Molecular cloning and functional characterization of porcine MyD88 essential for TLR signaling.
We isolated cDNA encoding porcine MyD88 (poMyD88) from Peyer's patches (Pps) of GALT. The complete open reading frame (ORF) of poMyD88 contains 879 bp encoding a deduced 293 aa residues. The amino acid sequence of poMyD88 was characterized by N-terminal death, intermediate and C-terminal Toll/IL-1 receptor (TIR) domains. The putative poMyD88 protein shares a higher level of homology with its human (87.2% amino acid identity) than with its mouse (77.4% amino acid identity) counterpart. Overexpression of poMyD88 participated in the further enhanced activation of NF-kappaB in human embryonic kidney (HEK) 293 cells expressing porcine TLR2 and porcine TLR4/MD-2, but not porcine RP105/MD-1 after stimulation with the corresponding ligands. The expression levels of MyD88 were highest in the spleen and mesenteric lymph nodes (MLNs), and lower in digestive tissues of newborn swine. In adult swine, the expression levels in the digestive tissues were lower than those in MLNs and the spleen. These results suggest that an MyD88-dependent signaling pathway is present in newborn as well as in adult swine and that it is involved in the innate immune system of these animals.


Imaging in the pre-operative staging of ovarian cancer.
The main prognostic factor in ovarian cancer is the stage of disease at diagnosis. The staging system in use (FIGO classification, updated in 2014) is based on the surgical-pathological findings. Although surgical staging is the gold standard in ovarian cancer, the initial patient management depends on the imaging-based pre-surgical staging assessment, in order to identify unresectable or difficult to resect disease. Radiologists need to be aware of the strengths of the available imaging modalities, as well as the imaging pitfalls. Clear understanding of pattern of disease spread and review areas are critical for accurate staging and treatment planning. The current standard of care for pre-surgical staging is CT of the thorax, abdomen, and pelvis. This allows a rapid evaluation of disease extent and is fairly accurate in identifying bulky disease but has definite limitations in assessing the extent of small volume disease and in the confirmation of certain sites of disease beyond the abdomen. Functional MRI has been reported to be superior in detecting small peritoneal deposits. PET/CT may be used as a problem-solving tool in some patients where determination remains unclear, particularly in confirmation of advanced stage beyond the abdomen.


The sociocultural model of eating disorders in Mexican American women: behavioral acculturation and cognitive marginalization as moderators.
White American cultural values of appearance are implicated in the development of body dissatisfaction. This study examined whether the relationships between awareness of White American appearance ideals, internalization of such ideals, and body dissatisfaction are moderated by behavioral acculturation and attitudinal marginalization in a sample of 94 Mexican American women. Results indicated that behavioral acculturation moderated the relationship between awareness and internalization and cognitive marginalization moderated the relationship between internalization and body dissatisfaction. Body size was positively correlated with body dissatisfaction and negatively correlated with behavioral acculturation. These findings have important implications for clinical practice and research with Mexican American women.


Geometric estimates of heritability in biological shape.
The recently developed geometric morphometrics methods represent an important contribution of statistics and geometry to the study of biological shapes. We propose simple protocols using shape distances that incorporate geometric techniques into linear quantitative genetic models that should provide insights into the contribution of genetics to shape variation in organisms. The geometric approaches use Procrustes distances in a curved shape space and distances in tangent spaces within and among families to estimate shape heritability. We illustrate the protocols with an example of wing shape variation in the honeybee, Apis mellifera. The heritability of overall shape variation was small, but some localized components depicting shape changes on distal wing regions showed medium to large heritabilities. The genetic variance-covariance matrix of the geometric shape variables was significantly correlated with the phenotypic shape variance-covariance matrix. A comparison of the results of geometric methods with the traditional multivariate analysis of interlandmark distances indicated that even with a larger dimensionality, the interlandmark distances were not as rich in shape information as the landmark coordinates. Quantitative genetics studies of shape should greatly benefit from the application of geometric methods.


Ossifying fibroma vs fibrous dysplasia of the jaw: molecular and immunological characterization.
Ossifying fibroma and fibrous dysplasia of the jaw are maxillofacial fibro-osseous lesions that should be distinguished each other by a pathologist because they show distinct patterns of disease progression. However, both lesions often show similar histological and radiological features, making distinction between the two a diagnostic dilemma. In this study, we performed immunological and molecular analyses of five ossifying fibromas, four cases of extragnathic fibrous dysplasia, and five cases of gnathic fibrous dysplasia with typical histological and radiographic features. First, we examined the difference between fibrous dysplasia and ossifying fibroma in the expression of Runx2 (which determined osteogenic differentiation from mesenchymal stem cells) and other osteogenic markers. Fibroblastic cells in fibrous dysplasia and ossifying fibroma showed strong Runx2 expression in the nucleus. The bone matrices of both lesions showed similar expression patterns for all markers tested except for osteocalcin. Immunoreactivity for osteocalcin was strong throughout calcified regions in fibrous dysplasia, but weak in ossifying fibroma lesions. Second, we performed PCR analysis with peptide nucleic acid (PNA) for mutations at the Arg(201) codon of the alpha subunit of the stimulatory G protein gene (GNAS), which has reported to be a marker for extragnathic fibrous dysplasia. All nine cases of extragnathic or gnathic fibrous dysplasia were positive for this mutation. On the other hand, none of the five cases of ossifying fibroma showed the mutation. These findings indicate that although fibrous dysplasia and ossifying fibroma are similar disease entities, especially in the demonstration of the osteogenic lineage in stromal fibroblast-like cells, they show distinct differences that can be revealed by immunohistochemical detection of osteocalcin expression. Furthermore, PCR analysis with PNA for GNAS mutations at the Arg(201) codon is a useful method to differentiate between fibrous dysplasia and ossifying fibroma.


Smiling Gurken gradient: An expansion of the Gurken gradient.
Morphogen gradients provide unique positional information within a tissue. Cells that are sensitive to the concentration of the morphogen integrate this signal and develop an appropriately distinct cell fate. A morphogen gradient is usually generated by a restricted source and shaped by the speed of diffusion and stability of the signaling molecule. In addition, the availability of receptor and Heparan Sulfate Proteoglycans (HSPGs) help to shape the gradient. We have shown that overexpression of Dally-like protein (Dlp) causes an expansion of Gurken distribution and a loss of cell fates which are specified by high levels of epidermal growth factor receptor (Egfr) signaling. In this article, we discuss how D-Cbl mediated Egfr endocytosis and the levels of Dlp affect the shape of the Gurken gradient.


Validation, Identification, and Biological Consequences of the Site-specific O-GlcNAcylation Dynamics of Carbohydrate-responsive Element-binding Protein (ChREBP).
O-GlcNAcylation of carbohydrate-responsive element-binding protein (ChREBP) is believed as an important modulator of ChREBP activities, however little direct evidence of O-GlcNAcylation on ChREBP and no exact O-GlcNAcylation sites have been reported so far. Here, we validate O-GlcNAcylation on ChREBP in cell-free coupled transcription/translation system and in cells by chemoenzymatic and metabolic labeling, respectively. Moreover, for the first time, we identify O-GlcNAcylation on Ser614 in the C-terminus of ChREBP by mass spectrometry and validate two important sites, Thr517 and Ser839 for O-GlcNAcylation and their function via molecular and chemical biological method. Under high glucose conditions, Ser514 phosphorylation enhances ChREBP O-GlcNAcylation, maintaining the transcriptional activity of ChREBP; Ser839 O-GlcNAcylation is essential for Mlx-heterodimerization and DNA-binding activity enhancement, consequently inducing transcriptional activity. Ser839 O-GlcNAcylation is also crucial for ChREBP nuclear export partially by strengthening interactions with CRM1 and 14-3-3. This work is a detailed study of ChREBP O-GlcNAcylation and highlights the biological consequences of the site-specific O-GlcNAcylation dynamics of ChREBP.


Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial.
To mitigate the effects of COVID-19, a vaccine is urgently needed. BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine formulated with a toll-like receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG) or alum (Algel). We did a double-blind, multicentre, randomised, controlled phase 1 trial to assess the safety and immunogenicity of BBV152 at 11 hospitals across India. Healthy adults aged 18-55 years who were deemed healthy by the investigator were eligible. Individuals with positive SARS-CoV-2 nucleic acid and/or serology tests were excluded. Participants were randomly assigned to receive either one of three vaccine formulations (3 μg with Algel-IMDG, 6 μg with Algel-IMDG, or 6 μg with Algel) or an Algel only control vaccine group. Block randomisation was done with a web response platform. Participants and investigators were masked to treatment group allocation. Two intramuscular doses of vaccines were administered on day 0 (the day of randomisation) and day 14. Primary outcomes were solicited local and systemic reactogenicity events at 2 h and 7 days after vaccination and throughout the full study duration, including serious adverse events. Secondary outcome was seroconversion (at least four-fold increase from baseline) based on wild-type virus neutralisation. Cell-mediated responses were evaluated by intracellular staining and ELISpot. The trial is registered at ClinicalTrials.gov (NCT04471519). Between July 13 and 30, 2020, 827 participants were screened, of whom 375 were enrolled. Among the enrolled participants, 100 each were randomly assigned to the three vaccine groups, and 75 were randomly assigned to the control group (Algel only). After both doses, solicited local and systemic adverse reactions were reported by 17 (17%; 95% CI 10·5-26·1) participants in the 3 μg with Algel-IMDG group, 21 (21%; 13·8-30·5) in the 6 μg with Algel-IMDG group, 14 (14%; 8·1-22·7) in the 6 μg with Algel group, and ten (10%; 6·9-23·6) in the Algel-only group. The most common solicited adverse events were injection site pain (17 [5%] of 375 participants), headache (13 [3%]), fatigue (11 [3%]), fever (nine [2%]), and nausea or vomiting (seven [2%]). All solicited adverse events were mild (43 [69%] of 62) or moderate (19 [31%]) and were more frequent after the first dose. One serious adverse event of viral pneumonitis was reported in the 6 μg with Algel group, unrelated to the vaccine. Seroconversion rates (%) were 87·9, 91·9, and 82·8 in the 3 μg with Algel-IMDG, 6 μg with Algel-IMDG, and 6 μg with Algel groups, respectively. CD4+ and CD8+ T-cell responses were detected in a subset of 16 participants from both Algel-IMDG groups. BBV152 led to tolerable safety outcomes and enhanced immune responses. Both Algel-IMDG formulations were selected for phase 2 immunogenicity trials. Further efficacy trials are warranted. Bharat Biotech International.


