Hybrid integration of injector and detector functions for microchip gas chromatography.
Hybrid microchips containing high aspect ratio gas chromatograph (GC) columns with an integrated on-chip split injection and a flame ionization detector were developed. Two different column configurations, spiral and serpentine, both 1 m long by 50 μm wide and 500 μm tall, were fabricated out of electrodeposited nickel. The hybrid chip allowed injection plugs on the order of 1-2 ms, which lowered the height equivalent to theoretical plates (HETP) and allowed a comparison of system level band broadening between the two column configurations. The gas phase band broadening was estimated by measuring the flow characteristics and peak broadening of an unretained compound, and the results were compared with kinetic models. Experimental results show that both spiral and serpentine column layouts had similar flow and band broadening, suggesting that gas phase band broadening may be independent of column layout. The necessity for narrow injection bands for fast micro-chip chromatographic analysis was demonstrated, which emphasized the importance of component integration in designing powerful micro-analytical systems.


Experimental coxsackie B-3 virus myocarditis in golden hamsters. Light and electron microscopy findings in a long-term follow-up study.
Following intraperitoneal inoculation with coxsackie B3 virus all weaning Syrian golden hamsters (60 animals) developed severe myocarditis. In the acute phase, light and electron microscopy revealed massive cellular infiltration and myocytolysis in the myocardium which were most prominent on the 5th day and least obvious in 3 weeks. In the necrotic myocytes, mitochondria contained moderately electron dense inclusions different from the calcified granules seen in the myocardium of mice with coxsackie B3 virus myocarditis. Macrophages ingested and digested necrotic cell debris, leaving moderate fibrosis but no calcification in the myocardium. Viruses were isolated from the myocardium on the 3rd to 9th day, and virus particles were seen in a necrotic cardiocyte on the 9th day. In the chronic phase, most animals developed no cardiomegaly; light microscopy revealed minimal myocardial fibrosis; electron microscopy showed various degenerative changes in some cardiocytes. A few animals (two animals) developed significant cardiomegaly with moderate to marked myocardial fibrosis in the 6th and 14th month. In one heart there was marked biventricular dilatation. In these animals with cardiomegaly, ultrastructural changes of the myocardial cells were similar to those described in congestive cardiomyopathy in man. Golden hamsters appear to be a unique model for a study of the possible relationship between viral myocarditis and idiopathic cardiomyopathy in man.


Ageing workers' mental health during COVID-19: a multilevel observational study on the association with the work environment, perceived workplace safety and individual factors.
The stress and anxiety associated with the predisposition of ageing workers to severe COVID-19 illness, once occupationally infected, jeopardise their mental health. This study aimed to investigate the association between individual level, work environment exposure factors and perceived workplace safety with a decline in mental health of ageing workers from different industry sectors. Observational study, prevalence assessment of survey added to longitudinal cohort data. The Survey of Health, Ageing and Retirement in Europe (SHARE) from 27 countries in Europe and Israel participating in the COVID-19 survey (summer 2020) and having prepandemic waves' SHARE data. Workers aged 50-70 (n=6449) who attended their workplaces at least partially after the pandemic broke out. Perceived decline in mental health compared with preoutbreak status. Multilevel analyses demonstrated that 24.5% (95% CI 23.5% to 25.5%) of ageing workers in Europe experienced mental health decline associated with national-level self-reported COVID-19 burden. Workplace safety perception was the strongest predictor, as each one-point increase in unsafe perception was associated with 60% of mental health decline (OR=1.6, 95% CI 1.47 to 1.74), explaining 30% of increased reported mental health symptoms of ageing workers. Safety perception mediates the mental health outcomes of the work environment, such as workplace contagion risk and work location. Female gender (OR=1.77, 95% CI 1.55 to 2.02), financial difficulties (OR=1.19, 95% CI 1.1 to 1.28), higher vulnerability index (comorbidities, age >60) (OR=1.11, 95% CI 1.05 to 1.18), pre-existing mental problems (OR=1.78, 95% CI 1.55 to 2.04) and increased national burden of COVID-19 (OR=1.01, 95% CI 1.0 to 1.02) were associated with declines in mental health, whereas exclusively working on-site was protective. Vulnerable subgroups for mental health declines among ageing workers were revealed, which warrant their screening and employers' evaluation of workplace conditions of ageing workers to prevent mental health-related implications. Workplace interventions should aim to reduce work environment influences on infection risk and mental distress.


Comparison of digital planimetry and ruler technique to measure ABSSSI lesion sizes in the ESTABLISH-1 study.
In August 2010, the U.S. Food and Drug Administration issued draft guidelines for developing antibiotics for treating acute bacterial skin and skin structure infections (ABSSSI), with the outcome measure of such treatment relying primarily on the cessation of spread or on the decrease in size of skin lesions at 48-72 h after the initiation of such treatment. In 2012, the Foundation for the National Institutes of Health proposed an interim outcome measure defined as a reduction in lesion size by ≥20% at a 48-72 h examination. These recent changes make it necessary to identify reliable methods for measuring the lesions in acute infections of the skin. In the first study of the Efficacy and Safety of 6-day Oral Tedizolid in Acute Bacterial Skin and Skin Structure Infections vs. 10-day Oral Linezolid Therapy (ESTABLISH-1), the sizes of ABSSSI lesions were evaluated with the two methodologies of: (1) Digital planimetry (DP) of photographed lesions, and (2) a ruler technique (RT) with measurement of the longest head-to-toe length and greatest perpendicular width of lesions, to compare the respective response rates of lesions to the two antimicrobial regimens in the study. The RT method and DP showed similar percentages of subjects in which treatment stopped the spread of ABSSSI lesions (93.2% vs. 94.2%, respectively) but showed less agreement for a reduction in lesion size, of ≥20% (87.7% vs. 62.0%, respectively) across all categories of lesions (cellulitis/erysipelas, major cutaneous abscess, and acute wound infection) at 48-72 h after the initiation of treatment. The results of the ESTABLISH-1 study show that both the RT method and DP are consistent and reliable techniques for measuring the sizes of ABSSSI lesions. Ultimately, changes in lesion size, rather than the absolute value of lesion size, will be used to assess the outcomes of treatment for ABSSSI in clinical research.


