TT virus in bone marrow transplant recipients.
TT virus (TTV) is a newly discovered transfusion-transmissible DNA virus, which may cause posttransfusion hepatitis. The virus was detected in 12% of Japanese blood donors. The aim of the study is to investigate the prevalence and clinical influence of TTV in bone marrow transplant (BMT) recipients. Sera from 25 BMT recipients obtained 6 to 12 weeks after the transplant were examined for TTV-DNA by the seminested polymerase chain reaction. Serial samples were additionally analyzed in patients with TTV-DNA. Fifteen of 25 recipients (60%) were positive for TTV-DNA after transplant, whereas it was detected in only two of 20 BMT donors (10%). In patients positive for TTV-DNA before BMT, the amount of TTV-DNA decreased to an undetectable level during the myelosuppressed period after BMT. We also found that there was a novel group of TTV, G3, classified by the nucleotide sequences. The median peak alanine aminotransferase (ALT) levels were 135.0 IU/L and 116.5 IU/L (normal range, 4 to 36 IU/L) in TTV-positive and TTV-negative recipients, respectively. In one of the seven TTV-positive patients who developed hepatic injury (ALT > 150 IU/L), a serial change in the serum TTV titer showed a good correlation with the ALT level. We concluded that (1) the prevalence of TTV is high in BMT recipients, (2) TTV might be replicated mainly in hematopoietic cells, (3) transfusion-transmitted TTV may cause persistent infection, (4) a novel genetic group of TTV, G3, was discovered, and (5) TTV does not seem to frequently cause hepatic injury, although one patient was strongly suggested to have TTV-induced hepatitis.


Sexual expression and the COVID-19 pandemic: The future of sexual intimacy after the COVID-19 pandemic.
Humans, as social beings, rely on interaction in order to survive and "flourish". By nature, they are "weak" and when in solitary, their freedom is jeopardized. Connecting with others, intimacy, physical contact, and the sense of belonging are core needs, and once recognized as such, they ultimately serve one's freedom. In this context, social interaction serves as a fundamental factor for survival. The creation of bonds improves one's position in the evolutionary process, and paves the way towards the ultimate "goal" of existence. The COVID-19 pandemic and the measures to control its spread have disrupted every aspect of human activity. Social, academic, cultural, business, and economic activities have been drastically modified.1 The conscious experience of the threat of life has been a ubiquitous "dramatic reminder of human vulnerability". The environment became unintelligible, death was "present" at all times. People tried to find a new meaning of life and discover a new sense of self-worth. The triggered vulnerability, the isolation from friends and relatives that to date validated one's self-esteem, the unprecedented obstacles with respect to career goals, and unexpected job losses affected the global view of things.1 The restrictive measures and the resulting urgent vaccination created "dystopian" conditions, under which deriving pleasure became a luxury. Scientific data have shown that social distancing has led to high levels of psychological distress. Primary research conducted during the social restrictions as well as subsequent meta-analytical studies have revealed increased irritability, emotional instability, and ultimately an increase in emotional and anxiety disorders' prevalence.2 Undoubtedly, mental and sexual health share a strong and bidirectional relationship.3 International health organizations emphasize the positive impact of a healthy sexual life on psychological well-being. Sexual well-being can serve - along with other factors - as a protective measure against the development of psychopathology, while stable sexual activity acts as a safeguard for well-being in general. The negative relationship between psychological symptoms and sexual gratification has been repeatedly documented by research, highlighting the impact of anxiety on sexual desire, arousal, and overall satisfaction with sexual life.4 Given this relationship and the increased emotional vulnerability during the pandemic, one might wonder how this reciprocal path has been affected. Physical intimacy, one of the basic expressions of the connection between partners, could not remain unaffected. During the first year of the pandemic and the restrictive measures, it became difficult for partners to meet. Due to the measures and discouragement of gatherings, a strong fear of infection gradually developed and avoidance behaviors emerged. In some countries, there were recommendations for physical-sexual interactions' limitation, and use of masks in intimate situations.5 The end result of these circumstances was that one in three individuals demonstrated such fear that they completely avoided engaging in sexual contact with the person they desired, even in cases they cohabited.6 The anxiety and reduced quality of life seemed to affect sexual function, especially aspects related to sexual desire and arousal. The fear and anxiety caused by the constant threat to life deprived individuals of the ability to derive satisfaction from intimate relationships, guiding sexual expression towards a safer "self-centered" orientation. As a result, self-gratification through masturbation increased for both single individuals as well as for stable, cohabiting partners.7 On the other hand, the newly formed living conditions served as a "vehicle' in an attempt to search for new paths towards pleasure. People, as in every past crisis, needed to "reinvent" themselves in order to adapt. Given that every sexual contact is a multi-sensory experience as well as a means of psychological discharge, they searched for or even created new paths that led to sexual release. The concept of "virtual sexuality" emerged even more strongly than it did before the pandemic. The pre-existing use of digital sexual content, which priorly simply facilitated individual sexual practices, took another form. The use of interactive technologies allowed people to create and share - in most cases for the first time - their personal erotic content.8 The internet emerged as an effective substitute for the discharge of sexual desire for people not in a stable romantic relationship, while for those with a stable partner in some cases facilitated their relationships, but for most of them prolonged behaviors of fear and avoidance of intimacy. The human need for connection, love, flirting, and sexual expression cannot be eliminated. The questions that arise whether the changes that have occurred are permanent, whether the need for real-life, physical contact has decreased, and whether the ways through which people connect with others have been permanently modified. It is possible that sexual intimacy is now conceptualized and experienced as something different, and perhaps the pandemic is a causal factor and a strong catalyst for a predetermined change of course with respect to close relationships. In any case, the clinical significance of the dynamic interaction between sexual factors and psychological well-being must be understood in depth. As mental health professionals, we must take into account the altered or new aspects of sexual expression, and with scientific rigor and respect for human nature, we should keep highlighting the unbreakable bond between sexuality and quality of life. We must recognize the timeless human need for intimacy and meaningful, stable connections, irrespective of threatening factors and uncertainty caused by conditions such as the recent pandemic.


Premutation in the Fragile X Mental Retardation 1 (FMR1) Gene Affects Maternal Zn-milk and Perinatal Brain Bioenergetics and Scaffolding.
Fragile X premutation alleles have 55-200 CGG repeats in the 5' UTR of the FMR1 gene. Altered zinc (Zn) homeostasis has been reported in fibroblasts from >60 years old premutation carriers, in which Zn supplementation significantly restored Zn-dependent mitochondrial protein import/processing and function. Given that mitochondria play a critical role in synaptic transmission, brain function, and cognition, we tested FMRP protein expression, brain bioenergetics, and expression of the Zn-dependent synaptic scaffolding protein SH3 and multiple ankyrin repeat domains 3 (Shank3) in a knock-in (KI) premutation mouse model with 180 CGG repeats. Mitochondrial outcomes correlated with FMRP protein expression (but not FMR1 gene expression) in KI mice and human fibroblasts from carriers of the pre- and full-mutation. Significant deficits in brain bioenergetics, Zn levels, and Shank3 protein expression were observed in the Zn-rich regions KI hippocampus and cerebellum at PND21, with some of these effects lasting into adulthood (PND210). A strong genotype × age interaction was observed for most of the outcomes tested in hippocampus and cerebellum, whereas in cortex, age played a major role. Given that the most significant effects were observed at the end of the lactation period, we hypothesized that KI milk might have a role at compounding the deleterious effects on the FMR1 genetic background. A higher gene expression of ZnT4 and ZnT6, Zn transporters abundant in brain and lactating mammary glands, was observed in the latter tissue of KI dams. A cross-fostering experiment allowed improving cortex bioenergetics in KI pups nursing on WT milk. Conversely, WT pups nursing on KI milk showed deficits in hippocampus and cerebellum bioenergetics. A highly significant milk type × genotype interaction was observed for all three-brain regions, being cortex the most influenced. Finally, lower milk-Zn levels were recorded in milk from lactating women carrying the premutation as well as other Zn-related outcomes (Zn-dependent alkaline phosphatase activity and lactose biosynthesis-whose limiting step is the Zn-dependent β-1,4-galactosyltransferase). In premutation carriers, altered Zn homeostasis, brain bioenergetics and Shank3 levels could be compounded by Zn-deficient milk, increasing the risk of developing emotional and neurological/cognitive problems and/or FXTAS later in life.


The Power of Radio to Promote Health and Resilience in Natural Disasters: A Review.
Humanitarian radio has been used in humanitarian aid efforts and after natural disasters over the last 15 years. However, the effects have barely been evaluated, and there are few scientific reports on the impact of radio as a disaster health response intervention. Therefore, this study aimed to provide an overview of the use and impact of humanitarian radio in natural disasters from a health perspective. A literature review of 13 scientific papers and grey literature resources was conducted. The results show that humanitarian radio could be used to promote both physical and psychosocial wellbeing by providing health-related information, advice and psychosocial support in natural disasters. Community resilience can be enhanced by the promotion of community engagement and can strengthen self-efficacy and community efficacy. Radio also has the potential to cost-effectively reach a large number of affected people in areas with severely damaged infrastructure. Radio could, therefore, contribute to health recovery and wellbeing from both individual and community perspectives. As such, health professionals; crises communication professionals, including radio journalists; and disaster-managing stakeholders should be prepared and trained to use humanitarian radio as an integrated part of the disaster health response in natural disasters.


Corticobasal degeneration with olivopontocerebellar atrophy and TDP-43 pathology: an unusual clinicopathologic variant of CBD.
Corticobasal degeneration (CBD) is a disorder affecting cognition and movement due to a progressive neurodegeneration associated with distinctive neuropathologic features, including abnormal phosphorylated tau protein in neurons and glia in cortex, basal ganglia, diencephalon, and brainstem, as well as ballooned neurons and astrocytic plaques. We identified three cases of CBD with olivopontocerebellar atrophy (CBD-OPCA) that did not have α-synuclein-positive glial cytoplasmic inclusions of multiple system atrophy (MSA). Two patients had clinical features suggestive of progressive supranuclear palsy (PSP), and the third case had cerebellar ataxia thought to be due to idiopathic OPCA. Neuropathologic features of CBD-OPCA are compared to typical CBD, as well as MSA and PSP. CBD-OPCA and MSA had marked neuronal loss in pontine nuclei, inferior olivary nucleus, and Purkinje cell layer. Neuronal loss and grumose degeneration in the cerebellar dentate nucleus were comparable in CBD-OPCA and PSP. Image analysis of tau pathology showed greater infratentorial tau burden, especially in pontine base, in CBD-OPCA compared with typical CBD. In addition, CBD-OPCA had TDP-43 immunoreactive neuronal and glial cytoplasmic inclusions and threads throughout the basal ganglia and in olivopontocerebellar system. CBD-OPCA met neuropathologic research diagnostic criteria for CBD and shared tau biochemical characteristics with typical CBD. These results suggest that CBD-OPCA is a distinct clinicopathologic variant of CBD with olivopontocerebellar TDP-43 pathology.


