The science of fibromyalgia.
Fibromyalgia (FM) is a common chronic widespread pain disorder. Our understanding of FM has increased substantially in recent years with extensive research suggesting a neurogenic origin for the most prominent symptom of FM, chronic widespread pain. Neurochemical imbalances in the central nervous system are associated with central amplification of pain perception characterized by allodynia (a heightened sensitivity to stimuli that are not normally painful) and hyperalgesia (an increased response to painful stimuli). Despite this increased awareness and understanding, FM remains undiagnosed in an estimated 75% of people with the disorder. Clinicians could more effectively diagnose and manage FM if they better understood its underlying mechanisms. Fibromyalgia is a disorder of pain processing. Evidence suggests that both the ascending and descending pain pathways operate abnormally, resulting in central amplification of pain signals, analogous to the "volume control setting" being turned up too high. Patients with FM also exhibit changes in the levels of neurotransmitters that cause augmented central nervous system pain processing; levels of several neurotransmitters that facilitate pain transmission are elevated in the cerebrospinal fluid and brain, and levels of several neurotransmitters known to inhibit pain transmission are decreased. Pharmacological agents that act centrally in ascending and/or descending pain processing pathways, such as medications with approved indications for FM, are effective in many patients with FM as well as other conditions involving central pain amplification. Research is ongoing to determine the role of analogous central nervous system factors in the other cardinal symptoms of FM, such as fatigue, nonrestorative sleep, and cognitive dysfunction.


Elafibranor Inhibits Chronic Kidney Disease Progression in NASH Mice.
Identification of new pharmacological approaches to inhibit the excessive fat intake-induced steatohepatitis and chronic kidney disease (CKD) is important. High-fat diet (HFD)-induced steatohepatitis and CKD share common pathogenesis involving peroxisome proliferator-activated receptor (PPAR)-α and -δ. Elafibranor, a dual PPARα/δ agonist, can ameliorate the HFD-induced steatohepatitis. Nonetheless, the effects of HFD-induced CKD had not yet explored. This study investigated the effects of elafibranor (elaf) on the progression of HFD-induced CKD in mice. In vivo and in vitro renal effects were evaluated in HFD-elaf mice receiving 12 weeks of elafibranor (from 13th to 24th week of HFD feeding) treatment. In elafibranor-treated HFD mice, increased insulin sensitivity, reduced obesity and body fat mass, decreased severity of steatohepatitis, increased renal expression of PPARα, PPARδ, SIRT1, and autophagy (Beclin-1 and LC3-II) as well as glomerular/renal tubular barrier markers [synaptopodin (podocyte marker), zona occludin-1, and cubulin], reduced renal oxidative stress and caspase-3, and less urinary 8-isoprostanes excretion were observed. Aforementioned benefits of elafibranor were associated with low renal tubular injury and tubulointerstitial fibrosis scores, less albuminuria, low urinary albumin-to-creatinine ratio, and preserved glomerular filtration rate. Acute incubation of podocytes and HK-2 cells with elafibranor or recombinant SIRT1 reversed the HFD-sera-induced oxidative stress, autophagy dysfunction, cell apoptosis, barrier marker loss, albumin endocytosis, and reuptake reduction. Besides hepatoprotective and metabolic beneficial effects, current study showed that elafibranor inhibited the progression of HFD-induced CKD through activation of renal PPARα, PPARδ, SIRT1, autophagy, reduction of oxidative stress, and apoptosis in mice with steatohepatitis.


Racial Discrimination, Disease Activity, and Organ Damage: The Black Women's Experiences Living With Lupus (BeWELL) Study.
Black women are disproportionately affected by systemic lupus erythematosus (SLE), a chronic, potentially debilitating autoimmune disease, and they also experience more rapid progression and worse outcomes compared with other groups. We examined if racial discrimination is associated with disease outcomes among 427 black women with a validated diagnosis of SLE, who live in the Atlanta, Georgia, metropolitan area, and were recruited to the Black Women's Experiences Living with Lupus Study (2015-2017). Frequency of self-reported experiences of racial discrimination in domains such as employment, housing, and medical settings was assessed using the Experiences of Discrimination measure. SLE activity in the previous 3 months, including symptoms of fatigue, fever, skin rashes, and ulcers, was measured using the Systemic Lupus Activity Questionnaire; irreversible damage to an organ or system was measured using the Brief Index of Lupus Damage. Results of multivariable linear regression analyses examining the Systemic Lupus Activity Questionnaire and log-transformed Brief Index of Lupus Damage scores indicated that increasing frequency of racial discrimination was associated with greater SLE activity (b = 2.00, 95% confidence interval: 1.32, 2.68) and organ damage (b = 0.08, 95% confidence interval: 0.02, 0.13). Comprehensive efforts to address disparities in SLE severity should include policies that address issues of racial discrimination.


Uterine diffuse adenomatoid tumor. Does it represent a different biological entity?
Adenomatoid tumor represents a type of mesothelioma apparently confined to the genital tract and characterized by its benign behavior. Its morphological aspects are well known and, until now, it has been described as a nodular mass except for a case diffusely infiltrating the entire myometrium in an immunosuppressed patient. We report a case of benign mesothelial tumor characterized by histological, immunophenotypical and ultrastructural features of an otherwise typical adenomatoid tumor but diffusely growing below uterine serosal surface into the myometrium without discernible borders. The existence of a diffuse type of adenomatoid tumor might reflect a different nature of this neoplasm leading to the hypothesis that this variant of benign mesothelioma represents a distinct biological entity.


Microneedle applications in improving skin appearance.
Microneedles (MNs) are micron-sized, minimally invasive devices that breach the outermost layer of the skin, the stratum corneum (SC), creating transient, aqueous pores in the skin and facilitating the transport of therapeutic molecules into the epidermis. Following many years of extensive research in the area of MN-mediated trans- and intra-dermal drug delivery, MNs are now being exploited in the cosmeceutical industry as a means of disrupting skin cell architecture, inducing elastin and collagen expression and deposition. They are also being used as vehicles to deliver cosmeceutic molecules across the skin, in addition to their use in combinatorial treatments with topical agents or light sources. This review explores the chronology of microneedling methodologies, which has led to the emergence of MN devices, now extensively used in cosmeceutical applications. Recent developments in therapeutic molecule and peptide delivery to the skin via MN platforms are addressed and some commercially available MN devices are described. Important safety and regulatory considerations relating to MN usage are addressed, as are studies relating to public perception of MN, as these will undoubtedly influence the acceptance of MN products as they progress towards commercialisation.


Biological availability to the rat of intrinsic and extrinsic iron with soybean protein isolates.
Evaluations were conducted to assess the biological availability of iron in three food grade isolated soybean proteins and to evanuate the influence of these proteins on iron added to the diet from a source of known high biological availability. Ferrous sulfate was used as the standard iron source in all experiments. The biological availability was measured by a 14-day hemoglobin repletion after a 4 week depletion period using multiple dose response and comparing the test samples and standard iron source by the slope ratio assay procedure. The relative iron bioavailability for three isolated soybean proteins was A = 60%; B = 64% and C = 59% with a mean value of 61%. Autoclaving isolated soybean protein B at 108.4 degrees improved iron bioavailability over the unheated samples while isolated soybean protein A was unaffected by this treatment. Iron added to the diets containing isolated soybean protein had bioavailabilities similar to that of iron present in the soybean which supports the common dietary iron pool hypothesis. The high iron content (0.18 mg/g protein) coupled with the bioavailability data make the isolated soybean proteins a good dietary iron source.


Energy and carbon footprints of sewage treatment methods.
The paper presents energy and carbon footprints of sewage treatment plants (STPs) operating at different scales and using different technology options based on primary data from 50 STPs operating in India and the UK. The study used a combination of fundamental mass-balance approach for energy consumption and the methodology defined by IPCC for the carbon emissions. Small-scale institutional STPs consume twelve times the energy consumed by large-scale municipal STPs, the corresponding energy intensities being 4.87 kWh/m(3) and 0.40 kWh/m(3) respectively. Embodied energy from construction material and chemicals accounted for 46% and 33% of the total energy intensity of the municipal and institutional STPs respectively. The average carbon footprint of large-scale STPs is 0.78 kgCO2eq/m(3) and for small-scale STPs it is 3.04 kgCO2eq/m(3). However, fugitive emissions from large-scale STPs constituted 74% of the total carbon emissions whereas the figure was only 0.05% for small-scale STPs. Average electrical energy intensity in STPs in India is much lower (0.14 kWh/m(3)) than that in the UK (0.46 kWh/m(3)). This is due to the reason that STPs in India do not have resource recovery processes and use solar heat for sludge drying. The paper offers information and insights for designing low carbon strategies for urban waste infrastructure.


Droplet formation and growth inside a polymer network: A molecular dynamics simulation study.
We present a molecular dynamics simulation study that focuses on the formation and growth of nanoscale droplets inside polymer networks. Droplet formation and growth are investigated by the liquid-vapor phase separation of a dilute Lennard-Jones (LJ) fluid inside regularly crosslinked, polymer networks with varying mesh sizes. In a polymer network with small mesh sizes, droplet formation can be suppressed, the extent of which is dependent on the attraction strength between the LJ particles. When droplets form in a polymer network with intermediate mesh sizes, subsequent growth is significantly slower when compared with that in bulk without a polymer network. Interestingly, droplet growth beyond the initial nucleation stage occurs by different mechanisms depending on the mesh size: droplets grow mainly by diffusion and coalescence inside polymer networks with large mesh sizes (as observed in bulk), whereas Ostwald ripening becomes a more dominant mechanism for droplet growth for small mesh sizes. The analysis of droplet trajectories clearly reveals the obstruction effect of the polymer network on the movement of growing droplets, which leads to Ostwald ripening of droplets. This study suggests how polymer networks can be used to control the growth of nanoscale droplets.