Review of systematic reviews on acute procedural pain in children in the hospital setting.
Acute pain is a common experience for hospitalized children. Despite mounting research on treatments for acute procedure-related pain, it remains inadequately treated. To critically appraise all systematic reviews on the effectiveness of acute procedure-related pain management in hospitalized children. Published systematic reviews and meta-analyses on pharmacological and nonpharmacological management of acute procedure-related pain in hospitalized children aged one to 18 years were evaluated. Electronic searches were conducted in the Cochrane Database of Systematic Reviews, Medline, EMBASE, the Cumulative Index to Nursing and Allied Health Literature and PsycINFO. Two reviewers independently selected articles for review and assessed their quality using a validated seven-point quality assessment measure. Any disagreements were resolved by a third reviewer. Of 1469 published articles on interventions for acute pain in hospitalized children, eight systematic reviews met the inclusion criteria and were included in the analysis. However, only five of these reviews were of high quality. Critical appraisal of pharmacological pain interventions indicated that amethocaine was superior to EMLA (AstraZeneca Canada Inc) for reducing needle pain. Distraction and hypnosis were nonpharmacological interventions effective for management of acute procedure-related pain in hospitalized children. There is growing evidence of rigorous evaluations of both pharmacological and nonpharmacological strategies for acute procedure-related pain in children; however, the evidence underlying some commonly used strategies is limited. The present review will enable the creation of a future research plan to facilitate clinical decision making and to develop clinical policy for managing acute procedure-related pain in children.


Outer membrane proteins of Neisseria gonorrhoeae associated with survival within human polymorphonuclear phagocytes.
The determinant(s) of gonococcal resistance to killing by human polymorphonuclear (PMN) phagocytes appear to be present in outer membrane vesicles (OMV) purified from lithium chloride extracts of Neisseria gonorrhoeae strain BS4 (agar) by wheat germ agglutinin (WGA) affinity chromatography. OMV neutralized the ability of antisera raised against whole gonococci to drastically reduce the capacity of strain BS4 (agar) to survive within PMN phagocytes. Furthermore, analysis by SDS-PAGE of OMV/WGA precipitates from lithium chloride extracts of strain BS4 (agar) and strain BSSH, which was more susceptible to phagocyte killing than strain BS4 (agar) and yielded OMV with poor antiserum-neutralizing activity, suggested that three proteins were associated with resistance to phagocyte killing.


Influenza virus multiplication in the chorioallantoic membrane in vitro: kinetic aspects of inhibition by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole.
A procedure is described for kinetic studies on the multiplication of Lee virus in the chorioallantoic membrane in vitro employing the hemagglutination technique for measurement of virus concentration. A linear relationship was found between the logarithm of virus adsorbed and the amount of membrane used. Of the virus adsorbed less than 10 per cent could be recovered from the membrane. Of the recoverable virus 90 per cent was eliminated by specific immune serum. Lee virus was adsorbed by the allantoic and chorionic layers of the membrane to a similar degree. Multiplication occurred in both layers and to a similar extent. When 10(7.66) EID(50) of Lee virus was inoculated per 2.9 cm.(2) of chorioallantoic membrane, the ratio of infectivity to hemagglutination titer in the yield was low, although the rate of appearance of virus particles was not diminished despite the large inocula. Virus produced in membranes was liberated rapidly and continually into the medium. 5,6-Dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB), 0.000055 M, prolonged the latent period by more than 100 per cent. The rate of increase during the period of rapid rise was similar in the presence or absence of DRB, but the yield was markedly reduced at the end of this period in the presence of DRB. The amount of the virus in the membranes continued to rise in the presence of DRB and eventually approached the maximal levels reached much earlier in the controls. Measurement of the amount of virus in the media indicated a greater degree of inhibition than did measurement in the membranes. Comparative studies with two benzimidazole derivatives on the dependence of the inhibitory effect on the time of addition of the compound showed that processes which could be inhibited by DRB were of shorter duration than those inhibited by 2,5-dimethylbenzimidazole (MB). With MB the relationship between the time of addition and the inhibitory effect was similar both for virus and for soluble complement-fixing antigen; with DRB the inhibitable processes were of shorter duration for the complement-fixing antigen than for virus particles. DRB was not only 35 times more active on a molar basis but also was more selective in its action than MB. DRB interfered with processes which preceded the emergence of either soluble complement-fixing antigen or virus particles. Some of the implications of these findings are discussed in relation to the mechanism of inhibition of influenza virus multiplication by benzimidazole derivatives.


Modulation of amino acid neurotransmitter actions by other neurotransmitters: some examples.
Developments in the field of central neurotransmission indicate that amino acids serve as important and widespread transmitters throughout the central nervous system. There are increasing indications from recent experimental studies that several of the other central neurotransmitters may exert potent effects on central neurons by modulating the actions of amino acids. Noradrenaline and serotonin have received particular attention as potential modulators, and a wide variety of actions has been reported for them. Modulatory actions have been reported at both pre- and post-synaptic levels, including both short- and long-term effects and facilitation or inhibition of amino acid actions. Selectivity has been found both for specific receptor subtypes of the neuromodulator and for specific effects of amino acids. Examples of such selectivity are modification of actions of an amino acid with little effect on spontaneous activity or membrane properties of the target cell, or in comparison to the actions of other neurotransmitters, or even other selective amino acid analogs. Modulatory actions on amino acids have also been reported for several other neurotransmitters including acetylcholine and various peptides. Recent studies of angiotensin II demonstrate that when iontophoretically applied, it can potently and selectively block the depolarizing action of glutamate on locus coeruleus neurons. It is possible that physiological influences of these various transmitter substances are expressed through modification of amino acid actions, rather than through direct effects on central neurons.


[Physiological mechanisms of the etiology of visual fatigue during work involving visual stress].
Physiological parameters of vision were studied in three professional groups (a total of 1204 subjects): microscope operators, subjects working with magnifying glasses, and computer users. General and specific features of visual system fatigue formation were identified. Because of complete (in microscope operators) or partial (in subjects working with magnifying glasses and display users) "deprivation" of accommodation, these subjects develop early presbyopia (at the age of 30-35 years). In microscope operators long strain of accommodation system leads to professional myopia, while display users develop pseudomyopia. The highest overstrain is observed after 4 years of work in microscope operators, after 5 years in magnifying glass users, and after 6 years in computer users.


Carcinogenic activity of cigarette smoke gas phase and its modulation by beta-carotene and N-acetylcysteine.
Male strain A/J mice were exposed for six hours a day, five days a week for six months to either full tobacco smoke or to tobacco smoke drawn through a HEPA filter that removed more than 99% of particulate matter. After another four months in air, the animals were sacrificed and lung tumors were counted for calculation of multiplicities and incidences. Analysis of the chamber atmospheres showed that in the filtered smoke the concentrations of polycyclic aromatic hydrocarbons and tobacco smoke specific nitrosamines were reduced to from below 18% to even nondetectable levels of the original values measured in the unfiltered smoke. Aldehydes and other volatile organic compounds such as 1,3-butadiene, benzene, or acrolein were reduced to about 50 to 90% of the concentrations found in unfiltered smoke. Some potentially carcinogenic metals reached levels in filtered smoke ranging from 77% to less than 1% found in full smoke. The mice exposed to the filtered smoke atmosphere had practically identical lung tumor multiplicities and incidence as had the animals exposed to full smoke, significantly higher than in air exposed controls. Diets containing 0.5% beta-carotene or 0.4% N-acetylcysteine afforded some chemoprevention. It was tentatively concluded that 1,3-butadiene might be an important contributor to lung tumorigenesis in this mouse model of tobacco smoke carcinogenesis.


Lymphocytic choriomeningitis virus infection in a province of Spain: analysis of sera from the general population and wild rodents.
Lymphocytic choriomeningitis virus (LCMV) is a rodent-borne virus belonging to the family Arenaviridae, genus Arenavirus, which causes a wide spectrum of human disease. However, data on LCMV infection in Spain is scant. To investigate whether this virus causes infection in Spain, 400 serum samples from the general population (191 males, 209 females) and 100 from wild rodents were studied by immunofluorescence assay (IFA) using L-929 cells infected with LCMV. The study was performed in the "Community of Madrid," a region with both rural and urban areas in different ecological settings. Of the 400 human serum samples tested, antibodies against LCMV were detected in 7 (1.7%). No statistical differences in prevalence were found with respect to either age or rural or urban residence, but differences were seen with respect to sex. Nine (9%) of the rodent serum samples were positive. These results confirm the occurrence of LCMV infections in Man and rodents in Spain.


The effect of temperature on haemoglobin-oxygen binding affinity in regionally endothermic and ectothermic sharks.
Haemoglobin (Hb)-O2 binding affinity typically decreases with increasing temperature, but several species of ectothermic and regionally endothermic fishes exhibit reduced Hb thermal sensitivity. Regionally endothermic sharks, including the common thresher shark (Alopias vulpinus) and lamnid sharks such as the shortfin mako shark (Isurus oxyrinchus), can maintain select tissues and organs warmer than ambient temperature by retaining metabolic heat with vascular heat exchangers. In the ectothermic bigeye thresher shark (Alopias superciliosus), diurnal movements above and below the thermocline subject the tissues, including the blood, to a wide range of operating temperatures. Therefore, blood-O2 transport must occur across internal temperature gradients in regionally endothermic species, and over the range of environmental temperatures encountered by the ectothermic bigeye thresher shark. While previous studies have shown temperature-independent Hb-O2 affinity in lamnid sharks, including shortfin mako, the Hb-O2 affinity of the common and bigeye thresher sharks is unknown. Therefore, we examined the effect of temperature on whole-blood Hb-O2 affinity in common thresher shark and bigeye thresher shark. For comparison, analyses were also conducted on the shortfin mako shark and two ectothermic species, blue shark (Prionace glauca) and spiny dogfish (Squalus acanthias). Blood-O2 binding affinity was temperature independent for common thresher shark and shortfin mako shark, which should prevent internal temperature gradients from negatively affecting blood-O2 transport. Blue shark and spiny dogfish blood-O2 affinity decreased with increasing temperature, as expected, but bigeye thresher shark blood exhibited both a reduced temperature dependence and a high Hb-O2 affinity, which likely prevents large changes in environment temperature and low environmental oxygen from affecting O2 uptake.