Management of a Large Frontal Encephalocoele With Supraorbital Bar Remodeling and Advancement.
Of all the craniofacial abnormalities, facial clefts are the most disfiguring. Facial clefts are classified according to the affected anatomical area as described by Tessier. Through this classification, the location and extent of the cleft can be designated numerically.A 2-month-old male infant was referred to authors' craniofacial unit, from a hospital in a rural province of South Africa, with a problem of a supranasal encephalocoele. Bilateral raised eyebrows were noted as was a right-sided upper lid central third coloboma. Computed tomography and magnetic resonance imaging scans confirmed the presence of a supranasal encephalocoele with a large frontal bone defect and splayed nasal bones. Bilateral enlarged orbits were noted with tented orbital roofs that we classified as Tessier number 10 facial clefts. The child was booked for an encephalocoele excision and calvarial reconstruction at 4 months of age.As a result of the encephalocoele, the supraorbital bar with its adjacent nasal bones was cleaved in 2, resulting in a significant frontal bone defect. Osteotomies were performed to remove the supraorbital bar and nasal bones from the calvarium. The supraorbital bar segment was remodeled and plated with absorbable poly-L-lactic acid plates. Osteotomies of the nasal bones allowed them to be united centrally, also with absorbable plates. This entire construct was transferred and secured to the calvarium, but in a more caudal position thereby obliterating the frontal bone and Tessier number 10 facial cleft defects with a naturally contoured construct.


Thermodynamics of complexation reactions of borate and phenylboronate with diol, triol and tetritol.
In order to fully elucidate the structures and stabilities of borate and phenylboronate complexes with polyols, the complexations with 1,2-ethanediol, 1,3-propanediol, 1,2,3-propanetriol, erythritol and threitol were investigated by NMR spectroscopy and DFT calculations. For the borate, 1 : 1 complexes binding with a ligand in a monodentate manner and 1 : 2 complexes binding with one ligand in an α,β- or α,γ-bidentate manner and the other in a monodentate manner were identified for the first time besides the well-known 1 : 1 and 1 : 2 complexes with five- and/or six-membered chelate rings. In addition, the formations of 1 : 1 α,β,δ-tridentate complexes with tetritol were confirmed. For the phenylboronate, the bidentate and tridentate complexes with 1 : 1 stoichiometries were identified. These complexations were enthalpy-driven processes accompanied by a negative entropic contribution. Linear enthalpy-entropy compensation relationships were observed for the stepwise complexations of borate and phenylboronate to form a five- or six-membered chelate ring. The TΔS° vs. ΔH° plots gave three different straight lines in parallel with one another depending on the number of OH groups outside the chelate ring. For the second intramolecular chelation to form the α,β,δ-tridentate complex from the α,β- or α,γ-bidentate complex with tetritol, the TΔS° vs. ΔH° plots gave different straight lines for the borate and phenylboronate, being more favorable in enthalpy for the phenylboronate.


Science Communication Training Imparts Confidence and Influences Public Engagement Activity.
The impacts of science are felt across all socio-ecological levels, ranging from the individual to societal. In order to adapt or respond to scientific discoveries, novel technologies, or biomedical or environmental challenges, a fundamental understanding of science is necessary. However, antiscientific rhetoric, mistrust in science, and the dissemination of misinformation hinder the promotion of science as a necessary and beneficial component of our world. Scientists can promote scientific literacy by establishing dialogues with nonexperts, but they may find a lack of formal training as a barrier to public engagement. To address this, the American Society for Biochemistry and Molecular Biology (ASBMB) launched the Art of Science Communication course in 2015 in order to provide scientists at all career stages with introductory science communication training. In 2020, we conducted a retrospective survey of former participants to evaluate how the course had impacted participants' science communication behaviors and their confidence engaging with nonexperts, as well as other benefits to their professional development. We found that scientists were significantly more likely to communicate with nonexpert audiences following the course compared to before (77% versus 51%; P < 0.0001). In addition, quantitative and qualitative data suggested that scientists were more confident in their ability to communicate science after completing the course (median of 8, standard deviation [SD] of 0.98 versus median of 5, SD of 1.57; P < 0.0001). Qualitative responses from participants supported quantitative findings. This suggested that the Art of Science Communication course is highly effective at improving the confidence of scientists to engage with the public and other nonexpert audiences regardless of career status. These data-driven perspectives provide a rationale for the implementation of broadly accessible science communication training programs that promote public engagement with science.


Menstrual cycle, tolerance and blood alcohol level discrimination ability.
Relationships between variations in blood alcohol level (BAL) and blood alcohol level discrimination accuracy were investigated as a function of menstrual cycle, hormonal variations, and behavioral tolerance to alcohol in 20 female social drinkers. All subjects consumed a moderate dose of alcohol on three occasions during one complete menstrual cycle. Subjects estimated their level of intoxication eight times during each drinking session. Each subject's behavioral tolerance to alcohol each session was assessed by a body sway procedure. Subjects also completed detailed questionnaires on symptoms related to menstrual period and familial history of alcohol use. Contrary to earlier reports, (1) no difference in total time of intoxication or in other indices of ethanol metabolism was found between women (N = 9) who were not taking birth control pills and those (N = 11) who were and (2) no difference was found in peak BAL as a function of menstrual cycle phase. Stage of menstrual cycle did not affect the accuracy of BAL estimation. A trend approaching significance suggested that, with increasing BAL, women in the oral contraceptive group were more accurate in their estimates of intoxication. A significant interaction between menstrual cycle phase and tolerance levels was found; high tolerant women were significantly less accurate than low tolerant women in estimating BAL during the midcycle phase of the menstrual cycle.


Identification by microsequencing of lipopolysaccharide-induced proteins secreted by mouse macrophages.
The conditioned medium of the murine macrophage PU5.1.8 was analyzed by two-dimensional gel electrophoresis in order to detect LPS-induced proteins. Spots of interest were identified by microsequencing of internal peptides generated by limited in situ acid hydrolysis. In total conditioned medium, several monokines (TNF-alpha and macrophage inflammatory protein-1 alpha and 1 beta) were identified as LPS-induced spots. Because minor spots could be masked by the complexity of the 2-D pattern, conditioned medium was successively fractionated by zinc precipitation and affinity chromatography (Procion red and Con A agarose). Zinc supernatant fraction, Procion red flow-through, and Con A eluate fractions were further analyzed by 2-D gel electrophoresis for the presence of LPS-induced spots. In these fractions serum amyloid A3, lipocalin 24p3, cathepsin B, and plasminogen activator inhibitor-I were characterized as LPS-induced proteins secreted by macrophages. Lipocalin 24p3 protein was retrieved for the first time. In addition to these proteins that follow a classical secretory pathway, several cellular proteins (mainly ribosomal proteins) were retrieved as LPS-induced proteins in the conditioned medium. Control experiments argue against the obvious explanation that the latter observation is caused solely by cellular leakage.


Systematic intervention of transcription for identifying network response to disease and cellular phenotypes.
A major challenge in post-genomic research has been to understand how physiological and pathological phenotypes arise from the networks of expressed genes. Here, we addressed this issue by developing an algorithm to mimic the behavior of regulatory networks in silico and to identify the dynamic response to disease and changing cellular conditions. With regulatory pathway and gene expression data as input, the algorithm provides quantitative assessments of a wide range of responses, including susceptibility to disease, potential usefulness of a given drug, or consequences to such external stimuli as pharmacological interventions or caloric restriction. The algorithm is particularly amenable to the analysis of systems that are difficult to recapitulate in vitro, yet they may have important clinical value. The hypotheses derived from the algorithm were biologically relevant and were successfully validated via independent experiments, as illustrated here in the analysis of the leukemia-associated BCR-ABL pathway and the insulin/IGF pathway related to longevity. The algorithm correctly identified the leukemia drug target and genes important for longevity, and also provided new insights into our understanding of these two processes. The software package is available upon request to the authors.


Novel Self-Forming Nanosized DDS Particles for BNCT: Utilizing A Hydrophobic Boron Cluster and Its Molecular Glue Effect.
BNCT is a non-invasive cancer therapy that allows for cancer cell death without harming adjacent cells. However, the application is limited, owing to the challenges of working with clinically approved boron (B) compounds and drug delivery systems (DDS). To address the issues, we developed self-forming nanoparticles consisting of a biodegradable polymer, namely, "AB-type Lactosome (AB-Lac)" loaded with B compounds. Three carborane isomers (o-, m-, and p-carborane) and three related alkylated derivatives, i.e., 1,2-dimethy-o-carborane (diC1-Carb), 1,2-dihexyl-o-carborane (diC6-Carb), and 1,2-didodecyl-o-carborane (diC12-Carb), were separately loaded. diC6-Carb was highly loaded with AB-Lac particles, and their stability indicated the "molecular glue" effect. The efficiency of in vitro B uptake of diC6-Carb for BNCT was confirmed at non-cytotoxic concentration in several cancer cell lines. In vivo/ex vivo biodistribution studies indicated that the AB-Lac particles were remarkably accumulated within 72 h post-injection in the tumor lesions of mice bearing syngeneic breast cancer (4T1) cells, but the maximum accumulation was reached at 12 h. In ex vivo B biodistribution, the ratios of tumor/normal tissue (T/N) and tumor/blood (T/Bl) of the diC6-Carb-loaded particles remained stably high up to 72 h. Therefore, we propose the diC6-Carb-loaded AB-Lac particles as a promising candidate medicine for BNCT.


