Single-Color Fluorescence Lifetime Cross-Correlation Spectroscopy In Vivo.
The ability to quantify protein concentrations and to measure protein interactions in vivo is key information needed for the understanding of complex processes inside cells, but the acquisition of such information from living cells is still demanding. Fluorescence-based methods like two-color fluorescence cross-correlation spectroscopy can provide this information, but measurement precision is hampered by various sources of errors caused by instrumental or optical limitations such as imperfect overlap of detection volumes or detector cross talk. Furthermore, the nature and properties of used fluorescent proteins or fluorescent dyes, such as labeling efficiency, fluorescent protein maturation, photostability, bleaching, and fluorescence brightness can have an impact. Here, we take advantage of previously published fluorescence lifetime correlation spectroscopy which relies on lifetime differences as a mean to discriminate fluorescent proteins with similar spectral properties and to use them for single-color fluorescence lifetime cross-correlation spectroscopy (sc-FLCCS). By using only one excitation and one detection wavelength, this setup avoids all sources of errors resulting from chromatic aberrations and detector cross talk. To establish sc-FLCCS, we first engineered and tested multiple green fluorescent protein (GFP)-like fluorescent proteins for their suitability. This identified a novel, to our knowledge, GFP variant termed short-lifetime monomeric GFP with the so-far shortest lifetime. Monte-Carlo simulations were employed to explore the suitability of different combinations of GFP variants. Two GFPs, Envy and short-lifetime monomeric GFP, were predicted to constitute the best performing couple for sc-FLCCS measurements. We demonstrated application of this GFP pair for measuring protein interactions between the proteasome and interacting proteins and for measuring protein interactions between three partners when combined with a red florescent protein. Together, our findings establish sc-FLCCS as a valid alternative for conventional dual-color fluorescence cross-correlation spectroscopy measurements.


Spatio-temporal variation of suspended and sedimentary organic matter quality in the Bay of Marseilles (NW Mediterranean) assessed by biochemical and isotopic analyses.
Isotopic and biochemical features of suspended particulate organic matter (POM) in the water column and of sedimentary organic matter (SOM) were investigated seasonally in the Bay of Marseilles. Biochemical compounds (carbohydrates, lipids and proteins) were consistently more concentrated in POM than in SOM, with SOM mainly composed of insoluble carbohydrates. POM displayed lower δ(13)C and higher δ(15)N values than SOM. Phytoplanktonic production represented the major contributor of POM year-round with spatial and seasonal variations. Climatic parameters and wind-induced currents created differences in POM contributions, with more important inputs of terrestrial OM at one sampling site. Spatial and seasonal variations were lower for SOM. The composition of this pool appeared to be linked with the permanent inputs of phytoplankton and Posidonia oceanica detritus. The combined use of biochemical and isotopic analyses was a useful tool to characterize OM pools and would help understanding the trophic functioning of this coastal environment.


Intraspecific variation of life history parameters in the terrestrial isopod, Armadillidium vulgare.
Individual populations of the terrestrial isopod, Armadillidium vulgare, were studied in three Texas coastal prairie habitats: Chinese tallow forest, oak forest, and a Baccharis-grassland area. Time-specific life tables were compared for each population to determine intraspecific variation in life history parameters. Survivorship was greatest in the Baccharis area but density was lower and fluctuated less in this area than in the tallow or oak forests. Density in the oak forest was higher than in the tallow or Baccharis habitat. Density in the tallow and oak forests increased sharply during spring and summer and declined throughout the winter. Reproductive capacity of females in all three areas increased directly with body length but did not differ significantly between habitats. Density and reproductive performance of isopods in the tallow and oak forests was asynchronous with autumn leaf fall; this asynchrony may be a response to tannins leached from fallen leaves of these trees. Density and reproductive potential of isopods in the Baccharis-grassland, however, did not exhibit such marked fluctuations. Isopods in this latter habitat responded moderately to annual input of detritus during the fall.


An Exploratory Study of the Prosecution of Fatal Child Maltreatment: Criminal Charges Filed Against Presumed Perpetrators in the United States in 2017.
In the United States child maltreatment fatalities (CMFs) do not usually meet the standard for manslaughter or murder, resulting in convictions of lesser crimes and little jail time. This exploratory study examined the charges brought against suspected CMF perpetrators in 2017. Univariate and bivariate analyses were conducted using data obtained from the Nexis Uni newspaper database, that has over 40,000 high quality media sources, for the year 2017. We found that the most frequently used charges were endangering the welfare of a child and murder, the former of which was more related to neglect-deaths and the latter to physical abuse-deaths. There was no difference between charges for male and female perpetrators. Practical implications for research, policy, and practice are discussed.


Use of liposomes in probing the uptake of liposomal phosphatidylcholine by rabbit lung in vitro.
The purpose of this study was to characterize the uptake of liposomal phosphatidylcholine by lung tissue and its subcellular organelles. Multilamellar liposomes were prepared from egg yolk phosphatidylcholine, dicetyl phosphate, and cholesterol (molar ratio 7 : 2 : 1). Liposomal phosphatidylcholine labeled with [1-14C]dipalmitoyl phosphatidylcholine was taken up by lung slices and incorporated into subcellular organelles including lamellar bodies, mitochondria, and microsomes. In addition, when liposomes were incubated with lamellar bodies, mitochondria, or microsomes, the transfer of liposomal phosphatidylcholine to these subcellular fractions was facilitated by the cytosolic fraction. In tissue slice experiments after 1 h of incubation, about 86% of the total radioactivity absorbed by lung slices and subcellular organelles was recovered in phosphatidylcholine. The ratio of the radioactivity of fatty acids at 1- and 2-positions of dipalmitoyl phosphatidylcholine recovered from all fractions was nearly 1 : 1. This suggests that most phosphatidylcholine molecules were taken up intact. In conclusion, this study provides a method using liposomes as a tool for probing the phosphatidylcholine transfer mechanism in lung.


[Angioid streaks].
Angioid streaks represent breaks in Bruch's membrane, appearing as dark or reddish radial streaks eminating from the optic disc. Usually asymptomatic, these streaks may develop neovascularisation and lead to a maculopathy with marked loss of vision. Some associations with systemic disease are classically described, especially pseudoxanthoma elasticum. This condition may involve cardiovascular complications. A mutation has been found in the ABCC6 gene, which encodes for a membrane transport protein involved in the synthesis of the extracellular matrix. Imaging allows for visualization of the extent of the streaks, and autofluorescence is particularly informative. Spectral domain OCT may also demonstrate early breaks in Bruch's membrane. Neovascular complications, previously responsible for inevitable visual impairment at some point after their occurrence, are now managed by intravitreal injections of anti-VEGFs with clear efficacity. The ophthalmologist must be aware of this condition, in order to guide the patient towards a systemic work-up if necessary, and also to insure quick and targeted treatment in the case of neovascular complications.


Smoking habits influence pain and functional and psychiatric features in fibromyalgia.
Numerous epidemiologic data have shown that smoking may play a role in the disease manifestations or severity of chronic musculoskeletal pain. The authors of the present study investigated the effect of smoking on clinical features such as pain, fatigue, functional impairment, and psychiatric features in the Korean population with fibromyalgia syndrome (FMS). A total of 336 patients with FMS were consecutively enrolled from 10 medical centers which participated in the Korean national fibromyalgia survey. Smoking was divided into current smokers and non-smokers. Instruments of FMS assessment included tender points, Fibromyalgia Impact questionnaire (FIQ), 36-item Medical Outcomes Study Short-Form Health Survey (SF-36), Brief Fatigue Inventory (BFI), Brief Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI)-1 and STAI-2, and social family support and social friend support. Statistical analyses included Chi-square test, Fisher's exact test, Mann-Whitney U test, and multivariate logistic regression analysis. Thirty-three patients (9.8%) out of 336 participants were current smokers. The number of tender points (P=0.037), BFI (P=0.026), general health of SF-36 (P=0.028), BDI (P=0.014), syncope (P=0.024), and reflex sympathetic dystrophy (P=0.003) showing significance between current smokers and non-smokers were not associated with smoking habits after adjustment. The significance of the number of tender points (P=0.009), scores of total tender points (P=0.032), BDI (P=0.038), general weakness (P=0.047), and reflex sympathetic dystrophy (P=0.011) was observed between randomized non-smokers (n=55) and smokers (n=33). In addition, the number of tender points (P=0.027, OR=1.379) was associated with smoking status after adjustment. The analysis between randomized non-smokers (n=45) and smokers (n=22) in female FMS patients showed that BDI in FMS was associated with smoking status (P=0.023, OR=1.077) after logistic regression analysis. This study revealed that smoking habits may, in part, influence pain or functional and psychiatric features in FMS patients. The impact of smoking on clinical features in FMS should be assessed in a larger study population.


Patterns of treatment for restless legs syndrome in primary care in the United Kingdom.
The dopamine agonists pramipexole and ropinirole are licensed for the treatment of moderate to severe idiopathic restless legs syndrome (RLS) in Europe and the United States. In addition, various drugs that are not approved for this indication have been used for symptomatic treatment of RLS, including analgesics, quinine, and anxiolytics. The purpose of this analysis was to describe patterns of treatment of newly diagnosed RLS, including treatment effectiveness and resource utilization, in primary care in the United Kingdom. This was a cohort study that employed the UK General Practice Research Database. Two cohorts were assembled, one consisting of patients with an initial diagnosis of RLS between 1990 and 2004 and the other consisting of patients without RLS matched to cases in a 10:1 ratio by general practice, year of birth, sex, and registration with the practice on the case index date (date of the RLS diagnosis). The frequency of RLS-specific symptoms was estimated based on records of prescriptions for sleep medications and antidepressants, and reported cramps and leg problems other than RLS. Rates of resource use in the 2 years before and after the index date were estimated for both cohorts based on the numbers of total prescriptions, referrals to secondary care, and laboratory tests. The RLS cohort comprised 8621 patients and the matched cohort 85,087 patients. Age and sex distributions were comparable between groups. The annual frequency of prescriptions for sleep medications in the RLS cohort increased significantly from 19.8% and 21.6% in the 2 years before the diagnosisof RLS to 27.4% in the first year after the diagnosis and 25.2% in the second year (all comparisons, P < 0.001). A similar pattern was observed for antidepressants in the RLS cohort (23.5%, 26.7%, 31.0%, and 29.6%, respectively; P < 0.001). Prescription rates were nearly constant in the matched cohort. The frequency of cramps and other leg problems was highest in the year before the diagnosis of RLS, declined in the first year after the diagnosis, and increased thereafter. Compared with the matched cohort, rates of prescriptions, referrals, and laboratory tests ranged from 49.7% to 59.0% higher in the RLS cohort in the 2 years before the diagnosis of RLS and from 63.4% to 91.4% higher in the 2 years after the diagnosis (all comparisons, P < 0.001). In patients with newly diagnosed RLS in this UK primary care cohort, use of medications that are not approved for the treatment of RLS was not associated with a reduction in clinical symptoms or health care resource utilization between 1990 and 2004.