Development of dopamine-beta-hydroxylase-positive fiber innervation in co-cultured hippocampus-locus coeruleus organotypic slices.
Development of the noradrenergic innervation of the rat hippocampus by the nucleus locus coeruleus was examined immunohistochemically in the roller tube organotypic cultured slice preparation. Slices of rat hippocampus and locus coeruleus were co-cultured on glass coverslips for 2-6 weeks and evaluated for the presence of dopamine-beta-hydroxylase (DBH) and tyrosine hydroxylase (TH) immunoreactive cells and fibers. Large, multipolar DBH- and TH-positive cells were visible within the locus coeruleus; an occasional cell appeared near or just within co-cultured hippocampal tissue and in connecting fiber tracts. DBH-positive cells tended to concentrate near the edges of locus coeruleus tissue. Locus coeruleus slices cultured alone showed little indication of fiber outgrowth in any direction. In co-cultures, however, beaded DBH- and TH-positive fibers were directed toward the hippocampus. The majority of these fibers entered the hippocampus in the hilar/CA3 region and formed extensive collateral branches. Light microscopy suggests that DBH-positive fiber growth was densest at or near the pyramidal cell layer in CA3b and CA3c and in the infragranular region of the dentate hilus. This pattern of noradrenergic innervation of hippocampus by co-cultured locus coeruleus in vitro appears very similar to the pattern established in vivo (see Moudy et al., companion article, this issue).


Baseline susceptibility of western corn rootworm (Coleoptera: Crysomelidae) to Cry3Bb1 Bacillus thuringiensis toxin.
Susceptibility to Cry3Bb1 toxin from Bacillus thuringiensis (Bt) was determined for western corn rootworm, Diabrotica virgifera virgifera LeConte, neonates from both laboratory and field populations collected from across the Corn Belt. Rootworm larvae were exposed to artificial diet treated with increasing Cry3Bb1 concentrations, and mortality and growth inhibition were evaluated after 4-7 d. The range of variation in Bt susceptibility indicated by growth inhibition was similar to that indicated by mortality. Although interpopulation variation in susceptibility was observed, the magnitude of the differences was comparable with the variability observed between generations of the same population. In general, the toxin was not highly toxic to larvae and estimated LC50 and EC50 values were several times higher than those reported for lepidopteran-specific Cry toxins by using similar bioassay techniques. These results suggest that the observed susceptibility differences reflect natural variation in Bt susceptibility among rootworm populations and provide a baseline for estimating potential shifts in susceptibility that might result from selection and exposure to Cry3Bb1-expressing corn hybrids.


Two-part fractures of the proximal humerus.
Between 1981 and 1991, 137 patients had 141 two-part proximal humerus fractures. One hundred thirteen surgical neck, 24 greater tuberosity, 2 anatomic neck, and 2 lesser tuberosity fractures were studied. Eleven patients had died in the interim; the remaining cases were reviewed. The mean age of patients with surgical neck fractures was 57 years (range 20 to 91 years), and 62.8% (71 cases) were women. In 38% of cases there was another significant medical problem. Eighty (70.8%) cases were treated with a sling and early isometric and pendulum exercises. Bony union was obtained in an average of 3.2 months (range 2 to 8 months), and 87.5% achieved satisfactory function. The mean age of patients with greater tuberosity fractures was 37 years (range 20 to 59 years), and 79.2% (19 cases) were men. Ten (41.7%) cases were treated with open reduction and internal fixation, and the remainder were treated without surgery. All patients improved to a satisfactory level of function. Anatomic neck fractures (two) were treated with surgery. Lesser tuberosity fractures (two) were treated conservatively and had good functional results. It appears that conservative measures when coupled with early isometric and pendulum exercises produce a satisfactory result in surgical neck fractures. Similarly, conservative treatment for nondisplaced greater tuberosity fractures and operative intervention for displaced fractures resulted in satisfactory function. Lesser tuberosity fractures without limitation of motion appear to do well with a sling and early motion.


High-efficiency gene transfer employing adenovirus-polylysine-DNA complexes.
Gene transfer may be accomplished via the receptor-mediated endocytosis pathway employing molecular conjugate vectors. These synthetic agents consist of two covalently linked functional components: a DNA-binding domain and a domain that is a ligand for a cell surface receptor. Recognition of the ligand by its appropriate cell surface receptor allows cellular internalization of the complex via receptor-mediated endocytosis. Since conjugates are limited because they lack a specific mechanism to accomplish cell vesicle escape, and since adenoviruses possess such a mechanism, we derived conjugates that incorporate adenovirus into their functional design. The adenovirus-polylysine conjugates mediated high-efficiency gene transfer. In this configuration, the viral moiety functions both as an endosomolysis agent and also as the ligand domain of the conjugate. To determine whether the adenovirus component of the conjugate could function exclusively in the former capacity, combination conjugates were constructed containing an alternative ligand in conjugation with an incorporated adenovirus. Internalization of these conjugates via the receptor for the alternative ligand in cells lacking adenovirus receptors demonstrated that the adenovirus moiety could function to enhance conjugate entry in this context. Thus, it is possible to design highly efficient molecular conjugate vectors that possess specific and distinct mechanisms to accomplish cellular internalization and cell vesicle escape.


[Intracranial hypotension syndrome].
Intracranial hypotension syndrome is an essential or, more frequently, secondary entity. This is characterized by orthostatic headaches and diffuse dural gadolinium enhancement on magnetic resonance imaging with or without subdural fluid collections or evidence of descent of the brain. What determines the various clinical and imaging features of intracranial hypotension syndrome is the cerebrospinal fluid volume depletion. In this article, we review the clinical and neuroimaging findings, pathophysiology, and treatment of this syndrome.


Quantitative confocal Raman microscopy study of ion-interaction retention at reversed-phase chromatographic interfaces.
Ion-interaction chromatography utilizes the addition of amphiphilic (surfactant) molecules to the mobile-phase solution in order to bring about the retention and separation of hydrophilic ionic analytes on reversed-phase liquid chromatographic stationary phases. The mechanism by which retention and separation in ion-interaction chromatography is accomplished remains unclear, although two primary mechanisms of this phenomenon have been proposed: preadsorption of the hydrophobic counterions to the hydrophobic stationary phase followed by interaction with the ionic analyte or adsorption of ion-paired species to the hydrophobic surface. There is evidence that both mechanisms contribute to ionic retention and separations. In this work, ion interactions at a C(18) stationary-phase interface are investigated by confocal Raman microscopy of individual stationary-phase particles, which is capable of quantifying surface concentrations of surfactants and model solutes. Raman spectra taken within the interior of the particle indicate that preadsorption of the hydrophobic surfactant cetylpyridinium to the stationary-phase interface is sensitive to ionic strength and concentration of organic modifier in the mobile phase. It was also determined that the presence of low concentrations of a model, ionic solute, nitrobenzenesulfonate, leads to greater adsorption of cetylpyridinium ion at the hydrophobic interface. As the concentration of nitrobenzenesulfonate is increased, the 1:1 increase in the cetylpyridinium ion interfacial concentration provides evidence of ion pairs forming at the stationary-phase surface.


3- and 4-phosphorylated phosphatidylinositols in the aquatic plant Spirodela polyrhiza L.
Labelling of Spirodela polyrhiza L. plants with [3H]inositol and [32P]Pi yielded a series of phosphoinositides which were identified as PtdIns, PtdIns4P and PtdIns(4,5)P2. In addition, systematic degradation of a phospholipid extract identified PtdIns3P. Analysis of the distribution of 32P label between the monoester and diester phosphate groups of PtdIns3P and PtdIns4P revealed differences in the labelling of the monoester phosphate, suggesting that the two PtdInsP species are not synthesized or metabolized in a co-ordinate manner.


Microbial community composition and ultrastructure of granules from a full-scale anammox reactor.
Granules in anammox reactors contain besides anammox bacteria other microbial communities whose identity and relationship with the anammox bacteria are not well understood. High calcium concentrations are often supplied to anammox reactors to obtain sufficient bacterial aggregation and biomass retention. The aim of this study was to provide the first characterization of bacterial and archaeal communities in anammox granules from a full-scale anammox reactor and to explore on the possible role of calcium in such aggregates. High magnification imaging using backscattered electrons revealed that anammox bacteria may be embedded in calcium phosphate precipitates. Pyrosequencing of 16S rRNA gene fragments showed, besides anammox bacteria (Brocadiacea, 32%), substantial numbers of heterotrophic bacteria Ignavibacteriacea (18%) and Anaerolinea (7%) along with heterotrophic denitrifiers Rhodocyclacea (9%), Comamonadacea (3%), and Shewanellacea (3%) in the granules. It is hypothesized that these bacteria may form a network in which heterotrophic denitrifiers cooperate to achieve a well-functioning denitrification system as they can utilize the nitrate intrinsically produced by the anammox reaction. This network may provide a niche for the proliferation of archaea. Hydrogenotrophic methananogens, which scavenge the key fermentation product H2, were the most abundant archaea detected. Cells resembling the polygon-shaped denitrifying methanotroph Candidatus Methylomirabilis oxyfera were observed by electron microscopy. It is hypothesized that the anammox process in a full-scale reactor triggers various reactions overall leading to efficient denitrification and a sink of carbon as biomass in anammox granules.


CONSTRUCTION AND APPLICATIONS OF A MYCORRHIZAL ARBUSCULAR SPECIFIC cDNA LIBRARY.
To exploit the potential benefits of mycorrhizas, we need to investigate the processes that occur in these symbiotic interactions, particularly in the arbuscular compartment where nutrients are exchanged between the plant and the fungus. Progress in this area is restricted due to the intricacy and complexity of this plant-fungus interface and many techniques that have been employed successfully in other plants and animal systems cannot be used. An effective approach to study processes in arbuscules is to examine transcript composition and dynamics. We applied laser capture microdissection (LCM) to isolate approximately 3000 arbuscules from Glomus intraradices colonised Me- dicago truncatula roots. Total RNA was extracted from microdissected arbuscules and subjected to T7 RNA polymerase-based linear amplification. Amplified RNA was then usedfor construction of a cDNA library. The presence and level of enrichment of mycorrhiza-specific transcripts was determined by quantitative Real-time and conventional PCR. To improve enrichment a cDNA library subtraction was performed. Complementation of yeast mutants deficient in the uptake of.potassium, phosphate, sulphate, amino acids, ammonium and of a Mn²⁺sensitive strain, demonstrates the functionality of our cDNA library.