Visual afterimages of emotional faces in high functioning autism.
Fixating an emotional facial expression can create afterimages, such that subsequent faces are seen as having the opposite expression of that fixated. Visual afterimages have been used to map the relationships among emotion categories, and this method was used here to compare ASD and matched control participants. Participants adapted to a facial expression for 45 s then saw a neutral face for 800 ms and chose a label to describe the latter. The ASD group showed evidence of afterimages, but atypical patterns of opposition: whereas fixating negative emotions uniformly evokes a positive afterimage in the control group, fixating negative emotions was more likely to evoke a negative afterimage in the ASD group. This study was the first to provide evidence of visual aftereffects in ASD and suggests a different psychological organization among emotions in those with ASD.


Absence of a red blood cell phenotype in mice with hematopoietic deficiency of SEC23B.
Congenital dyserythropoietic anemia type II (CDAII) is an autosomal recessive disease of ineffective erythropoiesis characterized by increased bi/multinucleated erythroid precursors in the bone marrow. CDAII results from mutations in SEC23B. The SEC23 protein is a core component of coat protein complex II-coated vesicles, which transport secretory proteins from the endoplasmic reticulum to the Golgi apparatus. Though the genetic defect underlying CDAII has been identified, the pathophysiology of this disease remains unknown. We previously reported that SEC23B-deficient mice die perinatally, exhibiting massive pancreatic degeneration, with this early mortality limiting evaluation of the adult hematopoietic compartment. We now report that mice with SEC23B deficiency restricted to the hematopoietic compartment survive normally and do not exhibit anemia or other CDAII characteristics. We also demonstrate that SEC23B-deficient hematopoietic stem cells (HSC) do not exhibit a disadvantage at reconstituting hematopoiesis when compared directly to wild-type HSC in a competitive repopulation assay. Secondary bone marrow transplants demonstrated continued equivalence of SEC23B-deficient and WT HSC in their hematopoietic reconstitution potential. The surprising discordance in phenotypes between SEC23B-deficient mice and humans may reflect an evolutionary shift in SEC23 paralog function and/or expression, or a change in a specific COPII cargo critical for erythropoiesis.


The epidemiology of diarrhoeal diseases in southeastern China.
In a community survey of 19,410 people for 12 months in southeastern China (Fujian Province), the overall annual incidence rate of diarrhoea was 729.9 episodes/1,000 population. The incidence varied with different age groups; children aged under five years had the highest rate, 2.25 episodes per child per year. A bacterial pathogen was isolated from 883 cases (44.03%), and 147 (14.76%) strains from 996 healthy controls. Enterotoxigenic Escherichia coli, enteropathogenic E. coli, and Shigella species were the most frequently isolated bacterial pathogens. Isolation was highest during the hot summer months. The investigation showed that the diarrhoea incidence was related to the status of economy, education, healthy, hygiene, food, and water.


Binge drinking, drinking and driving, and riding with a driver who had been drinking heavily among Air National Guard and Air Force Reserve Personnel.
Heavy drinking is associated with significant health problems and increased risk for injury and death. Although several studies have investigated alcohol use among active duty and civilian populations, little is known about the alcohol use patterns of reserve personnel. This study examined the prevalence and correlates of binge drinking, driving after drinking, and riding in a vehicle with a driver who had consumed alcohol among 4,836 guardsmen and reservists who were taking part in basic military training (mean age = 21.3 years; 29.4% female). Forty-six percent reported one or more binge drinking episodes in the month before basic military training. Four percent drove after consuming five or more drinks, while 8.9% rode as a passenger with a driver who had been drinking heavily. Several demographic, behavioral, and attitudinal correlates of risky drinking patterns were identified. Findings have potentially important implications for the health, safety, and military readiness of reserve personnel.


Expanding the spectrum of tyrosine kinase fusions in calcified chondroid mesenchymal neoplasms: Identification of a novel PDGFRA::USP8 gene fusion.
Calcified chondroid mesenchymal neoplasms represent a distinct, and recently recognized, spectrum of tumors. To date most cases have been reported to be characterized by FN1 gene fusions involving multiple potential tyrosine kinase partners. Following incidental identification of a tumor morphologically corresponding to calcified chondroid mesenchymal neoplasm, but with a PDGFRA::USP8 gene fusion, we undertook a retrospective review to identify and characterize additional such cases. A total of four tumors were identified. Each was multilobulated and composed of polygonal-epithelioid-stellate cells with a background of chondroid matrix containing distinctive patterns of calcification. Targeted RNA sequencing revealed an identical PDGFRA (exon 22)::USP8 (exon 5) gene fusion in each case. Subsequent immunohistochemical staining confirmed the presence of PDGFRα overexpression. In summary, we report a series of four tumors within the morphologic spectrum of calcified chondroid mesenchymal neoplasms. In contrast to prior reports, these tumors harbored a novel PDGFRA::USP8 gene fusion, rather than FN1 rearrangement. Our findings expand the molecular diversity of these neoplasms, and suggest they are united through activation of protein kinases.


A fucose containing polymer-rich fraction from the brown alga Ascophyllum nodosum mediates lifespan increase and thermal-tolerance in Caenorhabditis elegans, by differential effects on gene and protein expression.
The extracts of the brown alga, Ascophyllum nodosum, which contains several bioactive compounds, have been shown to impart biotic and abiotic stress tolerance properties when consumed by animals. However, the physiological, biochemical and molecular mechanism underlying such effects remain elusive. We investigated the effect of A. nodosum fucose-containing polymer (FCP) on tolerance to thermally induced stress using the invertebrate animal model, Caenorhabditis elegans. FCP at a concentration of 150 μg mL(-1) significantly improved the life span and tolerance against thermally induced stress in C. elegans. The treatment increased the C. elegans survival by approximately 24%, when the animals were under severe thermally induced stress (i.e. 35 °C) and 27% under mild stress (i.e. 30 °C) conditions. The FCP induced differential expression of genes and proteins is associated with stress response pathways. Under thermal stress, FCP treatment significantly altered the expression of 65 proteins (54 up-regulated & 11 down-regulated). Putative functional analysis of FCP-induced differential proteins signified an association of altered proteins in stress-related molecular and biochemical pathways of the model worm.


Psychiatric symptoms, bone density and non-specific symptoms in patients with mild hypercalcemia due to primary hyperparathyroidism: a systematic overview of the literature.
To determine (1) the relationship between primary hyperparathyroidism with mild hypercalcemia and psychiatric disturbances, bone density, or non-specific symptoms, and (2) the effect of parathyroidectomy on these outcomes, a systematic and critical review of the literature was conducted. Relevant citations were identified using MEDLINE (1966 to August, 1995) and PsycINFO (1967 to August, 1995). Studies were included for the overview if they described patients with mild hypercalcemia (< 12 mg/dl), and if they dealt with at least one of the following outcomes: psychiatric disturbances, bone density, joint pain, constipation, polyuria/nocturia or weight loss. Either a calculated effect size or Z score was used to estimate the effect of the disease or parathyroidectomy on these outcomes. Seven studies met the inclusion criteria for this overview. Two out of three case-control studies on psychiatric symptoms found a significant association between primary hyperparathyroidism with mild hypercalcemia and psychiatric disturbances (effect sizes; 0.17, 1.2 and 1.6). One of the three studies also examined the effect of parathyroidectomy on psychiatric symptoms, and found an effect size of 1.5. All four cross-sectional studies that measured bone mass showed significantly reduced bone density in the forearm and the lumbar spine. The bone loss ranged from 0.9 to 1.4 standard deviation below the age- and sex-adjusted mean value in the forearm, and was 0.5 in the spine. There was no relevant study regarding non-specific symptoms. Among the seven studies, five did not explicitly indicate whether the patients had classical symptoms of either osteitis fibrosa cystica or renal stones. Primary hyperparathyroidism with mild hypercalcemia is associated with psychiatric disturbances and reduced bone density. Nevertheless, further research is needed to determine the symptoms, particularly for a group of patients without either classical bone disease or renal stones. The effects of parathyroidectomy on these outcomes also remain to be determined.


A novel self-assembled oligopeptide amphiphile for biomimetic mineralization of enamel.
Researchers are looking for biomimetic mineralization of ena/mel to manage dental erosion. This study evaluated biomimetic mineralization of demineralized enamel induced by a synthetic and self-assembled oligopeptide amphiphile (OPA). The results showed that the OPA self-assembled into nano-fibres in the presence of calcium ions and in neutral acidity. The OPA was alternately immersed in calcium chloride and sodium hypophosphate solutions to evaluate its property of mineralization. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) showed nucleation and growth of amorphous calcium phosphate along the self-assembled OPA nano-fibres when it was repetitively exposed to solutions with calcium and phosphate ions. Energy dispersive spectrometry (EDS) confirmed that these nano-particles contained calcium and phosphate. Furthermore, electron diffraction pattern suggested that the nano-particles precipitated on OPA nano-fibres were comparable to amorphous calcium phosphate. Acid-etched human enamel slices were incubated at 37°C in metastable calcium phosphate solution with the OPA for biomimetic mineralization. SEM and X-ray diffraction indicated that the OPA induced the formation of hydroxyapatite crystals in organized bundles on etched enamel. TEM micrographs revealed there were 20-30 nm nano-amorphous calcium phosphate precipitates in the biomimetic mineralizing solution. The particles were found separately bound to the oligopeptide fibres. Biomimetic mineralization with or without the oligopeptide increased demineralized enamel microhardness. A novel OPA was successfully fabricated, which fostered the biomimetic mineralization of demineralized enamel. It is one of the primary steps towards the design and construction of novel biomaterial for future clinical therapy of dental erosion.