Ribotoxins Kill Cells by Chopping off the Head of tRNAs.
In this issue of Structure, Gucinski et al. (2019) have described structural and enzymatic characterizations of two tRNase ribotoxins. The study significantly advances our understanding on the evolution and the mode of action of a group of ribotoxins that cleave the accepting stem of tRNAs for cell killing.


Receptor-mediated actin assembly in electropermeabilized neutrophils: role of intracellular pH.
Neutrophil activation by a variety of stimuli is accompanied by an intracellular acidification, which has been postulated to mediate actin polymerization (Yuli and Oplatka, Science 1987, 235, 340). This hypothesis was tested using 7-nitrobenz-2-oxa-1,3-diazole (NBD)-phallacidin staining and flow cytometry, or right angle light scattering to study actin assembly in intact and electrically permeabilized human neutrophils. Intracellular pH was measured fluorimetrically using a pH sensitive dye. In cells stimulated with N-formyl-methionyl-leucyl-phenylalanine (fMLP) at 21 degrees C, actin assembly clearly preceded the intracellular acidification in response to fMLP. Moreover, actin polymerization persisted in cells where intracellular pH was clamped near the resting (unstimulated) level using nigericin/K+. Finally, fMLP induced a significant increase in F-actin content in electropermeabilized neutrophils equilibrated with an extracellular medium containing up to 50 mM HEPES. These observations indicate that fMLP-stimulated F-actin assembly is not mediated by a decrease in intracellular pH and suggest that changes in transmembrane potential and ionic gradients are unlikely to mediate actin polymerization.


Mesopic spectral responses and the Purkinje shift of macaque lateral geniculate nucleus cells.
Spectral responsiveness of different classes of macaque LGN cells at eccentricities smaller than 12 degrees was studied at low light intensities. Cone thresholds of cells varied from 1 to 10 td. Rod inputs were found in all classes of cells, including inhibitory inputs in some cells. Rod inputs were not apparent above 10-40 td, giving a total mesopic range of about 1-40 td. Strong rod-mediated responses could be evoked in broadband phasic cells and in spectrally opponent cells excited by short wavelengths. Only weak if any excitatory responses could be evoked by short wavelengths at scotopic levels in spectrally opponent long-wavelength excited cells. Hence, rod inputs do not confound the spectral responsiveness of cells because no spectrally opponent cell excited by long-wavelength stimuli at photopic levels became significantly responsive to short wavelength stimuli at mesopic or scotopic intensities. The so-called "rod color" may be blue. An increase in the dominance of wide-band cell responses that may explain the Bezold-Brücke hue shift was observed at higher stimulus radiances at wavelengths near 450 and 650 nm.


The limitations and validities of senescence associated-beta-galactosidase activity as an aging marker for human foreskin fibroblast Hs68 cells.
The senescence associated-beta-galactosidase (SA-betaG) assay has become one of the most commonly used markers of cell-aging. However, the reliability of the assay is questionable because the enzyme is a non-specific marker for cell-aging. In this study, we found that the SA-betaG activity increased with cell age as well as in confluent quiescent cells or cells under serum starvation, and in cells treated with H2O2. Importantly, we found that SA-betaG activity was irreversibly increased in the senescent cells or H2O2-teated cells, but was reversible in quiescent cells induced by serum starvation or confluence. Using fluorescein di-beta-d-galactopyranoside (FDG) method for SA-betaG detection, we showed that senescent human foreskin fibroblast Hs68 cells did not express a specific enzyme that has a maximal activity at pH 6.0. In the pH profile of the cellular betaG activity in senescent Hs68 cells, only a single peak was found (with maximum at pH 4.6), and no addition peak was found at or around pH 6.0 that could be attributed to the SA-betaG activity. These results support the contention that SA-betaG is the lysosomal betaG that is detectable at suboptimal pH (i.e. pH 6.0) and demonstrate that cell-aging is not the only factor that can increase SA-betaG activity, rendering SA-betaG activity unspecific for cell-aging. Thus, the assay for cell-aging is only reliable when these confounding factors are controlled or excluded.


Changing Prevalence of Lower Airway Infections in Young Children with Cystic Fibrosis.
Rationale: Historical studies suggest that airway infection in cystic fibrosis initiates with Staphylococcus aureus and Haemophilus influenzae, with later emergence of Pseudomonas aeruginosa. Aspergillus species are regarded as relatively infrequent, late-occurring infections.Objectives: To assess the prevalence and change in prevalence of early lower airway infections in a modern cohort of children with cystic fibrosis.Methods: All infants diagnosed with cystic fibrosis after newborn screening participating in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) cohort study between 2000 and 2018 were included. Participants prospectively underwent BAL at 3-6 months, 1 year, and annually up to 6 years of age. Lower airway infection prevalence was described. Changes in prevalence patterns were assessed longitudinally using generalized estimating equations controlling for age and repeated visits.Measurements and Main Results: A total of 380 infants underwent 1,759 BALs. The overall prevalence and median age of first acquisition of the most common infections were as follows: S. aureus, 11%, 2.5 years; P. aeruginosa, 8%, 2.4 years; Aspergillus species, 11%, 3.2 years; and H. influenzae, 9%, 3.1 years. During the study, a significant decrease in prevalence of P. aeruginosa (P < 0.001) and S. aureus (P < 0.001) was observed with a significant change toward more aggressive treatment. Prevalence of Aspergillus infections did not significantly change (P = 0.669).Conclusions:Aspergillus species and P. aeruginosa are commonly present in the lower airways from infancy. The decrease in prevalence of P. aeruginosa and S. aureus since 2000, coinciding with a more aggressive therapeutic approach, has resulted in Aspergillus becoming the most commonly isolated pathogen in young children. Further research is warranted to understand the implication of these findings.


General practitioners choose within a narrow range of drugs when initiating new treatments: a cohort study of cardiovascular drug formularies.
The aims of this study were (1) to develop and evaluate a new method for investigating personal drug formularies in general practice and (2) to test the hypothesis that there is a difference between personal drug formularies for incident and ongoing drug use. In 2002, we studied prescribing patterns of beta-blockers, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin-II antagonists and statins in the County of Funen, Denmark (180 general practices, 472,000 inhabitants). For each practice, we distinguished between an incident drug formulary consisting of prescriptions for new users and an ongoing drug formulary including prescriptions for patients already in treatment. Prescription data were retrieved from the Odense University Pharmacoepidemiologic Database (OPED). Four different formulary measures were evaluated and used for comparing incident and ongoing drug use. General practitioners' (GPs') incident drug formularies comprised significantly fewer drugs than their ongoing drug formularies for all drug groups except angiotensin-II antagonists. The difference in the total number of drugs used was between 1.8 and 3.3. We found differences between 0.5 and 1.6 analogues in the DU 90% (number of analogues accounting for 90% of the prescribed volume measured in defined daily doses) segment and the formulary selectivity index between 0.05 and 0.12. The preference for the most prescribed analogue was 9-18% higher among incident patients. The formulary selectivity index was highly correlated with the other formulary measures and quantified both range and skewed distribution of drug choice. Analysing GPs' prescriptions to incident patients is a simple and inexpensive method for studying their own current personal drug formularies. GPs choose within a narrow range of analogues for incident patients.


Genetics and pharmacological treatment of dystonia.
Dystonia consists of involuntary repetitive twisting (torsion) or directional movements, sometimes leading to sustained postures. The movements are stereotyped and characterized by co-contraction of agonist and antagonist muscles. There is a broad clinical spectrum of dystonia which derives in part from the differential distribution of involvement. Dystonia may be localized, affecting a single body region, or generalized, affecting multiple extremities along with the trunk. Intermediate dystonic involvement can be described as segmental, designating two affected contiguous body regions, or multifocal, designating two or more noncontiguous affected body regions. Hemidystonia refers to dystonia affecting only one side of the body. Dystonia can also be categorized by age of onset and etiology. Early onset dystonia, occurring in childhood or adolescence (in some studies younger than 26 years old), is associated with more progressive disease [Greene et al. (1995). Mov. Disord. 10, 143]. In this age group, dystonia usually first appears in a limb and then spreads to involve other limbs and axial muscles; some early-onset patients may have involvement of laryngeal and other cranial muscles. Adult or late-onset dystonia typically begins in the neck, arm, or cranial muscles. Compared to early-onset dystonia, the area of involvement is more likely to remain focal or segmental. Dystonia can be considered either primary or nonprimary. Primary torsion dystonia (PTD), historically called dystonia musculorum deformans and Oppenheim's dystonia, describes dystonia in isolation, excepting tremor, without brain degeneration and without an identified acquired cause. Nonprimary or secondary dystonia encompasses a heterogeneous group of syndromes and etiologies including inherited (with or without brain degeneration), acquired, and complex neurological disorders. Monogenic forms of dystonia are labeled DYT and enumerated in the order in which they were discovered. The current 20 DYT loci comprise a heterogeneous group of disorders. (Table I) They can be divided into PTDs, dystonia-plus syndromes without brain degeneration, dystonia-parkinsonism with brain degeneration (i.e. DYT3), and paroxysmal dyskinesias. There are many neurodegenerative genetic disorders that share dystonia as a common feature of disease (Table II). This chapter will review the genetics of PTD, dystonia-plus syndromes without brain degeneration, and X-linked dystonia-parkinsonism. Other genetic dystonia-parkinsonism syndromes and the paroxysmal dyskinesias will not be discussed.