Factors Associated With Benefit of Treatment of Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-Analysis.
Context: There is an ongoing debate on the optimal management of patent ductus arteriosus (PDA) in preterm infants. Identifying subgroup of infants who would benefit from pharmacological treatment might help. Objective: To investigate the modulating effect of the differences in methodological quality, the rate of open-label treatment, and patient characteristics on relevant outcome measures in randomized controlled trials (RCTs). Data Sources: Electronic database search between 1950 and May 2020. Study Selection: RCTs that assessed pharmacological treatment compared to placebo/no treatment. Data Extraction: Data is extracted following the PRISMA guidelines. Outcome measures were failure to ductal closure, surgical ligation, incidence of necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, periventricular leukomalacia, intraventricular hemorrhage (IVH) grade ≥3, retinopathy of prematurity and mortality. Results: Forty-seven studies were eligible. The incidence of IVH grade ≥3 was lower in the treated infants compared to the placebo/no treatment (RR 0.77, 95% CI 0.64-0.94) and in the subgroups of infants with either a gestational age <28 weeks (RR 0.77, 95% CI 0.61-0.98), a birth weight <1,000 g (RR 0.77, 95% CI 0.61-0.97), or if untargeted treatment with indomethacin was started <24 h after birth (RR 0.70, 95% CI 0.54-0.90). Limitations: Statistical heterogeneity caused by missing data and variable definitions of outcome parameters. Conclusions: Although the quality of evidence is low, this meta-analysis suggests that pharmacological treatment of PDA reduces severe IVH in extremely preterm, extremely low birth weight infants or if treatment with indomethacin was started <24 h after birth. No other beneficial effects of pharmacological treatment were found.


Do depressive symptoms influence cognitive-motor coupling in multiple sclerosis?
There is evidence that motor and cognitive impairments often co-occur in multiple sclerosis (MS). There is little research on influences of cognitive-motor coupling, particularly depressive symptoms. This study examined depressive symptoms as a moderator and/or confounder of cognitive-motor coupling in persons with MS. The sample included 131 persons with MS who were allocated into elevated and nonelevated depressive symptom groups based on a cutoff score of 8 on the Hospital Anxiety Depression Scale. We assessed lower (i.e., 6-Minute Walk Test, Timed 25-Foot Walk Test) and upper (i.e., Nine-Hole Peg Test) body function as well as cognition (i.e., the Symbol Digit Modalities Test, CA Verbal Learning Test, and Brief Visuospatial Memory Test) in a research laboratory. Depressive symptomology was investigated as a moderator and/or confounder of cognitive-motor coupling using correlation and linear regression analyses. Upper and lower body function, but not cognition, differed significantly between depressive symptoms groups (p < .05). Scores on the motor and cognitive tests were uniformly correlated between depressive symptom groups. Depressive symptom category did not confound the coupling between motor and cognitive functions, and explained additional, but minimal, variation in the lower body motor function scores (p < .05). Strong coupling between motor function and cognitive processing speed in MS appeared to be consistent between depressive symptom groups. Elevated depressive symptoms might influence motor functioning more strongly than cognitive functioning in MS. (PsycINFO Database Record


Poverty, Material Hardship and Depression.
Mental health disorders are of great social, economic, and policy concern. A higher incidence of major depressive disorder has been reported among those living in or near poverty. Our study examines the extent to which the relationship between income and depression is mediated by measures of material hardship. We use measures of depression at two points in time from the longitudinal Fragile Families Survey to better discern the causal direction of the relationship between income poverty, hardship, and depression. More specifically, we use conditional logistic fixed-effect models that control for time-invariant unmeasured heterogeneity in the sample. We found a strong relationship between hardships and depression. The most prominent hardships were problems paying bills and phone turned off. We also found that hardship helped mediate much, though not all, of the link between poverty and depression in the conditional fixed effect logistic regression models. Our policy simulations suggest that public health efforts to reduce depression may be enhanced from efforts that focus on specific forms of material hardship.


Inhibition of cancer cell proliferation by 5-fluoro-2'-deoxycytidine, a DNA methylation inhibitor, through activation of DNA damage response pathway.
Multiple epigenetic changes, including alterations in DNA methylation occur during tumorigenesis. Various inhibitors of DNA methylation have been developed to prevent proliferation of cancer cells. 5-fluoro-2(')-deoxycytidine (FCdR) is one such DNA methylation inhibitor, which is currently in phase II clinical trial. To investigate the molecular mechanism/s by which FCdR might mediate repression of tumor cell proliferation, we analyzed the toxicity of FCdR in various cell lines established from different sarcomas. We found HCT116, a colon cancer cell line, is much more sensitive to FCdR compared to others. FCdR treatment inhibited HCT116 cells at G2/M check point and up-regulated expression of multiple cancer-related genes, which could be due to its inhibitory activity towards DNA methylation. Furthermore, we found that FCdR activates DNA damage response pathway. Using an inhibitor for ATM and ATR kinases activity, which are required for amplifying the DNA damage repair signal, we show that FCdR induced inhibition of HCT116 cells at G2/M is mediated through activation of DNA damage response pathway. The online version of this article (doi:10.1186/2193-1801-1-65) contains supplementary material, which is available to authorized users.


Quality-of-Life Priorities in Patients with Thyroid Cancer: A Multinational European Organisation for Research and Treatment of Cancer Phase I Study.
The objectives of this study were to determine quality of life (QoL) issues that are relevant to thyroid cancer patients cross-culturally, and to identify those with highest relevance to them in addition to the more general issues covered by the core European Organisation for Research and Treatment of Cancer QoL questionnaire (EORTC QLQ-C30). A systematic literature search provided a list of potentially relevant QoL issues to supplement the core questionnaire EORTC QLQ-C30, which is widely used in research and in care and addresses QoL issues relevant to all groups of cancer patients. A panel of experts revised this list, and thyroid cancer patients rated the issues regarding their relevance for QoL by selecting the 25 issues that they would include in a thyroid cancer-specific QoL module. The literature search and expert discussion provided a list of 71 QoL issues that was rated by thyroid cancer patients (n = 110) from seven countries. All issues were of high priority to at least some of the patients. The most frequently selected issues were sudden attacks of tiredness, exhaustion, quality of sleep, employment, social support, fear of cancer progression, fear of second operation, difficulties swallowing, and globus sensation. Thyroid cancer patients cross-culturally rate fatigue-related issues as highly important for their QoL, calling for increased efforts to find successful treatments for this problem. Vocational rehabilitation is also highly relevant for them and should therefore be an important aim of multidisciplinary care. The third important area of concern is psychological issues, especially fear of progression and of additional treatments.


Sex Differences in Cardiovascular Pathophysiology: Why Women Are Overrepresented in Heart Failure With Preserved Ejection Fraction.
Consistent epidemiological data demonstrate that patients with heart failure with preserved ejection fraction (HFpEF) are more likely to be women than men. Exploring mechanisms behind this sex difference in heart failure epidemiology may enrich the understanding of underlying HFpEF pathophysiology and phenotypes, with the ultimate goal of identifying therapeutic approaches for the broader HFpEF population. In this review we evaluate the influence of sex on the key domains of cardiac structure and function, the systemic and pulmonary circulation, as well as extracardiac factors and comorbidities that may explain the predisposition of women to HFpEF. We highlight the potential role of factors exclusive to or more prevalent in women such as pregnancy, preeclampsia, and iron deficiency. Finally, we discuss existing controversies and gaps in knowledge, as well as the clinical importance of known sex differences in the context of the potential need for sex-specific diagnostic criteria, improved risk stratification models, and targeted therapies.


A self-organized 2-dimensional bifunctional structure formed by supramolecular design.
The production of a novel two-dimensional bimolecular surface structure using weak noncovalent interactions is demonstrated and observed by scanning tunneling microscopy. This work follows the three-dimensional (3D) ideas of crystal engineering and applies the concepts of supramolecular synthons to molecular systems constrained to 2D by physisorption on a conducting surface. We demonstrate a well-ordered planar structure that self-assembles through the influence of fluorine-phenyl interactions. This study provides a concrete example of the "bottom up" construction of nanostructures and of the systematic design of self-organized layers. To our knowledge, this is the first in a new class of fully 2D materials based both upon weak intermolecular interactions and upon image charges and weak interactions associated with adsorption on metal surfaces.


Salmonella enterica BcfH Is a Trimeric Thioredoxin-Like Bifunctional Enzyme with Both Thiol Oxidase and Disulfide Isomerase Activities.
Aims: Thioredoxin (TRX)-fold proteins are ubiquitous in nature. This redox scaffold has evolved to enable a variety of functions, including redox regulation, protein folding, and oxidative stress defense. In bacteria, the TRX-like disulfide bond (Dsb) family mediates the oxidative folding of multiple proteins required for fitness and pathogenic potential. Conventionally, Dsb proteins have specific redox functions with monomeric and dimeric Dsbs exclusively catalyzing thiol oxidation and disulfide isomerization, respectively. This contrasts with the eukaryotic disulfide forming machinery where the modular TRX protein disulfide isomerase (PDI) mediates thiol oxidation and disulfide reshuffling. In this study, we identified and structurally and biochemically characterized a novel Dsb-like protein from Salmonella enterica termed bovine colonization factor protein H (BcfH) and defined its role in virulence. Results: In the conserved bovine colonization factor (bcf) fimbrial operon, the Dsb-like enzyme BcfH forms a trimeric structure, exceptionally uncommon among the large and evolutionary conserved TRX superfamily. This protein also displays very unusual catalytic redox centers, including an unwound α-helix holding the redox active site and a trans-proline instead of the conserved cis-proline active site loop. Remarkably, BcfH displays both thiol oxidase and disulfide isomerase activities contributing to Salmonella fimbrial biogenesis. Innovation and Conclusion: Typically, oligomerization of bacterial Dsb proteins modulates their redox function, with monomeric and dimeric Dsbs mediating thiol oxidation and disulfide isomerization, respectively. This study demonstrates a further structural and functional malleability in the TRX-fold protein family. BcfH trimeric architecture and unconventional catalytic sites permit multiple redox functions emulating in bacteria the eukaryotic PDI dual oxidoreductase activity. Antioxid. Redox Signal. 35, 21-39.


SOMEViz: a web service for site of metabolism estimating and visualizing.
Phase I metabolism is an important consideration in drug discovery because it profoundly affects the toxicity and activity profile of a drug candidate. In these metabolic processes, CYP450 family is responsible for the majority of biotransformation events. However, it is still an important challenge to predict sites of metabolism (SOM) of a new chemical entity due to the complex reaction mechanism and variety in CYP450 enzymes. SOMEViz is an online service designed for predicting and visualizing human cytochromes P450 (CYP450)-mediated sites of metabolism (SOM) of a molecule, on the basis of a previously reported model. The service provides an access for predicting sites of metabolism of molecules with reasonable accuracy, and predicted results are shown in a user-friendly as well as interactive way, which may help chemists explore metabolism properties of chemicals in the early stage of drug discovery. The web-based GUI of SOMEViz offers user a straightforward way to manage and visualize the sites of metabolism (SOM) prediction results. The service and examples are available free of charge at http://www.dddc.ac.cn/some.


