Electrodermal measures of Jing-Well points and their clinical relevance in endometriosis-related chronic pelvic pain.
To determine whether electrodermal measures at Jing-Well acupuncture points, "indicator" points located at the tips of fingers and toes are associated with clinical measures in adolescent women with chronic pelvic pain. The design of this study was a randomized sham-controlled trial. Analyses of electrodermal measures were based on longitudinal, multivariable analyses using generalized estimating equations. The subjects were 14 young women (ages 14-22) with laparoscopically diagnosed endometriosis and chronic pelvic pain. Subjects were randomized to sham acupuncture or Japanese-style active acupuncture. Sixteen (16) treatments were administered over 8 weeks. Using a Hibiki-7 device, electrodermal impedance measures were obtained at all 24 Jing-Well points for each treatment visit. From these readings, measures of "imbalance" were determined by calculating statistical dispersion (statistical deviation and Gini coefficient) and level of asymmetry (left-right, top-bottom, and yin-yang). Clinical outcome measures were obtained at baseline, week 4, and week 8 and included level of pelvic pain, Endometriosis Health Profile, Pediatric Quality of Life, perceived stress, and inflammatory cytokine levels (interleukin-6 and tumor necrosis factor-alpha). Participants designated to the acupuncture group had, on average, a substantial decrease in statistical dispersion and asymmetry of Hibiki-7 values over the course of treatment compared to the sham group. Electrodermal asymmetry variables, specifically either yin-yang or left-right measure, were significantly associated with pelvic pain, Endometriosis Health Profile, Pediatric Quality of Life, and Perceived Stress even after adjusting for treatment designation. No associations between electrodermal balance measures and inflammatory cytokines were found. Electrodermal measures may be significantly associated with clinical outcome and acupuncture treatments in adolescent women with chronic pelvic pain.


Stem cell-derived porcine macrophages as a new platform for studying host-pathogen interactions.
Infectious diseases of farmed and wild animals pose a recurrent threat to food security and human health. The macrophage, a key component of the innate immune system, is the first line of defence against many infectious agents and plays a major role in shaping the adaptive immune response. However, this phagocyte is a target and host for many pathogens. Understanding the molecular basis of interactions between macrophages and pathogens is therefore crucial for the development of effective strategies to combat important infectious diseases. We explored how porcine pluripotent stem cells (PSCs) can provide a limitless in vitro supply of genetically and experimentally tractable macrophages. Porcine PSC-derived macrophages (PSCdMs) exhibited molecular and functional characteristics of ex vivo primary macrophages and were productively infected by pig pathogens, including porcine reproductive and respiratory syndrome virus (PRRSV) and African swine fever virus (ASFV), two of the most economically important and devastating viruses in pig farming. Moreover, porcine PSCdMs were readily amenable to genetic modification by CRISPR/Cas9 gene editing applied either in parental stem cells or directly in the macrophages by lentiviral vector transduction. We show that porcine PSCdMs exhibit key macrophage characteristics, including infection by a range of commercially relevant pig pathogens. In addition, genetic engineering of PSCs and PSCdMs affords new opportunities for functional analysis of macrophage biology in an important livestock species. PSCs and differentiated derivatives should therefore represent a useful and ethical experimental platform to investigate the genetic and molecular basis of host-pathogen interactions in pigs, and also have wider applications in livestock.


Polarization contrasts and their effect on the gaze stabilization of crustaceans.
Many animals go to great lengths to stabilize their eyes relative to the visual scene and do so to enhance the localization of moving objects and to functionally partition the visual system relative to the outside world. An important cue that is used to control these stabilization movements is contrast within the visual surround. Previous studies on insects, spiders and fish have shown that gaze stabilization is achromatic ('colour blind'), meaning that chromatic contrast alone (in the absence of apparent intensity contrasts) does not contribute to gaze stabilization. Following the assumption that polarization vision is analogous in many ways to colour vision, the present study shows that five different crustacean species do not use the polarization of light alone for gaze stabilization, despite being able to use this modality for detecting predator-like objects. This work therefore suggests that the gaze stabilization in many crustaceans cannot be elicited by the polarization of light alone.


Investigating risk factors for Internet gaming disorder: a comparison of patients with addictive gaming, pathological gamblers and healthy controls regarding the big five personality traits.
Engaging in online games has become increasingly important as a part of leisure activity in adolescents and adults. While the majority of people use these games in a healthy way, epidemiological studies show that some develop excessive use and symptoms that are related to those of substance-related addictions. Despite increasing research concerning the epidemiology of internet gaming disorder (IGD), predisposing factors have been examined to a lesser extent. Knowing about specific risk factors would help clarify the nosological features of IGD and enhance prevention and intervention. This study aimed to evaluate the relationships between personality traits and IGD. A total of 115 patients meeting the criteria for IGD were compared to 167 control subjects displaying either regular or intense use of online games. Additionally, 115 patients meeting diagnostic criteria for pathological gambling were included. IGD was associated with higher neuroticism, decreased conscientiousness and low extraversion. The comparisons to pathological gamblers indicate that low conscientiousness and low extraversion in particular are characteristic of IGD. An integration of personality variables into an etiopathological model describing presumable mechanisms fostering and maintaining addictive online gaming is proposed. This model could be helpful for the theoretical understanding of addictive gaming, public health campaigns and psychoeducation within therapeutic settings.


Inflammatory mediators and modulators release in organ culture from rabbit skin lesions produced in vivo by sulfur mustard. II. Evans blue dye experiments that determined the rates of entry and turnover of serum protein in developing and healing lesions.
Extravasated serum seems to be the major modulator of the local inflammatory response, because it provides both proinflammatory and antiinflammatory components. This report describes the rates of entry and turnover of extravasated serum protein in dermal inflammatory lesions produced by the military vesicant sulfur mustard (SM). Rabbits, bearing SM skin lesions, were given an intravenous injection of Evans blue dye, so that at the time of sacrifice, 2 hours later, their skin lesions were 2 hours and 1,2,3,6, and 10 days of age. Evans blue labels serum albumin, a representative serum protein. By multiplying the amount of Evans blue contained in the lesions by a factor that converted micrograms of Evans blue into milligrams of serum protein, the authors could estimate the 2-hour rate of entry of serum protein into these lesions. Serum protein in the lesions was both bound and unbound. The unbound protein was extractable from the lesions into the culture fluids, and, electrophoretically, was similar in composition to serum protein. Grossly edematous peak lesions (1 day of age) contained 7.8 mg of unbound serum protein per square centimeter of skin. Healing lesions (6 and 10 days of age) contained about 4.5 mg/sq cm, and normal skin about 1.7 mg/sq cm. Lesions 1 day of age had the highest rate of serum albumin entry, and about 36% of this Evans-blue-labeled protein was unbound, ie, extractable into the culture fluids. Lesions 3 and 6 days of age had a rate of serum albumin entry that was roughly half that of 1-day lesions, and only about 13% of this entering protein was unbound. Normal skin had a very low rate of serum albumin entry, and only 8% of this entering protein was unbound. The turnover rate of the unbound (extractable) serum protein could be estimated from the 2-hour entry rate of the Evans-blue-labeled albumin and the total protein in the culture fluids. In 1-day lesions, about 25% of the serum protein in the culture fluids was protein which had entered during the last 2 hours, so that 100% of this unbound protein should have been replaced once in 8 hours. In contrast, in 3- and 6-day lesions, this unbound serum protein should have been replaced once in about 35 hours, and in normal skin once in 80 hours. Evans-blue-labeled serum albumin continuously entered both the bound and unbound compartments of the SM lesions, even during the healing stages.(ABSTRACT TRUNCATED AT 400 WORDS)


Targeting of voltage-gated potassium channel isoforms to distinct cell surface microdomains.
Voltage-gated potassium (Kv) channels regulate action potential duration in nerve and muscle; therefore changes in the number and location of surface channels can profoundly influence electrical excitability. To investigate trafficking of Kv2.1, 1.4 and 1.3 within the plasma membrane, we combined the expression of fluorescent protein-tagged Kv channels with live cell confocal imaging. Kv2.1 exhibited a clustered distribution in HEK cells similar to that seen in hippocampal neurons, whereas Kv1.4 and Kv1.3 were evenly distributed over the plasma membrane. Using FRAP, surface Kv2.1 displayed limited mobility; approximately 40% of the fluorescence recovered within 20 minutes of photobleach (M(f)=0.41+/-0.04). Recovery occurred not by diffusion from adjacent membrane but probably by transport of nascent channel from within the cell. By contrast, the Kv1 family members Kv1.4 and Kv1.3 were highly mobile, both showing approximately 80% recovery (Kv 1.4 M(f)=0.78+/-0.07; Kv1.3 M(f)=0.78+/-0.04; without correction for photobleach); unlike Kv2.1, recovery was consistent with diffusion of channel from membrane adjacent to the bleach region. Studies using PA-GFP-tagged channels were consistent with the FRAP results. Following photoactivation of a small region of plasma membrane PA-GFP-Kv2.1 remained restricted to the photoactivation ROI, while PA-GFP-Kv1.4 rapidly diffused throughout the cell surface. Additionally, PA-GFP-Kv2.1 moved into regions of the cell membrane not adjacent to the original photoactivation ROI. Sucrose density gradient analysis indicated that half of Kv2.1 is part of a large, macromolecular complex while Kv1.4 sediments as predicted for the tetrameric channel complex. Disruption of membrane cholesterol by cyclodextrin minimally altered Kv2.1 mobility (M(f)=0.32+/-0.03), but significantly increased surface cluster size by at least fourfold. By comparison, the mobility of Kv1.4 decreased following cholesterol depletion with no change in surface distribution. The mobility of Kv1.3 was slightly increased following cyclodextrin treatment. These results indicate that (1) Kv2.1, Kv1.4 and Kv1.3 exist in distinct compartments that exhibit different trafficking properties, (2) membrane cholesterol levels differentially modulate the trafficking and localization of Kv channels and (3) Kv2.1 expressed in HEK cells exhibits a surface distribution similar to that seen in native cells.