Binding of motion and colour is early and automatic.
At what stages of the human visual hierarchy different features are bound together, and whether this binding requires attention, is still highly debated. We used a colour-contingent motion after-effect (CCMAE) to study the binding of colour and motion signals. The logic of our approach was as follows: if CCMAEs can be evoked by targeted adaptation of early motion processing stages, without allowing for feedback from higher motion integration stages, then this would support our hypothesis that colour and motion are bound automatically on the basis of spatiotemporally local information. Our results show for the first time that CCMAE's can be evoked by adaptation to a locally paired opposite-motion dot display, a stimulus that, importantly, is known to trigger direction-specific responses in the primary visual cortex yet results in strong inhibition of the directional responses in area MT of macaques as well as in area MT+ in humans and, indeed, is perceived only as motionless flicker. The magnitude of the CCMAE in the locally paired condition was not significantly different from control conditions where the different directions were spatiotemporally separated (i.e. not locally paired) and therefore perceived as two moving fields. These findings provide evidence that adaptation at an early, local motion stage, and only adaptation at this stage, underlies this CCMAE, which in turn implies that spatiotemporally coincident colour and motion signals are bound automatically, most probably as early as cortical area V1, even when the association between colour and motion is perceptually inaccessible.


Roles of the tissue-type plasminogen activator in immune response.
The COVID-19 pandemic has once again brought to the forefront the existence of a tight link between the coagulation/fibrinolytic system and the immunologic processes. Tissue-type plasminogen activator (tPA) is a serine protease with a key role in fibrinolysis by converting plasminogen into plasmin that can finally degrade fibrin clots. tPA is released in the blood by endothelial cells and hepatocytes but is also produced by various types of immune cells including T cells and monocytes. Beyond its role on hemostasis, tPA is also a potent modulator of inflammation and is involved in the regulation of several inflammatory diseases. Here, after a brief description of tPA structure, we review its new functions in adaptive immunity focusing on T cells and antigen presenting cells. We intend to synthesize the recent knowledge on proteolysis- and receptor-mediated effects of tPA on immune response in physiological and pathological context.


Neural correlates of training-related memory improvement in adulthood and aging.
Cognitive studies show that both younger and older adults can increase their memory performance after training in using a visuospatial mnemonic, although age-related memory deficits tend to be magnified rather than reduced after training. Little is known about the changes in functional brain activity that accompany training-induced memory enhancement, and whether age-related activity changes are associated with the size of training-related gains. Here, we demonstrate that younger adults show increased activity during memory encoding in occipito-parietal and frontal brain regions after learning the mnemonic. Older adults did not show increased frontal activity, and only those elderly persons who benefited from the mnemonic showed increased occipito-parietal activity. These findings suggest that age-related differences in cognitive reserve capacity may reflect both a frontal processing deficiency and a posterior production deficiency.


Metabolic control and diabetic retinopathy.
The Early Treatment Diabetic Retinopathy Study (ETDRS) identified important risk factors for progression to high risk proliferative diabetic retinopathy (PDR) including retinopathy severity, decreased visual acuity, and high levels of hemoglobin A1C (HbA1c). Additional risk factors for progression to PDR are decreased hematocrit and increased serum lipids. The long-term benefit of improving glycemic control was evaluated by three large studies: the Diabetes Control and Complications Trial (DCCT), the Stockholm Interventional Study, and the UK prospective study. Several small studies, notably the Kuwamoto study, also evaluated the relationship between the glycemic control and diabetic retinopathy. Intensive glycemic control reduces the risk of any retinopathy by approximately 27%. Intensive therapy is most effective when initiated early in the course of the diabetes, demonstrating a beneficial effect over the course and progression of retinopathy. The long term benefits of the intensive glycemic control greatly outweigh the risk of "early worsening." Lowering elevated serum lipid levels has been shown to decrease the risk of cardiovascular morbidity. The ETDRS data suggest that lipid lowering may also decrease the risk of hard exudate formation and associated vision loss in patients with diabetic retinopathy. Preservation of vision may be an additional motivating factor for lowering serum lipid levels in persons with diabetic retinopathy and elevated serum lipid levels.


An RCT to Facilitate Implementation of School Practices Known to Increase Physical Activity.
Although comprehensive school-based physical activity interventions are efficacious when tested under research conditions, they often require adaptation in order for implementation at scale. This paper reports the effectiveness of an adapted efficacious school-based intervention in improving children's moderate to vigorous physical activity. The impact of strategies to support program implementation was also assessed. A cluster RCT of low socioeconomic elementary schools in New South Wales, Australia. Consenting schools were randomized (25 intervention, 21 control) using a computerized random number function. Follow-up measures were taken at 6 months post-randomization (May-August 2015) by blinded research assistants. The multicomponent school-based intervention, based on an efficacious school-based physical activity program (Supporting Children's Outcomes using Rewards, Exercise and Skills), consisted of four physical activity strategies and seven implementation support strategies. The intervention was adapted for scalability and delivery by a local health service over 6 months. The primary outcome was accelerometer assessed, student mean daily minutes spent in moderate to vigorous physical activity. Physical education lesson quality and other school physical activity practices were also assessed. Participants (n=1,139, 49% male) were third- through sixth-grade students at follow-up (May-August 2015). Valid wear time and analysis of data were provided for 989 (86%) participants (571 intervention, 568 control). At 6-month follow-up, there were no significant effects in overall daily minutes of moderate to vigorous physical activity between groups (1.96 minutes, 95% CI= -3.49, 7.41, p=0.48). However, adjusted difference in mean minutes of overall vigorous physical activity (2.19, 95% CI=0.06, 4.32, p=0.04); mean minutes of school day moderate to vigorous physical activity (2.90, 95% CI=0.06, 5.85, p=0.05); and mean minutes of school day vigorous physical activity (1.81, 95% CI=0.78, 2.83, p≤0.01) were significantly different in favor of the intervention group. Physical education lesson quality and school physical activity practices were significantly different favoring the intervention group (analyzed October 2015-January 2016). The modified intervention was not effective in increasing children's overall daily minutes of moderate to vigorous physical activity, when adapted for implementation at scale. However, the intervention did improve daily minutes of vigorous physical activity and school day moderate to vigorous physical activity, lesson quality, and school physical activity practices. Australian New Zealand Clinical Trials Registry: ACTRN12615000437561.


'At risk mental state' clinics for psychosis - an idea whose time has come - and gone!
At Risk Mental State (ARMS) clinics are specialised mental health services for young, help-seeking people, thought to be at ultra-high risk of developing psychosis. Their stated purpose is to reduce transitions from the ARMS state to clinical psychotic disorder. Reports of ARMS clinics provide 'evidence-based recommendations' or 'guidance' for the treatment of such individuals, and claim that such clinics prevent the development of psychosis. However, we note that in an area with a very well-developed ARMS clinic (South London), only a very small proportion (4%) of patients with first episode psychosis had previously been seen at this clinic with symptoms of the ARMS. We conclude that the task of reaching sufficient people to make a major contribution to the prevention of psychosis is beyond the power of ARMS clinics. Following the preventative approaches used for many medical disorders (e.g. lung cancer, coronary artery disease), we consider that a more effective way of preventing psychosis will be to adopt a public health approach; this should attempt to decrease exposure to environmental factors such as cannabis use which are known to increase risk of the disorder.