Photocatalytical transformation of fluorotelomer- and perfluorosulfonamide-based PFAS on mineral surfaces and soils in aqueous suspensions.
Per- and polyfluorinated substances (PFAS) are widely used industrial and household chemicals and occur on various contaminated field sites. To better understand their behavior on soils, spike experiments were performed with 6:2 diPAP (6:2 polyfluoroalkyl phosphate diester) on pure mineral phases (titanium dioxide, goethite and silicon dioxide) in aqueous suspensions under artificial sunlight. Further experiments were performed with uncontaminated soil and four precursor PFAS. Titanium dioxide (referenced as 100 %) showed the highest reactiveness to transform 6:2 diPAP to its primary metabolite 6:2 fluorotelomer carboxylic acid, followed by goethite with the addition of oxalate (4.7 %), silicon dioxide (1.7 %) and soil (0.0024 %). Experiments with four precursors [6:2 diPAP, 6:2 fluorotelomer mercapto alkyl phosphate (FTMAP), N-ethyl perfluorooctane sulfonamide ethanol-based phosphate diester (diSAmPAP), N-ethyl perfluorooctane sulfonamidoacetic acid (EtFOSAA)] on natural soils showed a transformation of all four precursors by simulated sunlight. The production of the primary intermediate from 6:2 FTMAP (6:2 FTSA, rate constant k = 2.7∗10-3h-1) was approximately 13-times faster than from 6:2 diPAP (6:2 FTCA, rate constant k = 1.9∗10-4h-1). EtFOSAA was completely decomposed within 48 h whereas only ~7 % diSAmPAP was transformed in the same time. The primary photochemical transformation product of diSAmPAP and EtFOSAA was PFOA, PFOS was not detected. The production rate constant of PFOA varied significantly between EtFOSAA (k = 0.01h-1) and diSAmPAP (k = 1.3∗10-3h-1). Photochemically produced PFOA consisted of branched and linear isomers and can therefore be used in source tracking. Experiments with different soils suggest that the oxidation of EtFOSAA to PFOA is expected to primarily be driven by hydroxyl radicals, whereas for the oxidation of EtFOSAA to further intermediates, another mechanism instead or in addition to the oxidation by hydroxyl radicals is responsible.


Blotting protein complexes from native gels to electron microscopy grids.
We report a simple and generic method for the direct transfer of protein complexes separated by native gel electrophoresis to electron microscopy grids. After transfer, sufficient material remains in the gel for identification and characterization by mass spectrometry. The method should facilitate higher-throughput single-particle analysis by substantially reducing the time needed for protein purification, as demonstrated for three complexes from Thermoplasma acidophilum.


Caregiving experiences of nurses working in a newly established intensive care unit during the COVID-19 pandemic: A qualitative study.
The coronavirus disease 2019 (COVID-19) has adversely affected intensive care nurses; for instance, they have fought against an unknown disease, and their workload has increased. In addition, the COVID-19 pandemic has led intensive care nurses to work in new settings and with new teams. The aim of this study was to explore and describe the caregiving experiences of nurses who were working in a new COVID-19 intensive care unit in Turkey and providing care for patients infected with SARS-CoV-2. In this descriptive qualitative study, semi-structured interviews were held from 22 July to 31 August 2020 and were recorded and analysed based on thematic analysis. The researchers followed the COREQ checklist in reporting the study. From interviews held with 11 nurses, four main themes (uncertainty and challenges in the 'danger zone', emotional and psychosocial changes, professional effects of the pandemic and being ready for a future pandemic) were derived from 11 sub-themes. The new setting and the ever-changing team make caring for the COVID-19 patient even more difficult. A good organization, an experienced permanent team, a known setting and good working conditions are essential to be prepared for possible pandemics in the future.


Biobased plastics in a bioeconomy.
Bioeconomy plans include a biobased industries sector in which some oil-derived plastics and chemicals are replaced by new or equivalent products derived, at least partially, from biomass. Some of these biobased products are here today, but to fulfil their societal potential, greater attention is required to promote awareness, and to improve their market share while making valuable contributions to climate change mitigation.


Integrative analysis of the gut microbiota and faecal and serum short-chain fatty acids and tryptophan metabolites in patients with cirrhosis and hepatic encephalopathy.
The purpose of this study was to describe the changes in the gut microbiome of patients with cirrhosis and hepatic encephalopathy (HE), as well as quantify the variations in short-chain fatty acid (SCFA) and tryptophan metabolite levels in serum and faeces. Fresh faeces and serum were collected from 20 healthy volunteers (NC group), 30 cirrhosis patients (Cir group), and 30 HE patients (HE group). Then, 16S rRNA sequencing and metabolite measurements were performed using the faeces. Gas chromatography‒mass spectrometry and ultrahigh-performance liquid chromatography-tandem mass spectrometry were used to measure SCFA and tryptophan levels, respectively. The results were analysed by SIMCA16.0.2 software. Differences in species were identified using MetaStat and t tests. The correlations among the levels of gut microbes and metabolites and clinical parameters were determined using Spearman correlation analysis. Patients with cirrhosis and HE had lower microbial species richness and diversity in faeces than healthy volunteers; these patients also had altered β-diversity. Serum valeric acid levels were significantly higher in the HE group than in the Cir group. Serum SCFA levels did not differ between the Cir and NC groups. Serum melatonin and 5-HTOL levels were significantly higher in the HE group than in the Cir group. The Cir and NC groups had significant differences in the levels of eight serum tryptophan metabolites. Furthermore, the levels of faecal SCFAs did not differ between the HE and Cir groups. Faecal IAA-Ala levels were significantly lower in the HE group than in the Cir group. There were significant differences in the levels of 6 faecal SCFAs and 7 faecal tryptophan metabolites between the Cir and NC groups. Certain gut microbes were associated with serum and faecal metabolites, and some metabolites were associated with certain clinical parameters. Reduced microbial species richness and diversity were observed in patients with HE and cirrhosis. In both serum and faeces, the levels of different SCFAs and tryptophan metabolites showed varying patterns of change. In HE patients, the levels of some serum tryptophan metabolites, and not SCFAs, were correlated with liver function and systemic inflammation. Systemic inflammation in patients with cirrhosis was correlated with faecal acetic acid levels. In summary, this study identified metabolites important for HE and cirrhosis.


Association of high maternal blood alpha-fetoprotein level with risk of delivering small for gestational age: a meta-analysis.
Early identification of pregnant women at risk of delivering small-for-gestational-age (SGA) infants is required to reduce the rates of mortality and morbidity in their whole life. This meta-analysis was performed to determine whether women with higher blood alpha-fetoprotein (AFP) levels are at increased risk of SGA. Studies identified by searching 11 databases, including PubMed, were assessed using the Newcastle-Ottawa Scale. Subgroup and meta-regression analyses and sensitivity analysis removing a potential outlier were performed. Publication bias was assessed using Egger's test. A total of 39 good-quality cohort studies involving 93,968 women and their newborn infants or fetuses ensured both internal and external validity. Relative risk of SGA among women with higher in comparison to lower blood AFP levels was 2.021 (95% CI: 1.751-2.334). Maternal blood AFP levels showed a dose-response relationship with risk of SGA. Relative risk was higher with diagnosis of SGA by ultrasound than actual birth weight (P = 0.004). Sources of heterogeneity, subgroups, confounding factors, or potential outliers did not alter the interpretations without publication bias (P = 0.320). Pregnant women with higher blood AFP levels are at increased risk of SGA compared to those with lower blood AFP levels. Pregnant women with higher blood alpha-fetoprotein levels (AFP) levels are at increased risk of small for gestational age (SGA) compared to those with lower blood AFP levels. High-quality evidence showed a dose-response relationship of maternal blood AFP levels with risk of delivering SGA and was robust to sources of heterogeneity, subgroups, confounding factors, potential outliers, or publication bias. Politically and practically, monitoring of maternal blood AFP level is strongly recommended to identify women at risk of delivering SGA.


Prognostic Assessment of Early Repolarization/J Wave Electrocardiographic Pattern in Patients With Stable Ischemic Heart Disease.
Recent studies suggested that early repolarization (ER)/J wave at the electrocardiogram (ECG) is associated with increased risk of sudden death and ventricular arrhythmias in patients with acute myocardial infarction. In this study, we prospectively assessed whether ER/J wave has any long-term prognostic implications in patients with stable ischemic heart disease (IHD). We enrolled consecutive clinically stable patients with documented IHD, referred to undergo a routine ECG. ER (typical concave ST-segment elevation) and J wave were diagnosed according to prospectively defined criteria. The final population included 617 patients with documented IHD (455 men; age 68.1 ± 11 years). ER/J wave was found in 138 patients (22.4%), 13 of whom (2.1%) showed ER and 133 (21.6%) a J wave. At a follow-up of 8.1±2.9 years, 160 deaths occurred (25.9%), 60 (9.7%) attributed to cardiovascular causes. Total mortality was lower in patients with versus those without ER/J wave (18.8% vs 28.0%; hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.40 to 0.93, p = 0.02). The difference, however, was not significant after adjustment for confounding clinical variables (HR 0.78, 95% CI 0.51 to 1.19, p = 0.25). No significant difference was found in cardiovascular death between patients with (7.2%) and those without (10.4%) ER/J wave (adjusted HR 0.78, 95% CI 0.40 to 1.55, p = 0.48). Similar results were obtained for ER and J wave separately, and for ECG location of ER/J wave (inferior or lateral/precordial) and type of J wave (notched or slurred). The ER/J wave pattern at the ECG is not associated with increased risk of long-term mortality in clinically stable patients with a documented history of IHD.


Imaging techniques for adrenal lesion characterization.
Imaging of the adrenal gland for characterization of adrenal lesions has made tremendous strides and new technologies continue to evolve. This article highlights the anatomic and physiologic imaging principles that underpin current major adrenal imaging modalities and the new techniques becoming available. This article focuses primarily on incidental adrenal lesions, which are encountered more frequently with increasing use of imaging. This article concludes with a brief discussion of the role of adrenal biopsy, performed less frequently because of the success of these noninvasive adrenal imaging advances.


Resurfacing large skin defects of the face and neck with expanded subclavicular flaps pedicled by the thoracic branch of the supraclavicular artery.
Supraclavicular flaps had been widely used as pedicled flaps to reconstruct face and neck defects. However, the size of this traditional flap was limited even after expansion. In this study, we present a flap pedicled by the thoracic branch of supraclavicular artery (TBSA). The flap is located at the subclavicular region, and has the advantage of large dimension, matching colour and thin thickness. In this series, 24 patients with ages ranging between 3 and 49 years (30 flaps with six patients in bilateral fashion) were treated in the authors' institution. The maximum size of the flap was 25 cm × 25 cm, whereas the minimum size was 15 cm × 10 cm. The average size of the flaps was 241.1 ± 95.7 cm(2). Twenty-six flaps (86.7%) survived completely. Total flap loss was seen in one patient (3.3%) and was treated with reverse harvesting skin graft. Partial flap necrosis occurred in three flaps (10.0%). Through a mean time of 10-month follow-up, the colour and the texture of the flaps matched with the recipient area. No conspicuous flap contracture was observed. This expanded subclavicular flap pedicled by the TBSA has proved to be a promising method with satisfactory outcome and high success rate.


