Cu(ii) as cocatalysts.
Cocatalysts are vital for improving photocatalytic activity. Incorporating nitrogen atoms on a graphene frame using an imidazole cycle resulted in a new N-doped graphene (denoted as ING). Cerium(iv) oxide (CeO2) nanoparticles were dispersed on ING sheets, producing an ING/CeO2 hybrid material. The ING/CeO2 hybrid material was characterized using X-ray diffraction, transmission electron microscopy, Raman spectroscopy, ultraviolet-visible diffuse reflectance spectroscopy and surface photovoltage spectroscopy. Copper(ii) ions [Cu(ii)] were adsorbed on the ING/CeO2 hybrid material to directly form Cu(ii)/ING/CeO2, which could capture the photogenerated electrons to reduce carbon dioxide (CO2) to methanol (CH3OH) under incident light irradiation. The results showed that the yield from reducing CO2 to CH3OH during the photocatalytic process using Cu(ii)/ING/CeO2 as the photocatalyst approached 385.8 μmol g-1 cat. h-1, whereas the yield was only 3.57 μmol g-1 cat. h-1 using ING/CeO2 as the photocatalyst. This shows that the Cu(ii) ions play a vital role during photocatalytic reduction of CO2 by forming copper(i) ions [Cu(i)]. The percentage of ING in the ING/CeO2 hybrid material was investigated, and the results indicated that 3.6% of ING achieved an optimal yield of CH3OH during the photo-reduction process. The simultaneous roles of Cu(ii) ions and ING sheets demonstrate a synergistic strategy for improving the photocatalytic CO2 reduction.


The Potential Effect of Fucoidan on Inhibiting Epithelial-to-Mesenchymal Transition, Proliferation, and Increase in Apoptosis for Endometriosis Treatment: In Vivo and In Vitro Study.
Endometriosis is common in reproductive-age women and its pathology is to increase proliferation and migration to enhance epithelial-to-mesenchymal transition progression (EMT). However, treatments are currently limited, so it is important to explore new therapeutic drugs. Hence, in this study, we investigate the therapeutic effect of fucoidan (FC) on the progression and mechanisms of endometriosis. The cell viability of endometrial cell lines End1/E6E7 and Vk2/E6E7 treated with different concentrations of FC were assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell counting. Cell migration was evaluated using wound-healing assay. In an in vivo experiment, female Balb/c mice received surgically induced endometriosis followed by different concentrations of fucoidan for 6 weeks. High-frequency ultrasound imaging was applied to detect subsequent lesion growth. The results demonstrated that fucoidan inhibited the viability and migration ability of End1/E6E7 and Vk2/E6E7 cells. Additionally, the administration of fucoidan reduced the volume and weight of endometriotic lesions, decreased inflammatory cytokines and vascular endothelial growth factor (VEGF) of serum and lesions, and improved EMT proliferation and apoptosis-related protein expression. For the first time, fucoidan indicated anti-proliferative and anti-inflammatory effects as well as inhibited EMT progression and induced apoptosis, improving endometriosis.


Strong infrared radiation through passive dispersive wave generation and its control.
We observe strong infrared (IR) radiation as a result of passive dispersive wave generation for a realistic microstructured fiber having two zero-dispersion wavelengths. The IR radiation frequency can be suitably controlled by varying the operational wavelength, which falls in the first normal dispersion regime. The amplitude of the radiation can be significantly increased by introducing a suitable amount of chirp in the input pulse. This strong phase-matching radiation can be considered as an alternative solution for the IR laser for different applications.


Decoupling sensory from decisional choice biases in perceptual decision making.
The contribution of sensory and decisional processes to perceptual decision making is still unclear, even in simple perceptual tasks. When decision makers need to select an action from a set of balanced alternatives, any tendency to choose one alternative more often-choice bias-is consistent with a bias in the sensory evidence, but also with a preference to select that alternative independently of the sensory evidence. To decouple sensory from decisional biases, here we asked humans to perform a simple perceptual discrimination task with two symmetric alternatives under two different task instructions. The instructions varied the response mapping between perception and the category of the alternatives. We found that from 32 participants, 30 exhibited sensory biases and 15 decisional biases. The decisional biases were consistent with a criterion change in a simple signal detection theory model. Perceptual decision making, thus, even in simple scenarios, is affected by sensory and decisional choice biases.