Complete Genome Sequence of a Carbapenem-Resistant Extraintestinal Pathogenic Escherichia coli Strain Belonging to the Sequence Type 131 H30R Subclade.
Here, we report the completed genome sequence of a carbapenem-resistant extraintestinal pathogenic Escherichia coli sequence type 131 (ST131) isolate, MNCRE44. The isolate was obtained in 2012 in Minnesota, USA, from a sputum sample from a hospitalized patient with multiple comorbidities, and it belongs to the H30R sublineage.


When to initiate highly active antiretroviral therapy: a cohort approach.
The appropriate immunologic stage of human immunodeficiency virus infection at which to initiate highly active antiretroviral therapy (HAART) among asymptomatic persons is a core question. A cohort approach using longitudinal data from the US Multicenter AIDS Cohort Study was used to mimic a clinical trial to assess the risk of acquired immunodeficiency syndrome (AIDS) by timing of therapy. Three treatment groups were defined according to CD4(+) count (cells/microl) at HAART initiation between July 1995 and January 2000: <200 (deferral to <200, n = 127), 200-349 (deferral to 200-349, n = 130), and 350-499 (immediate treatment, n = 92). Survival analysis was used to compare time to AIDS between groups from the index visit until July 2000. The index visit for the immediate group was the one prior to HAART initiation. For the deferral groups, the index visit was a randomly selected, pre-HAART, AIDS-free visit after July 1990 at which CD4(+) counts were 350-499 cells/microl. This strategy accounted for lead time bias. Compared with immediate treatment, the relative hazards of AIDS were 2.68 (p = 0.003) and 1.05 (p = 0.897) for deferral to <200 cells/microl and 200-349 cells/ micro l, respectively. These results support recent US public health guidelines for deferring HAART initiation until a count of <350 cells/microl. Furthermore, results suggest a potential threshold for HAART initiation in the neighborhood of 275 cells/microl.


Occupational medicine at the verge of the twenty first century: evaluation of accomplished and expected changes in the preventive approach.
The World Bank in its document under the title 'Investing in Health' (1993) states that the health status of the population, including the working population, and working conditions in individual countries depend essentially on the value of gross national product per capita. The attitudes towards the role and objectives of occupational medicine have changed significantly over the last three decades. A high priority given to primary prevention reflects the mainstream of a new approach to preventive measures. Advancements in technology, production and services, common use of computers and flattening of work organisation structures have brought about the need for workers' active participation in planning of activities and shaping working conditions in own enterprise. At the same time, workers are required to possess much higher qualifications facilitating their participation in applying new technologies and using new information systems, which resulted in a fierce competition on the labour market. In the countries in the political, social and economic transition, the conditions for introducing a new system of sustained development, described by Gustavsen at the 25th International Congress on Occupational Health have not as yet been established. A procedure-based system involving negotiations between employers and workers' representatives failed to be successful in improving working conditions as the roles of the state, employers and trade unions had not been defined precisely. It is expected that further health promotion at the worksites in these countries will depend mainly on the economic progress and the reformed system of education.


Dense Semantic 3D Reconstruction.
Both image segmentation and dense 3D modeling from images represent an intrinsically ill-posed problem. Strong regularizers are therefore required to constrain the solutions from being 'too noisy'. These priors generally yield overly smooth reconstructions and/or segmentations in certain regions while they fail to constrain the solution sufficiently in other areas. In this paper, we argue that image segmentation and dense 3D reconstruction contribute valuable information to each other's task. As a consequence, we propose a mathematical framework to formulate and solve a joint segmentation and dense reconstruction problem. On the one hand knowing about the semantic class of the geometry provides information about the likelihood of the surface direction. On the other hand the surface direction provides information about the likelihood of the semantic class. Experimental results on several data sets highlight the advantages of our joint formulation. We show how weakly observed surfaces are reconstructed more faithfully compared to a geometry only reconstruction. Thanks to the volumetric nature of our formulation we also infer surfaces which cannot be directly observed for example the surface between the ground and a building. Finally, our method returns a semantic segmentation which is consistent across the whole dataset.


Effect of 50 mg/kg intravenous tranexamic acid on coagulation assessed by rotational thromboelastometry (ROTEM) in healthy Beagle dogs.
In people, the antifibrinolytic drug tranexamic acid reduces bleeding and the need for blood products with both normal and exaggerated fibrinolysis without increasing the number of thromboembolic events. In dogs, in addition to prevention and treatment of bleeding, higher doses of tranexamic acid can be used to induce vomiting. The objective of this study was to evaluate the effect of a high dose of tranexamic acid on the coagulation of healthy Beagle dogs. A prospective trial was conducted in eight healthy Beagles receiving tranexamic acid for a concurrent trial evaluating different antiemetics. Rotational thromboelastometry (ROTEM) analysis (EXTEM, APTEM, FIBTEM, INTEM) was performed before and 30 minutes after intravenous administration of 50 mg/kg tranexamic acid. ROTEM parameters before and after tranexamic acid administration and between EXTEM and APTEM were compared with Wilcoxon matched-pairs signed rank test and data is presented as median (range). After tranexamic acid administration, FIBTEM clotting time became significantly shorter (p=0.03) from 37 s (28-124 s) to 33 s (27-40 s) and INTEM clot formation time significantly decreased (p=0.02) from 82 s (47-132 s) to 60 s (43-107 s). After tranexamic acid APTEM MCF was significantly weaker (p=0.01) with 45 mm (30-63 mm) than EXTEM MCF with 55 mm (43-69 mm) and than APTEM MCF before tranexamic acid with 55 mm (43-69 mm) (p=0.02). All other analysed parameters including maximum lysis did not change after administration of tranexamic acid. The administration of 50 mg/kg intravenous tranexamic acid resulted in small changes in ROTEM profiles without inducing a hypercoagulable clot. In conclusion, tranexamic acid can safely be administered to healthy dogs with normal coagulation profiles. As an additional finding, APTEM parameters measured in the current study do not support the use of this test in dogs.