Fertility among women living with HIV in western Ethiopia and its implications for prevention of vertical transmission: a cross-sectional study.
This study aimed to examine fertility (live births) in the last 3 years and its associated factors among women living with HIV (WLHIV) in western Ethiopia . Participants were recruited into a cross-sectional survey using systematic sampling. Four healthcare facilities in western Ethiopia were included. Eligible participants were WLHIV of reproductive age (15-49 years) from western Ethiopia who found out about their HIV-positive status more than 3 years ago (N=866). The fertility (live births) of HIV-positive women in the last 3 years was surveyed using face-to-face interviews (March-June 2018). Logistic regression analyses were conducted to examine factors influencing fertility in the last 3 years. A total of 108 (12.5%) HIV-positive women gave birth to 121 live children in the last 3 years. Of these births, 18.2% were reported as mistimed at conception, while 26.4% were reported as unwanted. Of the live births, 8.3% ended in death. Of the 76 (62.8%) children with known HIV status born to HIV-positive women in the last 3 years, 7.9% were HIV-positive. In terms of predictors of fertility, women aged 15-24 years (adjusted OR (AOR) 2.72; 95% CI 1.14 to 6.49) and 25-34 years (AOR 4.34; 95% CI 2.61 to 7.21) had increased odds of fertility compared with women aged 35-49 years. Women using antiretroviral therapy (ART) for less than 5 years were more likely to have given birth in the last 3 years compared with those using ART for 10 years or more (AOR 2.96; 95% CI 1.19 to 7.36), even after controlling for age. WLHIV in Ethiopia are having children and so it is imperative that safe conception strategies are readily available as well as support to reduce HIV-related risks for children born to these mothers. Strengthening reproductive health services for HIV-positive women in order to achieve their family planning goals is therefore important.


Clinical heterogeneity and potential high pathogenicity of the Mmalton Alpha 1 antitrypsin allele at the homozygous, compound heterozygous and heterozygous states.
Alpha 1 antitrypsin (A1AT) deficiency (A1ATD) is potentially associated with a high degree of liver and/or lung disease. Apart from the most frequent deficiency alleles, Pi S and Pi Z, some A1AT alleles of clinical significance may be easily misdiagnosed. This is typically the case of the Pi Mmalton variant which shares the same 'gain-of-function' liver toxicity than Pi Z and the same 'loss of function' lung disease as well. The biological diagnosis of A1ATD typically relies on a low serum concentration associated with an abnormal isoelectric focusing (IEF) pattern of migration. However, Sanger direct DNA sequencing may be required for deficiency alleles without biochemical expression (Null alleles) or for A1AT variants whose IEF profiles resemble the wild-type and sub-types M allele but with a low concentration. We report four cases of A1ATD involving the deficient Pi Mmalton allele with very different clinical expressions: (i) one Mmalton/Mmalton with liver fibrosis and cirrhosis, (ii) two Mmalton/Z with chronic pulmonary obstructive disease in one case and (iii) one M/Mmalton without liver or lung disease. In both cases, the correct diagnosis has necessitated a genetic analysis. Our study provides another example of Pi Mmalton homozygosity associated with a severe liver disease that emphasizes the necessity of a not delayed diagnosis. The great clinical heterogeneity of the other genotypes (which is in agreement with the literature data) questions about the role of environmental and other modifier genes in the pathogenicity of A1ATD.


Selective effects of trypsinization on established and tumour-derived mouse 3T3 cells.
Explanted tumour cells are much more sensitive to the deleterious effects of routine trypsinization than are the parent 3T3 or SV40 transformed established cell lines. This differential sensitivity causes the disappearance of tumour-derived cells when grown in co-culture with untransformed 3T3 cells and accounts in some tumor explants for the emergence of trypsin-resistant varient cells which have lost tumour-specific properties.


Measurement of erythropoietin in anephric children. A report of the Southwest Pediatric Nephrology Study Group.
Serum erythropoietin (Ep) levels were measured using a highly sensitive radioimmunoassay in 69 children undergoing chronic dialysis; 31 were anephric, whereas 38 were non-nephrectomized (nephric). Twenty-nine normal children were studied as controls. Serum Ep levels in the anephric group were much higher than anticipated (mean 19.7 +/- 1.8 mU/ml), albeit significantly lower than those measured in normal children (mean 26.2 +/- 2.4 mU/ml, P less than 0.05), or in nephric children on dialysis (33.0 +/- 2.9 mU/ml, P less than 0.001). Anephric children on peritoneal dialysis (PD) had significantly (P less than 0.05) higher serum levels of Ep (22.7 +/- 2.4 mU/ml, n = 19) than anephric children on hemodialysis (HD) (15.1 +/- 2.3 mU/ml, n = 12). There was no significant difference between Ep levels in anephric patients dialyzed for less than or equal to 1 year (19.6 +/- 2.0 mU/ml, n = 20) compared with anephric patients dialyzed for more than 1 year (20.0 +/- 3.9 mU/ml, n = 11). Although serum Ep levels showed a tendency to increase with time after nephrectomy, the mean values for less than 3 months (14.7 +/- 1.9), 3 months-12 months (21.0 +/- 2.7), and greater than 12 months (21.6 +/- 6.0) were not significantly different from each other. This demonstration of relatively normal levels of serum Ep in anephric children suggests that extrarenal sites of Ep production are able to exert a significant response to severe anemia in patients who are devoid of renal parenchyma.


Access to Health Services in Older Minority Ethnic Groups with Dementia: A Systematic Review.
While it is acknowledged that minority ethnic (ME) groups across international settings face barriers to accessing care for dementia, it is not clear whether ME groups access services less frequently as a result. The objective of this review is to examine whether ME groups have longer delays before accessing dementia/memory services, higher use of acute care and crisis services and lower use of routine care services based on existing literature. We also examined whether ME groups had higher dementia severity or lower cognition when presenting to memory services. Systematic review with narrative synthesis. Nonresidential medical, psychiatric, memory, and emergency services. Twenty studies totaling 94,431 older adults with dementia or mild cognitive impairment. We searched Embase, Ovid MEDLINE, Global Health, and PsycINFO from inception to November 2018 for peer-reviewed observational studies which quantified ethnic minority differences in nonresidential health service use in people with dementia. Narrative synthesis was used to analyze findings. Twenty studies were included, mostly from the U.S. (n = 13), as well as the UK (n = 4), Australia (n = 1), Belgium (n = 1), and the Netherlands (n = 1). There was little evidence that ME groups in any country accessed routine care at different rates than comparison groups, although studies may have been underpowered. There was strong evidence that African American/Black groups had higher use of hospital inpatient services versus U.S. comparison groups. Primary care and emergency services were less well studied. Study quality was mixed, and there was a large amount of variability in the way ethnicity and service use outcomes were ascertained and defined. There is evidence that some ME groups, such as Black/African American groups in the U.S., may use more acute care services than comparison populations, but less evidence for differences in routine care use. Research is sparse, especially outside the U.S.


Expression of TopBP1 in hereditary breast cancer.
TopBP1 protein displays structural as well as functional similarities to BRCA1 and is involved in DNA replication, DNA damage checkpoint response and transcriptional regulation. Aberrant expression of TopBP1 may lead to genomic instability and can have pathological consequences. In this study we aimed to investigate expression of TopBP1 gene at mRNA and protein level in hereditary breast cancer. Real-time quantitative PCR was performed in 127 breast cancer samples. Expression of TopBP1 mRNA in lobular carcinoma was significantly lower compared with ductal carcinoma (p < 0.05). The level of TopBP1 mRNA appeared to be lower in poorly differentiated (III grade) hereditary breast cancer in comparison with moderately (II grade) and well-differentiated cancer (I grade) (p < 0.05 and p < 0.001 respectively). We analyzed TopBP1 protein expression using immunohistochemistry and Western blot techniques. Expression of TopBP1 protein was found to be significantly increased in poorly differentiated breast cancer (III grade) (p < 0.05). The percentage of samples with cytoplasmic apart from nuclear staining increased with increasing histological grade. There was no significant association between level and intracellular localization of TopBP1 protein in hereditary breast cancer and other clinicopathological parameters such as estrogen and progesterone receptors status, appearance of metastasis in the axillary lymph nodes and type of cancer. Our data suggest that decreased level of TopBP1 mRNA and increased level of TopBP1 protein might be associated with progression of hereditary breast cancer.


Adsorption of 2,4-Dichlorophenoxyacetic Acid from an Aqueous Solution on Fly Ash.
The adsorption of 2,4-dichlorophenoxyacetic acid (2,4-D) on fly ash was studied. The effects of adsorbent dose, contact time, pH, ionic strength, and temperature on the adsorption were investigated. Adsorption kinetic data were analyzed using pseudo-first and pseudo-second order models, and results showed that adsorption kinetics were better represented by the pseudo-second order model. Adsorption isotherms of 2,4-D on fly ash were analyzed using the Freundlich and Langmuir models. Thermodynamic parameters (ΔG°, ΔH°, and ΔS°) indicated that the adsorption process was spontaneous and endothermic. The negative values of ΔG° and the positive value of ΔH° indicate the spontaneous nature of 2,4-D adsorption on fly ash, and that the adsorption process was endothermic. Results showed that fly ash is an efficient, low-cost adsorbent for removal of 2,4-D from water.


Neonicotinoid Clothianidin reduces honey bee immune response and contributes to Varroa mite proliferation.
The neonicotinoid Clothianidin has a negative impact on NF-κB signaling and on immune responses controlled by this transcription factor, which can boost the proliferation of honey bee parasites and pathogens. This effect has been well documented for the replication of deformed wing virus (DWV) induced by Clothianidin in honey bees bearing an asymptomatic infection. Here, we conduct infestation experiments of treated bees to show that the immune-suppression exerted by Clothianidin is associated with an enhanced fertility of the parasitic mite Varroa destructor, as a possible consequence of a higher feeding efficiency. A conceptual model is proposed to describe the synergistic interactions among different stress agents acting on honey bees.


Maternal age and low birth weight: a reinterpretation of their association under a demographic transition in southern Brazil.
To evaluate the relationship between changes in fecundity rates and maternal age and the impact of maternal age on low birth weight (LBW) rates in a developed region in southern Brazil. A time series study evaluating birth weight and maternal ages through the born alive information system (SINASC) in Porto Alegre from 1996 to 2008. The Chi-square test for trends was used to evaluate the trend of LBW and fecundity rates at each maternal age. Population attributed risk (PAR) was used to calculate the impact of maternal age on LBW rates. The study included 271,100 newborns. There was a significant reduction in fecundity rates in all age groups younger than 34 years, but especially in the groups between 20 and 29 years. Overall LBW increased from 9.3 to 10.7 % (P < 0.001). The PAR for LBW showed a reduction in the group from 17 to 19 years (from 1.7 % in 1996-1999 to 0.1 % in 2004-2008), and an increase in the groups from 35 to 39 years (from 2.0 % in 1996-1999 to 2.3 % in 2004-2008) and above 40 (from 1.1 % in 1996-1999 to 1.5 % in 2004-2008). There was a significant change in fecundity pattern in the last 12 years in southern Brazil. Adolescent mothers were surpassed by mothers over 30 years of age in terms of vulnerability for LBW babies. The results show a change in the maternal age distribution towards older mothers, accompanied by an increasing incidence of LBW. This demographic transition also involved a paradoxical pattern with a remarkable reduction in fecundity rates in intermediate maternal age groups with concomitant increase in their risk for LBW.