Functional neural correlates of facial affect recognition impairment following TBI.
Facial affect recognition deficits following traumatic brain injury (TBI) have been well documented, as has their relationship with impairment in several other cognitive domains. However, little is known about the neurobiological mechanisms underlying affect recognition deficits, in particular mechanisms underlying different aspects of facial affect recognition (e.g., perceptual and interpretive processes). In the current study, 33 adults with moderate-to-severe TBI and 24 demographically matched healthy comparison (HC) participants completed an fMRI facial affect recognition study. While in the scanner, participants were asked to match the affect of a target face to either (a) one of two faces differing in affect (perceptual condition) or (b) one of two written affect labels (interpretative condition). In both groups we found activations in regions typically involved in affect recognition. Our results revealed that in the perceptual condition individuals with TBI tended to activate the left dorsolateral prefrontal cortex less than HCs, and within the HC group individuals with higher perceptual affect recognition scores showed higher levels of activation in the same brain region. Individuals with TBI who were specifically impaired at interpretative affect recognition showed less activation than HCs in the right fusiform gyrus. Moreover, in the labeling condition individuals with TBI tended to de-activate medial prefrontal regions less than HCs. A region of interest analysis revealed that individuals with TBI showed significantly less activation than HCs in the FFA for all the contrasts of interest. Our results suggest involvement of several brain regions in facial affect recognition impairment post TBI, and provide neurobiological support for the notion that distinct aspects of facial affect recognition can be differentially impaired following TBI.


The source scaling and seismic productivity of slow slip transients.
Slow slip events (SSEs) represent a slow faulting process leading to aseismic strain release often accompanied by seismic tremor or earthquake swarms. The larger SSEs last longer and are often associated with intense and energetic tremor activity, suggesting that aseismic slip controls tremor genesis. A similar pattern has been observed for SSEs that trigger earthquake swarms, although no comparative studies exist on the source parameters of SSEs and tremor or earthquake swarms. We analyze the source scaling of SSEs and associated tremor- or swarm-like seismicity through our newly compiled dataset. We find a correlation between the aseismic and seismic moment release indicating that the shallower SSEs produce larger seismic moment release than deeper SSEs. The scaling may arise from the heterogeneous frictional and rheological properties of faults prone to SSEs and is mainly controlled by temperature. Our results indicate that similar physical phenomena govern tremor and earthquake swarms during SSEs.


Visible-Light-Driven, Iridium-Catalyzed Hydrogen Atom Transfer: Mechanistic Studies, Identification of Intermediates, and Catalyst Improvements.
The harvesting of visible light is a powerful strategy for the synthesis of weak chemical bonds involving hydrogen that are below the thermodynamic threshold for spontaneous H2 evolution. Piano-stool iridium hydride complexes are effective for the blue-light-driven hydrogenation of organic substrates and contra-thermodynamic dearomative isomerization. In this work, a combination of spectroscopic measurements, isotopic labeling, structure-reactivity relationships, and computational studies has been used to explore the mechanism of these stoichiometric and catalytic reactions. Photophysical measurements on the iridium hydride catalysts demonstrated the generation of long-lived excited states with principally metal-to-ligand charge transfer (MLCT) character. Transient absorption spectroscopic studies with a representative substrate, anthracene revealed a diffusion-controlled dynamic quenching of the MLCT state. The triplet state of anthracene was detected immediately after the quenching events, suggesting that triplet-triplet energy transfer initiated the photocatalytic process. The key role of triplet anthracene on the post-energy transfer step was further demonstrated by employing photocatalytic hydrogenation with a triplet photosensitizer and a HAT agent, hydroquinone. DFT calculations support a concerted hydrogen atom transfer mechanism in lieu of stepwise electron/proton or proton/electron transfer pathways. Kinetic monitoring of the deactivation channel established an inverse kinetic isotope effect, supporting reversible C(sp2)-H reductive coupling followed by rate-limiting ligand dissociation. Mechanistic insights enabled design of a piano-stool iridium hydride catalyst with a rationally modified supporting ligand that exhibited improved photostability under blue light irradiation. The complex also provided improved catalytic performance toward photoinduced hydrogenation with H2 and contra-thermodynamic isomerization.


Environmental sustainability comparison of a hypothetical pneumatic waste collection system and a door-to-door system.
Waste collection is one of the life cycle phases that influence the environmental sustainability of waste management. Pneumatic waste collection systems represent a new way of arranging waste collection in densely populated urban areas. However, limited information is available on the environmental impacts of this system. In this study, we compare the environmental sustainability of conventional door-to-door waste collection with its hypothetical pneumatic alternative. Furthermore, we analyse whether the size of the hypothetical pneumatic system, or the number of waste fractions included, have an impact on the results. Environmental loads are calculated for a hypothetical pneumatic waste collection system modelled on an existing dense urban area in Helsinki, Finland, and the results are compared to those of the prevailing, container-based, door-to-door waste collection system. The evaluation method used is the life-cycle inventory (LCI). In this study, we report the atmospheric emissions of greenhouse gases (GHG), SO(2) and NO(x). The results indicate that replacing the prevailing system with stationary pneumatic waste collection in an existing urban infrastructure would increase total air emissions. Locally, in the waste collection area, emissions would nonetheless diminish, as collection traffic decreases. While the electricity consumption of the hypothetical pneumatic system and the origin of electricity have a significant bearing on the results, emissions due to manufacturing the system's components prove decisive.


Reprogramming of carbon metabolism by the transcriptional activators AcuK and AcuM in Aspergillus nidulans.
The ability of fungi to use carbon sources metabolized via the TCA cycle requires gluconeogenesis. In Aspergillus nidulans the AcuK and AcuM transcription factors regulate the expression of the gluconeogenic genes acuF, encoding phosphoenolpyruvate carboxykinase, and acuG, encoding fructose-1,6-bisphosphatase. Expressed proteins containing the AcuK/AcuM N-terminal DNA-binding domains bind together in vitro to motifs containing repeats of CGG separated by seven bases (CCGN7CCG) and the functionality of these sequences was verified in vivo by acuF-lacZ reporter studies. Chromatin immunoprecipitation analysis showed inter-dependent DNA binding of the proteins to the promoters of gluconeogenic genes in vivo independent of the carbon source. Deletion of the mdhC gene encoding a cytoplasmic/peroxisomal malate dehydrogenase showed that this activity is not essential for gluconeogenesis and indicated that induction of AcuK/AcuM regulated genes might result from malate accumulation. Deletion of the gene for the alternative oxidase did not affect growth on gluconeogenic carbon sources; however, expression was absolutely dependent on AcuK and AcuM. Orthologues of AcuK and AcuM, are present in a wide range of fungal taxa and the CCGN7CCG motif is present in the 5' of many genes involved in gluconeogenesis indicating a fundamental role for these transcription factors in reprogramming fungal carbon metabolism.


Visual Hallucinations Are Characterized by Impaired Sensory Evidence Accumulation: Insights From Hierarchical Drift Diffusion Modeling in Parkinson's Disease.
Models of hallucinations emphasize imbalance between sensory input and top-down influences over perception, as false perceptual inference can arise when top-down predictions are afforded too much precision (certainty) relative to sensory evidence. Visual hallucinations in Parkinson's disease (PD) are associated with lower-level visual and attentional impairments, accompanied by overactivity in higher-order association brain networks. PD therefore provides an attractive framework to explore contributions of bottom-up versus top-down disturbances in hallucinations. We characterized sensory processing during perceptual decision making in patients with PD with (n = 20) and without (n = 25) visual hallucinations and control subjects (n = 12), by fitting a hierarchical drift diffusion model to an attentional task. The hierarchical drift diffusion model uses Bayesian estimates to decompose task performance into parameters reflecting drift rates of evidence accumulation, decision thresholds, and nondecision time. We observed slower drift rates in patients with hallucinations, which were less sensitive to changes in task demand. In contrast, wider decision boundaries and shorter nondecision times relative to control subjects were found in patients with PD regardless of hallucinator status. Inefficient and less flexible sensory evidence accumulation emerges as a unique feature of PD hallucinators. We integrate these results with evidence accumulation and predictive coding models of hallucinations, suggesting that in PD sensory evidence is less informative and may therefore be down-weighted, resulting in overreliance on top-down influences. Considering impaired drift rates as an approximation of reduced sensory precision, our findings provide a novel computational framework to specify impairments in sensory processing that contribute to development of visual hallucinations.


The More You Have, The More You Lose: Criminal Justice Involvement, Ascribed Socioeconomic Status, and Achieved SES.
In the present study, we examine the relationship between involvement in the criminal justice system and achieved socioeconomic status (SES), as well as the moderating effect of ascribed SES. Using data from the National Longitudinal Study of Adolescent to Adult Health, we find a nonlinear relationship between criminal justice involvement and achieved SES, such that deeper involvement leads to increasingly negative consequences on achieved SES. Furthermore, those coming from the highest socioeconomic backgrounds are not "protected" from the deleterious consequences of system involvement, but instead experience the greatest declines in achieved SES relative to where they started. In contrast, the effect of criminal justice involvement for those from below average ascribed SES is not significant. Our findings reinforce how normal such experiences are for people with the fewest resources, and also how system involvement inevitably destroys human capital, undermines future life chances, and ultimately promotes a "rabble" class.


The volume effect in paediatric oncology: a systematic review.
For several adult cancer types, there is evidence that treatment in high volume hospitals, high case volume providers, or in specialised hospitals leads to a better outcome. The aim of this study is to give an overview of the existing evidence regarding the volume effect in paediatric oncology related to the quality of care or survival. An extensive search was carried out for studies on the effect of provider case volume on the quality of care or survival in childhood cancer. Information about study characteristics, comparisons, results, and quality assessment were abstracted. In total, 14 studies were included in this systematic review. Studies with a low risk of bias provide evidence that treatment of children with brain tumours, acute lymphoblastic leukaemia, osteosarcoma, Ewing's sarcoma, or children receiving treatment with allogenic bone marrow transplantation in higher volume hospitals, specialised hospitals, or by high case volume providers, is related with a better outcome. This systematic review provides support for the statement that higher volume hospitals, higher case volume providers, and specialised hospitals are related to the better outcome in paediatric oncology. No studies reported a negative effect of a higher volume.