Negative Ion Mode nanoLC-ESI-MS/MS Analyses of Permethylated Sulfated Glycans.
We have developed enabling techniques for sulfoglycomics based on MALDI-MS mapping and MS/MS sequencing of permethylated sulfated glycans. We then extended further the analytical workflow to C18 reverse phase (RP)-nanoLC-nanoESI-MS/MS analyses of permethylated sulfated glycans in the negative ion mode. The advantages are that extra sulfates on permethylated di- and multiply sulfated glycans will survive in nanoESI conditions to allow detection of multiply charged intact molecular ions, and more comprehensive MS/MS can be performed in an automated fashion at higher sensitivity, compared with MALDI-MS/MS. Parallel higher energy collision dissociation (HCD) and ion trap collision induced dissociation (CID)-based MS2, coupled with product-dependent MS3 in data dependent acquisition mode proved to be highly productive when applied to resolve and identify the isomeric sulfated glycan structures. In-house glycomic data mining software, GlyPick, was developed and used to automate the downstream process of identification and relative quantification of target sulfated glycotopes based on summed intensity of their diagnostic MS2 ions extracted from thousands of HCD-MS2 and/or CID-MS2 data.


[Musculoskeletal diseases, work and lifestyle among public workers at a health institution].
This is a cross-sectional study developed with 651 workers of various occupations. They answered a questionnaire covering general, labor and lifestyle data, in addition to the Work Ability Index, which has been developed by researchers from Finland. In terms of sociodemographics, the analysis of the factors associated with the occurrence of musculoskeletal disorder revealed them to be female, older, and with low level of schooling. As for labor characteristics, the disease was associated with those individuals with physically demanding work, longer working hours on a second job and longer working hours at the institution itself. Regarding lifestyle, the characteristics associated with the occurrence of the disease were obesity, long housework hours and absence of leisure activities.


Sensory acquisition in active sensing systems.
A defining feature of active sensing is the use of self-generated energy to probe the environment. Familiar biological examples include echolocation in bats and dolphins and active electrolocation in weakly electric fish. Organisms that utilize active sensing systems can potentially exert control over the characteristics of the probe energy, such as its intensity, direction, timing, and spectral characteristics. This is in contrast to passive sensing systems, which rely on extrinsic energy sources that are not directly controllable by the organism. The ability to control the probe energy adds a new dimension to the task of acquiring relevant information about the environment. Physical and ecological constraints confronted by active sensing systems include issues of signal propagation, attenuation, speed, energetics, and conspicuousness. These constraints influence the type of energy that organisms use to probe the environment, the amount of energy devoted to the process, and the way in which the nervous system integrates sensory and motor functions for optimizing sensory acquisition performance.


Nocturnal rapid eye movement sleep latency for identifying patients with narcolepsy/hypocretin deficiency.
Narcolepsy, a disorder associated with HLA-DQB1*06:02 and caused by hypocretin (orexin) deficiency, is diagnosed using the Multiple Sleep Latency Test (MSLT) following nocturnal polysomnography (NPSG). In many patients, a short rapid eye movement sleep latency (REML) during the NPSG is also observed but not used diagnostically. To determine diagnostic accuracy and clinical utility of nocturnal REML measures in narcolepsy/hypocretin deficiency. Observational study using receiver operating characteristic curves for NPSG REML and MSLT findings (sleep studies performed between May 1976 and September 2011 at university medical centers in the United States, China, Korea, and Europe) to determine optimal diagnostic cutoffs for narcolepsy/hypocretin deficiency compared with different samples: controls, patients with other sleep disorders, patients with other hypersomnias, and patients with narcolepsy with normal hypocretin levels. Increasingly stringent comparisons were made. In a first comparison, 516 age- and sex-matched patients with narcolepsy/hypocretin deficiency were selected from 1749 patients and compared with 516 controls. In a second comparison, 749 successive patients undergoing sleep evaluation for any sleep disorders (low pretest probability for narcolepsy) were compared within groups by final diagnosis of narcolepsy/hypocretin deficiency. In the third comparison, 254 patients with a high pretest probability of having narcolepsy were compared within group by their final diagnosis. Finally, 118 patients with narcolepsy/hypocretin deficiency were compared with 118 age- and sex-matched patients with a diagnosis of narcolepsy but with normal hypocretin levels. Sensitivity and specificity of NPSG REML and MSLT as diagnostic tests for narcolepsy/hypocretin deficiency. This diagnosis was defined as narcolepsy associated with cataplexy plus HLA-DQB1*06:02 positivity (no cerebrospinal fluid hypocretin-1 results available) or narcolepsy with documented low (≤ 110 pg/mL) cerebrospinal fluid hypocretin-1 level. Short REML (≤15 minutes) during NPSG was highly specific (99.2% [95% CI, 98.5%-100.0%] of 516 and 99.6% [95% CI, 99.1%-100.0%] of 735) but not sensitive (50.6% [95% CI, 46.3%-54.9%] of 516 and 35.7% [95% CI, 10.6%-60.8%] of 14) for patients with narcolepsy/hypocretin deficiency vs population-based controls or all patients with sleep disorders undergoing a nocturnal sleep study (area under the curve, 0.799 [95% CI, 0.771-0.826] and 0.704 [95% CI, 0.524-0.907], respectively). In patients with central hypersomnia and thus a high pretest probability for narcolepsy, short REML remained highly specific (95.4% [95% CI, 90.4%-98.3%] of 132) and similarly sensitive (57.4% [95% CI, 48.1%-66.3%] of 122) for narcolepsy/hypocretin deficiency (area under the curve, 0.765 [95% CI, 0.707-0.831]). Positive predictive value in this high pretest probability sample was 92.1% (95% CI, 83.6%-97.0%). Among patients being evaluated for possible narcolepsy, short REML (≤15 minutes) at NPSG had high specificity and positive predictive value and may be considered diagnostic without the use of an MSLT; absence of short REML, however, requires a subsequent MSLT.


Transgenic APP expression during postnatal development causes persistent locomotor hyperactivity in the adult.
Transgenic mice expressing disease-associated proteins have become standard tools for studying human neurological disorders. Transgenes are often expressed using promoters chosen to drive continuous high-level expression throughout life rather than temporal and spatial fidelity to the endogenous gene. This approach has allowed us to recapitulate diseases of aging within the two-year lifespan of the laboratory mouse, but has the potential for creating aberrant phenotypes by mechanisms unrelated to the human disorder. We show that overexpression of the Alzheimer's-related amyloid precursor protein (APP) during early postnatal development leads to severe locomotor hyperactivity that can be significantly attenuated by delaying transgene onset until adulthood. Our data suggest that exposure to transgenic APP during maturation influences the development of neuronal circuits controlling motor activity. Both when matched for total duration of APP overexpression and when matched for cortical amyloid burden, animals exposed to transgenic APP as juveniles are more active in locomotor assays than animals in which APP overexpression was delayed until adulthood. In contrast to motor activity, the age of APP onset had no effect on thigmotaxis in the open field as a rough measure of anxiety, suggesting that the interaction between APP overexpression and brain development is not unilateral. Our findings indicate that locomotor hyperactivity displayed by the tet-off APP transgenic mice and several other transgenic models of Alzheimer's disease may result from overexpression of mutant APP during postnatal brain development. Our results serve as a reminder of the potential for unexpected interactions between foreign transgenes and brain development to cause long-lasting effects on neuronal function in the adult. The tet-off APP model provides an easy means of avoiding developmental confounds by allowing transgene expression to be delayed until the mice reach adulthood.


Patients presenting with somatic complaints in general practice: depression, anxiety and somatoform disorders are frequent and associated with psychosocial stressors.
Mental disorders in primary care patients are frequently associated with physical complaints that can mask the disorder. There is insufficient knowledge concerning the role of anxiety, depression, and somatoform disorders in patients presenting with physical symptoms. Our primary objective was to determine the prevalence of depression, anxiety, and somatoform disorders among primary care patients with a physical complaint. We also investigated the relationship between cumulated psychosocial stressors and mental disorders. We conducted a multicentre cross-sectional study in twenty-one private practices and in one academic primary care centre in Western Switzerland. Randomly selected patients presenting with a spontaneous physical complaint were asked to complete the self-administered Patient Health Questionnaire (PHQ) between November 2004 and July 2005. The validated French version of the PHQ allowed the diagnosis of mental disorders (DSM-IV criteria) and the analyses of exposure to psychosocial stressors. There were 917 patients exhibiting at least one physical symptom included. The rate of depression, anxiety, and somatoform disorders was 20.0% (95% confidence interval [CI] = 17.4% to 22.7%), 15.5% (95% CI = 13.2% to 18.0%), and 15.1% (95% CI = 12.8% to 17.5%), respectively. Psychosocial stressors were significantly associated with mental disorders. Patients with an accumulation of psychosocial stressors were more likely to present anxiety, depression, or somatoform disorders, with an increase of 2.2 fold (95% CI = 2.0 to 2.5) for each additional stressor. The investigation of mental disorders and psychosocial stressors among patients with physical complaints is relevant in primary care. Psychosocial stressors should be explored as potential epidemiological causes of mental disorders.


Urban air pollution and emergency visits for respiratory complaints in Pisa, Italy.
Emergency room visits for respiratory complaints, considered an indicator of deterioration of respiratory health, have been positively correlated to traffic-related air pollution. This is an ecological study to evaluate the association between daily levels of urban air pollutants and emergency visits for respiratory complaints, in children and the elderly residing in Pisa, Italy. Daily records of emergency department visits for respiratory complaints were selected from computerized registries, and paper medical reports were identified. Pollutant daily means were computed from hourly values obtained from the public network. Poisson regression, allowing for overdispersion and autocorrelation, was used to evaluate the percent change in daily visits associated with variations of air pollution measures. Among children, an increase in emergency visits of 10% (95% CL: 2.3; 18.2) was associated with a 10-microg/m3 increase in PM10 concentrations of the previous day and an increase of 11.8% (95% CL:1.4; 23.3) was associated with an analogous increment of NO2 during the 2 previous days. Among elderly the same increment of PM10 level during the 2 previous days was correlated with a 8.5% (95% CL: 1.5; 16.1) increase in the risk of recurring emergency department visits for respiratory complaints; this risk increased to 26.5% (95% CL: 3.4; 54.8) if the daily level of CO over the 4 previous days increased by 1 mg/m3. Evidence of morbidity related to short- and long-term air pollution exposures provided in this small study and larger studies conducted in other countries suggests the need for actions to improve air quality in any urban context.


[Population genetics of the inhabitants of the European northern RSFSR. VI. The dynamics of the genetic load].
The dynamics of the lethal equivalents in two rural populations of Archangelsk regions during the periods from 1930 to 1953 and from 1954 to 1970 was investigated. The outcomes of 1617 pregnancies for 500 couples were analysed. The coefficient of inbreeding varied fo these couples from 0.001 to 0.08. For computing the genetic load, we followed the the methodology suggested by Morton, Crow and Muller in S. Smith's modification. The importance of comprehensive determination of inbreeding coefficient for reliable estimation of the genetic load was demonstrated. By comparing the two groups, it was shown that the coefficient B diminished approximately twice and the B/A ratio increased in both populations also by the factor of two. It is supposed that the diminishing of the number of lethal equivalents can be explained by a decrease in natural selection pressure. It is also supposed, that the segregational load is more sensitive to the decrease in natural selection pressure.'