Effect of Photoperiod and White LED on Biomass Growth and Protein Production by Spirulina.
The constant increase in demand for food, valued bio-based compounds and energy demand has prompted the development of innovative and sustainable resources. New technologies and strategies must be implemented to boost microalgae biomass production, such as using different photoperiods along with (LED) light-emitting diodes to stimulate biomass production and boost profits. This work investigates the cultivation of blue-green microalgae (Spirulina) in a closed lab condition. The current study aims to boost Spirulina biomass production by creating ideal growth conditions using different photoperiods (12:12; 10:14; 14:10) light/dark with a constant light intensity of 2000 lx from White LED lights. The obtained optical density and protein content was highest for photoperiod 14L: 10D and values were 0.280 OD, with a protein content of 23.44 g/100 g, respectively. This study is a crucial first step in identifying the best photoperiod conditions to help S. platensis produce more biomass. The study results showed that increasing photoperiod for S. platensis farming can improve the quality and amount of biomass generated in those cultures without negatively affecting growth.


Early-life short-term environmental enrichment counteracts the effects of stress on anxiety-like behavior, brain-derived neurotrophic factor and nuclear translocation of glucocorticoid receptors in the basolateral amygdala.
Early life is a decisive stage for the development of physiological and psychological characteristics of an individual. Any stress or disruption of healthy development at this stage has serious long-lasting consequences for the remaining life. Unfortunately, early life stress is a common occurrence in humans and other animals. In this context, we investigated if the provision of environmental enrichment during the pre-weaning phase of rat pups and dams could alter the consequences of early-life maternal-separation stress. Pre-weaning enrichment rescued the effects of maternal separation on the excess secretion of adrenal stress hormones and anxiety-like behavior during adulthood. Enrichment also reduced the effect of stress on the spine density of basolateral amygdala neurons, a brain region critical for stress-induced facilitation of emotional behaviors. Pre-weaning enrichment, provided during early-life, blunted the effects of maternal separation stress on decreased intra-nuclear translocation of glucocorticoid receptors within the amygdala neurons when tested later in adulthood. Early-life, pre-weaning environmental enrichment also increased the amount of brain-derived neurotrophic factor within adult basolateral amygdala. Our observations showed that environmental manipulation during early formative years could be utilized to build lifelong resilience to stress. Complex naturalistic housing and sensory enrichment is, thus, an useful buffer against an impoverished and stressful childhood.


Portal hypertension treated by left gastro-epiploic to left renal vein anastomosis: case report.
A case of portal hypertension is presented in which because of the presence of multiple thromboses of the main portal branches one of the usual portasystemic shunts could not be performed. An anastomosis between an enlarged left gastro-epiploc vein and the left renal vein was successfully carried out. Six months after surgery the patient was well and no further haemorrhage had occured.


Vascular adhesion protein-1 expression is reduced in the intestines of infants with necrotizing enterocolitis: an observational research study.
Necrotizing enterocolitis (NEC) is an inflammatory bowel disease in preterm neonates with high morbidity and mortality. The only treatment available is supportive with broad-spectrum antibiotics and gastrointestinal rest. Better understanding of the pathogenesis is crucial for the development of new therapies. Vascular adhesion protein-1 (VAP-1), expressed in human blood vessels and lymphatic, plays a crucial role in the pathogenesis of inflammatory diseases in adults. The aim of the study was to investigate the VAP-1 expression in the intestines of infants affected by NEC. Intestinal tissues from 42 preterm infants with NEC were examined with immunohistochemical staining using antibodies against VAP-1 and semi-automated digital image analysis was performed to determine tissue protein expression of VAP-1 in blood vessels located in the submucosa. Intestinal tissue from 26 neonates that underwent laparotomy and ileostomy due to other intestinal surgical conditions served as controls. Clinical data and protein expression were compared between the NEC-group and Controls. Mean gestational age was lower in NEC infants compared to controls, 26.6 ± 3.0 gestational weeks versus 36.5 ± 4.0 (p < 0.001) but without any significant difference in median postnatal age at surgery; for NEC 8 (5-27) days and for controls 3 (1-36) days (p = 0.6). Low VAP-1 correlated with increased risk for developing NEC in the logistic regression (p < 0.001). Multiple linear regression showed that both gestational age and NEC were independent predictors of VAP-1 expression. VAP-1 may play a role in the pathogenesis of NEC. Diminished expression of VAP-1 independent of maturation could indicate arrested vascular development in infants suffering from NEC. Further studies are needed to elucidate the role of VAP-1 in NEC.


Identification of novel series of human CCR1 antagonists.
A hit-to-lead optimization process was carried out on the high throughput screening hit compound 1 resulting in the identification of several potent and selective CCR1 receptor antagonists. Compound 37 shows the best overall profile with IC(50) values of <100 nM in binding and functional assays.


Indoor wood-burning from stoves and fireplaces and incident lung cancer among Sister Study participants.
Epidemiological studies conducted mostly in low- and middle-income countries have found a positive association between household combustion of wood and lung cancer. However, most studies have been retrospective, and few have been conducted in the United States where indoor wood-burning usage patterns differ. We examined the association of exposure to indoor wood smoke from fireplaces and stoves with incident lung cancer in a U.S.-wide cohort of women. We included 50,226 women without prior lung cancer participating in the U.S.-based prospective Sister Study. At enrollment (2003-2009), women reported frequency of use of wood-burning stoves and/or fireplaces in their longest-lived adult residence. Cox regression was used to estimate adjusted hazard ratios (HRadj) and 95 % confidence intervals (CI) for the association between indoor wood-burning fireplace/stove use and incident lung cancer. Lung cancer was self-reported and confirmed with medical records. During an average 11.3 years of follow-up, 347 medically confirmed lung cancer cases accrued. Overall, 62.3 % of the study population reported the presence of an indoor wood-burning fireplace/stove at their longest-lived adult residence and 20.6 % reported annual usage of ≥30 days/year. Compared to those without a wood-burning fireplace/stove, women who used their wood-burning fireplace/stove ≥30 days/year had an elevated rate of lung cancer (HRadj = 1.68; 95 % CI = 1.27, 2.20). In never smokers, positive associations were seen for use 1-29 days/year (HRadj = 1.64; 95 % CI = 0.87, 3.10) and ≥30 days/year (HRadj = 1.99; 95 % CI = 1.02, 3.89). Associations were also elevated across all income groups, in Northeastern, Western or Midwestern U.S. regions, and among those who lived in urban or rural/small town settings. Our prospective analysis of a cohort of U.S. women found that increasing frequency of wood-burning indoor fireplace/stove usage was associated with incident lung cancer, even among never smokers.


Context effects: translation of UAG codon by suppressor tRNA is affected by the sequence following UAG in the message.
The efficiency of various suppressor tRNAs in reading the UAG amber codon has been measured at 42 sites in the lacI gene. Results indicate that: (1) for all suppressors, efficiency is not an a priori value; rather, it is determined at each site by the specific reading context of the suppressed codon; (2) the degree of sensitivity to context effects differs among suppressors. Most affected is amber suppressor supE (su2), whose activity varies over a 20-fold range depending on context; (3) context effects are produced by residues present at the 3' side of the UAG codon. The most important role appears to be played by the base that is immediately adjacent to the codon. When this base is a purine, the amber codon is suppressed more efficiently than when a pyrimidine is in the same position. Superimposed on this initial pattern, the influence of bases further downstream to the UAG triplet can be detected also. The possibility is discussed that context effects are produced by the whole codon following UAG in the message.


Struggling behavior during restraint is regulated by stress experience.
Restraint elicits a number of physiological stress responses that can be increased or decreased in magnitude based on prior stress history. For instance, repeated exposure to restraint leads to habituation of hypothalamic-pituitary-adrenal (HPA) activation to restraint. In contrast, acute restraint after a different repeated stressor leads to facilitation of HPA activity to the novel stress. Acute restraint also elicits a variety of behaviors, including struggling, but the effect of prior stress in regulating behavioral responses to restraint is not clear. The goal of the present studies was to assess struggling during restraint with or without a prior history of repeated stress. Using automated behavioral analysis software (EthoVision), we quantified struggling during restraint. We found that acutely restrained rats exhibited vigorous struggling behavior that declined during a single restraint period. Repeated restraint lead to habituated struggling behavior, whereas acute restraint after repeated swim elicited facilitated struggling behavior. These effects on struggling were found alongside expected differences in HPA activity. Removing stress-induced increases in corticosterone via adrenalectomy did not significantly affect struggling responses to restraint. Overall, restraint-induced struggling appears to be regulated in a manner similar to HPA responses to restraint, but is not dictated by adrenal hormones.


Isocitrate Dehydrogenase Mutant Grade II and III Glial Neoplasms.
Mutations in isocitrate dehydrogenase (IDH) 1 or IDH2 occur in most of the adult low-grade gliomas and, less commonly, in cholangiocarcinoma, chondrosarcoma, acute myeloid leukemia, and other human malignancies. Cancer-associated mutations alter the function of the enzyme, resulting in production of R(-)-2-hydroxyglutarate and broad epigenetic dysregulation. Small molecule IDH inhibitors have received regulatory approval for the treatment of IDH mutant (mIDH) leukemia and are under development for the treatment of mIDH solid tumors. This article provides a current view of mIDH adult astrocytic and oligodendroglial tumors, including their clinical presentation and treatment, and discusses novel approaches and challenges toward improving the treatment of these tumors.