Phonetic convergence in spontaneous conversations as a function of interlocutor language distance.
This study explores phonetic convergence during conversations between pairs of talkers with varying language distance. Specifically, we examined conversations within two native English talkers and within two native Korean talkers who had either the same or different regional dialects, and between native and nonnative talkers of English. To measure phonetic convergence, an independent group of listeners judged the similarity of utterance samples from each talker through an XAB perception test, in which X was a sample of one talker's speech and A and B were samples from the other talker at either early or late portions of the conversation. The results showed greater convergence for same-dialect pairs than for either the different-dialect pairs or the different-L1 pairs. These results generally support the hypothesis that there is a relationship between phonetic convergence and interlocutor language distance. We interpret this pattern as suggesting that phonetic convergence between talker pairs that vary in the degree of their initial language alignment may be dynamically mediated by two parallel mechanisms: the need for intelligibility and the extra demands of nonnative speech production and perception.


Distinct transport vesicles mediate the delivery of plasma membrane proteins to the apical and basolateral domains of MDCK cells.
Immunoisolation techniques have led to the purification of apical and basolateral transport vesicles that mediate the delivery of proteins from the trans-Golgi network to the two plasma membrane domains of MDCK cells. We showed previously that these transport vesicles can be formed and released in the presence of ATP from mechanically perforated cells (Bennett, M. K., A. Wandinger-Ness, and K. Simons, 1988. EMBO (Euro. Mol. Biol. Organ.) J. 7:4075-4085). Using virally infected cells, we have monitored the purification of the trans-Golgi derived vesicles by following influenza hemagglutinin or vesicular stomatitis virus (VSV) G protein as apical and basolateral markers, respectively. Equilibrium density gradient centrifugation revealed that hemagglutinin containing vesicles had a slightly lower density than those containing VSV-G protein, indicating that the two fractions were distinct. Antibodies directed against the cytoplasmically exposed domains of the viral spike glycoproteins permitted the resolution of apical and basolateral vesicle fractions. The immunoisolated vesicles contained a subset of the proteins present in the starting fraction. Many of the proteins were sialylated as expected for proteins existing the trans-Golgi network. The two populations of vesicles contained a number of proteins in common, as well as components which were enriched up to 38-fold in one fraction relative to the other. Among the unique components, a number of transmembrane proteins could be identified using Triton X-114 phase partitioning. This work provides evidence that two distinct classes of vesicles are responsible for apical and basolateral protein delivery. Common protein components are suggested to be involved in vesicle budding and fusion steps, while unique components may be required for specific recognition events such as those involved in protein sorting and vesicle targeting.


Shifts in Mutation Bias Promote Mutators by Altering the Distribution of Fitness Effects.
AbstractRecent experimental evidence demonstrates that shifts in mutational biases-for example, increases in transversion frequency-can change the distribution of fitness effects of mutations (DFE). In particular, reducing or reversing a prevailing bias can increase the probability that a de novo mutation is beneficial. It has also been shown that mutator bacteria are more likely to emerge if the beneficial mutations they generate have a larger effect size than observed in the wild type. Here, we connect these two results, demonstrating that mutator strains that reduce or reverse a prevailing bias have a positively shifted DFE, which in turn can dramatically increase their emergence probability. Since changes in mutation rate and bias are often coupled through the gain and loss of DNA repair enzymes, our results predict that the invasion of mutator strains will be facilitated by shifts in mutation bias that offer improved access to previously undersampled beneficial mutations.


Role of the PDZ domain-binding motif of the oncoprotein E6 in the pathogenesis of human papillomavirus type 31.
A number of PDZ domain-containing proteins have been identified as binding partners for the oncoprotein E6 of the high-risk type human papillomaviruses (HPVs). These include hDlg, hScrib, MAGI-1, MAGI-2, MAGI-3, and MUPP1. The PDZ domain-binding motif (-X-T-X-V) at the carboxy terminus of E6 is essential for targeting PDZ proteins for proteasomal degradation. The presence of this motif only in the high-risk HPVs suggests its possible role in HPV-induced oncogenesis. To investigate the role of the PDZ domain-binding motif of E6 in the HPV life cycle, two mutant HPV31 genomes were constructed: E6ValDelta, with a deletion of the last amino acid residue of E6 (valine), and E6ETQVDelta, with a deletion of the entire PDZ domain-binding motif of E6 (ETQV). Three human foreskin keratinocyte (HFK) cell lines were established which maintained transfected wild-type HPV31 or either of two mutant genomes. Cells containing either of two mutant genomes were significantly retarded in their growth rates and reduced in their viral copy numbers compared to those transfected with wild-type genomes. Western analysis did not reveal any significant changes in the levels of PDZ proteins following stable transfection of any HPV31 genomes into HFKs. Although the E6ETQVDelta-transfected HFKs exhibited a pattern of morphological differentiation that appeared different from the HPV31 wild-type-transfected HFKs in organotypic raft cultures, immunohistochemical analysis failed to identify substantial changes in the differentiation-dependent membrane localization of hDlg proteins. These results suggest that binding of E6 to PDZ proteins modulates the early viral functions such as proliferation and maintenance of the viral copy number in undifferentiated cells.


Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting.
Lymphatic vessel growth, or lymphangiogenesis, is regulated by vascular endothelial growth factor-C (VEGF-C) and -D via VEGF receptor 3 (VEGFR-3). Recent studies suggest that VEGF, which does not bind to VEGFR-3, can also induce lymphangiogenesis through unknown mechanisms. To dissect the receptor pathway that triggers VEGFR-3-independent lymphangiogenesis, we used both transgenic and adenoviral overexpression of placenta growth factor (PlGF) and VEGF-E, which are specific activators of VEGFR-1 and -2, respectively. Unlike PlGF, VEGF-E induced circumferential lymphatic vessel hyperplasia, but essentially no new vessel sprouting, when transduced into mouse skin via adenoviral vectors. This effect was not inhibited by blocking VEGF-C and -D. Postnatal lymphatic hyperplasia, without increased density of lymphatic vessels, was also detected in transgenic mice expressing VEGF-E in the skin, but not in mice expressing PlGF. Surprisingly, VEGF-E induced lymphatic hyperplasia postnatally, and it did not rescue the loss of lymphatic vessels in transgenic embryos where VEGF-C and VEGF-D were blocked. Our data suggests that VEGFR-2 signals promote lymphatic vessel enlargement, but unlike in the blood vessels, are not involved in vessel sprouting to generate new lymphatic vessels in vivo.


Pharmacological assessment of the antithrombotic activity of the peptide thrombin inhibitor, D-methyl-phenylalanyl-prolyl-arginal (GYKI-14766), in a canine model of coronary artery thrombosis.
The antithrombotic activity of the tripeptide thrombin inhibitor, D-methyl-phenylalanyl-prolyl-arginal (GYKI-14766), was compared to heparin in a model of canine coronary artery thrombosis. Thrombogenesis was initiated by electrolytic injury of the intimal surface of the left circumflex coronary artery. Drug administration was started 15 min before initiation of intimal injury. Clotting times and ex vivo platelet aggregation were determined on citrated blood samples. Gingival template bleeding times were determined. Clotting times (thrombin time; activated partial thromboplastin time, APTT; prothrombin time, PT) increased in a dose-dependent manner with both anticoagulants. The two anticoagulants selectively inhibited thrombin-induced platelet aggregation. GYKI-14766 and heparin were found to delay thrombosis significantly when compared to vehicle-treated animals; minimum effective antithrombotic doses were 0.25 mg/kg/h and 80 U/kg + 30 U/kg/h, respectively. GYKI-14766 (0.25 mg/kg/h) had no effect on template bleeding time, APTT or PT. Heparin (80 U/kg + 30 U/kg/h), however, was associated with a 2.5- to 3.0-min increase in template bleeding time, a 1.8-fold and 1.7-fold increase in APTT and PT, respectively. Antithrombotic efficacy was achieved at doses of GYKI-14766 that did not affect APTT, PT or template bleeding time, whereas antithrombotic efficacy observed with heparin was associated with significant increases in APTT, PT and template bleeding time. These data demonstrate that the tripeptide thrombin inhibitor, GYKI-14766, could potentially prove to be a safer and more effective antithrombotic agent than heparin.


[Caustic injury of upper gastrointestinal tract: 20 year experience at a tertiary referral center].
Caustic ingestion can cause severe injury to upper gastrointestinal tract. There were few studies about clinical characteristics and treatments of caustic injury in Korea. We investigated the changes in clinical features of caustic injury over the past 20 years including pattern of endoscopic mucosal injury and treatment modality. This study was a retrospective review of medical records from patients with caustic injury from September 1993 through December 2012. Patients were classified into two groups based on the year when caustic ingestion occurred: patients who visited the hospital from 1993 to 2002 (early group) and patients who visited the hospital from 2003 to 2012 (late group). A total 140 patients were included (early group [n=50] vs. late group [n=90]). Annual number of caustic ingestions did not show decreasing tendency over the past 20 years. Alkali ingestion increased (20.0% vs. 65.6%, p<0.001) and cases with more than grade 2b of esophageal mucosal injury decreased (41.3% vs. 20.7%, p=0.012) in late group. There were no differences between two groups in sex, age, proportion of accidental ingestion, and systemic/gastrointestinal complications. Use of gastric lavage (p<0.01) and broad spectrum antibiotics (p=0.03) decreased in late group. However, there was no difference in use of steroid between two groups. In this study, overall caustic ingestion did not decrease and ingestion of alkali agents increased over the past 20 years. Tighter legislation on caustic agents is required and we need to be alert to the best management of caustic injury.