A non-connexon protein (MIP) is involved in eye lens gap-junction formation.
New immunolocalization data put the role of the lens MP26 (MIP) protein in a new perspective. During maturation of lens fibre cells, MIP is found to associate specifically with two structures, gap junctions and cell interlocking processes (known as ball and socket domains). It is significant that the zone in which these associations are most striking is discrete, coinciding with the zone of rapidly enlarging junctional plaques and newly forming ball and socket domains. Observation of domain-specific interactions of MIP with forming gap junctions and ball and socket domains suggests that MIP may be involved in the formation of close membrane appositions. Furthermore, previous ambiguities in the literature over the presence of MIP in gap junctions are clarified by the knowledge that, in situ, MIP associates strongly with gap junctions for only a brief period (with less than about 5% of all lens gap junctions at any one time) during the assembly of junctional plaques.


The Tailored Implementation in Chronic Diseases (TICD) project: introduction and main findings.
The Tailored Implementation in Chronic Diseases (TICD) project aims to contribute knowledge on how to improve healthcare for patients with chronic diseases and, at the same time, knowledge on concepts and methods of tailoring interventions to local conditions. In this contribution, the project is briefly introduced and its main findings are discussed. The tailored implementation programs in the TICD project had little impact, for which we provide a range of potential explanations. Structured group interviews with informed stakeholders, such as clinicians and researchers, were used to generate perceived determinants of practice and suggestions for tailored implementation strategies. They were productive and valid, yet incomplete, if compared to perceptions of healthcare providers who received the tailored implementation programs. Ongoing monitoring of determinants of practice during intervention delivery seems required to adapt the interventions to emerging needs and opportunities.


International COVID-19 Palliative Care Guidance for Nursing Homes Leaves Key Themes Unaddressed.
COVID-19 mortality disproportionally affects nursing homes, creating enormous pressures to deliver high-quality end-of-life care. Comprehensive palliative care should be an explicit part of both national and global COVID-19 response plans. Therefore, we aimed to identify, review, and compare national and international COVID-19 guidance for nursing homes concerning palliative care, issued by government bodies and professional associations. We performed a directed documentary and content analysis of newly developed or adapted COVID-19 guidance documents from across the world. Documents were collected via expert consultation and independently screened against prespecified eligibility criteria. We applied thematic analysis and narrative synthesis techniques. We identified 21 eligible documents covering both nursing homes and palliative care, from the World Health Organization (n = 3), and eight individual countries: U.S. (n = 7), The Netherlands (n = 2), Ireland (n = 1), U.K. (n = 3), Switzerland (n = 3), New Zealand (n = 1), and Belgium (n = 1). International documents focused primarily on infection prevention and control, including only a few sentences on palliative care-related topics. Palliative care themes most frequently mentioned across documents were end-of-life visits, advance care planning documentation, and clinical decision making toward the end of life (focusing on hospital transfers). There is a dearth of comprehensive international COVID-19 guidance on palliative care for nursing homes. Most have a limited focus both regarding breadth of topics and recommendations made. Key aspects of palliative care, that is, symptom management, staff education and support, referral to specialist services or hospice, and family support, need greater attention in future guidelines.


Serum carnitine and selenium levels in children with celiac disease.
Celiac disease (CD) is a gluten-induced enteropathy that results in malabsorption of nutrients. We studied the serum levels of carnitine and selenium in children with CD. Serum levels of free carnitine and selenium were studied in 30 children (mean age 8.1 [4.4] years) with CD and 30 age- and gender-matched healthy children. All patients had type 3 duodenal lesions. The mean (SD) serum levels of free carnitine and selenium were lower among patients with CD (24.5 [7.7] micromol/mL and 52.1 (12.9) micromol/mL, respectively) than among healthy controls (29.4 [9.2] and 65.1 [17.2] micromol/mL; p < 0.05 each). Levels were similar in children with and without diarrhea. Serum carnitine and selenium levels are decreased in children with CD, probably due to malabsorption.