Morphogenesis of the truncus arteriosus of the chick embryo heart: tissue reorganization during septation.
Septation of the truncus arteriosus of the normal chick embryo heart was surveyed systematically with the light microscope. Tissue from replicate samples at successive periods of development was sectioned within an arbitrary coordinate system based on positional reference points along the external surface of the heart. Correlation of several aspects of tissue morphology within this spatial and temporal reference-frame yielded a new description of tissue associations and kinetics during septation. A stable complex of tissue structures appeared in the downstream, distal truncus at Stage 25 and persisted throughout the septation process. This complex consisted of (1) the cephalic margin of the myocardial sheath, and (2) the adjacent bifurcation of the vascular lumen, linked together by (3) the newly condensed Y-shaped strap of cells forming the aorticopulmonary septum. The apparent motion of this septation-complex toward the ventricle(s), the appearance within the thoracic cavity of the adjacent segments of the aortic arches, and measures of tissue length and width suggested that septation was accompanied, and perhaps initiated, by increased tension along the truncus. The truncal ridges remained upstream from the complex, with mesenchymal condensations beneath the endocardium differentiating into the definitive semilunar valves. Downstream from the bifurcation, mesenchyme in the aortic arch region condensed around the separate lumens to form the smooth muscular tunica media of the great arteries. The epicardium developed in a caudocephalic direction along the heart tube. Vagal innervation approached the heart cephalocaudally. Capillaries formed along the dividing truncus in both directions. Autoradiography following 3H-thymidine labelling demonstrated reduced DNA synthetic activity in the cephalic margin of the myocardium and aorticopulmonary septum, compared with the associated loose mesenchyme.


Overcoming bioprocess bottlenecks in the large-scale expansion of high-quality hiPSC aggregates in vertical-wheel stirred suspension bioreactors.
Human induced pluripotent stem cells (hiPSCs) hold enormous promise in accelerating breakthroughs in understanding human development, drug screening, disease modeling, and cell and gene therapies. Their potential, however, has been bottlenecked in a mostly laboratory setting due to bioprocess challenges in the scale-up of large quantities of high-quality cells for clinical and manufacturing purposes. While several studies have investigated the production of hiPSCs in bioreactors, the use of conventional horizontal-impeller, paddle, and rocking-wave mixing mechanisms have demonstrated unfavorable hydrodynamic environments for hiPSC growth and quality maintenance. This study focused on using computational fluid dynamics (CFD) modeling to aid in characterizing and optimizing the use of vertical-wheel bioreactors for hiPSC production. The vertical-wheel bioreactor was modeled with CFD simulation software Fluent at agitation rates between 20 and 100 rpm. These models produced fluid flow patterns that mapped out a hydrodynamic environment to guide in the development of hiPSC inoculation and in-vessel aggregate dissociation protocols. The effect of single-cell inoculation on aggregate formation and growth was tested at select CFD-modeled agitation rates and feeding regimes in the vertical-wheel bioreactor. An in-vessel dissociation protocol was developed through the testing of various proteolytic enzymes and agitation exposure times. CFD modeling demonstrated the unique flow pattern and homogeneous distribution of hydrodynamic forces produced in the vertical-wheel bioreactor, making it the opportune environment for systematic bioprocess optimization of hiPSC expansion. We developed a scalable, single-cell inoculation protocol for the culture of hiPSCs as aggregates in vertical-wheel bioreactors, achieving over 30-fold expansion in 6 days without sacrificing cell quality. We have also provided the first published protocol for in-vessel hiPSC aggregate dissociation, permitting the entire bioreactor volume to be harvested into single cells for serial passaging into larger scale reactors. Importantly, the cells harvested and re-inoculated into scaled-up vertical-wheel bioreactors not only maintained consistent growth kinetics, they maintained a normal karyotype and pluripotent characterization and function. Taken together, these protocols provide a feasible solution for the culture of high-quality hiPSCs at a clinical and manufacturing scale by overcoming some of the major documented bioprocess bottlenecks.


Effects of isothiocyanates on tumorigenesis by benzo[a]pyrene in murine tumor models.
Previous studies have shown that benzyl isothiocyanate (BITC) inhibited lung tumorigenesis induced in A/J mice by benzo[a]pyrene (BaP), but other experiments using a somewhat different protocol demonstrated that phenethyl isothiocyanate (PEITC) had no effect on lung tumorigenesis induced by BaP in this strain. In contrast, PEITC but not BITC had been shown to inhibit lung tumorigenesis induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice. Therefore, one goal of this study was to directly compare the chemopreventive activities of BITC and PEITC on BaP-induced lung tumorigenesis in A/J mice. In the same experiment we also compared the tumorigenic activities of BaP and NNK. Either BITC or PEITC was administered by gavage 15 min before gavage of BaP. This regimen was carried out three times at 2-week intervals, and the mice were sacrificed 26 weeks after the first treatment. As assessed by tumor multiplicity, BITC but not PEITC significantly inhibited lung tumorigenesis by BaP, whereas PEITC but not BITC significantly inhibited forestomach tumorigenesis. Comparison of the tumorigenic activities of NNK and BaP demonstrated that NNK was about ten times more potent than BaP as a lung tumorigen, while BaP but not NNK induced forestomach tumors. In a second set of experiments we evaluated the effects of isothiocyanates on the mouse skin tumor-initiating activity of BaP. The isothiocyanates tested were BITC, PEITC, 6-phenylhexyl isothiocyanate (PHITC) and a series of isothiocyanates structurally related to polynuclear aromatic hydrocarbons: 9-phenanthryl isothiocyanate (9-PhenITC), 9-phenanthrylmethyl isothiocyanate (9-PhenMeITC), 6-chrysenyl isothiocyanate (6-ChrysITC) and 6-benzo[a]pyrenyl isothiocyanate (6-BaPITC). None of the isothiocyanates inhibited tumor development by BaP, and three of them--PHITC, 9-PhenITC and 9- PhenMeITC--enhanced skin tumor multiplicity. Taken together with available literature data, the results of this study suggest that different isothiocyanates selectively inhibit cytochrome P450 enzymes involved in the metabolic activation or detoxification of BaP and therefore have differing effects on BaP tumorigenesis.


Persistence of DNA damage following exposure of human bladder cells to chronic monomethylarsonous acid.
Malignant transformation was demonstrated in UROtsa cells following 52-weeks of exposure to 50 nM monomethylarsonous acid (MMA(III)); the result was the malignantly transformed cell line, URO-MSC. URO-MSC cells were used to study the induction of DNA damage and the alteration of DNA repair enzymes in both the presence of MMA(III) [URO-MSC(+)] and after subsequent removal of MMA(III) [URO-MSC(-)] following chronic, low-level exposure. In the presence of MMA(III), URO-MSC(+) cells demonstrated a sustained increase in DNA damage following 12-weeks of exposure; in particular, a significant increase in DNA single-strand breaks at 12-weeks of exposure consistently elevated through 52 weeks. The persistence of DNA damage in URO-MSC cells was assessed after a 2-week removal of MMA(III). URO-MSC(-) cells demonstrated a decrease in DNA damage compared to URO-MSC(+); however, DNA damage in URO-MSC(-) remained significantly elevated when compared to untreated UROtsa and increased in a time-dependent manner. Reactive oxygen species (ROS) were demonstrated to be a critical component in the generation of DNA damage determined through the incubation of ROS scavengers with URO-MSC cells. Poly (ADP-ribose) polymerase (PARP) is a key repair enzyme in DNA single-strand break repair. URO-MSC(+) resulted in a slight increase in PARP activity after 36-weeks of MMA(III) exposure, suggesting the presence of MMA(III) is inhibiting the increase in PARP activity. In support, PARP activity in URO-MSC(-) increased significantly, coinciding with a subsequent decrease in DNA damage demonstrated in URO-MSC(-) compared to URO-MSC(+). These data demonstrate that chronic, low-level exposure of UROtsa cells to 50 nM MMA(III) results in: the induction of DNA damage that remains elevated upon removal of MMA(III); increased levels of ROS that play a role in MMA(III) induced-DNA damage; and decreased PARP activity in the presence of MMA(III).


Nucleotide recognition by histone H1 involves specific protein structures.
We have reported previously that histone H1 is capable of binding nucleotides such as ATP, GTP, ADP, and GDP in a specific manner. It is demonstrated here using labeling with the uv-crosslinkable ATP analog 8-azido-[alpha-32P]ATP that this ability is a unique characteristic of H1 among the histone proteins. Phosphate analogs such as AlF-4 efficiently counteract the labeling of H1, while they do not compete for labeling of histones H2A, H2B, H3, and H4. Consistent with the assumption that this labeling is due to specific binding, nucleotides competed for the labeling of H1 in a manner similar to labeling of the catalytic subunit of cAMP-dependent protein kinase, casein kinase-II, and heat shock protein-90, all of which are ATP/GTP-binding proteins. The site of nucleotide interaction was subsequently located in a Gly-rich region of H1 which displays homology with the protein kinases, using either radioactive labeling with nucleotide analogs and endoproteinase Glu-C digestion or synthetic peptides corresponding to the putative binding site. The results imply that specific protein structures are involved in nucleotide binding to H1 and that the ability of H1 to bind nucleotides may provide a mechanism for the regulation of eukaryotic gene expression.


Asymmetric Transfer Hashing With Adaptive Bipartite Graph Learning.
Thanks to the efficient retrieval speed and low storage consumption, learning to hash has been widely used in visual retrieval tasks. However, the known hashing methods assume that the query and retrieval samples lie in homogeneous feature space within the same domain. As a result, they cannot be directly applied to heterogeneous cross-domain retrieval. In this article, we propose a generalized image transfer retrieval (GITR) problem, which encounters two crucial bottlenecks: 1) the query and retrieval samples may come from different domains, leading to an inevitable domain distribution gap and 2) the features of the two domains may be heterogeneous or misaligned, bringing up an additional feature gap. To address the GITR problem, we propose an asymmetric transfer hashing (ATH) framework with its unsupervised/semisupervised/supervised realizations. Specifically, ATH characterizes the domain distribution gap by the discrepancy between two asymmetric hash functions, and minimizes the feature gap with the help of a novel adaptive bipartite graph constructed on cross-domain data. By jointly optimizing asymmetric hash functions and the bipartite graph, not only can knowledge transfer be achieved but information loss caused by feature alignment can also be avoided. Meanwhile, to alleviate negative transfer, the intrinsic geometrical structure of single-domain data is preserved by involving a domain affinity graph. Extensive experiments on both single-domain and cross-domain benchmarks under different GITR subtasks indicate the superiority of our ATH method in comparison with the state-of-the-art hashing methods.