Prevalent HBV genotypes and subtypes in a South Indian population.
Genotypes or genetic subtypes describe genetically related strains and have been described for viruses belonging to several different families. The eight major genotypes of hepatitis B virus (HBV) have distinct geographic distribution. Recent studies suggest possible pathogenic and therapeutic differences among HBV genotypes. To evaluate the HBV genotypes of 85 samples by RFLP analysis and sequence the desired region to look for variations and identify the subtypes of the surface region. We studied 85 patients with HBV in order to identify the most prevalent genotype and subtype. Patients with HBV-related liver disease attending the Department of Gastroenterology at Owaisi Hospital and Research Centre were studied. Genotype D1 was most prevalent. Genotyping was carried out by RFLP analysis and confirmed by sequencing. Nucleotide sequences showed significant homology (96-97%) with the other genotypes that have been reported. Subtype ayw was the most prevalent subtype within the surface region. Construction of a phylogenetic tree incorporating these isolates and other published HBV sequences showed that the isolates are derived from the same evolutionary tree. The study adds to our understanding of the genetic diversity of HBV and the geographical distribution of its subtypes, and will be useful for reconstructing the evolutionary history of HBV.


The response of paroxysmal supraventricular tachycardia to overdrive atrial and ventricular pacing: can it help determine the tachycardia mechanism?
Standard electrophysiologic techniques generally allow discrimination among mechanisms of paroxysmal supraventricular tachycardia. The purpose of this study was to determine whether the response of paroxysmal supraventricular tachycardia to atrial and ventricular overdrive pacing can help determine the tachycardia mechanism. Fifty-three patients with paroxysmal supraventricular tachycardia were studied. Twenty-two patients had the typical form of atrioventricular (AV) junctional (nodal) reentry, 18 patients had orthodromic AV reentrant tachycardia, 10 patients had atrial tachycardia, and 3 patients had the atypical form of AV nodal reentrant tachycardia. After paroxysmal supraventricular tachycardia was induced, 15-beat trains were introduced in the high right atrium and right ventricular apex sequentially with cycle lengths beginning 10 msec shorter than the spontaneous tachycardia cycle length. The pacing cycle length was shortened in successive trains until a cycle of 200 msec was reached or until tachycardia was terminated. Several responses of paroxysmal supraventricular tachycardia to overdrive pacing were useful in distinguishing atrial tachycardia from other mechanisms of paroxysmal supraventricular tachycardia. During decremental atrial overdrive pacing, the curve relating the pacing cycle length to the VA interval on the first beat following the cessation of atrial pacing was flat or upsloping in patients with AV junctional reentry or AV reentrant tachycardia, but variable in patients with atrial tachycardia. AV reentry and AV junctional reentry could always be terminated by overdrive ventricular pacing whereas atrial tachycardia was terminated in only one of ten patients (P < 0.001). The curve relating the ventricular pacing cycle length to the VA interval on the first postpacing beat was flat or upsloping in patients with AV junctional reentry and AV reentry, but variable in patients with atrial tachycardia. The typical form of AV junctional reentry could occasionally be distinguished from other forms of paroxysmal supraventricular tachycardia by the shortening of the AH interval following tachycardia termination during constant rate atrial pacing. Atrial and ventricular overdrive pacing can rapidly and reliably distinguish atrial tachycardia from other mechanisms of paroxysmal supraventricular tachycardia and occasionally assist in the diagnosis of other tachycardia mechanisms. In particular, the ability to exclude atrial tachycardia as a potential mechanism for paroxysmal supraventricular tachycardia has important implications for the use of catheter ablation techniques to cure paroxysmal supraventricular tachycardia.


Ophthalmic complications of water sports.
Those who participate in aquatic sports are at risk for some special ocular problems. These have been outlined here and include optical problems and refractive errors, pressure related disease, ocular trauma, infections and irritations, toxins, and complications of exposure to sun and wind. Awareness of these disorders may allow better management and prevention.


Kielin/chordin-like protein deficiency causes cardiac aging in male mice.
Previous studies have demonstrated that bone morphogenetic proteins (BMPs) play important roles in cardiovascular diseases, including atherosclerosis, artery calcification, myocardial remodeling, pulmonary arterial hypertension, and diabetic cardiomyopathy. Kielin/chordin-like protein (KCP) is a secreted protein that regulates the expression and function of BMPs. However, the role of KCP in cardiac aging remains unknown. In this study, we aimed to investigate the role of KCP in cardiac aging and its possible mechanisms. Echocardiogram showed that heart function was impaired in aged mice (24 months). In addition, analysis of heart structure showed that KCP knockout (KO) aggravated cardiac remodeling in aged mice. Moreover, KCP KO increased p-smad2/3 and TGF-β expression, while decreased BMP-2 expression in aged mice. Furthermore, KCP KO increased the expression of cardiac senescence-related proteins in aged mice. KCP KO aggravated the imbalance of oxidants and antioxidants and increased the expression of proinflammatory cytokines and cardiomyocyte apoptosis in aged mice. Our study demonstrated that KCP KO aggravated cardiac aging in mice by increasing the levels of oxidative stress, inflammation, and cardiomyocyte apoptosis. KEY MESSAGE: KCP KO aggravated aging-related cardiac dysfunction and remodeling in male mice. KCP KO aggravated cardiac aging by increasing the levels of oxidative stress, inflammation, and cardiomyocyte apoptosis.


Selective inhibition of DNA synthesis by a protein released from spleen cells.
Spleen cells cultured release proteins into the culture medium, some of which shows both binding activity to single stranded DNA (ss-DNA) and inhibitory activity to 3H-thymidine incorporation into cells. The inhibitory protein of DNA synthesis was purified to near homogeneity by ammonium sulfate precipitation, ss-DNA-cellulose affinity chromatography, and gel filtration chromatography. The molecular weight of the major band of this protein, as estimated by sodium dodecyl-sulfate gel electrophoresis, was approximately 14,000. The effect of the protein was compared with various cell lines and primary cell culture, and it was found that the protein strongly inhibited DNA synthesis of HeLa, L, and HEp2 cells, but only inhibited to a minor extent synthesis of Ehrlich cells and primary culture of mouse embryo.


Expression of minor histocompatibility antigen, HA-1, in solid tumor cells.
Minor histocompatibility antigen (mHag) induces and mounts graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Among several mHags, HA-1 is one that acts alone and is the most studied. It is suggested that HA-1 may be one of the immunodominant antigens inducing not only graft-versus-host disease but also graft-versus-malignancy effects. There are some reports that mHag HA-1-specific cytotoxic T lymphocytes generated from an HA-1-negative donor can lyse HA-1-positive leukemic cells. However, the tissue distribution of HA-1 has been described as restricted to the cells of the hematopoietic lineage. We examined the HA-1 expression in peripheral blood mononuclear cells (PBMNC), leukemia/lymphoma cell lines, solid tumor cell lines, and paired samples of tumor and normal tissues from individual cancer patients by quantitative reverse-transcription polymerase chain reaction. We found that mRNA of HA-1 is expressed in all leukemia/lymphoma cell lines and PBMNC. Most of the leukemia/lymphoma cell lines have the same levels of HA-1 expression as a leukemia/lymphoma cell line, Raji. The expression levels of human PBMNC were 14- to 19-fold higher than those of Raji. Among 32 solid tumor cell lines, 7 showed >50% expression levels compared with Raji. HA-1 expression in the mRNA level is higher in cells of hematopoietic origin, but this tissue distribution is not strictly restricted. Some solid tumor cells and tissues express HA-1 gene equal to hematopoietic cells.


Current status of stress echocardiography: is it a required procedure for every sonographer?
Stress echocardiography is a versatile modality in the clinical cardiology. In its earlier days, its sole indication was restricted to diagnosing coronary artery disease. However, in response to the rapid development of ultrasound technology and analysis software, the indications have now evolved with expansion to several fields of cardiovascular disease. I reviewed previous stress echocardiography publications, and discussed the current status of stress echocardiography in routine clinical setting. Although its portability and online assessment make possible for immediate diagnosis even at the bedside, establishment of an appropriate procedure and an accurate assessment require some experience. Other imaging competitors, such as multidetector computed tomography and cardiac magnetic resonance are gradually replacing the role of stress echocardiography in some fields. However, stress echocardiography has a potential for other new fields, including valvular heart disease and congestive heart failure. Although primary indication of stress echocardiography for coronary artery disease seems to be not relevant especially in Japan, novel indication of stress echocardiography in other field of cardiovascular disease is rapidly expanding in conjunction with the advent of new technology. Stress echocardiography is not a tool for limited researchers, but rather a fundamental routine method of choice for every sonographer.


Nucleus Pulposus-Targeting Nanocarriers Facilitate Mirna-Based Therapeutics for Intervertebral Disc Degeneration.
Intervertebral disc degeneration (IDD) is a common cause of low back pain. Understanding its molecular mechanisms is the basis for developing specific treatment. To demonstrate that miR-22-3p is critical in the regulation of IDD, miRNA microarray analyses are conducted in conjunction with in vivo and in vitro experiments. The miR-22-3p knockout (KO) mice show a marked decrease in the histological scores. Bioinformatic analysis reveals that miR-22-3p plays a mechanistic role in the development of IDD by targeting SIRT1, which in turn activates the JAK1/STAT3 signaling pathway. This is confirmed by a luciferase reporter assay and western blot analysis. Therapeutically, the delivery of miR-22-3p inhibitors and mimics through the synthesized nanoparticles in the IDD model alleviates and aggravates IDD, respectively. The nanocarriers enhance transportation of miR-22-3p to nucleus pulposus cells, thus enabling the in vivo inhibition of miR-22-3p for therapeutic purposes and consequently promoting the development of miRNA-specific drugs for IDD.


Biomass and nutrient allocation in a neotropical dioecious palm.
The sexes of Chamaedorea ernesti-augusti are largely undifferentiated in the distribution of biomass, nitrogen, phosphorus, potassium, and total non-structural carbohydrates, among leaves and stems. Males bear more inflorescences that are cheaper except in nitrogen, but most females bear greater annual energetic and nutritional burdens due to seed production. The ratio of vegetative to reproductive biomass is 3.5 for males but only 1.2 for females on a per module basis.


A novel method to establish microglia-free astrocyte cultures: comparison of matrix metalloproteinase expression profiles in pure cultures of astrocytes and microglia.
Increased matrix metalloproteinase (MMP) proteolytic activity contributes to the pathogenesis of many neuroinflammatory and neurodegenerative conditions in the CNS. To fully understand this process, it is important to define the MMP expression profile of specific cell types, including the CNS-resident cells astrocytes and microglia. While previous studies have characterized astrocyte MMP expression by using mixed glial cultures, these results are likely complicated by the presence of contaminating microglia within these cultures. In the current study, we sought to clarify this complexity, by taking a novel approach to prepare pure astrocyte cultures entirely devoid of microglia, by promoting neural stem cell (NSC) differentiation into astrocytes. The MMP expression profile of mixed glial cultures, neurosphere-derived astrocytes, and pure microglia was characterized by RNase protection assay. This revealed that MMP gene expression is largely cell-type specific. Astrocytes constitutively expressed MMP-11, MMP-14, and MMP-2 and showed induction of MMP-3 in response to IL-1beta but did not respond to lipopolysaccharide (LPS). In contrast, microglia constitutively expressed high levels of MMP-12 and showed strong induction of MMP-9 and MMP-14 in response to LPS. Gelatin zymography confirmed that LPS and TNF-alpha induced strong expression of MMP-9 in microglia but not astrocytes. In summary, these studies demonstrate that neurosphere-derived astrocytes represent an attractive alternative system in which to study astrocyte behavior in vitro. Using this system, we have shown that astrocytes and microglia express distinct sets of MMP genes and that microglia, not astrocytes, are the major source of MMP-9 in response to LPS or TNF-alpha.