5' --> 3' molecular polarity of human replication protein A (hRPA) binding to pseudo-origin DNA substrates.
Human replication protein A (hRPA) was previously seen to efficiently bind a 48 bp simian virus 40 (SV40) "pseudo-origin" (PO) substrate that mimics a DNA structure found within the SV40 T antigen-origin (ori) complex. To understand the role of hRPA during the initiation of replication, we examined the PO sequence and structure requirements for hRPA interaction. Binding and unwinding were found to be most efficient when both strands of the central 8 nt single-stranded DNA (ssDNA) bubble region contained a polypyrimidine structure, with these activities proportionately reduced when the bubble region was replaced with a purine tract on one or both strands. Examination of the importance of the two duplex flanks indicates that the early gene side contains a DNA structural feature located one duplex turn from the bubble whose mutation significantly affects the affinity of hRPA for the substrate. When present in the context of ori, mutation of this sequence was seen to have significant effects on SV40 DNA replication in vitro and on the denaturation of ori, indicating that origin activity can be modulated by cis-acting elements which alter the hRPA binding affinity. Use of fork and overhang substrates containing 8 nt pyrimidine or purine arms demonstrates that hRPA binding to DNA involves a particular molecular polarity in which initial hRPA binding occurs on the 5' side of a ssDNA substrate, and then extends in the 3' direction to create a stably bound hRPA. These data have implications on the mechanism of the initiation of eukaryotic DNA replication as well as on the sites of nascent strand synthesis within the origin.


Direct evidence for the adaptive role of copy number variation on antifolate susceptibility in Plasmodium falciparum.
Resistance to antimalarials targeting the folate pathway is widespread. GTP-cyclohydrolase (gch1), the first enzyme in this pathway, exhibits extensive copy number variation (CN) in parasite isolates from areas with a history of longstanding antifolate use. Increased CN of gch1 is associated with a greater number of point mutations in enzymes targeted by the antifolates, pyrimethamine and sulphadoxine. While these observations suggest that increases in gch1 CN are an adaptation to drug pressure, changes in CN have not been experimentally demonstrated to directly alter drug susceptibility. To determine if changes in gch1 expression alone modify pyrimethamine sensitivity, we manipulated gch1 CN in several parasite lines to test the effect on drug sensitivity. We report that increases in gch1 CN alter pyrimethamine resistance in most parasites lines. However we find evidence of a detrimental effect of very high levels of gch1 overexpression in parasite lines with high endogenous levels of gch1 expression, revealing the importance of maintaining balance in the folate pathway and implicating changes in gch1 expression in preserving proper metabolic flux. This work expands our understanding of parasite adaptation to drug pressure and provides a possible mechanism for how specific mutations become fixed within parasite populations.


Complete rpoB gene sequencing as a suitable supplement to DNA-DNA hybridization for bacterial species and genus delineation.
DNA-DNA hybridization (DDH), the gold standard for bacterial species delineation, is a laborious method and the alternative, average nucleotide identity (ANI), a genomic sequence-derived parameter, is not applicable to non-sequenced species. A universal cut-off value to delineate bacterial species does not exist, yet a DDH value <70 % and ANI <95+/-0.5 % have proved useful in selected examples. We herein compare published values for DDH and ANI with sequence similarity of rpoB gene sequences retrieved from GenBank for strains of 230 bacterial species representative of 45 genera. Intraspecific rpoB sequence similarity was 98.2-100 %. We observed that an rpoB gene sequence similarity <or=97.7 % significantly correlated with a DDH value <70 % and an ANI value <94.3 %. An rpoB gene sequence similarity <85.5 % correlated with membership of different genera. When applied to fastidious and as-yet-uncultivated organisms lacking experimental DDH values, these cut-off values suggested that 'Candidatus Blochmannia pennsylvanicus' and 'Candidatus Blochmannia floridarius' may belong to different genera, that the different endosymbiotic Buchnera aphidicola organisms may belong to different genera and that, while the tsetse fly enteric symbiont Sodalis glossinidius may belong to the Enterobacteriaceae, the endocellular obligate symbiont Wigglesworthia glossinidia from the same host may belong to the group of as-yet-uncultivated gammaproteobacteria. rpoB gene sequence similarity provides an efficient supplement to DDH and ANI measurements to delineate bacterial species and genera, including delineation of as-yet-uncultivated, non-sequenced organisms.


Determination of the intracellular sites and topology of glucosylceramide synthesis in rat liver.
We examined the intracellular site(s) and topology of glucosylceramide (GlcCer) synthesis in subcellular fractions from rat liver, using radioactive and fluorescent ceramide analogues as precursors, and compared these results with those obtained in our recent study of sphingomyelin (SM) synthesis in rat liver [Futerman, Stieger, Hubbard & Pagano (1990) J. Biol. Chem. 265, 8650-8657]. In contrast with SM synthesis, which occurs principally at the cis/medial Golgi apparatus, GlcCer synthesis was more widely distributed, with substantial amounts of synthesis detected in a heavy (cis/medial) Golgi-apparatus subfraction, a light smooth-vesicle fraction that is almost devoid of an endoplasmic-reticulum marker enzyme (glucose-6-phosphatase), and a heavy vesicle fraction. Furthermore, no GlcCer synthesis was detected in an enriched plasma-membrane fraction after accounting for contamination by Golgi-apparatus membranes. These results suggest that a significant amount of GlcCer may be synthesized in a pre- or early Golgi-apparatus compartment. Unlike SM synthesis, which occurs at the luminal surface of the Golgi apparatus, GlcCer synthesis appeared to occur at the cytosolic surface of intracellular membranes, since (i) limited proteolytic digestion of intact Golgi-apparatus vesicles almost completely inhibited GlcCer synthesis, and (ii) the extent of UDP-glucose translocation into the Golgi apparatus was insufficient to account for the amount of GlcCer synthesis measured. These findings imply that, after its synthesis, GlcCer must undergo transbilayer movement to the luminal surface to account for the known topology of higher-order glycosphingolipids within the Golgi apparatus and plasma membrane.


[Appropriateness evaluation of short hospital admissions using Appropriateness Evaluation Protocol (Italian version): experience of a teaching hospital].
Italian version of Appropriateness Evaluation Protocol (AEP) is a tool for evaluating the appropriateness of hospitalization for acute patients. In particular, it aims to verify and quantify the reasons of appropriateness associated to the day of admission and the single days of hospital stay. The aim of the present paper is to evaluate the appropriateness of ordinary, 2-3 days lasting, hospital admissions within an university hospital. We examined a sample of 518 hospital admissions: 370 admissions (71%) lasting 2 days, and 148 admissions (29%) lasting 3 days. Results analysis showed different levels of appropriateness between the 2-days and the 3-days admissions: the appropriate admissions were 18% in the sample of the 2-days admissions and 38% in the sample of 3-days admissions. Most inappropriate days of admission and stay in hospital are due to attended or to the execution of diagnostic procedures. In order to evaluate accuracy by means of AEP methodology, it is necessary to improve the quality of medical documentation using standardized medical records. AEP, in the framework of the continuous quality improvement, is a valid tool to reorganise health care processes.


Inosine-5'-monophosphate dehydrogenase is a rate-determining factor for p53-dependent growth regulation.
We have proposed that reduced activity of inosine-5'-monophosphate dehydrogenase (IMPD; IMP:NAD oxidoreductase, EC 220.127.116.11), the rate-limiting enzyme for guanine nucleotide biosynthesis, in response to wild-type p53 expression, is essential for p53-dependent growth suppression. A gene transfer strategy was used to demonstrate that under physiological conditions constitutive IMPD expression prevents p53-dependent growth suppression. In these studies, expression of bax and waf1, genes implicated in p53-dependent growth suppression in response to DNA damage, remains elevated in response to p53. These findings indicate that under physiological conditions IMPD is a rate-determining factor for p53-dependent growth regulation. In addition, they suggest that the impd gene may be epistatic to bax and waf1 in growth suppression. Because of the role of IMPD in the production and balance of GTP and ATP, essential nucleotides for signal transduction, these results suggest that p53 controls cell division signals by regulating purine ribonucleotide metabolism.


Oncostatin M promotes STAT3 activation, VEGF production, and invasion in osteosarcoma cell lines.
We have previously demonstrated that both canine and human OSA cell lines, as well as 8 fresh canine OSA tumor samples, exhibit constitutive phosphorylation of STAT3, and that this correlates with enhanced expression of matrix metalloproteinase-2 (MMP2). While multiple signal transduction pathways can result in phosphorylation of STAT3, stimulation of the cytokine receptor gp130 through either IL-6 or Oncostatin M (OSM) is the most common mechanism through which STAT3 is activated. The purpose of this study was to evaluate the role of IL-6 and OSM stimulation on both canine and human OSA cell lines to begin to determine the role of these cytokines in the biology of OSA. RT-PCR and Western blotting were used to interrogate the consequences of OSM and IL-6 stimulation of OSA cell lines. OSA cells were stimulated with OSM and/or hepatocyte growth factor (HGF) and the effects on MMP2 activity (gel zymography), proliferation (CyQUANT), invasion (Matrigel transwell assay), and VEGF production (Western blotting, ELISA) were assessed. The small molecule STAT3 inhibitor LLL3 was used to investigate the impact of STAT3 inhibition following OSM stimulation of OSA cells. Our data demonstrate that the OSM receptor (OSMR), but not IL-6 or its receptor, is expressed by all human and canine OSA cell lines and canine OSA tumor samples; additionally, OSM expression was noted in all tumor samples. Treatment of OSA cell lines with OSM induced phosphorylation of STAT3, Src, and JAK2. OSM stimulation also resulted in a dose dependent increase in MMP2 activity and VEGF expression that was markedly reduced following treatment with the small molecule STAT3 inhibitor LLL3. Lastly, OSM stimulation of OSA cell lines enhanced invasion through Matrigel, particularly in the presence of rhHGF. In contrast, both OSM and HGF stimulation of OSA cell lines did not alter their proliferative capacity. These data indicate OSM stimulation of human and canine OSA cells induces STAT3 activation, thereby enhancing the expression/activation of MMP2 and VEGF, ultimately promoting invasive behavior and tumor angiogenesis. As such, OSM and its receptor may represent a novel target for therapeutic intervention in OSA.