Blood flow and oxygen consumption in active soleus and gracilis muscles in cats.
The results of the present study indicate that, although there are quantitative differences, there are no fundamental, qualitative differences in the vascular and metabolic responses to muscle contraction between slow-twitch soleus muscle and fast-twitch gracilis muscle in cats. Vascularly isolated muscles were perfused under free-flow conditions and were stimulated to contract isometrically for 12 min. Venous outflow was measured with a drop counter. Resting blood flow (6.3 +/- 1.3 ml . min-1 . 100 g-1) and oxygen consumption (0.27 +/- 0.04 ml O2 . min-1 . 100g-1) in soleus muscle did not differ significantly from the respective values in gracilis muscle. Blood flow increased by as much as sixfold above control values in both soleus and gracilis muscles in response to muscle contraction. Oxygen consumption increased linearly as a function of muscle performance in both muscles. However, the oxygen cost per kilogram of force developed was about threefold greater in gracilis compared with soleus muscle. The lower oxygen cost of contraction, coupled with an apparent maximal oxygen consumption twice that of gracilis muscle, enabled soleus muscle to maintain a greater level of muscle performance.


Buprenorphine Maintenance Subjects Are Hyperalgesic and Have No Antinociceptive Response to a Very High Morphine Dose.
Acute pain management in opioid-dependent persons is complicated because of tolerance and opioid-induced hyperalgesia. Very high doses of morphine are ineffective in overcoming opioid-induced hyperalgesia and providing antinociception to methadone-maintained patients in an experimental setting. Whether the same occurs in buprenorphine-maintained subjects is unknown. Randomized double-blind placebo-controlled. Subjects were tested on two occasions, at least five days apart, once with intravenous morphine and once with intravenous saline. Subjects were tested at about the time of putative trough plasma buprenorphine concentrations. Ambulatory. Twelve buprenorphine-maintained subjects: once daily sublingual dose (range = 2-22 mg); no dose change for 1.5-12 months. Ten healthy controls. Intravenous morphine bolus and infusions administered over two hours to achieve two separate pseudo-steady-state plasma concentrations one hour apart. Pain tolerance was assessed by application of nociceptive stimuli (cold pressor [seconds] and electrical stimulation [volts]). Ten blood samples were collected for assay of plasma morphine, buprenorphine, and norbuprenorphine concentrations until three hours after the end of the last infusion; pain tolerance and respiration rate were measured to coincide with blood sampling times. Cold pressor responses (seconds): baseline: control 34 ± 6 vs buprenorphine 17 ± 2 (P = 0.009); morphine infusion-end: control 52 ± 11(P = 0.04), buprenorphine 17 ± 2 (P > 0.5); electrical stimulation responses (volts): baseline: control 65 ± 6 vs buprenorphine 53 ± 5 (P = 0.13); infusion-end: control 74 ± 5 (P = 0.007), buprenorphine 53 ± 5 (P > 0.98). Respiratory rate (breaths per minute): baseline: control 17 vs buprenorphine 14 (P = 0.03); infusion-end: control 15 (P = 0.09), buprenorphine 12 (P < 0.01). Infusion-end plasma morphine concentrations (ng/mL): control 23 ± 1, buprenorphine 136 ± 10. Buprenorphine subjects, compared with controls, were hyperalgesic (cold pressor test), did not experience antinociception, despite high plasma morphine concentrations, and experienced respiratory depression. Clinical implications are discussed.


Characterization of [3H]di-isopropyl phosphorofluoridate-binding proteins in hen brain. Rates of phosphorylation and sensitivity to neurotoxic and non-neurotoxic organophosphorus compounds.
The experiments described in this paper were designed to isolate [3H]di-isopropyl phosphorofluoridate-binding proteins by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis for the purpose of characterizing and identifying potential initiation sites for organophosphorus-compound-induced delayed neurotoxicity. The major Paraoxon-insensitive Mipafox-sensitive binding protein (Mr 160 000) was found to be identical with one previously identified as neurotoxic esterase, an enzyme that has been proposed to be the target site for organophosphorus-compound-induced delayed neurotoxicity. However, two other binding proteins with suitable binding characteristics were also found in smaller amounts, one of which has not been detected previously. Di-isopropyl phosphorofluoridate was found to phosphorylate all three of these proteins at rates similar to the rate at which neurotoxic esterase is inhibited by di-isopropyl phosphorofluoridate. Varying the concentration of di-isopropyl phosphorofluoridate or the time of incubation produced similar increases in binding to each of the labelled proteins. This suggests that the reaction rates of di-isopropyl phosphorofluoridate with proteins may be described by first-order kinetics, and the concentration of the Michael is complex formed during binding is minimal for all the phosphorylated proteins. The recovery of the binding activity in the 160 000-Mr band was found to be similar to the recovery of neurotoxic esterase activity, lending further support to the contention that this band is identical with neurotoxic esterase.


Enhanced production of infectious rotavirus in BSC-1 cell cultures by various factors in the presence of absence of trypsin.
Bovine rotavirus infectivity for continuous green monkey kidney (BSC-1) cells was enhanced in hypertonic medium and following incorporation of cortisol, retinoic acid and vitamin B12 into the cell culture maintenance medium. The virus yields produced under these conditions were similar whether obtained in the presence or absence of trypsin. Infectivity titres were increased following the incorporation of trypsin in the maintenance medium throughout the infection cycle but remained unchanged after trypsin treatment of infected cell extracts. Bovine rotavirus infectivity was not affected by incorporation of phytohaemagglutinin, thyroid gland extracts or foetal calf serum in similar experiments. Unexpectedly, serum promoted virus growth when used with cells treated with actinomycin D. Marked differences in the stability of the newly produced infectious rotavirus were observed, suggesting that cell permissiveness to rotavirus infection may vary following the physiological state of the host cell.


Actinomycin D: effects on mouse L-cells.
The lethal and inhibitory effects of actinomycin D (Act D) on asynchronous and synchronized populations of mouse L-cells have been studied. It has been shown that the survival curve of populations in the logarithmic phase of growth can be approximated by two exponential survival curves corresponding to a sensitive and resistant moiety. The size and sensitivity of both moieties vary during the growth of the population. As the cell population moves through logarithmic and into stationary phase, the sensitive moiety becomes smaller but more resistant whereas the resistant moiety increases in size and also becomes more resistant. This variation appears to be related to a reduced uptake of Act D and also a reduced rate of DNA and RNA synthesis. Variations in sensitivity to the drug have also been observed during the division cycle of synchronized cells with cells in the S phase showing the greatest uptake of the drug and also the greatest sensitivity. However, no direct correlation between uptake and sensitivity has been established. Actinomycin D has inhibitory effects on both RNA and DNA synthesis. RNA synthesis is inhibited rapidly but does not seem to drop to less than 5% of the control value. The inhibition of DNA synthesis appears to occur over a longer period and may reach values as low as 0.25% of control. In both cases the degree of inhibitions appears to be dependent on both the length of exposure and the concentration of the drug. Certain similarities between the response of cells to Act D and X-rays have been observed and are discussed.