Structure and function of sawB, a gene involved in differentiation of Streptomyces ansochromogenes.
A partial DNA library of Streptomyces ansochromogenes 7100 was constructed by using plasmid pl J702 as vector and white mutant W19 as recipient. About 3 000 clones were obtained, two of which gave rise to the grey phenotype as wild type 7100. The plasmids were isolated from two transformants. The result indicated that the 5.2 kb and 5.8 kb DNA fragments were inserted into plJ702. The resulting recombinant plasmids were designated as pNL-1 and pNL-2 respectively. The 1.25 kb Pstl I -Apa I DNA fragment from pNL-1 was recognized as its complementarity to W19 strain. The nucleotide sequence of the 3.0 kb Pst I DNA fragment including 1.25 kb was determined and analyzed. The result indicated that this DNA fragment contains one complete open reading frame (ORF1) which encodes a protein with 295 amino acid residues, and this gene was designated as sawB. The deduced protein has 81% amino acid identities in comparison with that encoded by whiH in Streptomyces coelicolor. The function of sawB gene was studied by using strategy of gene disruption, and the resulting sawB mutant failed to form spores and produced loosely coiled aerial hyphal. The result showed that sawB is closely related to hyphal coiling and sporulation in S. ansochromogenes, and also indicated that the sawB can complement whiH mutant (C119) to restore the grey phenotype of Streptomyces coelicolor J 1501 (wild type).


Sex-Specific Effects of Nanoparticle-Encapsulated MitoQ (nMitoQ) Delivery to the Placenta in a Rat Model of Fetal Hypoxia.
Pregnancy complications associated with chronic fetal hypoxia have been linked to the development of adult cardiovascular disease in the offspring. Prenatal hypoxia has been shown to increase placental oxidative stress and impair placental function in a sex-specific manner, thereby affecting fetal development. As oxidative stress is central to placental dysfunction, we developed a placenta-targeted treatment strategy using the antioxidant MitoQ encapsulated into nanoparticles (nMitoQ) to reduce placental oxidative/nitrosative stress and improve placental function without direct drug exposure to the fetus in order to avoid off-target effects during development. We hypothesized that, in a rat model of prenatal hypoxia, nMitoQ prevents hypoxia-induced placental oxidative/nitrosative stress, promotes angiogenesis, improves placental morphology, and ultimately improves fetal oxygenation. Additionally, we assessed whether there were sex differences in the effectiveness of nMitoQ treatment. Pregnant rats were intravenously injected with saline or nMitoQ (100 μl of 125 μM) on gestational day (GD) 15 and exposed to either normoxia (21% O2) or hypoxia (11% O2) from GD15 to 21. On GD21, placentae from both sexes were collected for detection of superoxide, nitrotyrosine, nitric oxide, CD31 (endothelial cell marker), and fetal blood spaces, Vegfa and Igf2 mRNA expression in the placental labyrinth zone. Prenatal hypoxia decreased male fetal weight, which was not changed by nMitoQ treatment; however, placental efficiency (fetal/placental weight ratio) decreased by hypoxia and was increased by nMitoQ in both males and females. nMitoQ treatment reduced the prenatal hypoxia-induced increase in placental superoxide levels in both male and female placentae but improved oxygenation in only female placentae. Nitrotyrosine levels were increased in hypoxic female placentae and were reduced by nMitoQ. Prenatal hypoxia reduced placental Vegfa and Igf2 expression in both sexes, while nMitoQ increased Vegfa and Igf2 expression only in hypoxic female placentae. In summary, our study suggests that nMitoQ treatment could be pursued as a potential preventative strategy against placental oxidative stress and programming of adult cardiovascular disease in offspring exposed to hypoxia in utero. However, sex differences need to be taken into account when developing therapeutic strategies to improve fetal development in complicated pregnancies, as nMitoQ treatment was more effective in placentae from females than males.


Negotiating the care-giving role: family members' experience during critical exacerbation of COPD in Norway.
Healthcare policies often state that complex conditions are to be treated outside hospital in various forms of public-private partnership. Chronic obstructive pulmonary disease (COPD) is a progressive illness that includes episodes of serious acute exacerbations characterised by extreme breathlessness. There is limited knowledge about COPD exacerbations from the perspective of family caregivers and implications of the changing boundary between hospital care and care at home. In this paper, we explore how caregivers negotiate their role as caregivers with patients and healthcare professionals during acute exacerbations. We conducted 10 qualitative interviews with family caregivers of COPD patients in 2011, all were spouses over the age of 60. The participants were recruited through the patient pool of ambulatory pulmonary services of two hospitals in Oslo, Norway. Data were interpreted using thematic analysis. The caregivers described a lack of understanding and support from health professionals in some situations. They shouldered considerable responsibility, but were not always acknowledged as competent carers by professionals. Caregivers had to balance their involvement. They noted that they could lose the professionals' co-operation if their involvement was perceived as interfering or preventing the professionals from exercising their expertise. However, by not sharing their personalised knowledge about the patients, they risked that the professionals would not understand the severity of the exacerbation, which could undermine their own ability to maintain a sense of safety and control. The negotiations caregivers participated in and the uncertainty they experienced shed new light on the complexity of their role, and the discrepancy between practice and ideals in healthcare policy regarding collaboration of care. It is crucial to develop further knowledge about structural, interactional and communicational facilitators and barriers for reaching shared understandings and facilitating mutual trust in these demanding situations.


Ordering of hard rectangles in strong confinement.
Using transfer operator and fundamental measure theories, we examine the structural and thermodynamic properties of hard rectangles confined between two parallel hard walls. The side lengths of the rectangle (L and D, L>D) and the pore width (H) are chosen such that a maximum of two layers is allowed to form when the long sides of the rectangles are parallel to the wall, while only one layer is possible in case the rectangles are perpendicular to the wall. We observe three different structures: (i) at low density, the rectangles align mainly parallel to the wall, (ii) at intermediate or high density, two fluid layers form in which the rectangles are parallel to the wall, and (iii) a dense single fluid layer with rectangles aligned mainly perpendicular to the wall. The transition between these structures is smooth without any non-analytic behaviour in the thermodynamic quantities; however, the fraction of particles perpendicular (or parallel) to the wall can exhibit a relatively sudden change if L is close to H. In this case, interestingly, even three different structures can be observed with increasing density.


[The role of the mast cells of the conjunctiva in the intercellular interactions in keratoconus and epithelial-endothelial corneal dystrophy].
The aim of this study was assessment of the role of mast cells in inflammatory processes associated with keratoconus and corneal epithelial-endothelial dystrophy and clinical assessment of Lecrolin, a specially designed dosage form (eye drops) of potassium cromoglycate (intal) used as an antiallergic drug in asthma, rhinitis, etc. Examinations of 43 biopsy specimens of the conjunctiva from patients with keratoconus and epithelial-endothelial corneal dystrophy demonstrated the significance of immune inflammation in the pathogenesis of these diseases. Mast cells are a typical cell element participating in inflammation at all stages. The count of mast cells increases from 2.5 during the acute stage to 8.86 during the chronic stage, which is explained by absence of the leukocytic stage and proteolysis and stabilization of mature labrocyte degranulation associated with it. Reactions of mast cells with lymphocytes and monocytes/macrophages lead to proliferation of fibroblasts and chronic development of collagen formation. Close relationships between microvessels and mast cells promote stable spasms of the vessels, impairing the microcirculatory bed and leading to ischemia of the anterior segment of the eye. In such cases sodium cromolyne drugs (lecrolin) inhibiting histamine release and stabilizing mast cell membranes are recommended.


Anti-diarrheal activities of phytol along with its possible mechanism of action through in-vivo and in-silico models.
Phytol (PHY), a chlorophyll-derived diterpenoid, exhibits numerous pharmacological properties, including antioxidant, antimicrobial, and anticancer activities. This study evaluates the anti-diarrheal effect of phytol (PHY) along with its possible mechanism of action through in-vivo and in-silico models. The effect of PHY was investigated on castor oil-induced diarrhea in Swiss mice by using prazosin, propranolol, loperamide, and nifedipine as standards with or without PHY. PHY at 50 mg/kg (p.o.) and all other standards exhibit significant (p < 0.05) anti-diarrheal effect in mice. The effect was prominent in the loperamide and propranolol groups. PHY co-treated with prazosin and propranolol was found to increase in latent periods along with a significant reduction in diarrheal section during the observation period than other individual or combined groups. Furthermore, molecular docking studies also suggested that PHY showed better interactions with the α- and β-adrenergic receptors, especially with α-ADR1a and β-ADR1. In the former case, PHY showed interaction with hydroxyl group of Ser192 at a distance of 2.91Å, while in the latter it showed hydrogen bond interactions with Thr170 and Lys297 with a distance of 2.65 and 2.72Å, respectively. PHY exerted significant anti-diarrheal effect in Swiss mice, possibly through blocking α- and β-adrenergic receptors.


Inhibitory effects of megakaryocytic cells in prostate cancer skeletal metastasis.
Prostate cancer cells commonly spread through the circulation, but few successfully generate metastatic foci in bone. Osteoclastic cellular activity has been proposed as an initiating event for skeletal metastasis. Megakaryocytes (MKs) inhibit osteoclastogenesis, which could have an impact on tumor establishment in bone. Given the location of mature MKs at vascular sinusoids, they may be the first cells to physically encounter cancer cells as they enter the bone marrow. Identification of the interaction between MKs and prostate cancer cells was the focus of this study. K562 (human MK precursors) and primary MKs derived from mouse bone marrow hematopoietic precursor cells potently suppressed prostate carcinoma PC-3 cells in coculture. The inhibitory effects were specific to prostate carcinoma cells and were enhanced by direct cell-cell contact. Flow cytometry for propidium iodide (PI) and annexin V supported a proapoptotic role for K562 cells in limiting PC-3 cells. Gene expression analysis revealed reduced mRNA levels for cyclin D1, whereas mRNA levels of apoptosis-associated specklike protein containing a CARD (ASC) and death-associated protein kinase 1 (DAPK1) were increased in PC-3 cells after coculture with K562 cells. Recombinant thrombopoietin (TPO) was used to expand MKs in the marrow and resulted in decreased skeletal lesion development after intracardiac tumor inoculation. These novel findings suggest a potent inhibitory role of MKs in prostate carcinoma cell growth in vitro and in vivo. This new finding, of an interaction of metastatic tumors and hematopoietic cells during tumor colonization in bone, ultimately will lead to improved therapeutic interventions for prostate cancer patients.