In situ growth of Fe2WO6 on WO3 nanosheets to fabricate heterojunction arrays for boosting solar water splitting.
We demonstrate the construction of heterojunction arrays for boosting solar water splitting by combining in situ guided growth of heterointerfaces and energy band tuning. By directly growing an ultrathin Fe2WO6 layer on a preformed WO3 nanosheet array in full coverage, a uniform and dense array of intimately contacted WO3/Fe2WO6 heterojunction was created. The heterojunction array shows not only a largely broadened visible light absorption range but also a built-in interface polarization to accelerate hole transfer from WO3 to Fe2WO6. Meanwhile, fine-tuning to match energy levels at the heterojunction was achieved by doping WO3 with Fe (Fe-WO3), leading to improved electrical conductivity and reduced charge recombination. Photoanodes based on such heterojunction arrays have shown significantly enhanced photoelectrochemical (PEC) water splitting performance, clearly arising from the above-mentioned efforts. Furthermore, by decorating FeOOH/NiOOH cocatalysts on the heterojunction arrays in tandem, the surface water oxidation kinetics was considerably accelerated, and the resulting Fe-WO3/Fe2WO6/FeOOH/NiOOH photoanode achieved a photocurrent density of 2.78 mA/cm2 at 1.23 V vs reversible hydrogen electrode. This work highlights the benefits of in situ construction of heterojunction arrays for enhancing the PEC performance.


Combining monoenergetic extrapolations from dual-energy CT with iterative reconstructions: reduction of coil and clip artifacts from intracranial aneurysm therapy.
To compare and to combine iterative metal artifact reduction (MAR) and virtual monoenergetic extrapolations (VMEs) from dual-energy computed tomography (DECT) for reducing metal artifacts from intracranial clips and coils. Fourteen clips and six coils were scanned in a phantom model with DECT at 100 and 150SnkVp. Four datasets were reconstructed: non-corrected images (filtered-back projection), iterative MAR, VME from DECT at 120 keV, and combined iterative MAR + VME images. Artifact severity scores and visibility of simulated, contrast-filled, adjacent vessels were assessed qualitatively and quantitatively by two independent, blinded readers. Iterative MAR, VME, and combined iterative MAR + VME resulted in a significant reduction of qualitative (p < 0.001) and quantitative clip artifacts (p < 0.005) and improved the visibility of adjacent vessels (p < 0.05) compared to non-corrected images, with lowest artifact scores found in combined iterative MAR + VME images. Titanium clips demonstrated less artifacts than Phynox clips (p < 0.05), and artifact scores increased with clip size. Coil artifacts increased with coil size but were reducible when applying iterative MAR + VME compared to non-corrected images. However, no technique improved the severe artifacts from large, densely packed coils. Combining iterative MAR with VME allows for an improved metal artifact reduction from clips and smaller, loosely packed coils. Limited value was found for large and densely packed coils.


Characterisation of hypertensive heart disease: pathological insights from a sudden cardiac death cohort to inform clinical practice.
Hypertensive heart disease refers to changes in the myocardium that result from hypertension. The relationship between hypertensive heart disease and sudden cardiac death is well established, but there are few pathological studies. We examined the clinical and pathological features of hypertensive heart disease in sudden cardiac death victims from a national cardiovascular pathology registry. We investigated 5239 cases of sudden cardiac death between 1994 and 2018. Hearts were examined by two expert cardiac pathologists. Diagnostic criteria included history of hypertension, increased heart weight and left ventricular wall thickness in the absence of other causes. Collagen was quantified using picrosirius red staining and imaging software. Of 75 sudden cardiac death cases due to hypertensive heart disease (age at death: 54 ± 16 years; 56% males), 56 (75%) reported no prior cardiac symptoms. Thirty-four (45%) recorded a BMI ≥ 30. Only two (2.7%) had hypertensive heart disease diagnosed antemortem. Four (5%) were diagnosed clinically with hypertrophic cardiomyopathy, but lacked myocyte disarray at autopsy. All hearts showed concentric left ventricular hypertrophy and myocyte hypertrophy. Fibrosis was identified microscopically in 59 cases (81%). The posterior left ventricular wall showed the greatest increase in the percentage of collagen in hypertensive diseased hearts compared to controls (25.2% vs 17.9%, p = 0.034). Most sudden deaths due to hypertensive heart disease occur without prior cardiac symptoms; thus, clinical risk stratification is challenging. Hypertensive heart disease can be misdiagnosed in life as hypertrophic cardiomyopathy which has major implications for relatives. Pathologists require a history of hypertension and histology for a definitive diagnosis of hypertensive heart disease.


Levetiracetam add-on for drug-resistant focal epilepsy: an updated Cochrane Review.
Epilepsy is an important neurological condition and drug resistance in epilepsy is particularly common in individuals with focal seizures. In this review, we summarise the current evidence regarding a new antiepileptic drug, levetiracetam, when used as add-on treatment for controlling drug-resistant focal epilepsy. This is an update to a Cochrane Review that was originally published in 2001. To evaluate the effectiveness of levetiracetam, added on to usual care, in treating drug-resistant focal epilepsy. We searched the Cochrane Epilepsy Group's Specialized Register (August 2012), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 7, 2012), and MEDLINE (1946 to August week 1, 2012). We also contacted the manufacturers of levetiracetam and researchers in the field to seek any ongoing or unpublished trials. Randomised, placebo-controlled trials of add-on levetiracetam treatment in people with drug-resistant focal epilepsy. Two review authors independently selected trials for inclusion, assessed trials for bias, extracted data, and evaluated the overall quality of evidence. Outcomes investigated included 50% or greater reduction in focal seizure frequency (response); less than 50% reduction in focal seizure frequency (non-response); treatment withdrawal; adverse effects (including a specific analysis of changes in behaviour); cognitive effects and quality of life (QoL). Risk ratios (RR) with 95% confidence intervals (CIs) were used as measures of effect (99% CIs for adverse effects). Primary analyses were Intention-to-Treat (ITT). Dose response and inter-trial heterogeneity were evaluated in regression models. Eleven trials (1861 participants) were included. They predominantly possessed low risks of bias. Participants were adults in nine trials (1565 participants) and children in the remaining two trials (296 participants). The dose of levetiracetam tested was 1000 to 4000 mg/day in adults, and 60 mg/kg/day in children. Treatment ranged from 12 to 24 weeks. For the 50% or greater reduction in focal seizure frequency outcome, the RR was significantly in favour of levetiracetam at all doses. The naive estimates, ignoring dose, showed children (52% responded) as better responders than adults (39% responded) on levetiracetam. 25% of children and 16% of adults responded to placebo. The Number Needed to Treat for an additional beneficial outcome for children and adults was four (95% CI three to seven) and five (95% CI four to six), respectively. The significant levels of statistical heterogeneity between trials on adults precluded valid provision of an overall RR (ignoring dose). Results for the two trials that tested levetiracetam 2000 mg on adults were sufficiently similar to be combined to give an RR for 50% or greater reduction in focal seizure frequency of 4.91 (95% CI 2.75 to 8.77), with an RR of 0.68 (95% CI 0.60 to 0.77) for non-response. At this dose, 37% and 8% of adults were responders in the levetiracetam and placebo groups, respectively. Regression analysis demonstrated that much of the heterogeneity between adult trials was likely to be explained by different doses of levetiracetam tested and different years of trial publication. There was no evidence of statistical heterogeneity between trials on children. For these trials, the RR for 50% or greater reduction in focal seizure frequency was 1.91 (95% CI 1.38 to 2.63), with an RR of 0.68 (95% CI 0.56 to 0.81) for non-response. 27% of children responded. Participants were not significantly more likely to have levetiracetam withdrawn (RR 0.98; 95% CI 0.73 to 1.32 and RR 0.80; 95% CI 0.43 to 1.46 for adults and children, respectively). For adults, somnolence (RR 1.51; 99% CI 1.06 to 2.17) and infection (RR 1.76; 99% CI 1.03 to 3.02) were significantly associated with levetiracetam. Accidental injury was significantly associated with placebo (RR 0.60; 99% CI 0.39 to 0.92). No individual adverse effect was significantly associated with levetiracetam in children. Changes in behaviour were negligible in adults (1% affected; RR 1.79; 99% CI 0.59 to 5.41) but significant in children (23% affected; RR 1.90; 99% CI 1.16 to 3.11). Cognitive effect and QoL outcomes suggested that levetiracetam had a positive effect on cognition and some aspects of QoL in adults. In children, levetiracetam did not appear to alter cognitive function but there was evidence of worsening in certain aspects of child behaviour. The overall quality of evidence used was high. This update adds seven more trials to the original review, which contained four trials. At every dose analysed, levetiracetam significantly reduced focal seizure frequency relative to placebo. This indicates that levetiracetam can significantly reduce focal seizure frequency when it is used as an add-on treatment for both adults and children with drug-resistant focal epilepsy. As there was evidence of significant levels of statistical heterogeneity within this positive effect it is difficult to be precise about the relative magnitude of the effect. At a dose of 2000 mg, levetiracetam may be expected to be 3.9 times more effective than placebo; with 30% of adults being responders at this dose. At a dose of 60 mg/kg/day, levetiracetam may be expected to be 0.9 times more effective than placebo; with 25% of children being responders at this dose. When dose was ignored, children were better responders than adults by around 4% to 13%. The results grossly suggest that one child or adult may respond to levetiracetam for every four or five children or adults, respectively, that have received levetiracetam rather than placebo. The drug seems to be well tolerated in both adults and children although non-specific changes in behaviour may be experienced in as high as 20% of children. This aspect of the adverse-effect profile of levetiracetam was analysed crudely and requires further investigation and validation. It seems reasonable to continue the use of levetiracetam in both adults and children with drug-resistant focal epilepsy. The results cannot be used to confirm longer-term or monotherapy effects of levetiracetam or its effects on generalised seizures. The conclusions are largely unchanged from those in the original review. The most significant contribution of this update is the addition of paediatric data into the analysis.


Identification of vegetative proteins for a two-dimensional protein index of Bacillus subtilis.
Twenty-three of the most prominent spots which are visible on two-dimensional (2-D) protein gels of Bacillus subtilis crude extracts were selected as marker spots for the construction of a 2-D protein index. N-terminal sequencing of the corresponding proteins resulted in the identification of enzymes involved in glycolysis, TCA cycle, pentose phosphate cycle, amino acid metabolism, nucleotide biosynthesis and translation. Using computer analysis of the 2-D protein gels, most of these metabolic enzymes were found to be synthesized at a reduced rate after different stresses and glucose starvation. Such an approach permits a rapid and global evaluation of the regulation of different branches of metabolism in response to various physiological conditions.