Prognostic factors and nomogram prediction of survival probability in primary spinal cord astrocytoma patients.
Knowledge on the management of spinal cord astrocytoma (SCA) remains scarce. Here, the authors constructed and validated a predictive nomogram, often used for individualized prognosis and evaluations, to estimate cancer-specific survival (CSS) and overall survival (OS) for patients with SCA. Epidemiological characteristics were compared between low-grade SCA (LGSCA) and high-grade SCA (HGSCA) patients from the Surveillance, Epidemiology, and End Results (SEER) database. Risk factors for CSS and OS were determined using univariate and multivariate analyses and Kaplan-Meier curves. A nomogram was developed to individually predict the 3-, 5-, and 10-year CSS and OS rates. The clinical usefulness of the nomogram was assessed using calibration plots, the concordance index (C-index), and time-dependent receiver operating characteristic curves. A total of 468 LGSCA and 165 HGSCA patients were eligible for inclusion. LGSCA and HGSCA patients demonstrated differences in age, tumor extension, insurance status, adjuvant treatment, and survival. Multivariate analysis demonstrated that in the LGSCA group, tumor extension, surgery type, and adjuvant therapy were individually associated with CSS. The distance of tumor extension and WHO grade were individually associated with CSS in the HGSCA group. The prognostic variables were further demonstrated using the Kaplan-Meier method, which also suggested that adjuvant treatment provided no advantage to HGSCA patients. A nomogram was constructed, and the C-index for CSS was 0.84 by internal validation (95% CI 0.79-0.90). This research suggests that the distance of tumor extension, type of surgery, and adjuvant therapy are significant risk factors for CSS using multivariate analysis in the LGSCA group. Adjuvant treatment provided no advantages for CSS or OS in patients with HGSCAs. The nomogram may be clinically useful to healthcare providers.


Conformational regulation of urokinase receptor function: impact of receptor occupancy and epitope-mapped monoclonal antibodies on lamellipodia induction.
The urokinase-type plasminogen activator receptor (uPAR) is a glycolipid-anchored membrane protein with an established role in focalizing uPA-mediated plasminogen activation on cell surfaces. Distinct from this function, uPAR also modulates cell adhesion and migration on vitronectin-rich matrices. Although uPA and vitronectin engage structurally distinct binding sites on uPAR, they nonetheless cooperate functionally, as uPA binding potentiates uPAR-dependent induction of lamellipodia on vitronectin matrices. We now present data advancing the possibility that it is the burial of the β-hairpin in uPA per se into the hydrophobic ligand binding cavity of uPAR that modulates the function of this receptor. Based on these data, we now propose a model in which the inherent interdomain mobility in uPAR plays a major role in modulating its function. Particularly one uPAR conformation, which is stabilized by engagement of the β-hairpin in uPA, favors the proper assembly of an active, compact receptor structure that stimulates lamellipodia induction on vitronectin. This molecular model has wide implications for drug development targeting uPAR function.


Lipid peroxidation, some extracellular antioxidants, and antioxidant enzymes in serum of patients with rheumatoid arthritis.
The aims of our study were to assess whether the increased oxidative stress in inflamed joints is reflected by serum lipid peroxidation and also to check alterations in the levels of extracellular antioxidants and antioxidant enzyme activities in patients with rheumatoid arthritis. Serum malondialdehyde and ceruloplasmin levels and the activity of CuZn superoxide dismutase were higher, while transferrin levels and the activities of glutathione peroxidase and catalase were lower in patients (n = 37) than in healthy controls (n = 30). Disease activity score correlated positively with serum malondialdehyde level and CuZn superoxide dismutase activity. Probably, superoxide radicals in serum could be dismutated to produce hydrogen peroxide by increased CuZn superoxide dismutase activity, but hydrogen peroxide could not have been detoxified due to decreased activities of serum glutathione peroxidase and catalase. Hydrogen peroxide possibly converted to hydroxyl radical by iron due to lower transferrin level might have led to increased serum lipid peroxidation in patients with rheumatoid arthritis.


Conservation of artists' acrylic emulsion paints: XPS, NEXAFS and ATR-FTIR studies of wet cleaning methods.
Works of art prepared with acrylic emulsion paints became commercially available in the 1960s. It is increasingly necessary to undertake and optimise cleaning and preventative conservation treatments to ensure their longevity. Model artists' acrylic paint films covered with artificial soiling were thus prepared on a canvas support and exposed to a variety of wet cleaning treatments based on aqueous or hydrocarbon solvent systems. This included some with additives such as chelating agents and/or surfactants, and microemulsion systems made specifically for conservation practice. The impact of cleaning (soiling removal) on the paint film surface was examined visually and correlated with results of attenuated total reflection Fourier transform infrared, XPS and near-edge X-ray absorption fine structure analyses - three spectroscopic techniques with increasing surface sensitivity ranging from approximately - 1000, 10 and 5 nm, respectively. Visual analysis established the relative cleaning efficacy of the wet cleaning treatments in line with previous results. X-ray spectroscopy analysis provided significant additional findings, including evidence for (i) surfactant extraction following aqueous swabbing, (ii) modifications to pigment following cleaning and (iii) cleaning system residues. © 2014 The Authors. Surface and Interface Analysis published by John Wiley & Sons, Ltd.


Intrathoracic blood volume index measured by thermodilution for preload monitoring after cardiac surgery.
To investigate the accuracy of measurement of intrathoracic blood volume index by single thermodilution (ITBVI*) and its sensitivity to detect changes in preload after cardiac surgery compared with conventional transpulmonary arterial dye dilution ITBVI and with conventional monitoring (central venous pressure [CVP] and left ventricular end-diastolic area index [EDAI] by transesophageal echocardiography). Prospective clinical study. University hospital. Nineteen patients immediately after cardiac surgery. Volume loading was administered with 20 mL of oxypoligelatine (Haemaccel [Behringwerke Aktiengesellschaft Corp, Marburg, Germany]) 3.5% times body mass index over 10 minutes. Intrathoracic blood volume index was measured by dye dilution (ITBVI) and thermodilution (ITBVI*) immediately before and after volume loading. Measurements of ITBVI and ITBVI* correlated closely (r = 0.94; p < 0.0001). With volume loading, ITBVI and ITBVI* increased significantly from 877 +/- 195 mL/m(2) to 967 +/- 180 mL/m(2) and from 889 +/- 195 mL/m(2) to 954 +/- 185 mL/m(2). Percent changes in ITBVI (deltaITBVI) and ITBVI* (deltaITBVI*) did not differ significantly and correlated closely (r = 0.90; p < 0.0001). Percent changes in cardiac index (CI) as a result of volume loading (deltaCI) revealed significant correlation to deltaITBVI (r = 0.85; p < 0.0001) and to deltaITBVI* (r = 0.76; p < 0.0005). No significant correlation could be found between deltaCI and deltaEDAI or deltaCVP. In patients undergoing cardiac surgery, determination of ITBVI* revealed close agreement with measurements derived by ITBVI. Enhancement in cardiac preload was adequately detected by ITBVI*.


Granulocyte-macrophage colony-stimulating factor can stimulate macrophage proliferation via persistent activation of Na+/H+ antiport. Evidence for two distinct roles for Na+/H+ antiport activation.
Macrophages respond to a variety of extracellular stimuli which can modulate the proliferation, development, activation and functional activity of these cells. The effects of two such agents, granulocytemacrophage colony-stimulating factor (GM-CSF, which stimulates proliferation) and platelet-activating factor (PAF, which stimulates chemotaxis and bactericidal activity), on cellular signal transduction mechanisms were compared. PAF can stimulate inositol lipid hydrolysis leading to Ca2+ mobilization. GM-CSF on the other hand has no effect on these events. Both agonists do, however, share an ability to activate an amiloride-sensitive Na+/H+ antiport and, furthermore, amiloride analogues are shown to inhibit the proliferative effects of GM-CSF on these cells. Long-term incubations with either PAF or GM-CSF demonstrate that it is only those cells pretreated with the latter which show a persistent activation of the antiport together with a sustained increase in intracellular pH. PAF-treated cells exhibit only a transitory increase in antiport activity, their intracellular pH levels returning to resting levels in spite of the continuous presence of the agonist in the medium. These effects of GM-CSF and PAF on Na+/H+ exchange are observed in both bicarbonate-free and bicarbonate-containing medium. These results lead us to suggest that the Na+/H+ antiport has a role in macrophage proliferation and in the regulation of intracellular pH during the oxidative burst stimulated by PAF and other agonists, and that differential mechanisms whereby this antiport is regulated exist in macrophages.


Pharmacologic treatments for acute respiratory distress syndrome and acute lung injury: systematic review and meta-analysis.
Multiple pharmacologic treatments have been studied for patients with acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Our objective was to systematically evaluate this literature to determine the effects of these interventions on important clinical outcomes. We searched OVID versions of CENTRAL (The Cochrane Library Issue 3, 2003), MEDLINE (1966-week 2, January 2004), EMBASE (1980-week 4, 2004), CINAHL (1982-week 2, January 2004), and HEALTHSTAR (1995-December 2003); proceedings from four conferences (1994-2003); and bibliographies of review articles and included studies. We included randomized controlled trials (RCTs) of pharmacologic treatments compared with no therapy or placebo for established ARDS and ALI in adults admitted to an intensive care unit, with measurement of early mortality, late mortality, duration of ventilation, ventilator-free days, non-pulmonary organ dysfunction, or adverse events. We excluded trials in other populations incorporating subgroup analyses of patients with ARDS and ALI and studies of nitric oxide, partial liquid ventilation, and fluid and nutritional interventions. Two reviewers independently screened studies and abstracted data from studies included in the analysis. Data were pooled using random effects models where appropriate. We retrieved 75 potentially relevant articles and abstracts, of which 33 trials randomizing 3272 patients met our selection criteria. Meta-analysis showed no effect on early mortality for alprostadil ([prostaglandin E(1)] seven studies; 693 patients; relative risk [RR] 0.95; 95% confidence interval [CI], 0.77, 1.17), acetylcysteine (five studies; 235 patients; RR 0.89; 95% CI, 0.65, 1.21), early high-dose corticosteroids (two studies; 180 patients; RR 1.12; 95% CI, 0.72, 1.74), or surfactant therapy (nine studies; 1418 patients; RR 0.93; 95% CI, 0.77, 1.12). Most trials of alprostadil, early high-dose corticosteroids, and surfactant therapy showed more adverse events in the active therapy arm. Single small RCTs demonstrated lower hospital mortality (24 patients, RR 0.20; 95% CI, 0.05, 0.81) with corticosteroids for late phase ARDS and lower 1-month mortality (30 patients, RR 0.67; 95% CI, 0.47, 0.95) with pentoxifylline for patients with metastatic cancer and ARDS. Individual trials of nine additional interventions failed to show beneficial effects on prespecified outcomes. Effective pharmacotherapy for ARDS is extremely limited. Corticosteroids for late phase ARDS and pentoxifylline for patients with metastatic cancer and ARDS reduced mortality in single small studies. However, further research is required to investigate their potential benefit in the treatment of ALI/ARDS.