Pupil responses to near visual demand during human visual development.
Pupil responses of adults to near visual demands are well characterized but those of typically developing infants and children are not. This study determined the following pupil characteristics of infants, children and adults using a PowerRefractor (25 Hz): i) binocular and monocular responses to a cartoon movie that ramped between 80 and 33 cm (20 infants, 20 2-4-yr-olds and 20 adults participated) ii) binocular and monocular response threshold for 0.1 Hz sinusoidal stimuli of 0.25 D, 0.5 D or 0.75 D amplitude (33 infants and 8 adults participated) iii) steady-state stability of pupil responses at 80 cms (8 infants and 8 adults participated). The change in pupil diameter with viewing distance (Δpd) was significantly smaller in infants and 2-4-yr-olds than in adults (p < 0.001) and significantly smaller under monocular than binocular conditions (p<0.001). The 0.75 D sinusoidal stimulus elicited a significant binocular pupillary response in infants and a significant binocular and monocular pupillary response in adults. Steady-state pupillary fluctuations were similar in infants and adults (p = 0.25). The results suggest that the contribution of pupil size to changes in retinal image quality when tracking slow moving objects may be smaller during development than in adulthood. Smaller monocular Δpd reflects the importance of binocular cues in driving near-pupillary responses.


Working memory relates to individual differences in speech category learning: Insights from computational modeling and pupillometry.
Across two experiments, we examine the relationship between individual differences in working memory (WM) and the acquisition of non-native speech categories in adulthood. While WM is associated with individual differences in a variety of learning tasks, successful acquisition of speech categories is argued to be contingent on WM-independent procedural-learning mechanisms. Thus, the role of WM in speech category learning is unclear. In Experiment 1, we show that individuals with higher WM acquire non-native speech categories faster and to a greater extent than those with lower WM. In Experiment 2, we replicate these results and show that individuals with higher WM use more optimal, procedural-based learning strategies and demonstrate more distinct speech-evoked pupillary responses for correct relative to incorrect trials. We propose that higher WM may allow for greater stimulus-related attention, resulting in more robust representations and optimal learning strategies. We discuss implications for neurobiological models of speech category learning.


Electroencephalographic Findings in Posthypoxic Myoclonus.
The physical examination findings of early posthypoxic myoclonus (PHM) are associated with poor prognosis. Recent findings indicate that patients with multifocal PHM, assumed to have a cortical origin, have a comparable outcome to resuscitated patients without PHM. Generalized PHM, assumed to have a subcortical myoclonus origin, is still associated with a bad clinical outcome. It is not known whether the electroencephalographic (EEG) findings differ between the multifocal and generalized myoclonus groups nor is the clinical significance clearly defined. Forty-three patients with PHM were retrospectively derived from an EEG database. Patients were categorized as having multifocal (i), generalized (ii), or undetermined (iii) PHM. Outcome was expressed in cerebral performance category scores. The EEG background was categorized into isoelectric (I), low voltage (II), burst suppression (III), status epilepticus (SE; IV), diffuse slowing (V), and mild encephalopathic or normal (VI). 17 patients had generalized PHM and 23 had multifocal PHM (3 undetermined). The EEG showed more SE in generalized compared to multifocal PHM (64% vs 13%, P< .001). Diffuse slowing was more often present in multifocal PHM (52% vs 17%, P < .05). Early-onset myoclonus occurred significantly more often in generalized PHM, and early generalized PHM was invariantly associated with poor outcome. In conclusion, patients with generalized PHM showed more SE. These EEG findings might be either subcortical corollaries or primarily cortical phenomena. Our retrospective results conflict with currently used clinical criteria for myoclonus classification, and we suggest that more refined difference may be needed for accurate assessment of PHM. To better understand PHM, prospective research with standardized clinical assessment and quantitative EEG analysis is needed.


Design method of nonsymmetric imaging systems consisting of multiple flat phase elements.
Imaging systems consisting of flat phase elements can realize the same functions and applications of conventional geometric optical systems, as well as the ones using aspherical or freeform optics, but can achieve more compactness, lighter-weight and easier-alignment. In addition, it is easy to integrate multiple phase elements into a single flat element. Here we propose a novel design method and realize the design of off-axis nonsymmetric imaging systems consisting of multiple flat phase elements. Compared with other traditional design methods of phase elements, the whole design process starts from an initial system using simple true geometric planes. The phase profiles or functions are generated point-by-point directly based on the given system specifications and configuration. In comparison with other direct or point-by-point design methods of flat phase elements, the rays of multiple fields and pupil positions are employed in the design framework. Closed-form phase functions of multiple flat elements are designed quickly and effectively by connecting and integrating the real three-dimensional space and the phase function space. This method can be taken as a fast phase retrieval method to some degree. To demonstrate the feasibility of the proposed design method, we present a high-performance compact system as design example. The design method and framework depicted in this paper can be applied in many areas, such as virtual reality (VR) and augmented reality (AR), miniature cameras, high-performance telescopy, microscopy, and illumination design.


Lost diagnoses in not otherwise specified headache in Emergency Department.
The diagnosis of Not Otherwise Specified (NOS) headaches in the Emergency Department (ED) is frequent despite many specialist visits performed. The aim of the study was to examine specialist visits carried out in the patients discharged from ED with diagnosis of NOS headache to evaluate discrepancies between specialist and ED diagnosis at discharge. We retrospectively (1.6.2018-31.12.2018) analyzed all the patients admitted with non-traumatic headache to the ED of the tertiary-care University Hospital of Trieste. We evaluated the patients discharged from ED with a final diagnosis of NOS headache and who underwent at least one specialist examination. Demographic data, specialist and ED diagnosis were analyzed. One hundred twenty-four patients (93 F, 31 M, mean age 44 ± 15 years) were included. 71.8% of patients were examined only by a neurologist, 12.9% by non-neurologists, 15.3% by both neurologist and non-neurologist. Only 37% of the patients received a precise diagnosis. Neurologist made a diagnosis slightly more frequently than the other consultants (40.5% vs 37.5%). Neurologists diagnosed primary headaches, headaches secondary to neurological diseases, and facial neuralgia, instead non-neurologists diagnosed only headaches secondary to non-neurological diseases. Primary headaches were diagnosed in 25.7% of cases, migraine being the most frequent. Physicians did not report any specialist diagnoses in the ED discharge sheet. Specialist consultants made specific diagnoses in about one-third of patients that were not reported as final in the discharge records by the ED physician. This leads to a loss of diagnoses and to an overestimation of NOS headache.


Effect of pindolol on potassium homeostasis in patients with essential hypertension.
A study of the effects of pindolol on potassium homeostasis was undertaken in 25 patients (19 women, 6 men) with essential hypertension. The patients were maintained on their usual diet and were withdrawn from antihypertensive therapy for three weeks before the study began. They were then randomly assigned to one of three treatment groups: (a) pindolol, 15 mg daily; (b) hydrochlorothiazide, 50 mg daily; and (c) both drugs combined. Total body potassium (TBK), urine aldosterone excretion, and plasma renin activity (PRA) were measured after eight weeks of therapy and compared with pretreatment values. Mean PRA remained unchanged in patients taking only pindolol or the drug combination, but it rose significantly in patients taking only hydrochlorothiazide. Mean urine aldosterone concentrations fell in patients taking only pindolol, rose in those taking only hydrochlorothiazide, and remained unchanged in those taking the combination. Mean TBK concentrations rose significantly in patients taking only pindolol or the combination, and fell significantly in those taking only hydrochlorothiazide. The rise in TBK concentrations with the combination clearly suggests that pindolol offsets the potassium wastage induced by diuretics, though probably by a mechanism outside the renin-aldosterone system. Because of this rise, it may be possible to eliminate potassium supplementation in patients taking the combination pindolol and hydrochlorothiazide.


Diet and serum cholesterol. An Australian family study.
Dietary intake patterns were studied in families in Busselton, Western Australia, known to have mothers and children with high, median, or low serum cholesterol values. There were no significant differences in the percentage contributions to total daily calories by protein, fat, or carbohydrate in mothers, children, or their families from these three groups. The results support the view that diet, per se, does not account for differences in observed serum cholesterol levels within a culturally homogeneous community.


Development of glutamic acid decarboxylase immunoreactivity in the cat's lateral geniculate nucleus.
The development of glutamic acid decarboxylase (GAD) immunoreactivity in the cat's dorsal LGN was studied during fetal and postnatal life. In the adult, inhibitory interactions within the LGN are known to be mediated by GABA. Here we have used an antiserum to GAD, the rate-limiting synthetic enzyme for GABA, to examine the development of the anatomical substrate for this inhibitory system. The pattern of immunostaining observed in the adult cat LGN was similar to that reported by Fitzpatrick et al. (1984), with heavily stained somata and proximal dendrites located within the LGN layers and the adjacent perigeniculate nucleus (PGN). The LGN also contained a complex array of terminal staining. In development, specific staining was seen about 2 weeks before birth and was confined to PGN somata and, to a lesser extent, to somata located in the future ventral C-layers. A similar pattern of immunostaining was seen using GABA antiserum. Not until birth did the A-layers of the LGN show appreciable staining of both somata and terminals; however, even then the pattern of immunostaining was far from mature. Furthermore, excessive numbers of PGN neurons appeared to stain. By 5 weeks after birth, the intensity of both soma and terminal staining within the A-layers of the LGN increased substantially relative to that of the PGN and ventral C-layers. The first glomerular clusters of terminal staining could also be seen, and the number of stained PGN neurons had diminished to levels similar to those seen in the adult. The pattern of immunostaining was almost adultlike by 2 months after birth, except within the C-complex, where the staining did not yet show the distinct difference in staining intensity present in the adult between dorsal layer C and ventral layers C1 and C2. The final adult pattern of GAD immunoreactivity appeared by 3 months after birth. These results suggest that during fetal life the PGN and ventral C-layers of the LGN may supply the first source of GABA-mediated inhibition to the nucleus, with the major portion of the inhibition supplied by intrinsic LGN neurons arising postnatally. Thus, PGN neurons may provide part of the anatomical substrate for the inhibitory interactions seen physiologically during late fetal development (Shatz and Kirkwood, 1984). Finally, the relatively late appearance of the adultlike pattern of GAD immunostaining suggests that intrageniculate inhibitory circuitry continues to develop well after birth.