Dialysis patients treated with Epoetin α show improved exercise tolerance and physical function: A new analysis of the Canadian Erythropoietin Study Group trial.
The risks/benefits of anemia treatment in dialysis patients have been redefined in the US Epoetin α label. This analysis was carried out to determine if increasing hemoglobin (Hb) levels improve exercise tolerance and physical function in anemic dialysis patients. This is a new analysis of the Canadian Erythropoietin Study Group trial, a double-blind, randomized, placebo-controlled trial in dialysis patients. Subjects were 18 to 75 years old, on hemodialysis for >3 months, and had a baseline Hb <9.0 g/dL. Patients with a history of diabetes mellitus, ischemic heart disease, or severe/uncontrolled hypertension were excluded. Patients were randomized to receive Epoetin α to a target Hb of 9.5 to 11.0 g/dL (n=40) or a target of 11.5 to 13.0 g/dL (n=38), or receive placebo (n=40). Results from patients in the Epoetin-α-treated arms were combined for this analysis. Hb level, exercise tolerance (Treadmill Stress Test and 6-Minute Walk Test) and patient-reported physical function measures (Physical Summary domain from the Kidney Disease Questionnaire, and 4 domains from the Sickness Impact Profile) were reported at baseline and months 2, 4, and 6. Differences in measures were statistically significant for exercise tolerance (Treadmill Stress, P=0.0001) and patient-reported physical function (Kidney Disease Questionnaire Physical, P=0.0001; Sickness Impact Profile Physical, P=0.0015) across all time points for Epoetin-α-treated patients compared with placebo. Improvements were seen at 2 months and were maintained through months 4 and 6. Dialysis patients receiving Epoetin α showed improved exercise tolerance and physical function. These findings should be considered as physicians weigh the risks and benefits of treatment.


Connexin40 imparts conduction heterogeneity to atrial tissue.
Impulse propagation in cardiac tissue is a complex process in which intercellular coupling through gap junction channels is a critical component. Connexin40 (Cx40) is an abundant gap junction protein that is expressed in atrial myocytes. Alterations in the expression of Cx40 have been implicated in atrial arrhythmogenesis. The purpose of the current study was to assess the role of Cx40 in atrial impulse propagation. High-resolution optical mapping was used to study conduction in the right and left atrial appendages of isolated Langendorff-perfused murine hearts. Wild-type (Cx40(+/+)), heterozygous (Cx40(+/-)), and knockout (Cx40(-/-)) mice, both adult and embryonic, were studied to assess the effects of reduced Cx40 expression on sinus node function and conduction velocity at different pacing cycle lengths (100 and 60 ms). In both adult and late-stage embryonic Cx40(+/+) mice, heterogeneity in CV was found between the right and left atrial appendages. Either partial (Cx40(+/-)) or complete (Cx40(-/-)) deletion of Cx40 was associated with the loss of conduction heterogeneity in both adult and embryonic mice. Additionally, sinus node impulse initiation was found to be ectopic in Cx40(-/-) mice at 15.5 days postcoitus, whereas Cx40(+/+) mice showed normal activation occurring near the crista terminalis. Our findings suggest that Cx40 plays an essential role in establishing interatrial conduction velocity heterogeneity in the murine model. Additionally, we describe for the first time a developmental requirement for Cx40 in normal sinus node impulse initiation at 15.5 days postcoitus.


Testing Cognitive and Emotion-Focused Models of Worry in Black and White Samples.
Several models have been proposed to conceptualize worry. Broadly, the models can be classified as cognitive (including the Avoidance Model, the Intolerance of Uncertainty Model, and the Metacognitive Model) and emotion-focused (including Emotion Dysregulation and Acceptance-Based models). Although these models have received strong empirical investigation in primarily non-Hispanic White samples, no known study has examined the applicability to racial and ethnic minority groups. The current study compared the proportion of variance explained by cognitive and emotion-focused models of worry in White and Black samples. Results indicated that cognitive and emotion-focused models significantly predicted worry in both Black and White samples. However, the overall amount of variance in worry explained by the models was less for Black samples. Specifically, controlling for gender, the cognitive models explained 53% of the variance in worry in the White sample compared with 19% in the Black sample. Similarly, the emotion-focused models explained 34% of the variance in worry in the White sample but only 13% in the Black sample. These findings suggest that well-established conceptual frameworks for worry failed to explain the bulk of the variance in worry in Black samples, leaving much unknown. Additional research is needed to identify key variables that may further explain worry in ethnic minority samples.


Using a Loneliness Measure to Screen for Risk of Mental Health Problems: A Replication in Two Nationally Representative Cohorts.
Loneliness co-occurs alongside many mental health problems and is associated with poorer treatment outcomes. It could therefore be a phenomenon of interest to clinicians as an indicator of generalised risk for psychopathology. The present study tested whether a short measure of loneliness can accurately classify individuals who are at increased risk of common mental health problems. Data were drawn from two nationally representative cohorts: the age-18 wave of the UK-based Environmental Risk (E-Risk) Longitudinal Twin Study and the age-38 wave of the New Zealand-based Dunedin Multidisciplinary Health and Development Study. In both cohorts, loneliness was assessed using the three-item UCLA Loneliness Scale, plus two stand-alone items about feeling alone and feeling lonely. Outcome measures consisted of diagnoses of depression and anxiety and self-reports of self-harm/suicide attempts, assessed via a structured interview. ROC curve analysis showed that the Loneliness Scale had fair accuracy in classifying individuals meeting criteria for all three outcomes, with a cut-off score of 5 (on a scale from 3 to 9) having the strongest empirical support. Both of the stand-alone items showed modest sensitivity and specificity but were more limited in their flexibility. The findings were replicated across the two cohorts, indicating that they are applicable both to younger and older adults. In addition, the accuracy of the loneliness scale in detecting mental health problems was comparable to a measure of poor sleep quality, a phenomenon which is often included in screening tools for depression and anxiety. These findings indicate that a loneliness measure could have utility in mental health screening contexts, as well as in research.


Antidiabetic effects of lithium.
Lithium carbonate was administered to a female manic depressive patient who also had maturity onset diabetes mellitus. She was found to have lowered blood glucose levels with administration of lithium without change in the other variables which could effect blood glucose levels. In could be concluded that lithium carbonate had antidiabetic effects in this case.


Implicit Solvation Methods for Catalysis at Electrified Interfaces.
Implicit solvation is an effective, highly coarse-grained approach in atomic-scale simulations to account for a surrounding liquid electrolyte on the level of a continuous polarizable medium. Originating in molecular chemistry with finite solutes, implicit solvation techniques are now increasingly used in the context of first-principles modeling of electrochemistry and electrocatalysis at extended (often metallic) electrodes. The prevalent ansatz to model the latter electrodes and the reactive surface chemistry at them through slabs in periodic boundary condition supercells brings its specific challenges. Foremost this concerns the difficulty of describing the entire double layer forming at the electrified solid-liquid interface (SLI) within supercell sizes tractable by commonly employed density functional theory (DFT). We review liquid solvation methodology from this specific application angle, highlighting in particular its use in the widespread ab initio thermodynamics approach to surface catalysis. Notably, implicit solvation can be employed to mimic a polarization of the electrode's electronic density under the applied potential and the concomitant capacitive charging of the entire double layer beyond the limitations of the employed DFT supercell. Most critical for continuing advances of this effective methodology for the SLI context is the lack of pertinent (experimental or high-level theoretical) reference data needed for parametrization.


Comparison of the characteristics of flow-through and flow-around leaching tests of Solidified heavy metal wastes
This paper introduces a research work on studying the possibility of using a flow-through leaching test method to simulate the leaching behaviour of the cement-based stabilized/solidified (S/S) hazardous wastes. Both the flow-through leaching and the more common flow-around (dynamic leaching) test methods were carried out in the study to compare the leaching behaviour of the solidified waste under different leaching environments. The solidified waste samples were prepared from five kinds of heavy metals with two kinds of binders. The metals were Pb2+, Zn2+, Cu2+, Ni2+ (positive ions as nitrate), and Cr6+ (as a negative ion in potassium dichromate), and the binders were type I Ordinary Portland Cement (OPC) and Pulverised Fuel Ash (PFA). The results of two series of flow-through and flow-around leaching experiments are reported and compared in this paper. Mathematical models for simulating the leaching behaviour of the flow-through and flow-around leaching conditions were used to determine the diffusivities of the contaminants. The results show that, since the matrix of the solid waste in a flow-through leaching test is always being degraded, the diffusivities continuously increased during the leaching period. The range of the diffusivities was 10E-8 to 10E-3 cm2/s, which corresponds to the case of liquid phase diffusion. But in the case of the flow-around (dynamic leaching) test, the range of the diffusivities was 10E-18 to 10E-9 cm2/s which was similar to solid phase diffusion, and the variation of the diffusivity with time was not regular.


Intracellular domains of NMDA receptor subtypes are determinants for long-term potentiation induction.
NMDA receptors (NMDARs) are essential for modulating synaptic strength at central synapses. At hippocampal CA3-to-CA1 synapses of adult mice, different NMDAR subtypes with distinct functionality assemble from NR1 with NR2A and/or NR2B subunits. Here we investigated the role of these NMDA receptor subtypes in long-term potentiation (LTP) induction. Because of the higher NR2B contribution in the young hippocampus, LTP of extracellular field potentials could be enhanced by repeated tetanic stimulation in young but not in adult mice. Similarly, NR2B-specific antagonists reduced LTP in young but only marginally in adult wild-type mice, further demonstrating that in mature CA3-to-CA1 connections LTP induction results primarily from NR2A-type signaling. This finding is also supported by gene-targeted mutant mice expressing C-terminally truncated NR2A subunits, which participate in synaptic NMDAR channel formation and Ca2+ signaling, as indicated by immunopurified synaptic receptors, postembedding immunogold labeling, and spinous Ca2+ transients in the presence of NR2B blockers. These blockers abolished LTP in the mutant at all ages, revealing that, without the intracellular C-terminal domain, NR2A-type receptors are deficient in LTP signaling. Without NR2B blockade, CA3-to-CA1 LTP was more strongly reduced in adult than young mutant mice but could be restored to wild-type levels by repeated tetanic stimulation. Thus, besides NMDA receptor-mediated Ca2+ influx, subtype-specific signaling is critical for LTP induction, with the intracellular C-terminal domain of the NR2 subunits directing signaling pathways with an age-dependent preference.


Use of the socio-ecological model to explore trusted sources of COVID-19 information in Black and Latinx communities in Michigan.
Identifying trusted sources of health information and exploring what makes these sources trustworthy is an important aspect of public health. This exploration requires embracing the cultural differences in minoritized communities, which are often treated as homogeneous. This qualitative study identifies and analyze the sources of trusted COVID-19 information among Black and Latinx communities in Michigan and assesses the rationale underlying this trust. Interviews were conducted with 24 Black and 16 Latinx participants (n = 40) in four Michigan counties significantly impacted by COVID-19. The socio-ecological model was applied as an analytical framework for understanding the entities considered trusted sources of information. Within each level of the model, the dimensions of trustworthiness most salient for participants were identified. We found that sources of information came from all levels of the model, including interpersonal (COVID-19 survivors, church representatives, friends, relatives), organizational (employers, healthcare providers, traditional news reports), social media (hybrid source), community (members and groups), and public policy (county health department, federal and state government). Furthermore, participants determined whether they could trust information about COVID-19 by cross-referencing multiple resources. We identified competence, confidence, communication, and system trust as the dimensions of trustworthiness most often reported by participants. Our research suggests public health communications should engage in cross-referencing practices, providing information from sources at all levels of interaction, cultural competency, and awareness of historical/structural inequities. These efforts would be further strengthened by attending to needs for both factual information as well as care and personal connection.