A study of Cryptosporidium parvum genotypes and population structure.
Genetic evidence for the occurrence of two Cryptosporidium parvum subgroups is presented. This evidence is based on restriction fragment length polymorphism analysis of several independent loci. Sequence analysis of the beta-tubulin intron revealed additional polymorphism. The stability of the genetic profiles following passage of C. parvum isolates between different hosts was investigated.


Clinical clue of severe aortic stenosis. Simultaneous palpation of the carotid and apical impulses.
In patients with severe aortic stenosis, simultaneous palpation of the carotid and apical impulses yields a palpable lag time between the two. Apexcardiograms and carotid pulse tracings were recorded in 66 control subjects and in 30 patients with aortic stenosis. Using QRS peak as reference, the peak appearance time of the carotid pulse tracings and apexcardiograms was measured, and the difference was calculated as palpable lag time; 21/30 patients had a palpable lag time, whereas nine did not; 22/30 patients with aortic stenosis had aortic valve areas of less than 1 sq cm. Twenty-one of these 22 patients had a palpable lag time. The sensitivity of a palpable lag time for aortic valve areas of less than 1 sq cm was 95%, specificity 100%, positive predictive value 100%, and negative predictive value 89%. The group means for measured lag times between controls (70 +/- 7 ms) and those patients with aortic stenosis (133 +/- 7 ms) showed a definite difference. The palpable lag time by linear regression analysis had an r of .68, third in rank to the aortic valve gradient and ECG for predicting aortic valve area. Multiple regression analysis found the palpable lag time, ECG, syncope, and shudder waves together able to predict the aortic valve area (r = .85).


A review of the most promising biomarkers for early diagnosis and prognosis prediction of tongue squamous cell carcinoma.
There is a great interest in developing biomarkers to enhance early detection and clinical management of tongue squamous cell carcinoma (TSCC). However, the developmental path towards a clinically valid biomarker remains extremely challenging. Ideally, the initial key step in moving a newly discovered biomarker towards clinical implementation is independent replication. Therefore, the focus of this review is on biomarkers that consistently showed clinical relevance in two or more publications. We searched PubMed database for relevant papers across different TSCC sample sources, i.e., body fluids (saliva, serum/plasma) and tissues. No restriction regarding the date of publication was applied except for immunohistochemistry (IHC); only studies published between 2010 and June 2017 were included. The search strategy identified 1429 abstracts, of which 96 papers, examining 150 biomarkers, were eventually included. Of these papers, 66% were exploratory studies evaluating single or a panel of biomarkers in one publication. Ultimately, based on studies that had undergone validation for their clinical relevance in at least two independent studies, we identified 10 promising candidates, consisting of different types of molecules (IL-6, IL-8, and Prolactin in liquid samples; HIF-1α, SOX2, E-cadherin, vimentin, MALAT1, TP53, and NOTCH1 in tissue biopsies) CONCLUSIONS: Although more exploratory research is needed with newer methods to identify biomarkers for TSCC, rigorous validation of biomarkers that have already shown unbiased assessment in at least two publications should be considered a high priority. Further research on these promising biomarkers or their combination in multi-institutional studies, could provide new possibilities to develop a specific panel for early diagnosis, prognosis, and individualized treatments.


Pre-marital sexual debut and its associated factors among in-school adolescents in Eastern Ethiopia.
More adolescents in Ethiopia are in school today than ever, but few studies have assessed the sexual behaviour of these learners. Thus, this study tried to assess pre-marital sexual debut and factors associated with it among in-school adolescents in Eastern Ethiopia. A cross-sectional school-based study was conducted using a facilitator guided selfadministered questionnaire. Respondents were students attending regular school classes in fourteen high schools. The proportion of adolescents involved in pre-marital sexual debut and the mean age at sexual debut was computed. Factors associated with pre-marital sexual debut were assessed using bivariate and multivariable logistic regression. About one in four, 686 (24.8%) never married in-school adolescent respondents reported pre-marital sexual debut of these 28.8% were males and 14.7% were females (p < 0.001). Pre-marital sexual debut was more common among adolescents who had their parents in urban areas (Adjusted OR and [95% CI] = 1.42 [1.17-1.73]), who received higher pocket money per month (Adjusted OR and [95% CI] = 1.56 [1.19-2.04]), who perceived low self-educational rank (Adjusted OR and [95% CI] = 1.89 [1.07-3.34]) and who lived in rented houses (Adjusted OR and [95% CI] = 1.32 [1.03-1.70]). The females and those who were less influenced by external pressure were more protected against pre-marital sexual debut (Adjusted OR and [95% CI] = 0.44 [0.35-0.56; 0.62 [0.52-0.74, respectively]) than their counterparts. A significant proportion of in-school adolescents were engaged in sexual relationship. Thus, public health interventions should consider the broader determinants of premarital sexual debut, including the ecological factors in which the behavior occurs.


Cell Surface Receptor Identification Using Genome-Scale CRISPR/Cas9 Genetic Screens.
Intercellular communication mediated by direct interactions between membrane-embedded cell surface receptors is crucial for the normal development and functioning of multicellular organisms. Detecting these interactions remains technically challenging, however. This manuscript describes a systematic genome-scale CRISPR/Cas9 knockout genetic screening approach that reveals cellular pathways required for specific cell surface recognition events. This assay utilizes recombinant proteins produced in a mammalian protein expression system as avid binding probes to identify interaction partners in a cell-based genetic screen. This method can be used to identify the genes necessary for cell surface interactions detected by recombinant binding probes corresponding to the ectodomains of membrane-embedded receptors. Importantly, given the genome-scale nature of this approach, it also has the advantage of not only identifying the direct receptor but also the cellular components that are required for the presentation of the receptor at the cell surface, thereby providing valuable insights into the biology of the receptor.


Per-channel basis normalization methods for flow cytometry data.
Between-sample variation in high-throughput flow cytometry data poses a significant challenge for analysis of large-scale data sets, such as those derived from multicenter clinical trials. It is often hard to match biologically relevant cell populations across samples because of technical variation in sample acquisition and instrumentation differences. Thus, normalization of data is a critical step before analysis, particularly in large-scale data sets from clinical trials, where group-specific differences may be subtle and patient-to-patient variation common. We have developed two normalization methods that remove technical between-sample variation by aligning prominent features (landmarks) in the raw data on a per-channel basis. These algorithms were tested on two independent flow cytometry data sets by comparing manually gated data, either individually for each sample or using static gating templates, before and after normalization. Our results show a marked improvement in the overlap between manual and static gating when the data are normalized, thereby facilitating the use of automated analyses on large flow cytometry data sets. Such automated analyses are essential for high-throughput flow cytometry.


Isolation and characterization of Tn5 insertion mutants of Erwinia chrysanthemi that are deficient in polygalacturonate catabolic enzymes oligogalacturonate lyase and 3-deoxy-D-glycero-2,5-hexodiulosonate dehydrogenase.
Mutants of Erwinia chrysanthemi EC16 deficient in the polygalacturonate catabolic enzymes oligogalacturonate lyase (Ogl-) and 3-deoxy-D-glycero-2,5-hexodiulosonate (ketodeoxyuronate) dehydrogenase (KduD-) were obtained by Tn5 mutagenesis using the R plasmid pJB4JI. Ogl- Exu+ (Exu+, D-galacturonate utilization) and KduD- Exu- strains macerated potato tuber tissue and utilized glucose, glycerol, and gluconate, but they did not utilize polygalacturonate, unsaturated digalacturonate, or saturated digalacturonate. Genetic and physical evidence indicated that the Ogl- mutants and a KduD- recombinant contained a single copy of Tn5 and that Tn5 (Kmr) was linked to the mutant phenotypes. In the Ogl+ parents, basal levels of oligogalacturonate lyase were present in glycerol-grown cells and induced levels were present with saturated or unsaturated digalacturonate, while oligogalacturonate lyase was undetectable under similar conditions in Ogl- strains. Pectate lyase, polygalacturonase, and ketodeoxyuronate dehydrogenase were induced in an Ogl- strain by 3-deoxy-D-glycero-2,5-hexodiulosonate and by the enzymatic products of unsaturated digalacturonate but not by the digalacturonates. The KduD- strains lacked the dehydrogenase activity but in the presence of the digalacturonates produced higher levels of pectate lyase, polygalacturonase, and oligogalacturonate lyase than the KduD+ parents did. In the KduD- strains, pectate lyase and oligogalacturonate lyase were induced by unsaturated digalacturonate in a "gratuitous" manner, suggesting an intracellular accumulation of the inducer(s). We conclude that an intermediate(s) of the ketodeoxyuronate pathway induces pectate lyase, polygalacturonase, oligogalacturonate lyase, and ketodeoxyuronate dehydrogenase in E. chrysanthemi.