Palmar crease release and secondary full-thickness skin grafts for contractures in primary full-thickness skin grafts during growth spurts in pediatric palmar hand burns.
Pediatric palmar hand burns are a difficult problem because of the serious hand deformity, with functional impairment resulting from rapid growth. In cases of severe pediatric palmar hand burns, a secondary full-thickness skin graft after a primary full-thickness skin graft offers a reliable way of obtaining the required functional and aesthetic outcomes.This study retrospectively evaluated 28 children who required palmar crease releases and secondary full-thickness skin grafts during the past 12 years. The case records were reviewed for sex and age distributions, injury mechanism, and time interval between the primary and secondary full-thickness skin grafts. Surgical procedures included secondary full-thickness skin grafts and incisional releases of grafted skin on the involved creases. There were 19 men and 9 women. The mean age at the time of the burn injury was 10.1 months (range, 5-19 months). The mean age at the time of the secondary full-thickness skin graft was 8.3 years (range, 3-17 years). The most common mechanism of burn injury was steam (n = 24). The median time interval from the primary to the secondary full-thickness skin graft was 67 months (range, 8-156 months). The number of released creases was 81. The number of palmar web contractures in 23 patients was 52. A secondary full-thickness skin graft was more frequently necessary in patients with a primary full-thickness skin graft in the proximal digital crease and palmar web areas. All patients achieved adequate digital length and palmar web contour after surgery. Our patients should be observed until the rapid pubertal growth period.


Antibiotic-resistant pneumococci in hospitalized children.
A search for nasopharyngeal carriers of Streptococcus pneumoniae was conducted in 573 children hospitalized in Durban, South Africa. Study subjects were divided into two groups, comprising 305 new admissions and 268 patients who had been hospitalized for more than 24 h. Of the 573 children 178 (31%) yielded pneumococci on nasopharyngeal culture; 99 (32%) and 79 (29%) children in the new admission and in-patient categories respectively. Twenty-one (12%) pneumococci were resistant to penicillin, including 11 strains that were resistant to more than one antibiotic. Resistant pneumococci belonged exclusively to serotypes 6 and 19 (Danish nomenclature), which were also the commonest serotypes among penicillin-sensitive strains. Factors that correlated with carriage of penicillin-resistant pneumococci were hospitalization for more than 24 h, young age and recent exposure to beta-lactam antibiotics.


ATM, ATR, CHK1, CHK2 and WEE1 inhibitors in cancer and cancer stem cells.
DNA inevitably undergoes a high number of damages throughout the cell cycle. To preserve the integrity of the genome, cells have developed a complex enzymatic machinery aimed at sensing and repairing DNA lesions, pausing the cell cycle to provide more time to repair, or induce apoptosis if damages are too severe. This so-called DNA-damage response (DDR) is yet considered as a major source of resistance to DNA-damaging treatments in oncology. Recently, it has been hypothesized that cancer stem cells (CSC), a sub-population of cancer cells particularly resistant and with tumour-initiating ability, allow tumour re-growth and cancer relapse. Therefore, DDR appears as a relevant target to sensitize cancer cells and cancer stem cells to classical radio- and chemotherapies as well as to overcome resistances. Moreover, the concept of synthetic lethality could be particularly efficiently exploited in DDR. Five kinases play pivotal roles in the DDR: ATM, ATR, CHK1, CHK2 and WEE1. Herein, we review the drugs targeting these proteins and the inhibitors used in the specific case of CSC. We also suggest molecules that may be of interest for preclinical and clinical researchers studying checkpoint inhibition to sensitize cancer and cancer stem cells to DNA-damaging treatments.


Entanglement is Necessary for Emergent Classicality in All Physical Theories.
One of the most striking features of quantum theory is the existence of entangled states, responsible for Einstein's so called "spooky action at a distance." These states emerge from the mathematical formalism of quantum theory, but to date we do not have a clear idea of the physical principles that give rise to entanglement. Why does nature have entangled states? Would any theory superseding classical theory have entangled states, or is quantum theory special? One important feature of quantum theory is that it has a classical limit, recovering classical theory through the process of decoherence. We show that any theory with a classical limit must contain entangled states, thus establishing entanglement as an inevitable feature of any theory superseding classical theory.


First report of Perkinsus olseni infections in blood cockles Tegillarca granosa on the south coast of Korea.
The protozoan parasite Perkinsus olseni has become a focus of attention since it has been responsible for mass mortalities and economic losses in a wide range of bivalve hosts globally. The P. olseni host range along the south coast of Korea may extend beyond what was previously understood, and blood cockles in the Family Arcidae are also suggested to be potential hosts of P. olseni. In the present study, we applied histology and molecular techniques to identify Perkinsus sp. infections in the blood cockles Tegillarca granosa, which have been commercially exploited on the south coast of Korea for several decades. Histology and molecular techniques, including genus-specific immunofluorescence assay, species-specific fluorescence in situ hybridization, and phylogeny based on the ribosomal DNA internal transcribed spacer region revealed that T. granosa is infected by P. olseni, although the prevalence was low (0.5%). Histology revealed massive hemocyte infiltrations in the mantle, gill, and digestive gland connective tissues, indicating that the infection exerts negative impacts on the host cockles.


Tanshinone IIA blocks dexamethasone-induced apoptosis in osteoblasts through inhibiting Nox4-derived ROS production.
Apoptosis of osteoblasts caused by glucocorticoids has been identified as an important contributor to the development of osteoporosis. Tanshinone IIA (Tan), an active ingredient extracted from the rhizome of the Salvia miltiorrhiza Bunge (Danshen), has been reported to cast positive effects on osteoporosis. However, the precise mechanisms accounting this action remain elusive. In this study, by using osteoblastic MC3T3-E1 cells as a model, we confirmed the protective effects of Tan against dexamethasone (Dex)-induced cell apoptosis and further clarified its molecular mechanism of action. Our results showed that treatment with Dex caused cell injury, increased cytosol cytochrome c level and Nox expression, induced apoptosis in caspase-9-dependent manner, and enhanced reactive oxygen species (ROS) production. Tan attenuated these deleterious consequence triggered by Dex. Moreover, Dex-induced ROS production and cell injury were inhibited by antioxidant, NADPH oxidases inhibitors, Nox4 inhibitor, and Nox4 small interfering RNA (siRNA). Overexpression of Nox4 almost abolished the inhibitory effect of Tan on Dex-induced cell injury and apoptosis. The results also demonstrated significant involvement of Nox4 in the Dex-induced apoptosis. Nox4-derived ROS led to apoptosis through activation of intrinsic mitochondrial pathway. Additionally, we evidenced that Tan reversed Dex-induced apoptosis via inactivation of Nox4. The present findings suggest that inhibition of Nox4 may be a novel therapeutic approach of Tan to prevent against glucocorticoids-induced osteoblasts apoptosis and osteoporosis.