Molecular Characterization of Mycoplasma pneumoniae Isolates in the United States from 2012 to 2018.
Mycoplasma pneumoniae is a major cause of community-acquired pneumonia. There are limited data in the United States on the molecular epidemiological characteristics of M. pneumoniae We collected 446 M. pneumoniae-positive specimens from 9 states between August 2012 and October 2018. Culture, antimicrobial susceptibility testing, P1 subtyping, and multilocus VNTR (variable-number tandem repeats) analysis (MLVA) were performed to characterize the isolates. Macrolide-resistant M. pneumoniae (MRMp) was detected in 37 (8.3%) specimens. P1 subtype 2 (P1-2) was the predominant P1 subtype (59.8%). P1 subtype distribution did not change significantly chronologically or geographically. The macrolide resistance rate in P1 subtype 1 (P1-1) samples was significantly higher than that in P1-2 (12.9% versus 5.5%). Six P1-2 variants were identified, including two novel types, and variant 2c was predominant (64.6%). P1-2 variants were distributed significantly differently among geographic regions. Classical P1-2 was more frequent in lower respiratory tract specimens and had longer p1 trinucleotide repeats. Classical P1-2 was most common in MRMp (35.7%), while variant 2c was most common in macrolide-susceptible M. pneumoniae (67.5%). Fifteen MLVA types were identified; 3-5-6-2 (41.7%), 4-5-7-2 (35.3%), and 3-6-6-2 (16.6%) were the major types, and four MLVA clusters were delineated. The distribution of MLVA types varied significantly over time and geographic location. The predominant MLVA type switched from 4-5-7-2 to 3-5-6-2 in 2015. MLVA type was associated with P1 subtypes and P1-2 variant types but not with macrolide resistance. To investigate the M. pneumoniae genotype shift and its impact on clinical presentations, additional surveillance programs targeting more diverse populations and prolonged sampling times are required.


Feasibility of using of a simplified question in assessing diet quality of adolescents.
This study aims to analyze the applicability of a simplified question in assessing diet quality of adolescents in a cross-sectional school-based study carried out in a sample of high school students. Diet quality self-perception was obtained when the participant was inquired about own diet considering "excellent", "good", "fair" or "poor" responses. We evaluated meals habits and food intake through food frequency questionnaire. The revised version of the Brazilian Healthy Eating Index (BHEI-R) was estimated and we identified three dietary patterns using factor analysis. "Good" self-perceived diet quality was reported by 56% of adolescents and was associated with regular consumption of fruits and vegetables, meal profile and high healthy eating index scores. However, consumption of foods harmful to health was not perceived as characteristic that affects diet quality. The evaluated question showed sensitivity of 28% to detect good quality diets and specificity of 79% to identify low nutritional value diets. The use of a simplified question to assess dietary habits of adolescents is limited, since the consumption of high-fat, high-sugar and high-sodium food was not recognized as an indicator of low quality diet.


Association of Primary Care Consultation Patterns With Early Signs and Symptoms of Psychosis.
Primary care is an important part of the care pathway for patients with psychosis; therefore, primary care physicians need to be able to accurately identify those at clinical high risk of psychosis. The difficulty of this task is increased because clinical high-risk symptoms are frequently nonspecific to psychosis. To determine whether the consultation patterns for a prespecified set of symptoms can be used to identify primary care patients who later developed a psychotic illness. This nested case-control study used primary care consultation data collected from 530 primary care practices in 13 UK regions from January 1, 2000, through September 30, 2009. Participants included 11 690 adults with a diagnosis of psychosis and 81 793 control participants who did not have a diagnosis of psychosis individually matched by age group, sex, and primary care practice. Data were analyzed from July 1, 2015, through June 2, 2017. Prespecified symptoms selected from literature included attention-deficit/hyperactivity disorder-like symptoms, bizarre behavior, blunted affect, problems associated with cannabis, depressive symptoms, role functioning problems, social isolation, symptoms of mania, obsessive-compulsive disorder-like symptoms, disordered personal hygiene, sleep disturbance, problems associated with cigarette smoking, and suicidal behavior (including self-harm). Case (diagnosis of psychosis) or control (no diagnosis of psychosis) status. Conditional logistic regression was used to investigate the association between symptoms and case-control status in the 5 years before diagnosis. Positive predictive values (PPVs) were calculated using the Bayes theorem for symptoms stratified by age group and sex. Repeated-measures Poisson regression was used to investigate symptom consultation rate. Of the total sample of 93 483 participants, 57.4% were female and 40.0% were older than 60 years (mean [SD] age, 51.34 [21.75] years). Twelve symptoms were associated with a later psychotic diagnosis (all prespecified symptoms except disordered personal hygiene). The strongest association was with suicidal behavior (odds ratio [OR], 19.06; 95% CI, 16.55-21.95). Positive predictive values were heterogeneous across age and sex. The highest PPVs were for suicidal behavior (33.0% in men 24 years or younger [95% CI, 24.2%-43.2%] and 19.6% in women aged 25-34 years [95% CI, 13.7%-27.2%]). Pairs of symptoms were associated with an increase in PPV. Consultation rates were higher in cases and increased 3 months before diagnosis. Most of the preselected nonspecific symptoms were associated with a later psychotic diagnosis, particularly among young men consulting for suicidal behavior, especially if consulting with increasing frequency. These symptoms should alert physicians to patients who may benefit from a further assessment of psychotic symptoms.


[Traditional artificial ventilation. General principles].
Mechanical ventilation is generally applied on patients affected by acute respiratory failure (ARF) on the basis of hemogasanalysis, hemodynamics and X-ray features. The modification of ventilatory pattern is based on problem the modification of data concerning mechanical variation. In this study the most important mechanical measures and their consequences on ventilatory strategy are discussed.


Dietary Copper/Zinc Ratio and Type 2 Diabetes Risk in Women: The E3N Cohort Study.
The serum copper (Cu) to zinc (Zn) ratio could be an important determinant of Type 2 diabetes (T2D) risk, but prospective epidemiological data are scarce. We aimed to investigate the association between T2D incidence and the dietary Cu/Zn ratio. A total of 70,991 women from the E3N cohort study were followed for 20 years. The intakes of copper and zinc were estimated at baseline using a validated food frequency questionnaire. We identified and validated 3292 incident T2D cases. Spline analysis showed that a Cu/Zn ratio < 0.55 was associated with a lower risk of T2D. Subgroup analyses comparing women in the highest versus the lowest quintile of Cu/Zn ratio showed the same pattern of association for obese women and those with zinc intake ≥8 mg/day. However, for women with zinc intake <8 mg/day, higher Cu/Zn ratio appeared to be associated with higher T2D risk. Our findings suggest that a lower dietary Cu/Zn ratio is associated with a lower T2D risk, especially among obese women and women with zinc intake >8 mg/day. Further studies are warranted to validate our results.


Cysteine proteases are activated in sensitive Amaranthus palmeri populations upon treatment with herbicides inhibiting amino acid biosynthesis.
The herbicides glyphosate and pyrithiobac inhibit the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) in the aromatic amino acid biosynthetic pathway and acetolactate synthase (ALS) in the branched-chain amino acid biosynthetic pathway, respectively. Here we characterise the protease activity profiles of a sensitive (S), a glyphosate-resistant (GR) and a multiple-resistant (MR) population of Amaranthus palmeri in response to glyphosate and pyrithiobac. Amino acid accumulation and cysteine protease activities were induced with both herbicides in the S population and with pyrithiobac in the GR population, suggesting that the increase in cysteine proteases is responsible for the increased degradation of the available proteins and the observed increase in free amino acids. Herbicides did not induce any changes in the proteolytic activities in the populations with target-site resistance, indicating that this effect was only induced in sensitive plants.


Toxicity and repair of DNA adducts produced by the natural product yatakemycin.
Yatakemycin (YTM) is an extraordinarily toxic DNA alkylating agent with potent antimicrobial and antitumor properties and is the most recent addition to the CC-1065 and duocarmycin family of natural products. Though bulky DNA lesions the size of those produced by YTM are normally removed from the genome by the nucleotide-excision repair (NER) pathway, YTM adducts are also a substrate for the bacterial DNA glycosylases AlkD and YtkR2, unexpectedly implicating base-excision repair (BER) in their elimination. The reason for the extreme toxicity of these lesions and the molecular basis for the way they are eliminated by BER have been unclear. Here, we describe the structural and biochemical properties of YTM adducts that are responsible for their toxicity, and define the mechanism by which they are excised by AlkD. These findings delineate an alternative strategy for repair of bulky DNA damage and establish the cellular utility of this pathway relative to that of NER.


Urinary IGF and IGF binding protein-3 in children with disordered growth. The North West Paediatric Endocrine Group.
Both IGF-I and IGFBP-3 reflect spontaneous GH secretion in healthy individuals. We have evaluated the clinical usefulness of urinary IGF-I and IGFBP-3 measurements in the diagnosis of children with disordered growth. Serum IGF-I and IGFBP-3 radioimmunoassays (RIA) were developed, and modified for quantitation in urine. The relationship between serum and urine levels, and the performance of these tests in the diagnosis of GH deficiency (GHD) were examined. Sixty-nine children (age 9.5 +/- 3.6 years; 37 boys, 32 girls) provided a timed overnight urine collection and a serum sample collected on the same morning. Subjects were defined as GHD (n = 22) or short normal (SN; n = 47) on the basis of medical history, clinical examination, auxology and peak response to a GH stimulation test (< 20 mU/L in GHD patients). IGF-I and IGFBP-3 in serum and urine were measured by RIA, urinary GH (uGH) by immunoradiometric assay (IRMA) after dialysis and urinary creatinine by the alkaline picrate method. Urine results were expressed as total amount excreted (tulGFBP-3 (microgram), tulGF-1 (ng), tuGH (ng), tuCrt (mmol). Urine IGF-I and IGFBP-3 excretion correlated significantly to serum levels of IGF-I and IGFBP-3 and also to tuGH excretion. There was a strong positive relationship between both urinary peptides and tuCrt, which suggested that renal filtration was the source of these peptides in urine. In addition, there were significant correlations with age, bone age and height SD score, of similar magnitude to those for tuGH. In prepubertal children, serum IGF-I and IGFBP-3 were significantly lower in GHD compared with SN children, while in puberty only serum IGFBP-3 was significantly lower in GHD. There was no difference however, in tulGF-I or tulGFBP-3 between GHD and SN children either prepubertally or in puberty with near complete overlap of the values between groups. Measurements of tulGF-I and tulGFBP-3 have no place in the diagnosis of childhood GHD. Nonetheless, the significant correlations between serum and urinary IGF-I and IGFBP-3 levels and their correlation to uGH indicate that these peptides could be used as non-invasive physiological markers of the GH-IGF axis.