The influence of relative humidity on the infectivity of air-borne influenza A virus, PR8 strain.
White mice were exposed to atmospheres containing known amounts of atomized influenza A virus (PR8 strain) of constant potency under conditions of varying humidity. It was found that an amount of atomized virus suspension which produced a 100 per cent mortality rate in animals exposed at 30 and 80 per cent relative humidity, respectively, resulted in the death of only 22.5 per cent of mice at a humidity of 50 per cent. The humidities between these values gave intermediate results. The infectivity of the air-borne virus decreased so rapidly at a humidity of 50 per cent that it was impossible to secure a 100 per cent mortality rate in the exposed mice even by greatly increasing the dose of virus atomized. The use of a dialyzed virus suspension at a humidity of 50 per cent resulted in the death of all exposed mice. This suggested that the deleterious influence of humidity was related to the presence of sodium chloride in the atomized suspension. These findings with influenza virus closely resembled those obtained by Dunklin and Puck with pneumococci, streptococci, and staphylococci which would suggest that the factor responsible for the lethal effect of humidity is common to moist particles containing either the above-mentioned bacteria or influenza A virus.


Effect of Plyometric Training on Vertical Jump Performance in Female Athletes: A Systematic Review and Meta-Analysis.
Plyometric training is an effective method to prevent knee injuries in female athletes; however, the effects of plyometric training on jump performance in female athletes is unclear. The aim of this systematic review and meta-analysis was to determine the effectiveness of plyometric training on vertical jump (VJ) performance of amateur, collegiate and elite female athletes. Six electronic databases were searched (PubMed, MEDLINE, ERIC, Google Scholar, SCIndex and ScienceDirect). The included studies were coded for the following criteria: training status, training modality and type of outcome measures. The methodological quality of each study was assessed using the physiotherapy evidence database (PEDro) scale. The effects of plyometric training on VJ performance were based on the following standardised pre-post testing effect size (ES) thresholds: trivial (<0.20), small (0.21-0.60), moderate (0.61-1.20), large (1.21-2.00), very large (2.01-4.00) and extremely large (>4.00). A total of 16 studies met the inclusion criteria. The meta-analysis revealed that plyometric training had a most likely moderate effect on countermovement jump (CMJ) height performance (ES = 1.09; 95 % confidence interval [CI] 0.57-1.61; I 2 = 75.60 %). Plyometric training interventions of less than 10 weeks in duration had a most likely small effect on CMJ height performance (ES = 0.58; 95 % CI 0.25-0.91). In contrast, plyometric training durations greater than 10 weeks had a most likely large effect on CMJ height (ES = 1.87; 95 % CI 0.73-3.01). The effect of plyometric training on concentric-only squat jump (SJ) height was likely small (ES = 0.44; 95 % CI -0.09 to 0.97). Similar effects were observed on SJ height after 6 weeks of plyometric training in amateur (ES = 0.35) and young (ES = 0.49) athletes, respectively. The effect of plyometric training on CMJ height with the arm swing was likely large (ES = 1.31; 95 % CI -0.04 to 2.65). The largest plyometric training effects were observed in drop jump (DJ) height performance (ES = 3.59; 95 % CI -3.04 to 10.23). Most likely extremely large plyometric training effects on DJ height performance (ES = 7.07; 95 % CI 4.71-9.43) were observed following 12 weeks of plyometric training. In contrast, a possibly small positive training effect (ES = 0.30; 95 % CI -0.63 to 1.23) was observed following 6 weeks of plyometric training. Plyometric training is an effective form of training to improve VJ performance (e.g. CMJ, SJ and DJ) in female athletes. The benefits of plyometric training on VJ performance are greater for interventions of longer duration (≥10 weeks).