Effect of psoriatic arthritis according to the affected categories of the international classification of functioning, disability and health.
To determine the categories of the International Classification of Functioning, Disability and Health (ICF) checklist and core sets of rheumatoid arthritis and ankylosing spondylitis frequently occurring in people with psoriatic arthritis (PsA) and to compare the number of such categories with scores on self-report measures of participation restrictions and activity limitations. Data were collected from 94 patients with PsA attending rheumatology clinics in 6 centers. For each ICF category affected by PsA in at least 30% of patients, the percentage of such patients was determined for Body Structures, Body Functions, Activities and Participation, and Environmental Factors. A count of all affected categories by ICF chapter was compared to patient self-report scores on a number of functional and health status instruments using Spearman's correlation. There were 25 categories in the Body Functions section, 6 categories in the Body Structures section, and 51 categories in the Activities and Participation section that were relevant in at least 30% of participants. Thirteen Environmental Factors were facilitating and 1 Environmental Factor (climate) was a barrier in at least 30% of participants. The number of involved Activities and Participation categories by chapter did not correlate in predictable ways with self-report measures of participation restrictions and activity limitations. PsA is associated with a wide range of impairments, limitations, and restrictions across the ICF categories. People with PsA find environmental factors to be helpful more often than to be barriers. The unexpected pattern of correlation between ICF chapters and self-report measures suggests the need for a better way of quantitatively representing the ICF concepts.


Protocol of a Nationwide Observational Study among Patients with Nontuberculous Mycobacterium Pulmonary Disease in South Korea (NTM-KOREA).
The burden of nontuberculous mycobacterial (NTM) pulmonary disease (PD) is increasing globally. To understand the treatment outcomes and prognosis of NTM-PD, a unified registry is needed. In this project, we aim to construct a multicenter prospective observational cohort with NTM-PD in South Korea (NTM-KOREA). The primary objective of this study is to analyze treatment outcomes according to the species. In addition, recurrence rate, adverse events, the impact of each drug on treatment outcomes as well as the impact of characteristics of mycobacteriology will be analyzed. The inclusion criteria for the study are as follows: fulfilling the criteria for NTM-PD having one of the following etiologic organisms: Mycobacterium avium complex, M. abscessus subspecies abscessus, M. abscessus subspecies massiliense, or M. kansasii; receiving the first treatment for NTM-PD after enrollment; age >20 years; and consenting to participate in the study. Seven institutions will participate in patient enrollment and about 500 patients are expected to be enrolled. Participants will be recruited from 1 March 2020 until 19 March 2024 and will be observed through 19 March 2029. During the follow-up period, participants' clinical course will be tracked and their clinical data as well as NTM isolates will be collected. NTM-KOREA will be the first nationwide observational cohort for NTM-PD in South Korea. It will provide the information to optimize treatment modalities and will contribute to deeper understanding of the treatment outcomes and long-term prognosis of patients with NTM-PD in South Korea.


[Selection criteria for referral to in-hospital intensive cardiac rehabilitation after transcatheter aortic-valve implantation].
Transcatheter aortic valve implantation (TAVI) is assuming a major role in the routine management of patients with aortic stenosis. There is a paucity of data to substantiate the referral of these patients to in-hospital intensive cardiac rehabilitation, widely recognized as the standard of care for cardiac patients in the post-acute phase. The patients considered to be candidates for TAVI were at high risk, defined by Euroscore > 20% or STS score > 10%, mainly because they had coexisting comorbidities, with high care and rehabilitative needs. Reasonable selection criteria for referral were: trans-apical approach, past history of heart failure or coronary artery disease, advanced therapy needs (e.g. ventilatory, inotropic, nutritional), worsening comorbidities, logistic or social problem, frailty, and need of educational and lifestyle support.


Ontogenetical aspects of nutritional requirements in fish.
Changes in morphology i.e. "metamorphosis", mode of respiration, allometric growth of organs, mode of swimming and efficiency of biochemical pathways are briefly reviewed. It is suggested that these processes form the basis for progressive changes in nutrient requirements involving formation and development of several organs, systems and function. Digestive tract morphology changes during ontogenesis and aspects of fish metabolism, protein synthesis rate and body growth rate are interconnected and an attempt is made to explain these processes so as to understand the specificity of larval and juvenile fish nutrient requirements as compared to subadults. Protein and amino acid requirements given the body mass perspective and the generalization of the protein maintenance requirement in protein requirements for maximum growth was estimated to amount to 5-20%. Several cases of amino acid deficiency symptoms showed strong dependence on fish weight (age), but even most numerous studies on salmonids are lacking complete research throughout the life history of one species in defined nutritional and environmental conditions. Larval and juvenile fish have reduced capacity of catabolic adaptability and this fact links them to strictly carnivorous mammals. An attempt is made, for the first time, to relate amino acid needs of fish to young and/or carnivorous mammals. Vitamin requirements of fish are reviewed, taking into account the relationship between body size and time of the first appearance of deficiency symptoms. These are virtually no studies on vitamin requirements in larval warm-water fishes and very few on first feeding salmonids. The same applies to the vitamin need in reproductory fish. Fatty acid deficiencies manifest themselves faster in juvenile fish, but larval fish might require separate classes of lipids, phosphatidylcholine, in the diet to develop and grow at all. It seems that the studies on nutrient requirements have so far not used an ontogenetical perspective, but evidence given throughout this work argues that it would be worthwhile.


Recycling and persistence of iodine 127 and 129 in forested environments: A modelling approach.
Differences in the source and behaviour of 129I compared to 127I isotopes have been described for a variety of surface environments, but little is known about the cycling rates of each isotope in terrestrial ecosystems. We developed a compartment model of the iodine cycle in a forest ecosystem, with a labile and non-labile pool to simplify the complex fate of iodine in the forest floor and soil. Simulations were performed using atmospheric 127I and 129I inputs for sites differing in climate, vegetation, and soil. In general, considering dry deposition in addition to wet deposition improved model simulations. Model results support the view that soil is the sink for atmospheric iodine deposited in forest ecosystems, while tree vegetation has little influence on long-term iodine budgets. Modelling also showed that iodine cycling reaches equilibrium after a period of about 5000 years, mainly due to a gradual incorporation of iodine into the bulk stabilised soil organic matter. At steady state, this pool of non-labile iodine in soil can retain about 20% of total deposition with a mean residence time of 900 years, while the labile iodine pool is renewed after 90 years. The proportions of modern anthropogenic 129I in each modelled pool reflect those of stable 127I at least several decades after input to the forest; this result explains why isotopic disequilibrium is common in field data analysis. Volatilisation plays a central role in regulating iodine storage in soil and, therefore, its residence time, while drainage is a minor export pathway, except at some calcareous sites. Dynamic modelling has been particularly helpful for gaining insight into the long-term response of iodine partitioning to continuous, single or even varying deposition. Our modelling study suggested that better estimates of dry deposition of atmospheric iodine, weathering of parent rock, and volatilisation of the deposited iodine from soil and vegetation will be required for reliable predictions of iodine cycling in specific forests, because these processes remain insufficiently explored.


Machine Learning-Based Gynecologic Tumor Diagnosis and Its Postoperative Incisional Infection Influence Factor Analysis.
Various factors influencing postoperative incisional infection in gynecologic tumors were analyzed, and the value of quality nursing intervention was studied. In this study, 74 surgically treated gynecologic tumor patients were randomly selected from within the hospital as the study population and were divided into study and control groups. For this purpose, the whole-group random sampling method is utilized to compare the postoperative incisional infection rates of the two groups, analyze their influencing factors, and develop quality nursing interventions. In this paper, a breast cancer diagnosis prediction model was developed by combining the self-attentive mechanism. The preprocessing work such as data quantification and normalization was performed first which is followed by adding the preprocessed data to the self-attentive mechanism. This model has solved the problem that recurrent neural networks (RNNs) could not extract and calculate the features at the same time. Likewise, it has solved the drawback that the RNN could not consider global features at the same time when extracting the features, and then, the feature matrix extracted by the self-attentive mechanism was added to the adaptive neural network. The adaptive neural network model for breast cancer diagnosis prediction was constructed and, finally, relevant parameters of the adaptive neural network model were adjusted according to different tasks to make the model performance optimal. Experimental results showed that the postoperative incision infection rate of patients in the study group was 2.70%, which was significantly lower than that of 21.62% in the control group (P < 0.05). Likewise, operation time, operation method, hospitalization time, preoperative fever, diabetes mellitus, and anemia were the main influencing factors of postoperative incision infection in women with gynecologic tumors. The time of surgery, surgical method, long hospital stay, preoperative fever, diabetes, and anemia are the main factors that lead to postoperative incisional infection in female gynecologic tumor patients.


"Back to the future": Influence of beliefs regarding the future on TTO answers.
A common approach to obtain health state valuations is the time-tradeoff (TTO) method. Much remains unknown regarding the influence of responder characteristics on TTO answers. The objective of this study is to increase understanding of the influence that beliefs regarding future health and death, as well as desires to witness certain life events, have on respondents' health state valuations. An online survey was designed, including three TTO questions using a 10 year timeframe. Moreover, respondents completed demographic questions, the Health-Risk Attitude Scale (HRAS), the Expectations Regarding Aging (ERA) questionnaire, questions about beliefs regarding future health (i.e. life expectancy) and death (i.e. fear of death, belief in life after death and opinion about euthanasia), and about important life events taking place within the TTO timeframe. Regression analyses were performed in order to assess the influence of these different variables. One thousand sixty-seven respondents were included in the analyses. The following variables were significantly associated with years traded off: ERA mental health (decrease), ERA physical health (increase), HRAS (increase), support for euthanasia (increase), fear of death (decrease) and consideration of an important life event (decrease). The explained variance of the final model was low (0.08). TTO responses may be influenced by considerations of future health, including life events and attitudes regarding health risks and death. Further investigation of TTO responses remains warranted.


Defining critical illness using immunological endotypes in patients with and without of sepsis: A cohort study.
Background: Sepsis is a heterogenous syndrome with limited therapeutic options. Identifying characteristic gene expression patterns, or endotypes, in septic patients may lead to targeted interventions. We investigated whether patients admitted to a surgical ICU with sepsis and with high risk of mortality express similar endotypes to non-septic, but still critically ill patients using two multiplex transcriptomic metrics obtained both on admission to a surgical intensive care unit (ICU) and at set intervals. Methods: We analyzed transcriptomic data from 522 patients in two single-site, prospective, observational cohorts admitted to surgical ICUs over a 5-year period ending in July 2020 . Using an FDA-cleared analytical platform (nCounter FLEX ® , NanoString, Inc.), we assessed a previously validated 29-messenger RNA transcriptomic classifier for likelihood of 30-day mortality (IMX-SEV-3) and a 33-messenger RNA transcriptomic endotype classifier. Clinical outcomes included all-cause (in-hospital, 30-, 90-day) mortality, development of chronic critical illness (CCI), and secondary infections. Univariate and multivariate analyses were performed to assess for true effect and confounding. Results: Sepsis was associated with a significantly higher predicted and actual hospital mortality. At enrollment, the predominant endotype for both septic and non-septic patients was adaptive , though with significantly different distributions. Inflammopathic and coagulopathic septic patients, as well as inflammopathic non-septic patients, showed significantly higher frequencies of secondary infections compared to those with adaptive endotypes (p<0.01). Endotypes changed during ICU hospitalization in 57.5% of patients. Patients who remained adaptive had overall better prognosis, while those who remained inflammopathic or coagulopathic had worse overall outcomes. For severity metrics, patients admitted with sepsis and a high predicted likelihood of mortality showed an inflammopathic (49.6%) endotype and had higher rates of cumulative adverse outcomes (67.4%). Patients at low mortality risk, whether septic or non-septic, almost uniformly presented with an adaptive endotype (100% and 93.4%, respectively). Conclusion : Critically ill surgical patients express different and evolving immunological endotypes depending upon both their sepsis status and severity of their clinical course. Future studies will elucidate whether endotyping critically ill, septic patients can identify individuals for targeted therapeutic interventions to improve patient management and outcomes.