Stimulation of iron(II) bleomycin activity by phosphate-containing compounds.
Orthophosphate and phosphate derivatives including pyrophosphate, hexametaphosphate, ATP, ADP, and inositol hexaphosphate enhance the extent of DNA degradation by iron(II) bleomycin. These phosphate-containing compounds increase both the release of free nucleic base and that of base propenals which are DNA cleavage products, probably by enhancing the efficiency with which Fe(II) is recruited into the drug. Phosphate action occurs during drug activation prior to the attack on DNA. In addition, phosphates affect the stability of the activated drug complex, overcome the inhibition observed with high concentrations of DNA, and reduce the size of the DNA fragment necessary for reacting with the drug. Phosphate derivatives bind to iron(II) bleomycin and alter its optical spectrum. An analysis of titration data for pyrophosphate and inositol hexaphosphate indicates that each phosphate compound binds to more than one iron(II) bleomycin molecule. With ATP, ADP, and 2,3-diphosphoglycerate, only a single phosphate-containing compound binds to the ferrous drug complex. The affinity for ATP is sufficiently high as to suggest that the ternary complex formed in vitro may exist physiologically.


Solution structure of the SH3 domain of phospholipase C-gamma.
SH3 (Src homology 3) domains are found in many signaling proteins and appear to function as binding modules for cytoplasmic target proteins. The solution structure of the SH3 domain of human phospholipase C-gamma (PLC-gamma) was determined by two-dimensional 1H NMR analysis. This SH3 domain is composed of eight antiparallel beta strands consisting of two successive "Greek key" motifs, which form a barrel-like structure. The conserved aliphatic and aromatic residues form a hydrophobic pocket on the molecular surface, and the conserved carboxylic residues are localized to the periphery. The hydrophobic pocket may serve as a binding site for target proteins. Analysis of the slowly exchanging amide protons by NMR measurements indicates that despite containing a high content of beta structure, the SH3 domain of PLC-gamma is flexible.


Invasive candidiasis and candidaemia in neonates and children: update on current guidelines.
Invasive candidiasis (IC) and candidaemia are leading causes of infectious morbidity and mortality among immunocompromised paediatric patients and those admitted to intensive care units. Despite improvements in diagnosis, prevention and treatment, both mortality rates and the economic burden of disease still remain high. To address this issue, several international societies and organisations have proposed guidelines for the management of IC/candidaemia in both neonates and children. In this article, we review current recommendations of the Infectious Diseases Society of America, the European Conference on Infection in Leukaemia, the European Society of Clinical Microbiology and Infectious Diseases and the German Speaking Mycological Society/Paul-Ehrlich Society for Chemotherapy for the management and prevention of IC/candidaemia in children and neonates.


Hearing preservation and tumour control after radiosurgery for NF2-related vestibular schwannomas.
We analyzed the effects of stereotactic radiosurgery on tumour control and cranial nerve function in patients with vestibular schwannomas (VS) secondary to neurofibromatosis type 2 (NF2). Irradiation was performed with a Gamma Knife, model C equipped with a high-precision, robotized positioning system (APS). This study included 18 patients with 25 VSs secondary to NF2 that were treated from 2001 to 2010 with radiosurgery at our Gamma Knife Center. The radiosurgical procedure included high-resolution conformational dose-planning with multiple, small-diameter isocenters, a single-fraction, low-dose irradiation prescription, and highly accurate gamma rays delivery to the target with the APS. The median follow-up time was 4.4 y. For 16 tumours in 12 patients with available follow-up data, we observed an actuarial tumour control of 87.5% at 2 y and 80.2% at 5 y, based on the Kaplan-Meier method. No patient developed facial weakness. Serviceable hearing was preserved in 78% of cases. Patients treated for bilateral and unilateral tumours had similar outcomes. Radiosurgery could control tumour growth and preserve hearing function and facial weakness in patients with VS secondary to NF2. The enhanced techniques of radiosurgical irradiation provided with the Gamma Knife model C have improved the results of this treatment alternative to microsurgery.


Serum triiodothyronine level as an indicator of inflammation in patients undergoing dialysis.
INTRODUCTION. It has been shown that inflammation affects thyroid function. In patients with end-stage renal disease, low plasma triiodothyronine (T3) may be an unsuspected expression of the inflammatory state of these patients. This study evaluated the correlation between T3 and high-sensitivity C-reactive protein (HSCRP) levels in patients on peritoneal dialysis (PD) and hemodialysis. MATERIALS AND METHODS. This is a cross-sectional study aiming at the correlation between T3 and HSCRP levels among 30 patients on PD, 30 patients on hemodialysis, and 20 healthy individuals. Serum levels of HSCRP, T3, thyroxine (T4), thyroid stimulating hormone, T3 resin uptake, and free T3 index (FT3I) and free T4 index (FT4I) were compared between the three groups. RESULTS. There were no significant differences between hemodialysis and PD patients in respect to T3, T4, FT3I, and FT4I. In PD and hemodialysis patients, T3 and FT3I were lower than in controls (P < .001), but there was no significant difference between PD and hemodialysis patients. T3 resin uptake and thyroid stimulating hormone differed significantly between PD and hemodialysis patients. There was a significant inverse correlation between HSCRP and T3 and FT3I among hemodialysis patients (P = .04); however, there was no such correlations in PD patients. CONCLUSIONS. The relationship between T3 and HSCRP suggests that inflammation might be involved in the low T3 syndrome in hemodialysis patients, but we did not find a significant correlation between T3 and HSCRP levels in patients on peritoneal dialysis.


Prevalence and correlates of low-grade systemic inflammation in adult psychiatric inpatients: An electronic health record-based study.
Low-grade inflammation is a risk factor for depression, psychosis and other major psychiatric disorders. It is associated with poor response to antidepressant and antipsychotics, and could potentially be a treatment target. However, there is limited data on the prevalence of low-grade inflammation in major psychiatric disorders, and on the characteristics of patients who show evidence of inflammation. We examined the prevalence of low-grade inflammation and associated socio-demographic and clinical factors in acute psychiatric inpatients. An anonymised search of the electronic patient records of Cambridgeshire and Peterborough NHS Foundation Trust was used to identify patients aged 18-65 years who were hospitalised between 2013 and 2016 (inclusive). We excluded patients on antibiotics or oral steroids, or with missing data. Inflammation was defined using serum C-reactive protein (>3 mg/L) or total white cell count (>9.4 × 109/L) as measured within 14 days of admission. Out of all 599 admissions, the prevalence of inflammation (serum CRP >3 mg/L) in the ICD-10 diagnostic groups of psychotic disorders (F20-29), mood disorders (F30-39), neurotic disorders (F40-48) and personality disorders (F60-69) was 32%, 21%, 22% and 42%, respectively. In multivariable analyses, low-grade inflammation was associated with older age, black ethnicity, being single, self-harm, diagnoses of schizophrenia, bipolar disorder, current treatments with antidepressants, benzodiazepines, and with current treatment for medical comorbidities. A notable proportion of acutely unwell psychiatric patients from all ICD-10 major diagnostic groups show evidence of low-grade inflammation, suggesting inflammation may be relevant for all psychiatric disorders.


Epicardial adipose tissue and carotid artery disease: Protocol for systematic review and meta-analysis.
Atherosclerosis is now widely recognized as a multifactorial disease with outcomes that arise from complex factors such as plaque components, blood flow, and inflammation. Epicardial adipose tissue (EAT) is a metabolically active fat depot, abundant in proinflammatory cytokines, and has been correlated with the extent and severity of carotid artery disease (CD). The locations most frequently affected by carotid atherosclerosis are the proximal internal carotid artery (ie, the origin) and the common carotid artery bifurcation. Progression of atheromatous plaque at the carotid bifurcation results in luminal narrowing, often accompanied by ulceration. However, there are no systematic analyses or well-conducted meta-analyses to evaluate the relationship between EAT and CD. The aim of this study is to examine this association of EAT with CD in different ages and sex. This systematic review and meta-analysis will be conducted using published studies that will be identified from electronic databases (ie, PubMed, EMBASE, Web of Science, and Google Scholar. Studies that (1) examined the association between EAT and CD, (2) focus on cohort, case-control and cross-sectional studies, (3) will conducted among in adults aged 40 to 70 years, (4) provided sufficient data for calculating ORs or relative risk with a 95% CI, (5) will published as original articles written in English or other languages, and (6) have been published until January 2018 will be included. Study selection, data collection, quality assessment and statistical syntheses will be conducted based on discussions among investigators. We propose the current protocol to evaluate the evaluation of EAT with ED. This systematic review will not need ethical approval, because it does not involve human beings. The results and findings of this study will be submitted and published in a scientific peer-reviewed journal. Ethics approval was not required for this study because it was based on published studies. The results and findings of this study will be submitted and published in a scientific peer-reviewed journal. PROSPERO (CRD42018083458).


Y-Chromosome Microdeletions: A Review of Prevalence, Screening, and Clinical Considerations.
Deletions within the male-specific region of the Y-chromosome, known as Y-Chromosome Microdeletions (YCMs), are present in as many as 5% and 10% of severe oligospermic and azoospermic men, respectively. These microdeletions are distinguished by which segment of the Y chromosome is absent, identified as AZFa (the most proximal segment), AZFb (middle), and AZFc (distal). The reported prevalence of YCMs within the world's populations of infertile men displays vast heterogeneity, ranging from less than 2% to over 24% based on region and ethnicity. AZFc is the most commonly identified YCM, and its phenotypic presentation provides for the highest chance for fertility through artificial reproductive techniques. Conversely, deletions identified in the subregions of AZFa, AZFb, or any combination of regions containing these segments, are associated with low probabilities of achieving pregnancy. A putative mechanism explaining this discrepancy lies within the expression of autosomal, DAZ-like genes which could serve to "rescue" wild type AZFc gene expression and hence spermatogenesis. Nevertheless, recent reports challenge this dogma and stress the importance of further analysis when an AZFb deletion is detected. The screening thresholds to determine which oligospermic and azoospermic men are tested for potential YCMs has been recently contested. More recent literature supports lowering the threshold from 5 million sperm/mL of ejaculate to 1 million/mL as the frequency of YCMs in men with sperm concentrations between 1 and 5 million sperm/mL is very low (~0.8%). As such, subsequent guidelines should recommend a lower screening threshold. While YCMs are extremely common globally, the understanding of their clinical significance in the field remains scattered and without consensus. Furthermore, very little is currently known about partial deletions within the AZFc region, such as b1/b3, b2/b3, and gr/gr. Hence, this review aimed to summarize and discuss modern trends in the epidemiology, screening guidelines, and clinical considerations pertaining to YCMs.