Effect of brain-derived neurotrophic factor Val66Met polymorphism and serum levels on the progression of mild cognitive impairment.
Abnormalities in neurotrophic systems have been reported in Alzheimer's disease (AD), as shown by decreased serum brain-derived neurotrophic factor (BDNF) levels and association with BDNF genetic polymorphisms. In this study, we investigate whether these findings can be detected in patients with mild cognitive impairment (MCI), which is recognized as a high risk condition for AD. We also address the impact of these variables on the progression of cognitive deficits within the MCI-AD continuum. One hundred and sixty older adults with varying degrees of cognitive impairment (30 patients with AD, 71 with MCI, and 59 healthy controls) were longitudinally assessed for up to 60 months. Baseline serum BDNF levels were determined by sandwich ELISA, and the presence of polymorphisms of BDNF and apolipoprotein E (Val66Met and APOE*E4, respectively) was determined by allelic discrimination analysis on real time PCR. Modifications of cognitive state were ascertained for non-demented subjects. Mean serum BDNF levels were reduced in patients with MCI and AD, as compared to controls (509.2+/-210.5; 581.9+/-379.4; and 777.5+/-467.8 pg/l respectively; P<0.001). Baseline serum BDNF levels were not associated with the progression of cognitive impairment upon follow-up in patients with MCI (progressive MCI, 750.8+/-463.0; stable MCI, 724.0+/-343.4; P=0.8), nor with the conversion to AD. Although Val66Met polymorphisms were not associated with the cross-sectional diagnoses of MCI or AD, the presence of Met-BDNF allele was associated with a higher risk of disease-progression in patients with MCI (OR=3.0 CI(95%) [1.2-7.8], P=0.02). We also found a significant interaction between the APOE*E4 and Met-BDNF allele increasing the risk of progression of cognitive impairment in MCI patients (OR=4.4 CI(95%) [1.6-12.1], P=0.004). Decreased neurotrophic support, as indicated by a reduced systemic availability of BDNF, may play role in the neurodegenerative processes that underlie the continuum from MCI to AD. The presence of Met-BDNF allele, particularly in association with APOE*E4, may predict a worse cognitive outcome in patients with MCI.


Environmental DNA Marker Development with Sparse Biological Information: A Case Study on Opossum Shrimp (Mysis diluviana).
The spread of Mysis diluviana, a small glacial relict crustacean, outside its native range has led to unintended shifts in the composition of native fish communities throughout western North America. As a result, biologists seek accurate methods of determining the presence of M. diluviana, especially at low densities or during the initial stages of an invasion. Environmental DNA (eDNA) provides one solution for detecting M. diluviana, but building eDNA markers that are both sensitive and species-specific is challenging when the distribution and taxonomy of closely related non-target taxa are poorly understood, published genetic data are sparse, and tissue samples are difficult to obtain. To address these issues, we developed a pair of independent eDNA markers to increase the likelihood of a positive detection of M. diluviana when present and reduce the probability of false positive detections from closely related non-target species. Because tissue samples of closely-related and possibly sympatric, non-target taxa could not be obtained, we used synthetic DNA sequences of closely related non-target species to test the specificity of eDNA markers. Both eDNA markers yielded positive detections from five waterbodies where M. diluviana was known to be present, and no detections in five others where this species was thought to be absent. Daytime samples from varying depths in one waterbody occupied by M. diluviana demonstrated that samples near the lake bottom produced 5 to more than 300 times as many eDNA copies as samples taken at other depths, but all samples tested positive regardless of depth.


Effect of centrifugation and washing on adipose graft viability: a new method to improve graft efficiency.
Adipose tissue grafting is a promising method in the field of surgical filling. We studied the effect of centrifugation on fat grafts, and we propose an optimised protocol for the improvement of adipose tissue viability. Adipose tissue was subjected to different centrifugations, and the volumes of interstitial liquid and oil released were measured to choose the optimal condition. Tissue from this condition was then compared to tissue obtained from two traditional techniques: strong centrifugation (commonly 3 min at 3000 rpm/900 g), and decantation, by injecting into immunodeficient mice. The cytokine interleukin-6 (IL-6) and chemokine monocyte chemotactic protein-1 (MCP-1) were assayed 24 h post-injection, and after 1 month of grafting the state of the lipografts was evaluated through macroscopic and histological analysis, with oil gap area measurement. Strong centrifugation (900 g, 1800 g) is deleterious for adipose tissue because it leads to until threefold more adipocyte death compared to low centrifugation (100 g, 400 g). In addition, mice injected with strong centrifuged and non-centrifuged adipose tissue have higher rates of blood IL-6 and MCP-1, compared to those grafted with soft centrifuged fat. Moreover, extensive lipid vacuoles were detectable on histological sections of the non-centrifuged lipografts, whereas lipografts from soft centrifugation contain a higher amount of connective tissue containing collagen fibres. It is necessary to wash and centrifuge adipose tissue before reinjection in order to remove infiltration liquid and associated toxic molecules, which in the long term are deleterious for the graft. However, strong centrifugation is not recommended since it leads very quickly to greater adipocyte death. Thus, soft centrifugation (400 g/1 min), preceded by washings, seems to be the most appropriate protocol for the reinjection of adipose tissue.


The Fast Gray Matter Acquisition T1 Inversion Recovery Sequence in Deep Brain Stimulation: Introducing the Rubral Wing for Dentato-Rubro-Thalamic Tract Depiction and Tremor Control.
The dentato-rubro-thalamic tract (DRT) is currently considered as a potential target in deep brain stimulation (DBS) for various types of tremor. However, tractography depiction can vary depending on the included brain regions. The fast gray matter acquisition T1 inversion recovery (FGATIR) sequence, with excellent delineation of gray and white matter, possibly provides anatomical identification of rubro-thalamic DRT fibers. This study aimed to evaluate the FGATIR sequence by comparison with DRT depiction, electrode localization, and effectiveness of DBS therapy. In patients with DBS therapy because of medication-refractory tremor, the FGATIR sequence was evaluated for depiction of the thalamus, red nucleus (RN), and rubro-thalamic connections. Deterministic tractography of the DRT, electrode localization, and tremor control were compared. The essential tremor rating scale was used to assess (hand) tremor. Tremor control was considered successful when complete tremor suppression (grade 0) or almost complete suppression (grade 1) was observed. In the postoperative phase, we evaluated 14 patients who underwent DRT-guided DBS: 12 patients with essential tremor, one with tremor-dominant Parkinson disease, and one with multiple sclerosis, representing 24 trajectories. Mean follow-up was 11.3 months (range 6-19 months). The FGATIR sequence provided a clear delineation of a hypointense white matter tract within the hyperintense thalamus. In coronal plane, this tract was most readily recognizable as a "rubral wing," with the round RN as base and lateral triangular convergence. The deterministic DRT depiction was consistently situated within the rubral wing. The number of active contacts located within the DRT (and rubral wing) was 22 (92%), of which 16 (73%) showed successful tremor control. The FGATIR sequence offers visualization of the rubro-thalamic connections that form the DRT, most readily recognizable as a "rubral wing" in coronal plane. This sequence contributes to tractographic depiction of DRT and provides a direct anatomical DBS target area for tremor control.


Cancer Testis Antigen Promotes Triple Negative Breast Cancer Metastasis and is Traceable in the Circulating Extracellular Vesicles.
Triple negative breast cancer (TNBC) has poor survival, exhibits rapid metastases, lacks targeted therapies and reliable prognostic markers. Here, we examined metastasis promoting role of cancer testis antigen SPANXB1 in TNBC and its utility as a therapeutic target and prognostic biomarker. Expression pattern of SPANXB1 was determined using matched primary cancer, lymph node metastatic tissues and circulating small extracellular vesicles (sEVs). cDNA microarray analysis of TNBC cells stably integrated with a metastasis suppressor SH3GL2 identified SPANXB1 as a potential target gene. TNBC cells overexpressing SH3GL2 exhibited decreased levels of both SPANXB1 mRNA and protein. Silencing of SPANXB1 reduced migration, invasion and reactive oxygen species production of TNBC cells. SPANXB1 depletion augmented SH3GL2 expression and decreased RAC-1, FAK, A-Actinin and Vinculin expression. Phenotypic and molecular changes were reversed upon SPANXB1 re-expression. SPANXB1 overexpressing breast cancer cells with an enhanced SPANXB1:SH3GL2 ratio achieved pulmonary metastasis within 5 weeks, whereas controls cells failed to do so. Altered expression of SPANXB1 was detected in the sEVs of SPANXB1 transduced cells. Exclusive expression of SPANXB1 was traceable in circulating sEVs, which was associated with TNBC progression. SPANXB1 represents a novel and ideal therapeutic target for blocking TNBC metastases due to its unique expression pattern and may function as an EV based prognostic marker to improve TNBC survival. Uniquely restricted expression of SPANXB1 in TNBCs, makes it an ideal candidate for targeted therapeutics and prognostication.