Transforming growth factor-beta1-mediated activation of NF-kappaB contributes to enhanced ADAM-12 expression in mammary carcinoma cells.
A disintegrin and metalloproteinase-12 (ADAM-12), a member of multifunctional family of proteins, is upregulated in many cancers, including breast, lung, liver, prostate, gastric, and bladder. The multidomain structure, composed of a prodomain, a metalloproteinase, disintegrin-like, epidermal growth factor-like, cysteine-rich and transmembrane domains, and a cytoplasmic tail, allows ADAM-12 to promote matrix degradation, cell-cell adhesion, and intracellular signaling capacities and thereby to play a critical role in cancer growth and metastasis. Despite ample evidence linking increased ADAM-12 expression with cancer, the mechanisms controlling its upregulation are still unknown. In the present study, transforming growth factor-β1 (TGF-β1) is shown to increase ADAM-12 mRNA expression in MDA-MB-231 breast carcinoma cells. We have identified a promoter element responsible for TGF-β1-mediated ADAM-12 induction. We show interaction of NF-κB with ADAM-12 promoter and that high level of NF-κB activity in breast carcinoma cells results in the upregulation of ADAM-12 expression. Site-directed mutagenesis of the NF-κB element in ADAM-12 promoter and inhibition of NF-κB activity by Bay-11-7085 and MG-132 significantly reduced TGF-β1-mediated increase of ADAM-12 promoter-driven gene expression. Transfection of cells with a dominant-negative mutant form of IκBα (IκBαΔN), which inhibits activation of NF-κB, significantly reduced transcription from ADAM-12 promoter-reporter in TGF-β1-stimulated MDA-MB-231 cancer cells. In correlation, overexpression of NF-κB induced ADAM-12 expression in a dose-dependent manner. DNA-binding and ChIP assays indicated that p65 subunit of NF-κB binds to ADAM-12 promoter. Together, our study identified a cellular mechanism for induction of ADAM-12, which involves NF-κB and its activation by TGF-β1.


Etiologic yield of subspecialists' evaluation of young children with global developmental delay.
To determine the etiologic yield of subspecialists' evaluation of young children with global developmental delay. In addition, variables that may predict finding an underlying etiology were also identified. All children <5 years of age, referred over an 18-month period to subspecialty services for initial evaluation of a suspected developmental delay, were prospectively enrolled. Diagnostic yield was ascertained after the completion of clinical assessments and laboratory investigations requested by the evaluating physician. Ninety-nine children (71 boys) were found to have global developmental delay; 96% had a mild or moderate delay documented. An etiologic diagnosis was determined in 44. Four diagnoses (cerebral dysgenesis, hypoxic-ischemic encephalopathy, toxin exposure, chromosomal abnormalities) accounted for 34 of 44 (77%) of the diagnoses made. The presence of co-existing autistic traits was associated with significantly decreased diagnostic yield (0/19 vs 44/80, P <.0001), whereas specific historical features (eg, family history, toxin exposure, and perinatal difficulty; 23/32 vs 21/67, P =.0002) and findings on physical examination (eg, dysmorphology, microcephaly, and focal motor findings; 35/48 vs 9/51, P <.0001) were significantly associated with identifying a diagnosis. Multiple logistic regression analysis identified antenatal toxin exposure, microcephaly, focal motor findings, and the absence of autistic traits as significant predictor variables for the identification of an etiology. An etiologic diagnosis is often possible in the young child with global developmental delay, particularly in the absence of autistic features. Etiologic yield is augmented by presence of specific findings on history or physical examination on initial assessment.


Assessment of electron density effects on dose calculation and optimisation accuracy for nasopharynx, for MRI only treatment planning.
Computed tomography (CT) is the gold standard for radiotherapy simulation and treatment planning, providing spatial accuracy, bony anatomy definition and electron density information for dose calculations. Magnetic resonance imaging (MRI) has been introduced in radiotherapy to improve visualisation of anatomy for accurate target definition and contouring, however lacks electron density information required for dose calculations, with various methods used to overcome this. The aim of this work is to assess the impact on dose calculation accuracy and optimisation results of different approaches to determine electron density, as could be used in MRI only treatment planning for nasopharyngeal datasets with VMAT treatment plans. Volumetric modulated arc therapy (VMAT) plans were created for 10 retrospective head and neck (H&N) nasopharyngeal patients. The VMAT plans were generated on the gold standard dataset, the original CT scan. Data sets with no density correction (water equivalent) and two different sets of bulk density correction for bone/air/tissue applied separately were generated for these patients and the VMAT plans were recalculated for each case. Plans were also reoptimised on these data sets, and recalculated. Optimisation error was assessed through equivalent uniform dose (EUD) differences. Additionally, point dose comparison, dose volume histogram (DVH) analysis and gamma analysis of dose were used to assess dose calculation error. The dose calculation error on average was an increase in EUD whereas the optimisation error on average was a reduction in EUD compared to the original plan for all datasets aside from the bone only override dataset where bone was set to 1.61 g/cm3. For the optimisation error, the largest mean absolute error (MAE) was 1.88 Gy EUD for the PTV, and 2.21 Gy EUD for the brainstem, for the reoptimisation completed on the air only overridden dataset, and recalculated on the original. Bulk density corrections for bone and air provide dose calculations within 3% of the original treatment plans. Optimisation errors have the potential to be greater than dose calculation errors if incorrect density corrections are utilized. Electron density correction using a bulk density approach achieves dose calculation uncertainties within 3%, however more advanced approaches, such as a voxel based approach, may improve accuracy and should be considered.


Use of stream chemistry for monitoring acidic deposition effects in the Adirondack region of New York.
Acid-neutralizing capacity (ANC) and pH were measured weekly from October 1991 through September 2001 in three streams in the western Adirondack Mountain region of New York to identify trends in stream chemistry that might be related to changes in acidic deposition. A decreasing trend in atmospheric deposition of SO4/2- was observed within the region over the 10-yr period, although most of the decrease occurred between 1991 and 1995. Both ANC and pH were inversely related to flow in all streams; therefore, a trend analysis was conducted on (i) the measured values of ANC and pH and (ii) the residuals of the concentration-discharge relations. In Buck Creek, ANC increased significantly (p < 0.05) over the 10 yr, but the residuals of ANC showed no trend (p > 0.10). In Bald Mountain Brook, ANC and residuals of ANC increased significantly (p < 0.01), although the trend was diatonic-a distinct decrease from 1991 to 1996 was followed by a distinct increase from 1996 to 2001. In Fly Pond outlet, ANC and residuals of ANC increased over the study period (p < 0.01), although the trend of the residuals resulted largely from an abrupt increase in 1997. In general, the trends observed in the three streams are similar to results presented for Adirondack lakes in a previous study, and are consistent with the declining trend in atmospheric deposition for this region, although the observed trends in ANC and pH in streams could not be directly attributed to the trends in acidic deposition.


Facile preparation of flexible binder-free graphene electrodes for high-performance supercapacitors.
A facile two-step strategy to prepare flexible graphene electrodes has been developed for supercapacitors using thermal reduction of graphene oxide (GO) and thermally reduced graphene oxide (TRGO) composite films. The tunable porous structure of the GO/TRGO film provided channels to release the high pressure generated by CO2 gas. The graphene electrode obtained from reduced-GO/TRGO (1 : 1 in mass ratio) film showed great flexibility and high film density (0.52 g cm-3). Using the EMI-BF4 electrolyte with a working voltage of 3.7 V, the as-fabricated free-standing reduced-GO/TRGO (1 : 1) film achieved a great gravimetric capacitance of 180 F g-1 (delivering a gravimetric energy density of 85.6 W h kg-1), a volumetric capacitance of 94 F cm-3 (delivering a volumetric energy density of 44.7 W h L-1), and a 92% retention after 10 000 charge/discharge cycles. In addition, the solid state flexible supercapacitor with the free-standing reduced-GO/TRGO (1 : 1) film as the electrodes and the EMI-BF4/poly (vinylidene fluoride hexafluopropylene) (PVDF-HFP) gel as the electrolyte also demonstrated a high gravimetric capacitance of 146 F g-1 with excellent mechanical flexibility, bending stability, and electrochemical stability. The strategy developed in this study provides great potentials for the synthesis of flexible graphene electrodes for supercapacitors.


An alpha-L-arabinofuranosidase from Trichoderma reesei containing a noncatalytic xylan-binding domain.
L-Sorbose, an excellent cellulase and xylanase inducer from Trichoderma reesei PC-3-7, also induced alpha-L-arabinofuranosidase (alpha-AF) activity. An alpha-AF induced by L-sorbose was purified to homogeneity, and its molecular mass was revealed to be 35 kDa (AF35), which was not consistent with that of the previously reported alpha-AF. Another species, with a molecular mass of 53 kDa (AF53), which is identical to that of the reported alpha-AF, was obtained by a different purification procedure. Acid treatment of the ammonium sulfate-precipitated fraction at pH 3.0 in the purification steps or pepsin treatment of the purified AF53 reduced the molecular mass to 35 kDa. Both purified enzymes have the same enzymological properties, such as pH and temperature effects on activity and kinetic parameters for p-nitrophenyl-alpha-L-arabinofuranoside (pNPA). Moreover, the N-terminal amino acid sequences of these enzymes were identical with that of the reported alpha-AF. Therefore, it is obvious that AF35 results from the proteolytic cleavage of the C-terminal region of AF53. Although AF35 and AF53 showed the same catalytic constant with pNPA, the former showed drastically reduced specific activity against oat spelt xylan compared to the latter. Furthermore, AF53 was bound to xylan rather than to crystalline cellulose (Avicel), but AF35 could not be bound to any of the glycans. These results suggest that AF53 is a modular glycanase, which consists of an N-terminal catalytic domain and a C-terminal noncatalytic xylan-binding domain.