Ovarian irradiation and prednisone following surgery and radiotherapy for carcinoma of the breast.
Following surgery and regional radiotherapy for operable carcinoma of the breast in premenopausal women, ovarian irradiation (2000 rad in five daily fractions) plus prednisone (7.5 mg per day) results in delayed recurrence and prolonged survival.


Heterogeneity and properties of transformation of corticosteroid receptors in spinal cord and hippocampus.
The central nervous system contains two classes of corticoid receptors, named types I and II following terminology accepted for the kidney. Phenotypically, type I sites are differentiated into a corticosterone (CORT)-preferring species (Ia) and a mineralocorticoid receptor (Ib). These populations were tentatively compared in the spinal cord and hippocampus. Using [3H]dexamethasone (DEX) and selective blockage of sites, we have observed that type II receptors were comparable in both tissues, while Ia was almost exclusive of the hippocampus. Saturation analysis using [3H]DEX demonstrated that type Ia was a low affinity receptor (Kd approximately equal to 2-5 nM) while type II was a higher affinity site (KdII less than KdI). Using [3H]CORT, or [3H]aldosterone (ALDO), as ligand, preferential labeling of type I sites was achieved, always showing higher concentrations in the hippocampus. Therefore, [3H]DEX seems a ligand of choice to visualize types Ia and II receptors. Another difference noted between the spinal cord and hippocampus, pertained to the sensitivity towards the enzyme RNAse A, which increases heat-induced transformation of the bound receptor, according to the results of DNA cellulose affinity chromatography. In these experiments, type I sites of both spinal cord and hippocampus, plus type II of hippocampus, showed sensitivity toward the enzyme, whereas type II of the spinal cord was refractory to RNAse A enhancement of transformation. These results indicate that the dynamics of transformation is different among receptors showing similar affinity and competition, suggesting further heterogeneity due to receptors themselves, or to tissue factors regulating their biochemical properties.


ASO Author Reflections: Broaden the Targeted Population of Synthetic Lethality for Taiwanese Breast Cancer.
Poly(ADP-ribose) polymerase (PARP) inhibitors selectively cause the failure of DNA single-stranded break (SSB) repair but do not affect double-stranded break (DSB) repair. Furthermore, antitumor activities have been reported for breast cancer, with germline BRCA1/2 mutations. The prevalence of germline BRCA1/2 mutations never exceed one-tenth; beyond BRCA1/2, genes recurrently altered (more than 5%) in the homologous repair pathway are ARID1A, PALB2, and PTEN. Altered homologous recombination repair genes can total up to one-quarter based on different definitions, and the potential of PARP inhibitors will be elucidated when further studies unraveling the impact of individual homologous recombination genes are conducted.


Short sleep duration in prevalent and persistent psychological distress in young adults: the DRIVE study.
Young people are sleeping less. Short sleep duration has a range of negative consequences including a hypothesized link with psychological distress, which has yet to be studied Prospective cohort study Community-based sample from Australia Twenty thousand (20,822) young adults (aged 17-24) identified through the state vehicle licensing authority. A random sample (n = 5000) was approached for follow-up 12-18 months later, with 2837 providing full data. Psychological distress, determined by a Kessler 10 score > 21, at baseline; and as both onset and persistence of distress at follow-up. Shorter sleep duration was linearly associated with prevalent psychological distress: relative risk (RR) 1.14 (95% CI 1.12 to 1.15). Only the very short (< 5 h) sleepers among those not distressed at baseline had an increased risk for onset of psychological distress (RR 3.25 [95% CI 1.84, 5.75]). Of 945 cohort participants reporting psychological distress at baseline, 419 (44%) were distressed at follow-up. Each hour less of sleep increased the risk of psychological distress persisting after adjustment for potential confounding variables: RR 1.05 (95% CI 1.01 to 1.10). Long sleep duration showed no association with distress at any time point. Self-reported shorter sleep duration is linearly associated with prevalent and persistent psychological distress in young adults. In contrast, only the very short sleepers had a raised risk of new onset of distress. Different approaches to sleep duration measurement yield different results and should guide any interventions to improve subjective sleep duration in young adults.


Characterization of exocytotic events from single PC12 cells: amperometric studies in native PC12h, DA-loaded PC12h and bovine adrenal chromaffin cells.
Exocytotic events from rat pheochromocytoma (PC12) cells were characterized by amperometric analysis. For single-cell amperometric recordings, PC12h cells cultured onto poly-L-lysine corted glass-base dish were incubated with 1 mM dopamine (DA) for 60 min. Amperometric recordings, with a carbon fiber microelectrode (5 mum diameter), of catecholamine release from the individual cells were conducted under an inverted microscope at 25 degrees C. To characterize a single exocytotic event that is detected as a single spike current, the spike number, spike parameters (rise time, middle width and area) and spike shape were analyzed. Exposure of DA-loaded PC12h cells to 60 mM KCl (1000 hps) for 5 min and for 4 s evoked a train of events with the event number of 114+/-19 (spikes/response for 5 min) and 12+/-3 (spikes/response for 15 s), respectively. We observed distinctive kinetics in the events (rise time=0.83+/-0.19 ms, middle width=2.89+/-0.62 ms, area=62+/-7.6 fC and the spikes with a "foot"=15.4+/-2.7% of total spikes). The number and mean height of the events were 3- to 4-fold higher than that in DA-unloaded cells, and the values of rise time and middle width in DA-loaded PC12h cells were approx. 5- and 10-fold less than those observed in cultured adrenal chromaffin cells. The successful application of amperometry to monitor DA released from secretory vesicles in DA-loaded PC12h cell suggest that this technique is applicable to characterize exocytotic events in neurons.


Optic nerve sheath diameter measurement for prediction of postdural puncture headache.
Intracranial hypotension due to cerebrospinal fluid leak is mainly the causal factor for the pathophysiology of postdural puncture headache (PDPH). In this study, we aimed to evaluate the effectiveness of optic nerve sheath diameter (ONSD) measurement in predicting the development of PDPH in patients undergoing spinal anesthesia. According to the American Society of Anesthesiology (ASA) physical classification I-III, 83 patients aged 18-65 years scheduled for spinal anesthesia for elective surgery were included in the study. Demographic data (age, ASA, sex, smoking, migraine, and PDPH history) and operative data were recorded. Preoperative ONSD measurements were taken in the right and left eye, axial, and sagittal planes. The mean of four measurements was recorded before and 24 h after the spinal anesthesia. A total of 83 patients (59 males and 24 females) were included in the study. In our study, the rate of PDPH development was determined as 22.9% (n = 19). There was a statistically significant difference in the preoperative and postoperative ONSD values between patients with and without PDPH development (p = 0.046). In the receiver operating characteristic analysis, the area under the curve was 0.843, and the cutoff value was 0.4. The difference between the ONSD values measured before and after spinal anesthesia may be an important parameter for predicting the risk of PDPH development.


The VAP protein family: from cellular functions to motor neuron disease.
The VAMP-associated proteins (VAPs) are highly conserved integral endoplasmic reticulum membrane proteins implicated in diverse cellular functions, including the regulation of lipid transport and homeostasis, membrane trafficking, neurotransmitter release, stabilization of presynaptic microtubules, and the unfolded protein response. Recently, a single missense mutation within the human VAP-B gene was identified in three forms of familial motor neuron disease. In this review, we integrate results from studies of yeast, fly and mammalian VAPs that provide insight into the structural features of these proteins, the network of VAP-interacting proteins, their possible physiological functions, and their involvement in motor neuron disease.


Parasympathetic withdrawal antedates dynamic myocardial ischemia in patients with syndrome X.
This study was to evaluate the dynamic changes in cardiac autonomic control preceding electrocardiographic (ECG) myocardial ischemia in patients with syndrome X. Twenty-four-hour ambulatory ECG was obtained in 34 consecutive patients in a drug-free state. Fourteen (41%) of them, aged 58.8+/-13.5 years, presented a total of 19 ischemic episodes, mean duration 12.4+/-19.8 min (ranged 1 to 90 min). Heart rate variability was measured for 24 h; for 3 min and 30 min before, and during the 15 min (in five 3-min intervals) immediately antedating ST segment depression; and for another 3 min after ST segment back to normal. There were significant progressive shortenings in sinus cycle lengths over the 30 min preceding myocardial ischemia (-30 vs -3 minute, 822+/-32 ms vs 637+/-23 ins, P<0.05; a decrement of 22.5%). The sinus cycle lengths lengthened after ischemia ceased. High frequency activity, pNNSO and rMSS.D. were significantly reduced from the -30 min baseline to a nidus in the last 3 min before ischemia (P<0.05), whereas low frequency band and low/high frequency ratio did not present significant change. These findings strongly argue that cardiac autonomic control, especially vagal withdrawal, is involved in the pathogenesis of dynamic myocardial ischemia in syndrome X.


Oct4 dependent chromatin activation is required for chicken primordial germ cell migration.
Primordial germ cells (PGCs) are the undifferentiated progenitors of the gametes. Unlike the poor maintenance of cultured mammalian PGCs, the avian PGCs can be expanded in vitro indefinitely while preserving pluripotency and germline competence. In mammals, the Oct4 is the master transcription factor that ensures the stemness of pluripotent cells such as PGCs, but the specific function of Oct4 in chicken PGCs remains unclear. As expected, the loss of Oct4 in chicken PGCs reduced the expression of key pluripotency factors and promoted the genes involved in endoderm and ectoderm differentiation. Furthermore, the global active chromatin was reduced as shown by the depletion of the H3K27ac upon Oct4 suppression. Interestingly, the de-activated chromatin caused the down-regulation of adjacent genes which are mostly known regulators of cell junction, chemotaxis and cell migration. Consequently, the Oct4-deficient PGCs show impaired cell migration and could not colonize the gonads when re-introduced into the bloodstream of the embryo. We propose that, in addition to maintaining pluripotency, the Oct4 mediated chromatin activation is dictating chicken PGC migration.