Sensory processing and categorization in cortical and deep neural networks.
Many recent advances in artificial intelligence (AI) are rooted in visual neuroscience. However, ideas from more complicated paradigms like decision-making are less used. Although automated decision-making systems are ubiquitous (driverless cars, pilot support systems, medical diagnosis algorithms etc.), achieving human-level performance in decision making tasks is still a challenge. At the same time, these tasks that are hard for AI are easy for humans. Thus, understanding human brain dynamics during these decision-making tasks and modeling them using deep neural networks could improve AI performance. Here we modelled some of the complex neural interactions during a sensorimotor decision making task. We investigated how brain dynamics flexibly represented and distinguished between sensory processing and categorization in two sensory domains: motion direction and color. We used two different approaches for understanding neural representations. We compared brain responses to 1) the geometry of a sensory or category domain (domain selectivity) and 2) predictions from deep neural networks (computation selectivity). Both approaches gave us similar results. This confirmed the validity of our analyses. Using the first approach, we found that neural representations changed depending on context. We then trained deep recurrent neural networks to perform the same tasks as the animals. Using the second approach, we found that computations in different brain areas also changed flexibly depending on context. Color computations appeared to rely more on sensory processing, while motion computations more on abstract categories. Overall, our results shed light to the biological basis of categorization and differences in selectivity and computations in different brain areas. They also suggest a way for studying sensory and categorical representations in the brain: compare brain responses to both a behavioral model and a deep neural network and test if they give similar results.


CVD and Oxidative Stress.
Nowadays, it is known that oxidative stress plays at least two roles within the cell, the generation of cellular damage and the involvement in several signaling pathways in its balanced normal state. So far, a substantial amount of time and effort has been expended in the search for a clear link between cardiovascular disease (CVD) and the effects of oxidative stress. Here, we present an overview of the different sources and types of reactive oxygen species in CVD, highlight the relationship between CVD and oxidative stress and discuss the most prominent molecules that play an important role in CVD pathophysiology. Details are given regarding common pharmacological treatments used for cardiovascular distress and how some of them are acting upon ROS-related pathways and molecules. Novel therapies, recently proposed ROS biomarkers, as well as future challenges in the field are addressed. It is apparent that the search for a better understanding of how ROS are contributing to the pathophysiology of CVD is far from over, and new approaches and more suitable biomarkers are needed for the latter to be accomplished.


The temporal window of ecological adaptation in postglacial lakes: a comparison of head morphology, trophic position and habitat use in Norwegian threespine stickleback populations.
Studying how trophic traits and niche use are related in natural populations is important in order to understand adaptation and specialization. Here, we describe trophic trait diversity in twenty-five Norwegian freshwater threespine stickleback populations and their putative marine ancestor, and relate trait differences to postglacial lake age. By studying lakes of different ages, depths and distance to the sea we examine key environmental variables that may predict adaptation in trophic position and habitat use. We measured trophic traits including geometric landmarks that integrated variation in head shape as well as gillraker length and number. Trophic position (Tpos) and niche use (α) were estimated from stable isotopes (δ(13)C, δ(15)N). A comparison of head shape was also made with two North American benthic-limnetic species pairs. We found that head shape differed between marine and freshwater sticklebacks, with marine sticklebacks having more upturned mouths, smaller eyes, larger opercula and deeper heads. Size-adjusted gillraker lengths were larger in marine than in freshwater stickleback. Norwegian sticklebacks were compared on the same head shape axis as the one differentiating the benthic-limnetic North American threespine stickleback species pairs. Here, Norwegian freshwater sticklebacks with a more "limnetic head shape" had more and longer gillrakers than sticklebacks with "benthic head shape". The "limnetic morph" was positively associated with deeper lakes. Populations differed in α (mean ± sd: 0.76 ± 0.29) and Tpos (3.47 ± 0.27), where α increased with gillraker length. Larger fish had a higher Tpos than smaller fish. Compared to the ecologically divergent stickleback species pairs and solitary lake populations in North America, Norwegian freshwater sticklebacks had similar range in Tpos and α values, but much less trait divergences. Our results showed trait divergences between threespine stickleback in marine and freshwater environments. Freshwater populations diverged in trophic ecology and trophic traits, but trophic ecology was not related to the elapsed time in freshwater. Norwegian sticklebacks used the same niches as the ecologically divergent North American stickleback species pairs. However, as trophic trait divergences were smaller, and not strongly associated with the ecological niche, ecological adaptations along the benthic-limnetic axis were less developed in Norwegian sticklebacks.