[Recent advances in pediatric non-Hodgkin lymphoma. Report on a retrospective single-center cohort and review of the literature].
Classification, staging and treatment response criteria of pediatric NHL have been revised. Long-term survival reaches ~90% at the expense of severe acute toxicities. The outcome of refractory and relapsed cases is poor. The small number of patients hinders introduction of targeted therapies. Here we summarize principles and perspectives of pediatric NHL supported by results of a retrospective clinical survey. Twenty-five patients (21 boys, 4 girls; mean age: 11.9 years) were registered between 2009 and 2018: 11 Burkitt lymphomas, 4 diffuse large B-cell lymphomas, 5 T-cell lymphoblastic lymphomas, and 1-1 grey-zone lymphoma, anaplastic large-cell lymphoma, cutaneous T-cell lymphoma, angioimmunoblastic lymphoma, and Castleman disease. Remission rate was 22/25, 20/25 patients survived (mean follow-up time: 3.9 years). Chemotherapies according to NHL-BFM 95, CHOP, FAB/LMB96, Inter-B-NHL Ritux 2010, Euro-LB02, and ALCL99 were applied. Adjuvant immunotherapy was applied in patients with mature B-cell NHL (rituximab in 7 cases, obinutuzumab in 2 relapsed cases). In Castleman disease siltuximab was applied.


Composition and quantitation of microalgal lipids by ERETIC ¹H NMR method.
Accurate characterization of biomass constituents is a crucial aspect of research in the biotechnological application of natural products. Here we report an efficient, fast and reproducible method for the identification and quantitation of fatty acids and complex lipids (triacylglycerols, glycolipids, phospholipids) in microalgae under investigation for the development of functional health products (probiotics, food ingredients, drugs, etc.) or third generation biofuels. The procedure consists of extraction of the biological matrix by modified Folch method and direct analysis of the resulting material by proton nuclear magnetic resonance (¹H NMR). The protocol uses a reference electronic signal as external standard (ERETIC method) and allows assessment of total lipid content, saturation degree and class distribution in both high throughput screening of algal collection and metabolic analysis during genetic or culturing studies. As proof of concept, the methodology was applied to the analysis of three microalgal species (Thalassiosira weissflogii, Cyclotella cryptica and Nannochloropsis salina) which drastically differ for the qualitative and quantitative composition of their fatty acid-based lipids.


Serum Amino Acid Concentrations in Infants from Malawi are Associated with Linear Growth.
Serum amino acid (AA) concentrations are correlated with childhood stunting, but their relation to linear growth velocity has not been explored. This was a secondary analysis of a clinical trial where Malawian infants aged 6-12 mo were given a legume supplement providing 8.2 g/d of protein; anthropometry was conducted at multiple intervals, and fasted serum AA concentrations were measured at 12 mo of age. Lysine, proline, tryptophan, tyrosine, and valine concentrations were higher in infants with a linear growth velocity z-score >0 than those <0. Corrected Spearman correlation coefficients between individual AA concentrations and weight-for-height and length velocity from 6 to 12 mo of age were positively correlated for glycine, isoleucine, proline, serine, threonine, tyrosine, and valine. Additionally, weight-for-height was correlated with arginine, asparagine, glutamine, leucine, lysine, methionine, and phenylalanine. The observed associations suggest that testing the hypothesis that essential AA provision will reduce linear growth faltering is warranted. This trial was registered at clinicaltrials.gov as NCT02472262.


False-negative prenatal exclusion of Wiskott-Aldrich syndrome by measurement of fetal platelet count and size.
The study of the fetal platelet count and size can, according to the literature, be used for the prenatal diagnosis of the Wiskott-Aldrich syndrome (WAS). So far, no affected fetuses have been identified by this method. All pregnancies in which this method had been applied to resulted, as correctly predicted, in the birth of normal children. Here we report on a familial case of WAS where the haematological parameters failed to reveal the affected second child. Hence we assume that the platelet count and size of platelets remain normal in fetuses with WAS to the gestational age of 22 weeks and cannot be used for prenatal diagnosis.


Hepatic progenitor cells in the form of ductular structures within a GIST liver metastasis: supporting a putative role in the hepatic metastatic niche.
Recent studies have highlighted the presence of hepatic progenitor cells (HPCs) in metastatic liver carcinomas. We provide further evidence of this phenomenon, presenting a case of a gastrointestinal stromal tumour (GIST) liver metastasis with evidence of intra- and peritumoral HPC. A 64-year-old man presented with a gastric mass diagnosed as a high-risk KIT-mutated GIST. The patient was treated with Imatinib, recurring five years later with a liver mass. Liver biopsy disclosed a GIST metastasis, hallmarked by a proliferation of ductular structures without cytological atypia intermingled with the tumour cells, with a CK7/CK19/CD56-positive immunophenotype and rare CD44 positivity. The patient underwent liver resection, and the same ductular structures were present in the tumour interior and at its periphery. We document for the time the presence of HPC in the form of ductular structures in a GIST liver metastasis, further supporting their role in the liver metastatic niche.


Divergent induced responses to an invasive predator in marine mussel populations.
Invasive species may precipitate evolutionary change in invaded communities. In southern New England (USA) the invasive Asian shore crab, Hemigrapsus sanguineus, preys on mussels (Mytlius edulis), but the crab has not yet invaded northern New England. We show that southern New England mussels express inducible shell thickening when exposed to waterborne cues from Hemigrapsus, whereas naïve northern mussel populations do not respond. Yet, both populations thicken their shells in response to a long-established crab, Carcinus maenas. Our findings are consistent with the rapid evolution of an inducible morphological response to Hemigrapsus within 15 years of its introduction.


Bisphenol A and its analogue bisphenol S exposure reduce estradiol synthesis via the ROS-mediated PERK/ATF4 signaling pathway.
As a kind of endocrine-disrupting chemicals, BPA may affect the human placenta. Due to consumer unease about BPA, many manufacturers are using alternatives to BPA, such as BPS. However, some reports suggest that BPS may produce similar results to BPA. To understand how BPA/BPS leads to reduced synthesis of placental estradiol (E2), we conducted studies using a human choriocarcinoma cell (JEG-3) model for research. In this study. Elisa assay revealed that both BPA/BPS exposures decreased E2 synthesis in JEG-3 cells. The results of RT-PCR showed that both BPA and BPS could reduce the mRNA expression of CYP19A1, a key enzyme for E2 synthesis in JEG-3 cells. In addition, Western blot assay showed that BPA/BPS-induced ER-stress PERK/eIF2α/ATF4 signaling protein expression was increased. The expression of ROS in cells after exposure to BPA/BPS was detected using the 2,7-dichlorodihydrofluorescein diacetate (DCF-DA) method. The results of this experiment showed that BPA/BPS significantly induced an inhibition of ROS in JEG-3 cells. The present study concluded that, firstly, BPS exposure induced almost the same effect as BPA in reducing E2 synthesis in JEG-3 cells. Second, BPA/BPS exposure may reduce E2 synthesis in JEG-3 cells by increasing ROS levels and thus activating endoplasmic reticulum stress.


Western hemisphere isolates of African swine fever virus: asymptomatic carriers and resistance to challenge inoculation.
Convalescent clinically normal pigs were tested for the persistence of African swine fever (ASF) infection. One group of pigs was examined 135 days after inoculation with a Brazilian isolate and a 2nd group was examined 110 days after inoculation with a Dominican Republic isolate. Susceptible pigs exposed by contact to these groups remained clinically normal. These contact pigs plus 2 more pigs added to each group developed ASF after being fed and inoculated with tissues collected from recovered pigs. African swine fever virus was not isolated in swine buffy coat cultures inoculated with supernatant fluid from the collected tissues. The remaining convalescent Brazilian and Dominican Republic ASF pigs were challenge inoculated with homologous virus and then with Lisbon 60 ASF virus. Pigs in both groups remained clinically normal after homologous virus challenge inoculation. Pigs in the Brazilian group remained clinically normal after inoculation of the lisbon 60 ASF viral isolate. Of 5 pigs in the Dominican Republic group, 3 developed a transient viremia after inoculation of the Lisbon 60 ASF viral isolate.


Substrate-regulated cyanide hydratase (chy) gene expression in Fusarium solani: the potential of a transcription-based assay for monitoring the biotransformation of cyanide complexes.
The fungus Fusarium solani detoxifies cyanide through induction of the cyanide hydratase gene activity (chy) in the presence of either KCN or the metal-complexed cyanides, K2Ni(CN)4 or K4Fe(CN)6, at pH 7.0 and 4.0 respectively. Sequence analysis of the chy gene identified primers for reverse transcriptase-polymerase chain reaction (RT-PCR)-directed analysis of mRNA transcripts, which demonstrated that activity correlated to the substrate-specific induction of gene expression. chy transcription was initiated 30-60 min after exposure of F. solani cultures to cyanide complexes. Maximum expression was detected within 4.5 h, after which chy mRNA synthesis declined below the limits of detection within 26 h. A lag period of approximately 2 h, following initial transcription, was recorded before cyanide complexes were converted to formamide. mRNA transcripts of chy were not detected in the absence of cyanide or cyanide complexes. The presence of introns within the gene resulted in a difference in size of 100 bp for DNA compared with mRNA of the corresponding 5' region. This size difference facilitated PCR detection of gene and transcript respectively. Comparisons of the predicted amino acid sequence of the F. solani chy gene and those of Gloeocerospora sorghi, Fusarium lateritium and Leptosphaeria maculans demonstrate that cyanide hydratase genes are highly conserved and of a similar evolutionary origin. These data predict that the functional assay described here to monitor the induction of chy gene expression and, potentially, cyanide degradation would be applicable to a variety of polluted environments.


Antigen-presenting cell population dynamics during murine silicosis.
Silicosis is an occupational lung disease resulting from the inhalation of silica particles over prolonged periods of time, which causes chronic inflammation and progressive pulmonary fibrosis. Alveolar macrophages (AM) are critical effector cells, while less is known about the role and function of pulmonary dendritic cells (DC) in silicosis. We hypothesize that a balance exists between the suppressive nature of AM and the stimulatory capacity of DC to regulate lung immunity, and that this equilibrium may be overcome by silica exposure in vivo. Our results demonstrate that in response to silica exposure, both the percent and absolute number of AM significantly decreased over time, with a concomitant significant increase in DC. Both AM and DC exhibited cellular activation in response to silica, indicated by increased expression of cell surface markers. In the absence of silica-induced AM apoptosis (TNFR 1/2-null and Gld mice), no change was observed in the percent or absolute number of either cell type. Furthermore, bone marrow-derived DC, but not bone marrow-derived macrophages, migrated from the alveoli into the lung parenchyma in response to silica, resulting in significantly increased numbers of activated T lymphocytes. Collectively, the results demonstrate that AM and DC are distinct antigen-presenting cells within the respiratory tract that respond to silica exposure in vivo in unique ways, with significant implications for immune reactivity of the lung in response to environmental pathogens.