Acquired nonmalignant tracheoesophageal fistula.
Acquired tracheoesophageal fistulas are rare and for the most part are due to a malignant tumour. Acquired nonmalignant fistulas, even more rare, are most commonly the result of trauma or infection. The authors describe two such cases seen at the Royal Victoria Hospital in Montreal, one in 1968, the other in 1978. Both patients were successfully treated by surgical excision of the fistula. The authors review the literature with respect to the cause, symptoms, diagnosis and treatment and conclude that acquired nonmalignant tracheoesophageal fistulas may be treated successfully by operation with minimal morbidity and mortality.


Interfacial tissue engineering of heart regenerative medicine based on soft cell-porous scaffolds.
Myocardial infarction (MI), occurs when the coronary artery is occluded resulting in the hypoxia of areas in heart tissue, is increasing in recent years because of the population ageing and lifestyle changes. Currently, there is no ideal therapeutic scheme because of the limitation of MI therapeutic strategies due to the lack of regenerative ability of the heart cells in adult humans. Recent advances in tissue engineering and regenerative medicine brings hope to the MI therapy and current studies are focusing on restoring the function and structure of damaged tissue by delivering exogenous cells or stimulating endogenous heart cells. However, attempts to directly inject stem cells or cardiomyocytes to the infract zone often lead to rapid cell death and abundant cell loss. To address this challenge, various soft repair cells and porous scaffold materials have been integrated to improve cell retention and engraftment and preventing left ventricle (LV) dilatation. In this article, we will review the current method for heart regeneration based on soft cell-porous scaffold interfacial tissue engineering including common stem cell types, biomaterials, and cardiac patch and will discuss potential future directions in this area.


Occurrence, diversity, and persistence of antibiotic resistant enterococci in full-scale constructed wetlands treating urban wastewater in Sicily.
Enterococci isolated from different sites of an urban wastewater treatment plant (consisting of three horizontal subsurface flow constructed wetlands) were investigated. One-hundred-thirty isolates were identified at species level and tested for resistance to eleven antibiotics, by microdilution method, and their clonal relatedness was established by SmaI-PFGE analysis. Results highlighted the persistence of enterococcal population in all effluents and the dominance of E. faecium species. A high incidence of antibiotic resistance against erythromycin, chloramphenicol, rifampicin and ampicillin was observed, with 120 strains (93%) showing a multi-drug-resistance. Numerous pulso-types with a unique pattern were detected indicating a high diversity within enterococcal population. The recurrence of some pulso-types in different effluents was disclosed and, within the same pulso-types, different resistance patterns were observed. Comparing the MIC values of strains from inlet and outlet, different trends were observed, highlighting a certain variability among constructed wetlands in affecting the antibiotic resistance among enterococcal population.


Localization of hepatitis delta virus RNA in the nucleus of human cells.
Hepatitis delta virus (HDV) is a human pathogen that can greatly increase the severity of liver damage caused by an hepatitis B infection. HDV contains a circular, single-stranded RNA genome that encodes a unique protein, the delta antigen. Two forms of the delta antigen, deltaAg-S and deltaAg-L, are derived from a single open reading frame by RNA editing. Here we analyze the subcellular distribution of HDV RNA and its spatial relationship to known intranuclear structures. The human hepatoma cell line Huh7 was stably transfected with wild-type HDV cDNA and the viral RNAs were localized by in situ hybridization and fluorescence confocal microscopy. HDV RNA is detected throughout the nucleoplasm, with additional concentration in focal structures closely associated with nuclear speckles or clusters of interchromatin granules. Both the smaller form of the delta antigen (deltaAg-S), which is required for HDV genomic replication, and the larger form of the delta antigen (deltaAg-L), which represses replication, co-localize with delta RNA throughout the nucleoplasm and in the foci. However, the foci do not incorporate bromo-UTP and do not concentrate either RNA polymerase II or cleavage and polyadenylation factors required for viral RNA synthesis and 3' end processing, respectively. Thus, it is unlikely that the delta foci represent major sites of viral transcription or replication. In conclusion, the data show that viral RNA-protein complexes accumulate in structures closely associated with interchromatin granules, a subnuclear domain highly enriched in small nuclear ribonucleoproteins, poly(A+) RNA, and RNA splicing protein factors. This implies a specific compartmentalization of ribonucleoproteins in the nucleus.


Antioxidant Blueberry Anthocyanins Induce Vasodilation via PI3K/Akt Signaling Pathway in High-Glucose-Induced Human Umbilical Vein Endothelial Cells.
Blueberries are rich in antioxidant anthocyanins. The hypotensive effects of blueberry anthocyanins in endothelial cells was investigated here. Pretreatment with blueberry anthocyanin extract, malvidin, malvidin-3-glucoside, and malvidin-3-galactoside significantly ameliorated high-glucose-induced damage by enhancing endogenous antioxidant superoxide dismutase (SOD) and heme oxygenase-1 (HO-1), lowering reactive oxygen species (ROS) generation and NADPH oxidase isoform 4 (NOX4) expression, and increasing the cell vitalities. They also effectively induced a vasodilatory effect by increasing the vasodilator nitric oxide (NO) and its promoters endothelial NO synthase (eNOS) and peroxisome proliferator-activated receptor-γ (PPARγ) levels as well as by decreasing the vasoconstrictor angiotensin-converting enzyme (ACE), xanthine oxidase-1 (XO-1), and low-density lipoprotein (LDL) levels. The activation of phosphoinositide 3-kinase (PI3K)/Akt signaling pathway and the breakdown of protein kinase C zeta (PKCζ) pathway were involved in the bioactivities. The results indicated blueberry anthocyanins protected endothelial function against high-glucose (HG) injury via antioxidant and vasodilatory mechanisms, which could be promising molecules as a hypotensive nutraceutical for diabetes patients.