Effectiveness, safety, and healthcare costs associated with rivaroxaban versus warfarin among venous thromboembolism patients with obesity: a real-world study in the United States.
Prior observational studies suggest rivaroxaban is safe and effective among patients with morbid obesity who suffered a venous thromboembolism (VTE) event, but existing data are more limited in the broader population of VTE patients with obesity. This study assessed VTE recurrence, major bleeding, healthcare resource utilization, and healthcare costs among VTE patients with obesity who received rivaroxaban versus warfarin. VTE patients with obesity who initiated rivaroxaban or warfarin after a first VTE (index date) were identified from the IQVIA PharMetrics® Plus database (01/02/2011-09/30/2019). The follow-up period spanned from the index date until health plan disenrollment, end of data availability, cancer diagnosis/treatment, end of the 12 month post-index period, or (for the analysis of major bleeding) anticoagulant discontinuation or switch. Patient characteristics were balanced using inverse probability of treatment weighting. The weighted rivaroxaban (N = 8666) and warfarin cohorts (N = 5946) were well balanced (mean age = 51 years, females = 52%). Over a 9.6 months mean observation period, rivaroxaban users had a significantly lower risk of VTE recurrence [7.0% vs. 8.2%, HR(95% CI) = 0.85(0.75;0.97)] and a similar risk of major bleeding [4.1% vs. 3.6%, HR(95% CI) = 1.11(0.89;1.37)] relative to warfarin users at 12 months. Relative to warfarin users, rivaroxaban users had significantly fewer all-cause outpatient visits [RR(95% CI) = 0.71(0.70;0.74)]. The higher pharmacy costs incurred by rivaroxaban recipients (cost difference = $1252) were offset by lower medical costs (cost difference = - $2515, all p < 0.05) compared with warfarin recipients. Our findings suggest that rivaroxaban is safe and effective versus warfarin, and associated with lower medical costs among VTE patients with obesity.


Bimetallic Nanoparticles as Efficient Catalysts: Facile and Green Microwave Synthesis.
This work deals with the development of a green and versatile synthesis of stable mono- and bi-metallic colloids by means of microwave heating and exploiting ecofriendly reagents: water as the solvent, glucose as a mild and non-toxic reducer and polyvinylpirrolidone (PVP) as the chelating agent. Particle size-control, total reaction yield and long-term stability of colloids were achieved with this method of preparation. All of the materials were tested as effective catalysts in the reduction of p-nitrophenol in the presence of NaBH₄ as the probe reaction. A synergistic positive effect of the bimetallic phase was assessed for Au/Cu and Pd/Au alloy nanoparticles, the latter showing the highest catalytic performance. Moreover, monoand bi-metallic colloids were used to prepare TiO₂- and CeO₂-supported catalysts for the liquid phase oxidation of 5-hydroxymethylfufural (HMF) to 2,5-furandicarboxylic acid (FDCA). The use of Au/Cu and Au/Pd bimetallic catalysts led to an increase in FDCA selectivity. Finally, preformed Pd/Cu nanoparticles were incorporated into the structure of MCM-41-silica. The resulting Pd/Cu MCM-41 catalysts were tested in the hydrodechlorination of CF₃OCFClCF₂Cl to CF₃OCF=CF₂. The effect of Cu on the hydrogenating properties of Pd was demonstrated.


The potential of incorporation of binary salts and ionic liquid in P(VP-co-VAc) gel polymer electrolyte in electrochemical and photovoltaic performances.
In this study, dye-sensitized solar cells (DSSCs) has been assembled with poly(1-vinylpyrrolidone-co-vinyl acetate) (P(VP-co-VAc)) gel polymer electrolytes (GPEs) which have been incorporated with binary salt and an ionic liquid. The potential of this combination was studied and reported. The binary salt system GPEs was having ionic conductivity and power conversion efficiency (PCE) that could reach up to 1.90 × 10(-3) S cm(-1) and 5.53%, respectively. Interestingly, upon the addition of the ionic liquid, MPII into the binary salt system the ionic conductivity and PCE had risen steadily up to 4.09 × 10(-3) S cm(-1) and 5.94%, respectively. In order to know more about this phenomenon, the electrochemical impedance studies (EIS) of the GPE samples have been done and reported. Fourier transform infrared studies (FTIR) and thermogravimetric analysis (TGA) have also been studied to understand more on the structural and thermal properties of the GPEs. The Nyquist plot and Bodes plot studies have been done in order to understand the electrochemical properties of the GPE based DSSCs and Tafel polarization studies were done to determine the electrocatalytic activity of the GPE samples.


Contribution of M470V variant to cystic fibrosis: First study in CF and normal Tunisian population.
Determining the frequency of M470V polymorphism in cystic fibrosis and healthy cohort in Tunisia to establish the contribution of M470V polymorphism in cystic fibrosis variable presentation and course. Additionally, studying the origin of cystic fibrosis transmembrane conductance regulator gene in Tunisian population and its evolution among populations worldwide. The genotyping of M470V marker was realized by PCR-RFLP technique in 34 unrelated patients and 50 healthy subjects. Statistical difference was found in the genotype and allelic distribution between CF and control groups. Exclusive association between F508del allele and M470 allele was noted. This study has contributed to better understanding involvement of the M470V polymorphism in the CF clinical expression in the Tunisian population and has confirmed the utility of this marker in the study of the origin and evolution of the CFTR locus in the human history.


Strategies used by Iranian nursing students for adjusting to internship: a qualitative study.
The internship setting is a highly challenging one for nursing students, and working in such an environment requires adjustment. Knowledge of the adjustment strategies used by students enhances the body of nursing knowledge and can help nursing officials adopt appropriate decisions to strengthen the students' effective adjustment skills and increase the benefits reaped from their internship. The present study was conducted to explore the strategies used by nursing students to adjust to internship. A total of 19 senior nursing interns (7 Female, and 12 Male) were selected by purposive sampling with maximum variation from one of the nursing and midwifery schools affiliated to a large metropolitan medical university in northern Iran. Data were collected using audio-taped semi-structured face-to-face interviews over an 18-month period and were carefully transcribed and analyzed using the Graneheim & Lundman qualitative conventional content analysis approach. The researchers analyzed the data in MAXQDA 10 software. Four main categories and eight subcategories emerged from the data analysis. Main categories include efforts to achieve clinical competency, efforts to be sociable or accepted, self-management and reaction to conflicts. All the participants attempted to attain adjustment by adopting strategies such as achieving clinical competence, trying to be sociable or accepted, self-management, and reaction to conflicts depending on the conditions of internship. Officials should help nursing students use effective strategies and achieve adjustment.


Giant Cavernous Hemangioma of the Liver in a Patient with Autosomal Dominant Polycystic Kidney Disease.
BACKGROUND Autosomal dominant polycystic kidney disease (ADPKD) is frequently associated with liver cysts, but an association with giant cavernous liver hemangioma is not mentioned in the literature. CASE REPORT We report the case of a 41-year-old man with ADPKD, secondary arterial hypertension, and stage 4 chronic kidney disease who presented with a 2-week history of persistent pain at the base of the right hemithorax and in the right hypochondrium. An ultrasound examination and a contrast-enhanced computed tomography scan revealed a giant cavernous liver hemangioma. Surgery was intially taken into account (however, twice delayed because of the COVID-19 pandemic) but later refused because it would have left the patient with dangerously few liver parenchyma. CONCLUSIONS To our knowledge, this is the first reported case of ADPKD associated with cavernous liver hemangioma. Vascular endothelial growth factor could be the pathophysiological link between the 2 conditions. Further research may unravel the molecular biology that underlies this possible association, pointing to new therapeutic avenues for ADPKD.


Unusual CT appearance of a thyroglossal duct cyst carcinoma.
This is the first report to describe the CT appearances of a solid midline cervical mass that proved to be a papillary carcinoma associated with a thyroglossal duct cyst.


The strength and form of natural selection on transcript abundance in the wild.
Gene transcription variation is known to contribute to disease susceptibility and adaptation, but we currently know very little about how contemporary natural selection shapes transcript abundance. Here, we propose a novel analytical framework to quantify the strength and form of ongoing natural selection at the transcriptome level in a wild vertebrate. We estimated selection on transcript abundance in a cohort of a wild salmonid fish (Salmo trutta) affected by an extracellular myxozoan parasite (Tetracapsuloides bryosalmonae) through mark-recapture field sampling and the integration of RNA-sequencing with classical regression-based selection analysis. We show, based on fin transcriptomes of the host, that infection by the parasite and subsequent host survival is linked to upregulation of mitotic cell cycle process. We also detect a widespread signal of disruptive selection on transcripts linked to host immune defence, host-pathogen interactions, cellular repair and maintenance. Our results provide insights into how selection can be measured at the transcriptome level to dissect the molecular mechanisms of contemporary evolution driven by climate change and emerging anthropogenic threats. We anticipate that the approach described here will enable critical information on the molecular processes and targets of natural selection to be obtained in real time.


Can we "effectivize" spacetime?
According to effective realism, scientific theories give us knowledge about the unobservable world, but not at the fundamental level. This view is supported by the well-received effective-field-theory (EFT) approach to high energy physics, according to which even our most successful physical theories are only applicable up to a certain energy scale and expected to break down beyond that. In this paper, I advance new challenges for effective realism and the EFT approach. I argue that effective quantum gravity (EQG) does not give us a realistic theory of spacetime even within its scope of validity. This also exposes a general interpretative dilemma faced by all EFTs concerning their indispensable references to classical spacetime beyond their scope of validity.


P2RX7 Gene rs1718125 Polymorphism is Related with Postoperative Pain and Fentanyl Intake in Esophageal Cancer Patients.
Prevention and control of postoperative pains are essential, which affects the prognosis and life quality of patients. Fentanyl is a widely used opioid drug for pre-, intra- and postoperative analgesia. Identifying a patient's genotype before surgery may help to control the fentanyl dose in the perioperative period. This study enrolling 645 esophageal cancer (EC) patients was aimed to investigate the associations of P2RX7 gene rs1718125 polymorphism with fentanyl intake and postoperative pains in a Chinese Han population. Genotyping was accomplished by direct sequencing and polymerase chain reaction. The GA/AA genotype carriers showed lower visual analog scale scores at postoperative 0, 6 and 24 h, but not at 48 h, compared with the GG genotype. The fentanyl consumption of GG genotype was remarkably more relative to the GA/AA genotype at 6 and 24 h after treatment. P2RX7 rs1718125 polymorphism is connected to the postoperative pains and fentanyl use for EC patients.