Expected ozone benefits of reducing nitrogen oxide (NOx) emissions from coal-fired electricity generating units in the eastern United States.
On hot summer days in the eastern United States, electricity demand rises, mainly because of increased use of air conditioning. Power plants must provide this additional energy, emitting additional pollutants when meteorological conditions are primed for poor air quality. To evaluate the impact of summertime NOx emissions from coal-fired electricity generating units (EGUs) on surface ozone formation, we performed a series of sensitivity modeling forecast scenarios utilizing EPA 2018 version 6.0 emissions (2011 base year) and CMAQ v5.0.2. Coal-fired EGU NOx emissions were adjusted to match the lowest NOx rates observed during the ozone seasons (April 1-October 31) of 2005-2012 (Scenario A), where ozone decreased by 3-4 ppb in affected areas. When compared to the highest emissions rates during the same time period (Scenario B), ozone increased ∼4-7 ppb. NOx emission rates adjusted to match the observed rates from 2011 (Scenario C) increased ozone by ∼4-5 ppb. Finally in Scenario D, the impact of additional NOx reductions was determined by assuming installation of selective catalytic reduction (SCR) controls on all units lacking postcombustion controls; this decreased ozone by an additional 2-4 ppb relative to Scenario A. Following the announcement of a stricter 8-hour ozone standard, this analysis outlines a strategy that would help bring coastal areas in the mid-Atlantic region closer to attainment, and would also provide profound benefits for upwind states where most of the regional EGU NOx originates, even if additional capital investments are not made (Scenario A). With the 8-hr maximum ozone National Ambient Air Quality Standard (NAAQS) decreasing from 75 to 70 ppb, modeling results indicate that use of postcombustion controls on coal-fired power plants in 2018 could help keep regions in attainment. By operating already existing nitrogen oxide (NOx) removal devices to their full potential, ozone could be significantly curtailed, achieving ozone reductions by up to 5 ppb in areas around the source of emission and immediately downwind. Ozone improvements are also significant (1-2 ppb) for areas affected by cross-state transport, especially Mid-Atlantic coast regions that had struggled to meet the 75 ppb standard.


Short term ambulatory oxygen for chronic obstructive pulmonary disease.
Ambulatory oxygen is defined as the use of supplemental oxygen during exercise and activities of daily living. Ambulatory oxygen therapy is often used for patients on long term oxygen therapy during exercise, or for non long term oxygen therapy users who achieve some subjective and/or objective benefit from oxygen during exercise. The evidence for the use of ambulatory oxygen therapy is extrapolated from two sources: longer term studies and single assessment studies. Longer term studies assess the impact of ambulatory oxygen therapy used at home during activities of daily living. Single assessment studies compare performance during an exercise test using oxygen with performance during an exercise test using placebo air. To determine the efficacy of ambulatory oxygen in patients with COPD using single assessment studies. The Cochrane Airways Group COPD register was searched with predefined search terms. Searches were current as of March 2004. Only randomised controlled trials were included. Studies did not have to be blinded. Studies had to compare oxygen and placebo when administered to people with COPD who were undergoing an exercise test. Two reviewers (JB, B'ON) extracted and entered data in to RevMan 4.2.7. Twenty-seven studies (contributing 29 data sets), randomising 469 participants met the inclusion criteria of the review. Oxygen improved all pooled outcomes relating to endurance exercise capacity (distance, time, number of steps) and maximal exercise capacity (exercise time and work rate). Data relating to VO2max could not be pooled and results from the original studies were not consistent. For the secondary outcomes of breathlessness, SaO2 and VE, comparisons were made at isotime. In all studies except two the isotime is defined as the time at which the placebo test ended. Oxygen improved breathlessness, SaO2/PaO2 and VE at isotime with endurance exercise testing. There was no data on breathlessness at isotime with maximal exercise testing. Oxygen improved SaO2/PaO2 at isotime; the reduction in VE did not reach statistical significance. This review provides some evidence from small, single assessment studies that ambulatory oxygen improves exercise performance in people with moderate to severe COPD. The results of the review may be affected by publication bias, and the small sample sizes in the studies. Although positive, the findings of the review require replication in larger trials with more distinct subgroups of participants. Maximal or endurance tests can be used in ambulatory oxygen assessment, but endurance tests may be more appropriate as they are more related to activities of daily living. Consideration should be given to the measurement of SaO2 and breathlessness at isotime as these provide important additional information. We recommend that these outcomes are included in the assessment for ambulatory oxygen. Future research needs to establish the level of benefit of ambulatory oxygen in specific subgroups of people with COPD.


Effect of estragole on leukocyte behavior and phagocytic activity of macrophages.
Estragole, a chemical constituent of the essential oils of many aromatic plants, is used as flavoring in beverage and food industries. In vivo and in vitro experimental assays have shown that EST has sedative, anticonvulsant, antioxidant, antimicrobial, and anesthetic activity. In this work, we evaluate the effect of EST on leukocyte behavior and phagocytic activity of macrophages. In the peritonitis model, EST (500 and 750 mg/kg) decreased the infiltration of peritoneal exudate leukocytes. In vitro chemotaxis assay showed that EST (3, 10, 30, and 60 μg/mL) inhibited neutrophil migration toward fMLP. In the in vivo microcirculation assay, EST at doses of 250, 500, and 750 mg/kg significantly reduced the number of rolling and adherent leukocytes and at doses of 250 and 500 mg/kg decreased number of leukocyte migrated to perivascular tissue. The results showed that EST (3, 10, and 30 μg/mL) was able to stimulate the macrophages phagocytosis but only at concentration of 10 μg/mL promoted an increase in nitric oxide (NO) production. In conclusion, this study showed that EST had potential anti-inflammatory effects, likely by inhibiting leukocyte migration and by stimulating macrophages phagocytosis.


The acute metabolic effects of tumor necrosis factor administration in humans.
It has been suggested that the monokine tumor necrosis factor (TNF) (cachectin) is responsible for metabolic abnormalities frequently accompanying malignant neoplasms. The acute metabolic effects of TNF in patients with cancer were studied. Subcutaneous administration of recombinant human TNF led to a rise in the C-reactive protein level (4.4 +/- 1.2 mg/dL vs 11.6 +/- 1.8 mg/dL) and a reduction in the serum zinc level (12.9 +/- 0.8 mumol/L vs 7.3 +/- 0.8 mumol/L [79 +/- 5 mg/dL vs 48 +/- 5 mg/dL]) (values are the mean +/- SEM). Forearm efflux of total amino acids more than doubled after intravenous TNF injection, principally because of increases in release of the gluconeogenic amino acids alanine and glutamine. Concomitantly, the arterial levels of alanine, glutamine, and total amino acids fell, indicating that TNF also stimulated the uptake of amino acids by other tissues. The observed amino acid pattern cannot be explained solely on the basis of measured changes in cortisol, glucagon, or insulin levels. These findings are discussed in relation to known alterations of amino acid metabolism in cancer-associated cachexia.


Prognostic value of stress echocardiography assessed by the ABCDE protocol.
The aim of this study was to assess the prognostic value of ABCDE-SE in a prospective, large scale, multicentre, international, effectiveness study. Stress echocardiography (SE) was recently upgraded to the ABCDE protocol: step A, regional wall motion abnormalities; step B, B lines; step C, left ventricular contractile reserve; step D, Doppler-based coronary flow velocity reserve in left anterior descending coronary artery; and step E, electrocardiogram-based heart rate reserve. From July 2016 to November 2020, we enrolled 3574 all-comers (age 65 ± 11 years, 2070 males, 58%; ejection fraction 60 ± 10%) with known or suspected chronic coronary syndromes referred from 13 certified laboratories. All patients underwent clinically indicated ABCDE-SE. The employed stress modality was exercise (n = 952, with semi-supine bike, n = 887, or treadmill, n = 65 with adenosine for step D) or pharmacological stress (n = 2622, with vasodilator, n = 2151; or dobutamine, n = 471). SE response ranged from score 0 (all steps normal) to score 5 (all steps abnormal). All-cause death was the only endpoint. Rate of abnormal results was 16% for A, 30% for B, 36% for C, 28% for D, and 37% for E steps. During a median follow-up of 21 months (interquartile range: 13-36), 73 deaths occurred. Global X2 was 49.5 considering clinical variables, 50.7 after step A only (P = NS (not significant)) and 80.6 after B-E steps (P < 0.001 vs. step A). Annual mortality rate ranged from 0.4% person-year for score 0 up to 2.7% person-year for score 5. ABCDE-SE allows an effective prediction of survival in patients with chronic coronary syndromes.


The p97/VCP adapter UBXD1 drives AAA+ remodeling and ring opening through multi-domain tethered interactions.
p97/VCP is an essential cytosolic AAA+ ATPase hexamer that extracts and unfolds substrate polypeptides during protein homeostasis and degradation. Distinct sets of p97 adapters guide cellular functions but their roles in direct control of the hexamer are unclear. The UBXD1 adapter localizes with p97 in critical mitochondria and lysosome clearance pathways and contains multiple p97-interacting domains. We identify UBXD1 as a potent p97 ATPase inhibitor and report structures of intact p97:UBXD1 complexes that reveal extensive UBXD1 contacts across p97 and an asymmetric remodeling of the hexamer. Conserved VIM, UBX, and PUB domains tether adjacent protomers while a connecting strand forms an N-terminal domain lariat with a helix wedged at the interprotomer interface. An additional VIM-connecting helix binds along the second AAA+ domain. Together these contacts split the hexamer into a ring-open conformation. Structures, mutagenesis, and comparisons to other adapters further reveal how adapters containing conserved p97-remodeling motifs regulate p97 ATPase activity and structure.


Elucidating mechanisms of drug-induced toxicity.
The early and high-throughput application of assays for non-genetic toxicity is of great interest to the pharmaceutical industry, although few systems have been validated as being of good predictive value. New technologies could enable toxicity to be studied in the context of systems biology. An important factor to be considered is the metabolism of drugs to reactive intermediates. Chemical reactions of these with cell and tissue nucleophiles are relatively well understood, but predicting how biological modifications will affect signalling and regulatory networks remains a challenge. Some of these pathways could be useful as sentinels for toxicity. This article will cover some examples of drug toxicity and the prospects for future technology development.


Correlates of jaw functional limitation, somatization and psychological distress among different temporomandibular disorder diagnostic subtypes.
This study investigated the jaw functional status and severity of somatic/psychological symptoms in different Diagnostic Criteria for temporomandibular disorders (DC/TMD) diagnostic subtypes and established the correlates between jaw functional limitation, somatization, depression and anxiety. Data were accrued from consecutive 'first-visit' patients seeking TMD treatment at a university-based oral medicine/diagnosis clinic. Axis I physical TMD diagnoses were derived using the DC/TMD methodology and patients were categorized into pain-related (PT), intra-articular (IT) and combined (CT) TMD groups. Axis II measures were also administered and included the Jaw Functional Limitation Scale-20 (JFLS-20), Patient Health Questionnaire-15 and 9 (PHQ-15 and PHQ-9) and General Anxiety Disorder Scale-7 (GAD-7). Chi-square/Kruskal-Wallis tests and Spearman's correlation were employed for statistical evaluations (α = .05). The final dataset consisted of 772 TMD patients (mean age of 37.7 ± 15.9 years; 70.2% females). The prevalence of PT, IT and CT was 11.9%, 15.7% and 72.4%, respectively. Significant differences in functional jaw limitations, somatization, depression (CT, PT > IT) and anxiety (CT > PT, IT) were observed. Moderate-to-severe somatization, depression and anxiety were detected in 12.6%-15.7% of patients. For all three TMD groups, JFLS global scale/subscale scores were weakly associated with somatization, depression and anxiety scores (rs < 0.4). Moderate-to-strong correlations were noted between somatization, depression and anxiety (rs = 0.50-0.74). Functional jaw limitations were associated with painful TMDs but appear to be unrelated to somatization and psychological distress. Somatization and depression/anxiety were moderately correlated, underscoring the importance of somatic symptom screening when managing TMD patients.