Investigating the underlying structure in sadomasochistically oriented behavior.
This study explores the extent to which 29 individual sexual behaviors, previously identified in L. Alison, P. Santtila, N. K. Sandnabba, and N. Nordling (2001), as each being associated with 1 of 4 different broad themes of sadomasochistically oriented behavior, represent different scales of intensity within each theme. The themes were as follows: hypermasculinity, administration and receipt of pain, physical restriction, and humiliation. For example, we wanted to establish whether skinbranding is a more intense expression of pain than spanking; whether faceslapping is a more intense expression of humilitation than flagellation, and so on. One hundred and eighty-four participants (22 women and 162 men) who were members of two sadomasochistically oriented clubs gave information concerning which of the 29 sexual behaviors they had participated in during the preceding 12 months. A multivariate analysis (POSAC; Shye, 1994) supported the existence of cumulative scales in each of the 4 themes, suggesting that the order in which people engage in different sadomasochistic behaviors is not random and that specific, less intense behaviors generally precede more intense behaviors.


Does the Earth's magnetic field serve as a reference for alignment of the honeybee Waggle dance?
The honeybee (Apis mellifera) waggle dance, which is performed inside the hive by forager bees, informs hive mates about a potent food source, and recruits them to its location. It consists of a repeated figure-8 pattern: two oppositely directed turns interspersed by a short straight segment, the "waggle run". The waggle run consists of a single stride emphasized by lateral waggling motions of the abdomen. Directional information pointing to a food source relative to the sun's azimuth is encoded in the angle between the waggle run line and a reference line, which is generally thought to be established by gravity. Yet, there is tantalizing evidence that the local (ambient) geomagnetic field (LGMF) could play a role. We tested the effect of the LGMF on the recruitment success of forager bees by placing observation hives inside large Helmholtz coils, and then either reducing the LGMF to 2% or shifting its apparent declination. Neither of these treatments reduced the number of nest mates that waggle dancing forager bees recruited to a feeding station located 200 m north of the hive. These results indicate that the LGMF does not act as the reference for the alignment of waggle-dancing bees.


Effect of source location on the scalp potential asymmetry in a numerical model of the head.
The correlation between source asymmetry in the brain and the potential amplitude asymmetry on the scalp was studied by a two-dimensional (2-D) numerical model of the head. The model employed computerized tomography (CT) images to define the different compartments of the head. The source was modeled by a dipole layer in the occiput for an occipital source (visual evoked potential generators) or a dipole layer around the cortex representing spontaneous activity generators. The volume conductor equation for the potential distribution was solved numerically using a finite volume method for two CT images; one had relatively symmetric left-right anatomy while the other had a falx deviation of 6 degrees between the occiput and the nasion-inion line. By examining several arrangements of sources, it has been demonstrated that source asymmetry can cause nonnegligible asymmetry in the potential amplitude at the homotopic points on the scalp. This asymmetry, that is not related to real physiologic or psychological origin, should be taken into consideration in any EEG potential distribution analysis.


Arsenic inhibits autophagic flux, activating the Nrf2-Keap1 pathway in a p62-dependent manner.
The Nrf2-Keap1 signaling pathway is a protective mechanism promoting cell survival. Activation of the Nrf2 pathway by natural compounds has been proven to be an effective strategy for chemoprevention. Interestingly, a cancer-promoting function of Nrf2 has recently been observed in many types of tumors due to deregulation of the Nrf2-Keap1 axis, which leads to constitutive activation of Nrf2. Here, we report a novel mechanism of Nrf2 activation by arsenic that is distinct from that of chemopreventive compounds. Arsenic deregulates the autophagic pathway through blockage of autophagic flux, resulting in accumulation of autophagosomes and sequestration of p62, Keap1, and LC3. Thus, arsenic activates Nrf2 through a noncanonical mechanism (p62 dependent), leading to a chronic, sustained activation of Nrf2. In contrast, activation of Nrf2 by sulforaphane (SF) and tert-butylhydroquinone (tBHQ) depends upon Keap1-C151 and not p62 (the canonical mechanism). More importantly, SF and tBHQ do not have any effect on autophagy. In fact, SF and tBHQ alleviate arsenic-mediated deregulation of autophagy. Collectively, these findings provide evidence that arsenic causes prolonged activation of Nrf2 through autophagy dysfunction, possibly providing a scenario similar to that of constitutive activation of Nrf2 found in certain human cancers. This may represent a previously unrecognized mechanism underlying arsenic toxicity and carcinogenicity in humans.


Radioimmunoprecipitation assay for quantitation of serum antibody to the hemagglutinin of type A influenza virus.
A double-antibody radioimmunoprecipitation (RIP) assay has been developed to provide a sensitive and specific measure of antibody to hemagglutinins of H3N2 influenza viruses. Chloramine T was used to radiolabel purified hemagglutinins to high specific activity without loss of antigenicity. The purity of the labeled hemagglutinin was confirmed by sodium dodecyl sulfate polyacrylamide gel electrophoresis, which also established that both the HA(1) and HA(2) polypeptides were iodinated. Radiolabeled hemagglutinins with a specific activity that did not exceed 12 muCi/mug of protein could be maintained for up to 30 days at -70 degrees C in the presence of supplemental protein. The RIP assay was compared with conventional methods, hemagglutination inhibition and viral neutralization tests, using H3N equine 1 hybrid viruses for determining serum antihemagglutinin antibody titers. The geometric mean titers for human convalescent sera after infection with A/England/72 virus were 118, 161, and 18,822 for hemagglutination inhibition, viral neutralization, and RIP tests, respectively, and the three tests demonstrated significant rises in antihemagglutinin antibody titers with equal efficiency. In general, a positive correlation existed between antihemagglutinin antibody titers determined by these three procedures; however, the antibody level determined by RIP assay for each individual could not be related to hemagglutination inhibition or viral neutralization titers by a constant factor. A similar lack of a constant relationship was found by using hyperimmune guinea pig antisera, which suggests that the RIP assay can detect antibody populations that exhibit differing efficiencies for inhibition of viral hemagglutination and replication.


Disc in flames: Roles of TNF-α and IL-1β in intervertebral disc degeneration.
The intervertebral disc is an important mechanical structure that allows range of motion of the spinal column. Degeneration of the intervertebral disc--incited by aging, traumatic insult, genetic predisposition, or other factors--is often defined by functional and structural changes in the tissue, including excessive breakdown of the extracellular matrix, increased disc cell senescence and death, as well as compromised biomechanical function of the tissue. Intervertebral disc degeneration is strongly correlated with low back pain, which is a highly prevalent and costly condition, significantly contributing to loss in productivity and health care costs. Disc degeneration is a chronic, progressive condition, and current therapies are limited and often focused on symptomatic pain relief rather than curtailing the progression of the disease. Inflammatory processes exacerbated by cytokines tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) are believed to be key mediators of disc degeneration and low back pain. In this review, we describe the contributions of TNF-α and IL-1β to changes seen during disc degeneration at both cellular and tissue level, as well as new evidence suggesting a link between infection of the spine and low back pain, and the emerging therapeutic modalities aimed at combating these processes.


The role of the Brazilian Unified Health System in combating the global syndemic and in the development sustainable food systems.
The undernutrition and obesity pandemics associated with climate change are a global syndemic. They have a point of convergence, which is the unsustainable current food systems. This paper aims to discuss the role of public health policies, particularly the Brazilian Unified Health System (SUS) in the context of Primary Health Care, in combating the global syndemic and in the development of sustainable food systems. In this scenario, the National Food and Nutrition Policy is a leading intersectoral tool for an adequate and healthy diet and food and nutrition security. Also, the Dietary Guidelines for the Brazilian population is a strategic tool to support food and nutrition education. We highlight the need to articulate health, agriculture, and environmental policies to achieve sustainable development. Thus, SUS can be the arena to promote the main discussions on this topic, potentiating individual, group, and institutional actions to provide a fairer, healthy, and sustainable food system.


Involvement of secondary metabolites in the pathogenesis of the American foulbrood of honey bees caused by Paenibacillus larvae.
The Gram-positive, spore-forming bacterium Paenibacillus larvae (P. larvae) is the causative agent of the epizootic American Foulbrood (AFB), a fatal brood disease of the western honey bee (Apis mellifera). AFB is one of the most destructive honey bee diseases since it is not only lethal for infected larvae but also for the diseased colonies. Due to the high impact of honey bees on ecology and economy this epizootic is a severe and pressing problem. Knowledge about virulence mechanisms and the underlying molecular mechanisms remain largely elusive. Recent genome sequencing of P. larvae revealed its potential to produce unknown secondary metabolites, like nonribosomal peptides and peptide-polyketide hybrids. This article highlights recent findings on secondary metabolites synthesized by P. larvae and discusses their role in virulence and pathogenicity towards the bee larvae.


Beyond where it started: a look at the "Healing Images" experience.
In March 2004, the Baltimore-based nonprofit organization Advocates for Survivors of Torture and Trauma (ASTT) initiated a photography-based therapeutic programme for clients. Developed by a professional photographer/teacher in collaboration with a psychologist, the programme has the goal of enabling clients to engage in creative self-exploration within a supportive, group setting. Since its inception, thirty survivors of conflict-related trauma and torture from five different countries have taken part in the programme, known as "Healing Images", using digital cameras to gather individually-chosen images that are subsequently shared and discussed within the group. These images include depictions of the natural and manmade environments in which clients find themselves; people, places and objects that offer comfort; and self-portraits that reflect the reality of the life of a refugee in the United States. This description of the "Healing Images" programme is based on comments gathered through discussion with participants and through interviews. Additional information was gathered from observation of early workshop sessions, review of numerous client photographs and captions, and pertinent organizational materials. A fundamental benefit of the programme was that it offered a mutually supportive group environment that diminished clients' feelings of psychological and physical isolation. Participants gained deep satisfaction from learning the technical skills related to use of the cameras, from the empowering experience of framing and creating specific images, and from exploring the personal significance of these images. Programme activities sparked a process of self-expression that participants valued on the level of personal discovery and growth. Some clients also welcomed opportunities to share their work publicly, as a means of raising awareness of the experience of survivors.