In situ localization of the secretion of lignin peroxidases in colonies of Phanerochaete chrysosporium using a sandwiched mode of culture.
Protein secretion and growth were investigated in Phanerochaete chrysosporium by using cultures sandwiched between perforated polycarbonate membranes. Labelling of colonies with radioactive N-acetylglucosamine and L-methionine indicated a close correlation between growth and general protein secretion, even in a central area of the colony secreting the idiophase enzymes lignin peroxidase (LiP) and manganese-dependent lignin peroxidase (MnP). Comparison of the sites of release into the medium of newly synthesized proteins and immuno-detected lignin peroxidases suggested that diffusion of the enzymes from the walls was a limiting step in the release of peroxidases into the medium. Microautoradiography of colonies exposed to N-acetyl[3H]glucosamine revealed the apical growth of thin hyphae and branches (4 to 5 microns diameter on average) in the central secreting area. These secondary hyphae showed peroxidase activity and reacted with lignin peroxidase antibodies. Although it was not possible to directly visualize secretion at hyphal tips, the results suggest that peroxidases (LiP and MnP) are initially secreted at the apex of secondary growing hyphae and later slowly released into the surrounding medium.


Benefits of Atrial Substrate Modification Guided by Electrogram Similarity and Phase Mapping Techniques to Eliminate Rotors and Focal Sources Versus Conventional Defragmentation in Persistent Atrial Fibrillation.
This prospective study compared the efficacy of atrial substrate modification guided by a nonlinear phase mapping technique with that of conventional substrate ablation. The optimal ablation strategy for persistent atrial fibrillation (AF) was unknown. In phase 1 study, we applied a cellular automation technique to simulate the electrical wave propagation to improve the phase mapping algorithm, involving analysis of high-similarity electrogram regions. In addition, we defined rotors and focal AF sources, using the physical parameters of the divergence and curvature forces. In phase 2 study, we enrolled 68 patients with persistent AF undergoing substrate modification into 2 groups, group-1 (n = 34) underwent similarity index (SI) and phase mapping techniques; group-2 (n = 34) received complex fractionated atrial electrogram ablation with commercially available software. Group-1 received real-time waveform similarity measurements in which a phase mapping algorithm was applied to localize the sources. We evaluated the single-procedure freedom from AF. In group-1, we identified an average of 2.6 ± 0.89 SI regions per chamber. These regions involved rotors and focal sources in 65% and 77% of patients in group-1, respectively. Group-1 patients had shorter ablation procedure times, higher termination rates, and significant reduction in AF recurrence compared to group-2 and a trend toward benefit for all atrial arrhythmias. Multivariate analysis showed that substrate mapping using nonlinear similarity and phase mapping was the independent predictor of freedom from AF recurrence (hazard ratio: 0.26; 95% confidence interval: 0.09 to 0.74; p = 0.01). Our study showed that for persistent AF ablation, a specified substrate modification guided by nonlinear phase mapping could eliminate localized re-entry and non-pulmonary focal sources after pulmonary vein isolation.


Evaluation of a feline leukemia virus vaccine in a controlled natural transmission study.
Twenty-six 8-week-old specific-pathogen-free cats were vaccinated subcutaneously with 2 doses of a commercially available FeLV vaccine, and 26 age-matched specific-pathogen-free cats were similarly vaccinated with a placebo vaccine containing the same adjuvant as the FeLV vaccine. Cats then were randomly assigned to 2 groups of 26 cats (13 FeLV-vaccinated cats and 13 control cats), and each group was housed with 5 cats previously inoculated with FeLV. All cats were tested biweekly for the next 26 weeks for evidence of FeLV antigenemia. Five of the 26 control cats developed antigenemia. However, 4 of these cats were only transiently antigenemic (positive results for 3 consecutive biweekly samples) and only 1 was persistently antigenemic. None of the FeLV-vaccinated cats developed antigenemia. Preventable fraction was calculated to be 100%.


The effects of sociodemographic factors on quality of life among people aged 50 years or older are not unequivocal: comparing SF-12, WHOQOL-BREF, and WHOQOL-OLD.
The effects of sociodemographic factors on quality of life in older people differ strongly, possibly due to the fact that different measurement instruments have been used. The main aim of this cross-sectional study is to compare the associations of sex, age, marital status, education, and income with quality of life assessed with the Short-Form Health Survey (SF-12), the World Health Organization Quality of Life Questionnaire-BREF (WHOQOL-BREF), and the World Health Organization Quality of Life Questionnaire-Older Adults Module (WHOQOL-OLD). The associations between sociodemographic factors and eleven quality of life domains were examined using a sample of 1,492 Dutch people aged ≥50 years. Participants completed the "Senioren Barometer", a web-based questionnaire including sociodemographic factors, the SF-12, the WHOQOL-BREF, and the WHOQOL-OLD. All the sociodemographic factors together explained a significant part of the variance of all the quality of life domains' scores, ranging from 5% to 17% for the WHOQOL-BREF, 5.8% to 6.7% for the SF-12, and 1.4% to 26% for the WHOQOL-OLD. Being a woman and being older were negatively associated with two and four quality of life domains, respectively. Being a woman, being married or cohabiting, and having higher education and a higher income were positively associated with six, six, one, and eleven quality of life domains, respectively. Our study showed that the associations of sociodemographic factors and quality of life in middle-aged and older people depend on the instruments used to assess quality of life. We recommend that health care and welfare professionals focus particularly on people with a low income and carry out interventions aimed at improving their quality of life.


Performance of single comb White Leghorn layers fed corn-soybean meal and barley-corn-soybean meal diets supplemented with a direct-fed microbial.
An experiment was conducted with Single Comb White Leghorn (SCWL) layers to determine the effect of feeding either corn-soybean meal (C-S) or barley-corn soybean meal (B-C-S) diets with or without condensed cane molasses solubles (CCMS) or with or without CCMS-1,100 mg Lactobacillus (Lacto)/kg (ppm) diet on performance, nutrient retentions, digesta passage rate, and histological changes of the gastrointestinal (GI) tracts. Six dietary treatments were fed for eight 28-d periods and consisted of C-S (control), C-S + CCMS, C-S + CCMS-1,100 ppm Lacto (4.4 x 107 cfu/mg Lacto), B-C-S (control), B-C-S + CCMS, and B-C-S + CCMS-1,100 ppm Lacto. The CCMS served as the carrier for the Lacto, and the CCMS-Lacto premix (55 g Lacto/kg) was incorporated at 2% of the diet. Lactobacillus supplementation in C-S diets improved (P < .05) egg weight, egg mass, egg size, and body weight gains, and in B-C-S diets improved body weight gains. There were no differences in feed consumption, feed conversion, internal egg quality, and egg specific gravity among the dietary treatments. Passage rates of digesta were increased (P < .05) when either C-S or B-C-S layer diets were supplemented with Lacto. Lactobacillus supplementations of the C-S and B-C-S diets increased (P < .05) fat and calcium, and fat, phosphorus, copper, and manganese retentions, respectively. Increased cellularity of Peyer's patches in the ileum indicated a stimulation of the mucosal immune system that responds to antigenic stimuli by secreting immunoglobulin (IgA).


Long-term oxygen therapy--state of the art.
Long-term oxygen therapy prolongs life in adults with chronic hypoxia caused by chronic bronchitis and emphysema who have cor pulmonale, pulmonary hypertension, and secondary polycythemia ('blue bloaters'). Good results require oxygen therapy for more than 15 hours and preferably 20-24 hours per day. The oxygen concentrator, delivering 1 to 3 l/min of oxygen by nasal prongs, is probably the most cost-effective method of providing this therapy. Dangers of the therapy include fires and burning of patients who smoke, and this is a contraindication to treatment. Excessive CO2 retention during sleep should not result from controlled low-dose oxygen therapy unless the patient also has an obstructive sleep apnea syndrome. Oxygen therapy during sleep may prevent hypoxemic episodes in blue bloaters, and it may thus reverse their pulmonary hypertension, which probably potentiates the risk of right-heart failure and cor pulmonale.


An alkaloid extract of Evanta, traditionally used as anti-Leishmania agent in Bolivia, inhibits cellular proliferation and interferon-gamma production in polyclonally activated cells.
Traditional medicine and scientific studies have shown that the raw extract of Evanta [Galipea longiflora, Angostura longiflora (Krause) Kallunki] exhibits anti-leishmanial activity. We hypothesized that the healing observed when using this plant might not only be due to the direct action on the parasite, but possibly to a parallel effect on the host immune response to the parasite involved in the healing process. We show here that an alkaloid extract of Evanta (AEE) directly killed the parasite already at a dose of 10 microg/ml, but at this low concentration, AEE did not have a major effect on viability and proliferation of eukaryotic cells. The whole extract was also found to be stronger than 2-phenylquinoline, the most prominent alkaloid in AEE. AEE was not directly stimulating B or T cells or J774 macrophages. However, it interfered with the activation of both mouse and human T cells, as revealed by a reduction of in vitro cellular proliferation and interferon-gamma (IFN-gamma) production. The effect was more evident when the cells were pretreated with AEE and subsequently stimulated with the polyclonal T-cell activators Concanavalin A and anti-CD3. Taken together, our results suggest that Evanta have a direct leishmanicidal effect and due to the effect on IFN-gamma production it might contribute to control the chronic inflammatory reaction that characterize Leishmania infection pathology, but in vivo studies are necessary to corroborate this finding.