A Randomised Control Trial Comparing the Outcomes of Anterior with Posterior Approach for Transfer of Spinal Accessory Nerve to Suprascapular Nerve in Brachial Plexus Injuries.
Background: In brachial plexus surgery, a key focus is restoring shoulder abduction through spinal accessory nerve (SAN) to suprascapular nerve (SSN) transfer using either the anterior or posterior approach. However, no published randomised control trials have directly compared their outcomes to date. Therefore, our study aims to assess motor outcomes for both approaches. Methods: This study comprises two groups of patients. Group A: anterior approach (29 patients), Group B: Posterior approach (29 patients). Patients were allocated to both groups using selective randomisation with the sealed envelope technique. Functional outcome was assessed by grading the muscle power of shoulder abductors using the British Medical Research Council (MRC) scale. Results: Five patients who were operated on by posterior approach had ossified superior transverse suprascapular ligament. In these cases, the approach was changed from posterior to anterior to avoid injury to SSN. Due to this reason, the treatment analysis was done considering the distribution as: Group A: 34, Group B: 24. The mean duration of appearance of first clinical sign of shoulder abduction was 8.16 months in Group A, whereas in Group B, it was 6.85 months, which was significantly earlier (p < 0.05). At the 18-month follow-up, both intention-to-treat analysis and as-treated analysis were performed, and there was no statistical difference in the outcome of shoulder abduction between the approaches for SAN to SSN nerve transfer. Conclusions: Our study found no significant difference in the restoration of shoulder abduction power between both approaches; therefore, either approach can be used for patients presenting early for surgery. Since the appearance of first clinical sign of recovery is earlier in posterior approach, therefore, it can be preferred for cases presenting at a later stage. Also, the choice of approach is guided on a case to case basis depending on clavicular fractures and surgeon preference to the approach. Level of Evidence: Level II (Therapeutic).


Farnesoid X Receptor Agonist GW4064 Protects Lipopolysaccharide-Induced Intestinal Epithelial Barrier Function and Colorectal Tumorigenesis Signaling through the αKlotho/βKlotho/FGFs Pathways in Mice.
The farnesoid X receptor (FXR)/βKlotho/fibroblast growth factors (FGFs) pathway is crucial for maintaining the intestinal barrier and preventing colorectal cancer (CRC). We used an FXR agonist, GW4064, and FXR-knockout (FXR-KO) mice to investigate the role of FXR/Klothos/FGFs pathways in lipopolysaccharide (LPS)-induced intestinal barrier dysfunction and colon carcinogenesis. The results showed that upregulation of FXR in enterocytes effectively ameliorated intestinal tight-junction markers (claudin1 and zonula occludens-1), inflammation, and bile acid levels, thereby protecting mice from intestinal barrier dysfunction and colon carcinogenesis. GW4064 treatment increased FXR, αKlotho, βKlotho, FGF19, FGF21, and FGF23 in wild-type mice exposed to LPS, while FXR-KO mice had decreased levels. FXR-KO mice exhibited elevated colon cancer markers (β-catenin, LGR5, CD44, CD34, and cyclin D1) under LPS, underscoring the pivotal role of FXR in inhibiting the development of colon tumorigenesis. The varying gut microbiota responses in FXR-KO mice versus wild-type mice post LPS exposure emphasize the pivotal role of FXR in preserving intestinal microbial health, involving Bacteroides thetaiotaomicron, Bacteroides acidifaciens, and Helicobacter hepaticus. Our study validates the effectiveness of GW4064 in alleviating LPS-induced disruptions to the intestinal barrier and colon carcinogenesis, emphasizing the importance of the FXR/αKlotho/βKlotho/FGFs pathway and the interplay between bile acids and gut microbiota.


A functional copy number variation in the WWOX gene is associated with lung cancer risk in Chinese.
WW domain-containing oxidoreductase (WWOX) is a tumor suppressor that has been reported to lose function due to genetic alterations in several cancers. WWOX maps to the common chromosomal fragile site FRA16D and several copy number variations (CNVs) were found within this gene. In this study, we investigated the association between the CNVs of WWOX and lung cancer risk in four independent case-control studies, which are on 2942 lung cancer cases and 3074 cancer-free controls of southern, eastern and northern Chinese. A common CNV-67048 was genotyped by the Taqman real-time PCR, and its biological effect was accessed with protein expression and sequencing assays. We found that in comparison with the common 2-copy genotype, the carriers of loss variant genotypes (1-copy or 0-copy) had a significantly increased risk of lung cancer (adjusted OR = 1.39, 95% CI = 1.24-1.55, P = 9.01×10(-9)) in a dose-response manner (Ptrend = 1.12 × 10(-10)), and the WWOX protein expressions in lung cancer tissues were significantly lower (P = 0.036), accompanying a higher rate of exons absence (P = 0.021) in subjects with loss genotypes of CNV-67048. Our data suggest that the loss genotypes of CNV-67048 in WWOX predispose their carriers to lung cancer; this might be related with altered WWOX gene expression and exons absence in them.


The Genomic Architecture of Flowering Time Varies Across Space and Time in Mimulus guttatus.
The degree to which genomic architecture varies across space and time is central to the evolution of genomes in response to natural selection. Bulked-segregant mapping combined with pooled sequencing provides an efficient means to estimate the effect of genetic variants on quantitative traits. We develop a novel likelihood framework to identify segregating variation within multiple populations and generations while accommodating estimation error on a sample- and SNP-specific basis. We use this method to map loci for flowering time within natural populations of Mimulus guttatus, collecting the early- and late-flowering plants from each of three neighboring populations and two consecutive generations. Structural variants, such as inversions, and genes from multiple flowering-time pathways exhibit the strongest associations with flowering time. We find appreciable variation in genetic effects on flowering time across both time and space; the greatest differences evident between populations, where numerous factors (environmental variation, genomic background, and private polymorphisms) likely contribute to heterogeneity. However, the changes across years within populations clearly identify genotype-by-environment interactions as an important influence on flowering time variation.


Efficacy and safety of a balanced salt solution versus a 0.9% saline infusion for the prevention of contrast-induced acute kidney injury (BASIC trial): a study protocol for a randomized controlled trial.
Contrast-induced acute kidney injury (CI-AKI) is one of the most common causes of iatrogenic kidney injury and, therefore, its prevention is an important issue. However, whether the administration of 0.9% saline is the optimal prophylaxis method remains uncertain due to its supra-physiologic chloride component. In particular, recent studies suggest that chloride-restricted solutions showed superiority over 0.9% saline in several clinical settings. The investigators designed a multicenter randomized controlled trial to compare the efficacy of a balanced salt solution and 0.9% saline in CI-AKI prophylaxis. This study will recruit patients who are scheduled for contrast-enhanced computed tomography (CT) scans with CI-AKI prophylaxis. In this study, participants will be randomized into two study arms; the study group will receive a balanced salt solution, and the control group will receive 0.9% saline. Fluids will be administered as designated in the protocol before and after the CT scan, and an evaluation of baseline clinical status will be performed by obtaining blood and urine samples. During the follow-up visits, the incidence of CI-AKI and long-term outcomes, including the start of renal replacement therapy or all-cause mortality, will be assessed. To our knowledge, this study will be the first study assessing the preventive value of a balanced salt solution over 0.9% saline for CI-AKI. If the trial shows that the balanced salt solution is as effective for CI-AKI prophylaxis as 0.9% saline, the use of the balanced salt solution could be promoted due to the reduced possibility of consequent metabolic acidosis compared to 0.9% saline. ClinicalTrials.gov, ID: NCT02799368 . Registered on 14 June 2016.


The Human and Mouse Islet Peptidome: Effects of Obesity and Type 2 Diabetes, and Assessment of Intraislet Production of Glucagon-like Peptide-1.
To characterize the impact of metabolic disease on the peptidome of human and mouse pancreatic islets, LC-MS was used to analyze extracts of human and mouse islets, purified mouse alpha, beta, and delta cells, supernatants from mouse islet incubations, and plasma from patients with type 2 diabetes. Islets were obtained from healthy and type 2 diabetic human donors, and mice on chow or high fat diet. All major islet hormones were detected in lysed islets as well as numerous peptides from vesicular proteins including granins and processing enzymes. Glucose-dependent insulinotropic peptide (GIP) was not detectable. High fat diet modestly increased islet content of proinsulin-derived peptides in mice. Human diabetic islets contained increased content of proglucagon-derived peptides at the expense of insulin, but no evident prohormone processing defects. Diabetic plasma, however, contained increased ratios of proinsulin and des-31,32-proinsulin to insulin. Active GLP-1 was detectable in human and mouse islets but 100-1000-fold less abundant than glucagon. LC-MS offers advantages over antibody-based approaches for identifying exact peptide sequences, and revealed a shift toward islet insulin production in high fat fed mice, and toward proglucagon production in type 2 diabetes, with no evidence of systematic defective prohormone processing.


The complement factor H R1210C mutation is associated with atypical hemolytic uremic syndrome.
Mutations in the gene encoding complement factor H (CFH) that alter the C3b/polyanions-binding site in the C-terminal region impair the capacity of factor H to protect host cells. These mutations are also strongly associated with atypical hemolytic uremic syndrome (aHUS). Although most of the aHUS-associated CFH mutations seem "unique" to an individual patient or family, the R1210C mutation has been reported in several unrelated aHUS patients from distinct geographic origins. Five aHUS pedigrees and 7 individual aHUS patients were analyzed to identify potential correlations between the R1210C mutation and clinical phenotype and to characterize the origins of this mutation. The clinical phenotype of aHUS patients carrying the R1210C mutation was heterogeneous. Interestingly, 12 of the 13 affected patients carried at least one additional known genetic risk factor for aHUS. These data are in accord with the 30% penetrance of aHUS in R1210C mutation carriers, as it seems that the presence of other genetic or environmental risk factors significantly contribute to the manifestation and severity of aHUS in these subjects. Genotype analysis of CFH and CFHR3 polymorphisms in the 12 unrelated carriers suggested that the R1210C mutation has a single origin. In conclusion, the R1210C mutation of complement factor H is a prototypical aHUS mutation that is present as a rare polymorphism in geographically separated human populations.