Characteristics and Outcomes of Acetaminophen Overdose and Hepatotoxicity in Thailand.
Background and Aims: Acetaminophen (APAP) is the leading cause of drug overdose and hepatotoxicity worldwide, including in Thailand. Patterns of overdose and hospital management are known to have significant impacts on the outcomes of APAP overdose, and these factors vary from country to country. Therefore, this study aimed to analyze clinical characteristics of Thai patients with APAP overdose in terms of overdose patterns, clinical presentation, treatment and outcomes. Methods: In this retrospective analytical study, medical records of adult patients hospitalized with a diagnosis of APAP overdose at Rajavithi Hospital, Bangkok, between January 2013 and December 2017 were reviewed. Results: A total of 184 patients diagnosed with APAP overdose were included. The median age was 22 (15-76) years and the majority were female (79.9%). Most overdoses were intended self-poisoning ingestion (90.8%) with a median dose of 10.5 g (4.5-50). A total of 121 patients were treated with N-acetylcysteine with a median visit-to-N-acetylcysteine time of 2 (0.5-15) h. Overall, 15.6% developed mild hepatotoxicity (aspartate aminotransferase or alanine aminotransferase >3 times the upper limit of normal), 6.4% developed severe hepatotoxicity (aspartate aminotransferase or alanine aminotransferase >10 times the upper limit of normal and international normalized ratio >2.0) and 3 patients developed acute liver failure (1 patient resolved spontaneously and 2 patients, neither of whom had a liver transplant, died). Significant predictors for hepatotoxicity included older age, chronic alcohol drinking, repeated taking of medication for more than 8 h (staggered ingestion), long duration between ingestion and hospital visit, alcohol coingestion, abdominal pain symptoms, and acute kidney injury. Conclusions: Most cases of APAP overdose in Thailand appear to be young women with intentional ingestion. With prompt management, most patients (76.4%) did not develop significant hepatotoxicity; nevertheless, despite N-acetylcysteine therapy, hepatotoxicity including acute liver failure was observed in a small proportion of patients, particularly those with unintentional overdose and chronic alcohol drinking.


Interleukin-37 (IL-37) Suppresses Pertussis Toxin-Induced Inflammatory Myopathy in a Rat Model.
BACKGROUND Recent data have demonstrated the potential immunosuppressive roles of interleukin-37 (IL-37) in several diseases, but whether it is involved in the pathogenesis of inflammatory myopathy has not been elucidated. MATERIAL AND METHODS An experimental autoimmune myositis (EAM) model was built by subcutaneous injections of pertussis toxin (PTX) and purified rabbit myosin (10mg/kg) emulsified with an equal volume of conventional complete Freund's adjuvant (CFA) in a Lewis model. Autoimmune myositis Lewis model rats were divided into 3 groups: group A rats (control group) were injected with CFA in saline weekly; group B (IL-37 group) rats were injected with saline with IL-37 and CFA in saline weekly; and group C (IL-37 + SIS3 group) rats were injected with IL-37, CFA, and SIS3. ELISA was also used to assess the expressions of TNF-α, IL-6, IL-1β, TGF-β1, and CK. HE staining was performed to assess pathological changes in lung and muscle tissues. RESULTS The expressions of TNF-α, IL-6, IL-1β, TGF-β1, and CK significantly increased in autoimmune myositis Lewis model rats. After IL-37 treatment, the expression of TNF-α, IL-6, IL-1β, TGF-β1, and CK was significantly reduced, as were the inflammatory responses of lung and muscle. However, SIS3 reduced the effects of IL-37 on the autoimmune myositis Lewis model rats. CONCLUSIONS These findings indicate that IL-37 protects against inflammatory response via regulating Smad3 in autoimmune myositis Lewis model rats.