Loss of trigeminal sensitivity reduces olfactory function.
The trigeminal and olfactory nerves share overlapping innervation areas in the nasal cavity and seem to work in an interactive way. Loss of olfactory function leads to a decreased trigeminal sensitivity, as shown in anosmic subjects. To report the impact of disturbed trigeminal sensitivity on the olfactory function, we present a patient with unilateral loss of trigeminal function resulting from a meningeoma. Thresholds to a selective olfactory stimulus were elevated by a factor of 64 on the affected side. Recordings of event-related potentials in response to olfactory stimuli showed a significantly reduced response on the affected side. This report indicates that loss of trigeminal function may affect the sense of smell.


The cervical anatomy of Samotherium, an intermediate-necked giraffid.
Giraffidae are represented by many extinct species. The only two extant taxa possess diametrically contrasting cervical morphology, as the okapi is short-necked and the giraffe is exceptionally long-necked. Samotherium major, known from the Late Miocene of Samos in Greece and other Eurasian localities, is a key extinct giraffid; it possesses cervical vertebrae that are intermediate in the evolutionary elongation of the neck. We describe detailed anatomical features of the cervicals of S. major, and compare these characteristics with the vertebrae of the two extant giraffid taxa. Based on qualitative morphological characters and a quantitative analysis of cervical dimensions, we find that the S. major neck is intermediate between that of the okapi and the giraffe. Specifically, the more cranial (C2-C3) vertebrae of S. major represent a mosaic of features shared either with the giraffe or with the okapi. The more caudal (C5-C7) S. major vertebrae, however, appear transitional between the two extant taxa, and hence are more unique. Notably, the C6 of S. major exhibits a partially excavated ventral lamina that is strong cranially but completely absent on the caudal half of the ventral vertebral body, features between those seen in the giraffe and the okapi. Comprehensive anatomical descriptions and measurements of the almost-complete cervical column reveal that S. major is a truly intermediate-necked giraffid. Reconstructions of the neck display our findings.


How Important is Bioturbation for Sediment-to-Water Flux of Polycyclic Aromatic Hydrocarbons in the Baltic Sea?
In the present study a recently developed benthic flow-through chamber was used to assess the sediment-to-water flux of polycyclic aromatic hydrocarbons (PAHs) at 4 sites on the Swedish Baltic Sea coast. The flow-through chamber allows for assessment of the potential effect of bioturbation on the sediment-to-water flux of hydrophobic organic contaminants. The sediments at the 4 investigated sites have both varying contamination degree and densities of bioturbating organisms. The flux of individual PAHs measured with the flow-through chamber ranged between 21 and 510, 11 and 370, 3 and 9700, and 62 and 2300 ng m-2 d-1 for the 4 sites. To assess the potential effect of bioturbation on the sediment-to-water flux, 3 flow-through and closed chambers were deployed in parallel at each site. The activity of benthic organisms is attenuated or halted because of depletion of oxygen in closed benthic chambers. Therefore, the discrepancy in flux measured with the 2 different chamber designs was used as an indication of a possible effect of bioturbation. A potential effect of bioturbation on the sediment-to-water flux by a factor of 3 to 55 was observed at sites with a high density of bioturbating organisms (e.g., Marenzelleria spp., Monoporeia affinis, and Macoma balthica of approximately 860-1200 individuals m-2 ) but not at the site with much lower organism density (<200 individuals m-2 ). One site had a high organism density and a low potential effect of bioturbation, which we hypothesize to be caused by the dominance of oligochaetes/polychaetes at this site because worms (Marenzelleria spp.) reach deeper into the sediment than native crustaceans and mollusks. Environ Toxicol Chem 2019;38:1803-1810. © 2019 SETAC.


Inhibitor of p42/44 mitogen-activated protein kinase, but not p38 MAPK, attenuated antigen challenge of guinea pig airways in vitro.
Upon cross-linking of the high-affinity IgE receptors on mast cells, a family of mitogen-activated protein kinases (MAPKs) is activated. The present study examined the effects of p42/44 MAPK kinase inhibitor U0126 and p38 MAPK inhibitors SB220025 and PD169316 on ovalbumin (OVA)-induced anaphylactic contraction of isolated guinea pig bronchi and release of histamine and peptidoleukotrienes from lung fragments. Guinea pigs were actively sensitized by OVA. OVA induced anaphylactic bronchial contractions, and release of histamine and peptidoleukotrienes from lung fragments. U0126 (0.3-30 microM), but not SB220025 and PD169316 (3-30 microM), slightly suppressed peak OVA-induced bronchial contraction but markedly reduced anaphylactical contraction over a 50-min period in a dose-dependent manner. U0126 did not inhibit bronchial contractions induced by KCl, histamine or leukotriene D4. U0126 produced a slight reduction in OVA-induced release of histamine but a significant inhibition on the release of peptidoleukotrienes from lung fragments. Exogenous arachidonic acid-induced release of peptidoleukotrienes was not blocked by U0126. SB220025 and PD169316 had no effect on OVA-induced release of histamine and peptidoleukotrienes. Our data indicate that inhibitor of p42/44 MAPK kinase, but not p38 MAPK, can reduce antigen-induced release of peptidoleukotrienes leading to a rapid resolution of anaphylactic bronchial contraction, and may have therapeutic potential for allergic asthma.


Psychological treatments for depression and anxiety disorders in low- and middle- income countries: a meta-analysis.
The objective of this meta-analysis was to determine the efficacy of psychological treatments for depression and anxiety disorders in low- and middle- income countries (LAMIC). Meta-analysis of randomized controlled trials on psychological treatment of depression and anxiety disorders in low-and middle income countries using an existing database (www.evidencebasedpsychotherapies.org), PubMed, Embase, Psychinfo, Dissertation Abstracts International and the Cochrane Central Register of Controlled Trials were searched for studies published in all languages. Additional studies were identified from reference lists of found studies. Randomized controlled trials in which a psychological intervention for anxiety or depression was compared to a control condition (care-as-usual, waiting list, placebo, or another control group) were included. The randomized controlled trials needed to be conducted in a LAMI country (classification of LAMI countries according to the World Bank's list of economies) to be eligible for inclusion in the meta-analysis. Psychological treatments were defined as interventions in which the core element of treatment consisted of verbal communication between a therapist and a patient. Seventeen studies met our inclusion criteria, with a total of 3,010 participants. The mean standardized difference between the treatment and control groups at post-test was 1.02 (95% CI: 0.76∼1.28) which corresponds well with the effects found in high-income countries. These results indicate that psychological treatments of depression and anxiety disorders are also effective in LAMI countries, and may encourage global dissemination of these interventions.


Evaluation of Effect of Aluminum Oxide on Flexural Strength and Surface Roughness of Conventional Heat-Cure Denture Base Resin.
Acrylic denture base tends to fracture frequently during their service due to poor strength. The surface roughness of denture base is a critical property because denture base with rough surface will cause accumulation of food particles ,thereby leading plaque retention . Microbes such as candida albicans are seen inhabitating the surface. Conventional heat cure denture base reins(DPI) and heat cure denture base resin with incorporation of 15wt% aluminium oxide was studied in two groups with 20 samples each. A mold of size 65 mm × 10 mm × 3 mm (ISO Standard) was obtained by investing brass rectangles. About forty specimens were prepared. Specimens were divided into two groups (n = 20) coded A and B. Group A was the control group (n = 20) without addition of aluminum oxide. Group B was the experimental group (n = 20) with addition of 15 wt % aluminum oxide. All the specimens were stored in distilled water for 14 days. The flexural strength was measured using a three-point bending test in a universal testing machine, and the surface roughness was measured using contact-type profilometer. Incorporation of 15wt% aluminum oxide leads to a significant increase in flexural strength and surface roughness of conventional heat-cure denture base resin.


Readout properties of the specklegram recorded in photorefractive Bi(12)SiO(20) crystal.
The readout properties of the specklegram recorded in a photorefractive Bi(12)SiO(20) (BSO) crystal plate have been investigated by observing the Young fringes and the polarization change of the light transmitted from the BSO plate. The Young fringes can be obtained without an analyzer by any linearly polarized readout beam; they have higher visibility than those obtained from a photographic plate specklegram, since the specklegram recorded in the BSO crystal can be read out by the spatial distribution of both the degree of polarization and the azimuth angle of polarization. Selective interference of a kind is performed.


Delayed allergy-like reactions to X-ray contrast media: mechanistic considerations.
Iodinated X-ray contrast media are among the most frequently used pharmaceuticals for intravascular administration. Although the newer low osmolality, nonionic contrast media, are generally well tolerated, it is well known that they, like the ionic contrast media, give rise to immediate or delayed adverse reactions in susceptible individuals. In the present review, the delayed allergy-like reactions, which by definition occur more than 1 h after contrast medium administration, are described, and the possible pathophysiological mechanisms discussed. Delayed allergy-like reactions to contrast media, which have been reported to occur in 0.5-2% of recipients, are mainly mild to moderate skin reactions of the maculopapular exanthematous and urticarial/angioedematous types. Most of the reactions become apparent after a latency of 3 h to 2 days and disappear within 1 week. The incidence of more severe reactions is extremely low. Main risk factors for delayed allergy-like reactions appear to be a previous contrast medium reaction, a history of allergy, IL-2 treatment and being of Japanese descent. At present, the exact pathogenesis of these delayed reactions is still unclear. There is, however, increasing evidence that a significant proportion of the reactions are T-cell mediated.


The importance of identifying and validating prognostic factors in oncology.
Prognosis plays a vital role in patient management and decision making. The assessment of prognostic factors, which relate baseline clinical and experimental covariables to outcomes, is one of the major objectives in clinical research. Historically, the impetus for the identification of prognostic factors has been the need to accurately estimate the effect of treatment adjusting for these variables. In oncology, the variability in outcome may be related to prognostic factors rather than to differences in treatments. In this article, we begin with a brief review of prognostic factors, and then subsequently offer a general discussion of their importance. Next, we describe the significance of study design before presenting various modeling approaches for identifying these factors and discussing the relative values of the different approaches. We illustrate the concepts within the framework of published and ongoing phase III trials in oncology.