"If you're strung out and female, they will take advantage of you": A qualitative study exploring drug use and substance use service experiences among women in Boston and San Francisco.
Significant disparities in substance use severity and treatment persist among women who use drugs compared to men. Thus, we explored how identifying as a woman was related to drug use and treatment experiences. The study recruited participants for a qualitative interview study in Boston and San Francisco from January-November 2020. Self-identified women, age ≥ 18 years, with nonprescribed opioid use in the past 14 days were eligible for inclusion. The study team developed deductive codes based on intersectionality theory and inductive codes generated from transcript review, and identified themes using grounded content analysis. The study enrolled thirty-six participants. The median age was 46; 58 % were White, 16 % were Black, 14 % were Hispanic, and 39 % were unstably housed. Other drug use was common with 81 % reporting benzodiazepine, 50 % cocaine, and 31 % meth/amphetamine use respectively. We found that gender (i.e., identifying as a woman) intersected with drug use and sex work practices and exacerbated experiences of marginalization. Violence was ubiquitous in drug use environments. Some women reported experiences of gender-based violence in substance use service settings that perpetuated cycles of trauma and reinforced barriers to care. Substance use services that were women-led, safe, and responsive to women's needs were valued and sought after. Women reported a cycle of trauma and drug use exacerbated by oppression in substance use services settings. In addition to increasing access to gender-responsive care, our study highlights the need for greater research and examination of practices within substance use service settings that may be contributing to gender-based violence.


Synergistic cytotoxicity of cisplatin and topotecan or SN-38 in a panel of eight solid-tumor cell lines in vitro.
The cytotoxicity of cisplatin alone and in combination with topotecan (TPT) or SN-38, two novel topoisomerase I (topo I) inhibitors, was determined in a panel of eight well-characterized human solid-tumor cell lines. Interactions between cisplatin and these topo I inhibitors were investigated using three different administration schedules: (1) simultaneous incubation (C + T and C + S), (2) cisplatin followed by TPT or SN-38 (C --> T and C --> S), and (3) TPT or SN-38 followed by cisplatin (T --> C and S --> C). Median-effect analysis revealed synergistic cytotoxicity in seven of the eight cell lines used. In addition, a significant schedule-dependent synergistic cytotoxicity was found in three of the cell lines used, with C --> T (or C --> S) being the most active schedule. The formation and repair of total cisplatin-DNA adducts in the IGROV-1 ovarian cancer cell line and its cisplatin-resistant subline IGROV(CDDP) was not significantly affected by TPT on simultaneous incubation. In contrast, the number of cisplatin-DNA interstrand cross-links detected in the IGROV-1 and IGROV(CDDP) lines at certain time points was significantly lower after coincubation of the cells with TPT. Assessment of the cell-cycle distribution revealed an accumulation of cells in the G2/M phase after exposure to cisplatin. After exposure to TPT a different pattern was observed that was cell-type-specific and dependent upon the TPT concentration. Although up to 4-fold differences in topo I activity were observed in this panel of cell lines, these differences did not appear to be related to the synergy observed between cisplatin and TPT or SN-38. The observed synergy may at least partly be explained by the increased retention of cisplatin-DNA interstrand cross-links in the presence of topo I inhibitors.


Pharmacokinetics of acetaminophen in children.
Acetaminophen absorption may occur at a somewhat greater rate in children if the syrup form is utilized. The overall plasma elimination of acetaminophen is somewhat slow in the neonate, but is comparable to that of adults in both children and adolescents, as judged by half-life determinations. This would suggest that the frequency of acetaminophen administration in children should be similar to the schedule recommended for adults and that a dosing interval of four hours should not result in drug accumulation. The question of a toxic quantity of acetaminophen for young children must remain open until adequate metabolic or retrospective toxicologic data become known. Since the volumes of distribution appear to be the same in both adults and children, the same dose should apply in both groups; currently, 10 mg/kg is considered to be both safe and effective for antipyresis.


Direct measurement of inner and outer wall thickening dynamics with epicardial echocardiography.
Simple geometric models of the left ventricle and indirect experimental measurements suggest that the inner myocardial wall contributes the largest fraction to total wall thickening. We measured transmural differences in regional wall thickening directly, using an epicardial M mode echocardiographic transducer (6 mm diameter, 5 MHz) placed on the anterior free wall of the left ventricle. Wall thickness was partitioned into inner and outer regions by inserting a waxed, 3-0 suture at different depths within the wall. The suture was used as an intramural echo target that was imaged simultaneously with the endocardium to determine inner and outer fractional contribution to total wall thickness. Data were collected in open-chest dogs at rest, during inotropic stimulation with isoproterenol, and during right heart bypass, which was used to vary cardiac output and preload. Results obtained with this method demonstrated that systolic wall thickness was nonuniform at rest and during each intervention. The fractional contributions to total wall thickening of the inner, middle, and outer thirds of the myocardial wall were estimated from the data to be 58%, 25%, and 17%, respectively. The experimental findings corresponded closely to theoretical predictions, supporting the conclusion that a gradient of thickening exists across the myocardial wall, with the inner portion of the wall contributing the largest fraction to total systolic thickening.


Reduced Laughter Contagion in Boys at Risk for Psychopathy.
Humans are intrinsically social animals, forming enduring affiliative bonds [1]. However, a striking minority with psychopathic traits, who present with violent and antisocial behaviors, tend to value other people only insofar as they contribute to their own advancement [2, 3]. Extant research has addressed the neurocognitive processes associated with aggression in such individuals, but we know remarkably little about processes underlying their atypical social affiliation. This is surprising, given the importance of affiliation and bonding in promoting social order and reducing aggression [4, 5]. Human laughter engages brain areas that facilitate social reciprocity and emotional resonance, consistent with its established role in promoting affiliation and social cohesion [6-8]. We show that, compared with typically developing boys, those at risk for antisocial behavior in general (irrespective of their risk of psychopathy) display reduced neural response to laughter in the supplementary motor area, a premotor region thought to facilitate motor readiness to join in during social behavior [9-11]. Those at highest risk for developing psychopathy additionally show reduced neural responses to laughter in the anterior insula. This region is implicated in auditory-motor processing and in linking action tendencies with emotional experience and subjective feelings [10, 12, 13]. Furthermore, this same group reports reduced desire to join in with the laughter of others-a behavioral profile in part accounted for by the attenuated anterior insula response. These findings suggest that atypical processing of laughter could represent a novel mechanism that impoverishes social relationships and increases risk for psychopathy and antisocial behavior.


Social and health care top managers' perceptions and aims of strategic work ability management in the midst of change.
Existing research has mostly focused on themes related to returning to or staying at work and studied organizations' operational rather than strategic level actions to support work ability. Top managers' understanding of work ability management (WAM) may influence how work ability support processes are implemented in organizations. To find out how top managers define WAM, what the aims of WAM were and whether the aims were on a strategic level. Altogether 28 semi-structured interviews among Finnish social and health care top managers were conducted during the years 2019-2021 and analyzed inductively using qualitative thematic analysis. Top managers' definition of WAM was mainly multidimensional. Two main aims were identified, i.e., to support work ability 1) at the individual and 2) at the organizational level. The aims of the former were to anticipate the decrease of health and functional capacity, to support workers already decrease in these, to develop competence, and to manage the effects of changes on work ability. The aims at the organizational level were to improve labor availability and personnel retention, to ensure the flow of work, and to increase trust and create shared values. Top managers described the aims as being at a strategic level, but this was not yet realized in their organizations because the actions were reactive rather than proactive. Top managers' multidimensional perception of WAM, emphasizing proactive actions, and strategic level aims are crucial and require the commitment of the top managers for strategic WAM, especially during constant changes.


Children and adolescents' mental health during the COVID-19 pandemic: A qualitative study of their experiences.
Public health measures implemented in response to the COVID-19 pandemic severely disrupted children and adolescents' (C&A) lives, affecting their sense of structure, predictability, and security. To examine C&A' experiences during the COVID-19 pandemic to better understand how this context and its associated public health measures affected them and their mental health, and to identify helpful coping strategies. The study was guided by a participatory hermeneutic framework. Semistructured interviews were conducted with 25 C&A aged 6-17 years during the first and second pandemic waves. Participants' interviews were analyzed following a narrative synthesis approach, through which C&A' experiences were contrasted and contextualized to highlight relevant themes. Participants described a distinct pattern related to their mental health as the pandemic unfolded, which followed the severity of the pandemic in the province. Negative repercussions on their mental health were linked to the loss of social activities, imposed public health measures, transition to online learning, and challenges with family relationships. Certain youth shared positive societal and moral reflections triggered by the pandemic context. Coping strategies reported include: having a variety of hobbies; expressing their emotions; and accessing financial and material resources. This study highlights the importance of supporting C&A' mental health during crisis situations such as a pandemic. Their perspectives are vital for clinical practice and policy improvement, particularly to find means for social engagement while maintaining safety.


Bumblebee flight distances in relation to the forage landscape.
1. Foraging range is a key aspect of the ecology of 'central place foragers'. Estimating how far bees fly under different circumstances is essential for predicting colony success, and for estimating bee-mediated gene flow between plant populations. It is likely to be strongly influenced by forage distribution, something that is hard to quantify in all but the simplest landscapes; and theories of foraging distance tend to assume a homogeneous forage distribution. 2. We quantified the distribution of bumblebee Bombus terrestris L. foragers away from experimentally positioned colonies, in an agricultural landscape, using two methods. We mass-marked foragers as they left the colony, and analysed pollen from foragers returning to the colonies. The data were set within the context of the 'forage landscape': a map of the spatial distribution of forage as determined from remote-sensed data. To our knowledge, this is the first time that empirical data on foraging distances and forage availability, at this resolution and scale, have been collected and combined for bumblebees. 3. The bees foraged at least 1.5 km from their colonies, and the proportion of foragers flying to one field declined, approximately linearly, with radial distance. In this landscape there was great variation in forage availability within 500 m of colonies but little variation beyond 1 km, regardless of colony location. 4. The scale of B. terrestris foraging was large enough to buffer against effects of forage patch and flowering crop heterogeneity, but bee species with shorter foraging ranges may experience highly variable colony success according to location.