Insight into the chemical adsorption properties of CO molecules supported on Au or Cu and hybridized Au-CuO nanoparticles.
Although nanosized Au clusters have been well developed for many applications, fundamental understanding of their adsorption/activation behaviors in catalytic applications is still lacking, especially when other elements provide promotion or hybridization functions. Au hybridized with Cu element is a highly investigated system; Cu is in the same element group as Au and thus displays similar physicochemical properties. However, their hybrids are not well understood in terms of their chemical states and adsorption/activation properties. In this work, typical γ-Al2O3-supported Au and CuO as well as Au-CuO nanoparticles were prepared and characterized to explore their adsorption/activation properties in depth using CO as a probe molecule using advanced techniques, such as XPS, HR-TEM, temperature programmed experiments and operando DRIFT combined with mass spectra. It was found that gold and copper can both act as active sites during CO adsorption and activation. The CO-TPD and operando DRIFT results also revealed that CO molecules were able to react with surface oxygenated species, resulting in the direct formation of CO2 over the three samples in the absence of gaseous O2. The gold step sites (Austep) participated more readily in the reaction, especially under gaseous O2-free conditions. During adsorption, CO molecules were more preferentially adsorbed on Au0 sites at lower temperature comparing with those on the Cu0 sites. However, competitive adsorption occurred between CO adsorbed on Au0 and Cu0 with increased reaction temperature, and the synergy between the Au and Cu compositions was too strong to suppress the adsorption and activation of the CO molecules. The dynamic adsorption equilibrium over 120 °C to 200 °C resulted in the appearance of a hysteresis performance platform.


[Adaptation of interacting populations to the environmental temperature regime].
The biological process of the passing of individuals from the active to the passive state when unfavourable environmental conditions occur has been formalized. This leads to a universal linear superstructing to nonlinear models of ecosystems. At certain rates of this jump, a stabilization of the oscillation instability is possible, and an increase in population vitality can occur. The adaptation processes were examined, and the areas of evolutionarily stable parameters for interacting population (competitors and antagonists) on regular temperature changes were found. A possibility of cyclic changes of parameters in the "prey-predator" system was shown.


Cost-effectiveness of Pomalidomide, Carfilzomib, and Daratumumab for the Treatment of Patients with Heavily Pretreated Relapsed-refractory Multiple Myeloma in the United States.
Pomalidomide plus low-dose dexamethasone (POM-d), daratumumab monotherapy (DARA), and carfilzomib monotherapy (CAR) have been approved for use in the treatment of patients with heavily pretreated relapsed-refractory multiple myeloma (RRMM) in the US, based on findings from the MM-002, SIRIUS, and PX-171-003-A1 studies, respectively. The objective of this study was to assess the cost-effectiveness of POM-d, DARA, and CAR in this patient population from a US payer's perspective. A cost-effectiveness model was developed to estimate the cost and health outcomes over a 3-year time horizon in 3 health states: progression-free, post-progression, and death. The main efficacy data source was a matching-adjusted indirect comparison using data from the aforementioned studies. Direct medical costs were considered, including: treatment acquisition and administration (initial line and subsequent line), pre- and post-medication, prophylaxis treatment, adverse event management, and health care resource utilization. Sensitivity analyses were conducted. A scenario analysis that assumed equal efficacy across all 3 treatments was conducted. Costs, life-years, and quality-adjusted life-years were estimated and discounted at 3% per annum. Over 3 years, the use of POM-d was associated with similar life-years and quality-adjusted life-years gained compared with DARA and CAR (incremental: life-years, +0.02 and +0.07, respectively; quality-adjusted life-years, +0.01 and +0.05), and with a cost less than that of DARA (-$8,919) and similar to that of CAR (-$195). Sensitivity analyses illustrated that the results were sensitive to progression-free survival, treatment duration, and drug costs. An equal efficacy scenario resulted in cost-savings relative to those of both DARA and CAR (-$11,779 and -$12,595). POM-d may be a cost-effective treatment option relative to DARA or CAR in heavily pretreated patients with RRMM in the US.


Exertional hemodynamics in women with chest pain--an aortic Doppler ultrasound study.
Aortic ultrasound Doppler recordings of stroke volume, maximal flow velocity, and acceleration can be used to assess central hemodynamic effects of exercise in coronary artery disease (CAD) and left ventricular dysfunction. We wanted to evaluate the time course and amplitude of changes in aortic Doppler ultrasound parameters in women during supine exercise and the potential diagnostic value of a submaximal supine exercise test. For this purpose, 18 women who had undergone coronary angiography because of incapacitating chest pain (10 with significant coronary stenoses and previous myocardial infarction, 8 without stenoses or infarction) were compared with 10 healthy controls. Pathological electrocardiographic (ECG) ST-segment depression during supine exercise was common in all groups. In the control group, a significant increase of stroke volume (10%), maximal aortic flow velocity (27%), and acceleration (43%) occurred at low load during exercise. Women with CAD showed no increase and a lower cardiac output during exercise, indicating left ventricular dysfunction. Women with syndrome X resembled the controls but had a higher maximal flow velocity at rest, which may indicate hyperdynamic circulation. We conclude that a test up to 40% of seated maximal load is valuable and often sufficient when assessing the hemodynamic effects of supine exercise by Doppler ultrasound in terms of stroke volume, maximal flow velocity, and acceleration. By characterizing left ventricular function in groups of female patients where false-positive stress ECG reactions are common, Doppler ultrasound may contribute to the understanding and clinical management of women with chest pain.


Developing a Heart Transplantation Self-Management Support Mobile Health App in Taiwan: Qualitative Study.
Heart transplantation (HTx) is the most effective treatment for end-stage heart failure patients. After transplantation, patients face physiological, psychological, social, and other health care problems. Mobile health (mHealth) apps can change the delivery of conventional health care to ubiquitous care and improve health care quality. However, a dearth of mHealth apps exists for patients with HTx worldwide, including in Taiwan. The aim of this study was to investigate the information needed and to develop a preliminary framework for an mHealth app for post-HTx patients. A qualitative approach with individual in-depth interviews was conducted at a heart center in the regional hospital of northern Taiwan from June to November 2017. Patients that had undergone HTx and their health professionals were recruited for purposeful sampling. A semistructured interview guideline was used for individual interviews and transcribed. Thematic analysis was used for data analysis. A total of 21 subjects, including 17 patients and 4 health professionals, were recruited for the study. The following five major themes were identified: reminding, querying, experience sharing, diet, and expert consulting. Minor themes included a desire to use the app with artificial intelligence and integration with professional management. An intelligent mHealth app that addresses the five main themes and integrates the processes of using a mobile app could facilitate HTx self-management for Taiwanese patients.