Propofol for endotracheal intubation in neonates: a dose-finding trial.
To find propofol doses providing effective sedation without side effects in neonates of different gestational ages (GA) and postnatal ages (PNA). Prospective multicentere dose-finding study in 3 neonatal intensive care units. Neonates with a PNA <28 days requiring non-emergency endotracheal intubation. Neonates were stratified into 8 groups based on GA and PNA. The first 5 neonates in every group received a dose of 1.0 mg/kg propofol. Based on sedative effect and side effects, the dose was increased or decreased in the next 5 patients until the optimal dose was found. The primary outcome was the optimal single propofol starting dose that provides effective sedation without side effects in each age group. After inclusion of 91 patients, the study was prematurely terminated because the primary outcome was only reached in 13% of patients. Dose-finding was completed in 2 groups, but no optimal propofol dose was found. Effective sedation without side effects was achieved more often after a starting dose of 2.0 mg/kg (28%) than after 1.0 mg/kg (3%) and 1.5 mg/kg (9%). Propofol-induced hypotension occurred in 59% of patients. Logistic regression analyses showed that GA and PNA did not predict effective sedation or the occurrence of hypotension. Effective sedation without side effects is difficult to achieve with propofol and the optimal dose in different age groups of neonates could not be determined. The sedative effect of propofol and the occurrence of hypotension are unpredictable and show large inter-individual variability in the neonatal population.


Circulatory responses to 2,4-dinitrophenol in dog limb during normoxia and hypoxia.
We tested whether blood flow to skeletal muscle would increase in proportion to an increase in O2 uptake caused by 2,4-dinitrophenol (DNP). We further tested the metabolic control in the face of a central challenge, hypoxic hypoxia. Three injections of DNP were made at 30-min intervals into the arterial supply of the left hindlimb in anesthetized dogs. Similar experiments were done on a second group of dogs ventilated with 12% O2-88% N2 (DNP and hypoxia). A third group served as time controls. Limb O2 uptake increased in a linear fashion in the DNP group with each injection. The increase in limb O2 uptake fell off with the second and third injections in the DNP and hypoxia group and appeared to be limited by the hypoxia. Limb blood flow increased only with the last injection in that group and not at all in the DNP group. Limb vascular resistance decreased in both the experimental groups relative to the time-related changes in the control group. This became more marked as the O2 extraction ratio exceeded 0.5. Even in the absence of nerve stimulation and active muscle contractions, both distribution and resistance control vessels responded in a coordinated fashion to an increase in O2 uptake. Mild hypoxia enhanced these responses but also appeared to limit a fraction of O2 uptake that may not have been concerned with maintaining tissue energy levels.


Isolation and proteomic characterization of the Arabidopsis Golgi defines functional and novel components involved in plant cell wall biosynthesis.
The plant Golgi plays a pivotal role in the biosynthesis of cell wall matrix polysaccharides, protein glycosylation, and vesicle trafficking. Golgi-localized proteins have become prospective targets for reengineering cell wall biosynthetic pathways for the efficient production of biofuels from plant cell walls. However, proteomic characterization of the Golgi has so far been limited, owing to the technical challenges inherent in Golgi purification. In this study, a combination of density centrifugation and surface charge separation techniques have allowed the reproducible isolation of Golgi membranes from Arabidopsis (Arabidopsis thaliana) at sufficiently high purity levels for in-depth proteomic analysis. Quantitative proteomic analysis, immunoblotting, enzyme activity assays, and electron microscopy all confirm high purity levels. A composition analysis indicated that approximately 19% of proteins were likely derived from contaminating compartments and ribosomes. The localization of 13 newly assigned proteins to the Golgi using transient fluorescent markers further validated the proteome. A collection of 371 proteins consistently identified in all replicates has been proposed to represent the Golgi proteome, marking an appreciable advancement in numbers of Golgi-localized proteins. A significant proportion of proteins likely involved in matrix polysaccharide biosynthesis were identified. The potential within this proteome for advances in understanding Golgi processes has been demonstrated by the identification and functional characterization of the first plant Golgi-resident nucleoside diphosphatase, using a yeast complementation assay. Overall, these data show key proteins involved in primary cell wall synthesis and include a mixture of well-characterized and unknown proteins whose biological roles and importance as targets for future research can now be realized.


Continuous measurement of oxygen consumption during cardiopulmonary bypass: description of the method and in vivo observations.
Systemic oxygen consumption is not routinely measured during cardiopulmonary bypass, despite its potential benefits. We aimed to develop a noninvasive method to continuously measure oxygen consumption using respiratory mass spectrometry during hypothermic cardiopulmonary bypass in pigs. Nine pigs weighing 18.5 (1.6) kg underwent hypothermic (32 degrees C) cardiopulmonary bypass for 180 minutes with 120 minutes of aortic cross clamping. An AMIS 2000 mass spectrometer (Innovision A/S, Odense, Denmark) was adapted for the on-line measurement of oxygen consumption by sampling the inlet and outlet gases of the membrane oxygenator together with measurement of the "expired" gas volume. Active cooling for 60 minutes reduced the venous blood temperature by 2.9 (0.8) degrees C and VO(2) by 0.70 (0.33) mL/kg/min. The 40-minute active rewarming restored the venous blood temperature by 4.4 (0.4) degrees C and oxygen consumption increased by 1.36 (0.33) mL/kg/min. There was wide interanimal variability, however, particularly at higher venous blood temperatures. Immediately after the release of aortic cross clamp, there was a noticeably acute increase in oxygen consumption in all the pigs (0.64 [0.21] mL/kg/min). A simple and safe adaptation of mass spectrometry allows continuous measurement of oxygen consumption during hypothermic cardiopulmonary bypass. The wide interindividual variations observed in this pilot study underscore the need to more accurately describe changes in oxygen consumption and how they are affected by temperature, oxygen delivery, and other interventions during cardiopulmonary bypass. As such, the technique may have an important role in clinical research and management of oxygen transport in patients undergoing cardiac surgery.


Walnut Supplementation in the Diet Reduces Oxidative Damage and Improves Antioxidant Status in Transgenic Mouse Model of Alzheimer's Disease.
Our previous study has shown beneficial effects of walnuts on memory and learning skills in transgenic mouse model of Alzheimer's disease (AD-tg). To understand underlying mechanism, we studied here whether walnuts can reduce oxidative stress in AD. From 4 months of age, experimental AD-tg mice were fed diets containing 6% (T6) or 9% walnuts (T9) (equivalent to 1 or 1.5 oz, of walnuts per day in humans) for 5, 10, or 15 months. The control groups, i.e., AD-tg (T0) and wild-type (Wt) mice, were fed diets without walnuts. Free radicals, i.e., reactive oxygen species (ROS), lipid peroxidation, protein oxidation, and antioxidant enzymes were assessed in these mice at different ages. AD-tg mice on control diet (T0) showed significant age-dependent increase in ROS levels, lipid peroxidation, and protein oxidation coupled with impaired activities of antioxidant enzymes [superoxide dismutase, catalase, and glutathione peroxidase] compared to Wt mice. Oxidative stress was significantly reduced in AD-tg mice on diets with walnuts (T6, T9), as evidenced by decreased levels of ROS, lipid peroxidation, and protein oxidation, as well as by enhanced activities of antioxidant enzymes compared to T0 mice. Long-term supplementation with walnuts for 10 or 15 months was more effective in reducing oxidative stress in AD-tg mice. Our findings indicate that walnuts can reduce oxidative stress, not only by scavenging free radicals, but also by protecting antioxidant status, thus leading to reduced oxidative damage to lipids and proteins in AD. Therefore, by reducing oxidative stress, a walnut-enriched diet may help reduce the risk or delay the onset and progression of AD.