BRCA1/2 Functional Loss Defines a Targetable Subset in Leiomyosarcoma.
Soft-tissue sarcomas (STS) describe a heterogeneous group of mesenchymal tumors with limited treatment options. Targeted therapies exist for BRCA1/2 gene alterations, but their prevalence and role have not been fully described in STS. Here, we present the largest effort to characterize the frequency of homologous recombination (HR) DNA repair pathway alterations in STS subtypes and highlight the unique nature of leiomyosarcoma (LMS). DNA sequencing data were analyzed for HR pathway alterations for 1,236 patients with STS. DNA sequencing data from an additional 1,312 patients were used to confirm the prevalence of HR pathway alterations in LMS. Four uterine LMS (uLMS) patients with functional BRCA2 loss were evaluated for response to poly (ADP-ribose) polymerase (PARP) inhibition. In an unselected STS study population, BRCA2 alterations were identified in 15 (1%) patients, and homozygous BRCA2 loss was detected in 9 (<1%). However, subset analysis revealed that these BRCA2 alterations were concentrated in uLMS as compared with any other STS subtype. Notably, 10% of uLMS tumors had a BRCA2 alteration. We further report that PARP inhibitors had demonstrated durable clinical benefit in four uLMS patients with BRCA2 loss. HR pathway alterations are rare in most STS. However, we identify uLMS to be enriched for BRCA2 loss and report the positive outcomes of a series of patients treated with PARP inhibitors. Our data suggest that patients with uLMS should be considered for somatic BRCA2 profiling. Prospective trials are necessary to confirm the efficacy of PARP inhibition in uLMS. Soft-tissue sarcomas are a highly morbid, diverse set of tumors with limited treatment options. This study identifies an increased prevalence of functional BRCA1/2 loss in patients with uterine leiomyosarcoma (uLMS). It also presents four patients with uLMS and BRCA2 loss who achieved durable clinical benefit from poly (ADP-ribose) polymerase inhibition. These data suggest that patients with uLMS in particular should be screened for BRCA1/2 alterations and may benefit from treatment targeted to these alterations.


Polycomb-mediated silencing in neuroendocrine prostate cancer.
Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer (PCa) for which the median survival remains less than a year. Current treatments are only palliative in nature, and the lack of suitable pre-clinical models has hampered previous efforts to develop novel therapeutic strategies. Addressing this need, we have recently established the first in vivo model of complete neuroendocrine transdifferentiation using patient-derived xenografts. Few genetic differences were observed between parental PCa and relapsed NEPC, suggesting that NEPC likely results from alterations that are epigenetic in nature. Thus, we sought to identify targetable epigenetic regulators whose expression was elevated in NEPC using genome-wide profiling of patient-derived xenografts and clinical samples. Our data indicate that multiple members of the polycomb group (PcG) family of transcriptional repressors were selectively upregulated in NEPC. Notably, CBX2 and EZH2 were consistently the most highly overexpressed epigenetic regulators across multiple datasets from clinical and xenograft tumor tissues. Given the striking upregulation of PcG genes and other transcriptional repressors, we derived a 185-gene list termed 'neuroendocrine-associated repression signature' (NEARS) by overlapping transcripts downregulated across multiple in vivo NEPC models. In line with the striking upregulation of PcG family members, NEARS was preferentially enriched with PcG target genes, suggesting a driving role for PcG silencing in NEPC. Importantly, NEARS was significantly associated with high-grade tumors, metastatic progression, and poor outcome in multiple clinical datasets, consistent with extensive literature linking PcG genes and aggressive disease progression. We have explored the epigenetic landscape of NEPC and provided evidence of increased PcG-mediated silencing associated with aberrant transcriptional regulation of key differentiation genes. Our results position CBX2 and EZH2 as potential therapeutic targets in NEPC, providing opportunities to explore novel strategies aimed at reversing epigenetic alterations driving this lethal disease.


Action perception is intact in autism spectrum disorder.
Autistic traits span a wide spectrum of behavioral departures from typical function. Despite the heterogeneous nature of autism spectrum disorder (ASD), there have been attempts at formulating unified theoretical accounts of the associated impairments in social cognition. A class of prominent theories capitalizes on the link between social interaction and visual perception: effective interaction with others often relies on discrimination of subtle nonverbal cues. It has been proposed that individuals with ASD may rely on poorer perceptual representations of other people's actions as returned by dysfunctional visual circuitry and that this, in turn, may lead to less effective interpretation of those actions for social behavior. It remains unclear whether such perceptual deficits exist in ASD: the evidence currently available is limited to specific aspects of action recognition, and the reported deficits are often attributable to cognitive factors that may not be strictly visual (e.g., attention). We present results from an exhaustive set of measurements spanning the entire action processing hierarchy, from motion detection to action interpretation, designed to factor out effects that are not selectively relevant to this function. Our results demonstrate that the ASD perceptual system returns functionally intact signals for interpreting other people's actions adequately; these signals can be accessed effectively when autistic individuals are prompted and motivated to do so under controlled conditions. However, they may fail to exploit them adequately during real-life social interactions.


Antigen-antibody reactions in allergic human tissues. I. Preparation and use of fluorescein-conjugated reagins for staining the reaction sites.
Skin sensitizing human antibodies were conjugated with various fluorescent dyes without significant loss in their ability to combine with specific antigen in vitro. A biopsy of the skin site challenged with egg albumin in a patient sensitive to this antigen could be stained specifically by the fluorescent reagins. The epithelial cells of the epidermis, sweat glands, hair follicles, and sebaceous glands in such a challenged site showed specific staining. In addition to the epithelial cells, the most intense staining was in macrophages and in pericapillary cells. The endothelium of the small blood vessels stained less intensely. Fibrous tissue bundles were specifically stained. The immunologic staining with the conjugated reagins was similar to but more intense than that obtained with conjugated rabbit anti-egg albumin globulins.


Identifying Quantum Many-Body Integrability and Chaos Using Eigenstate Trace Distances.
While the concepts of quantum many-body integrability and chaos are of fundamental importance for the understanding of quantum matter, their precise definition has so far remained an open question. In this Letter, we introduce an alternative indicator for quantum many-body integrability and chaos, which is based on the statistics of eigenstates by means of nearest-neighbor subsystem trace distances. We show that this provides us with a faithful classification through extensive numerical simulations for a large variety of paradigmatic model systems including random matrix theories, free fermions, Bethe-ansatz solvable systems, and models of many-body localization. While existing indicators, such as those obtained from level-spacing statistics, have already been utilized with great success, they also face limitations. This concerns, for instance, the quantum many-body kicked top, which is exactly solvable but classified as chaotic in certain regimes based on the level-spacing statistics, while our introduced indicator signals the expected quantum many-body integrability. We discuss the universal behaviors we observe for the nearest-neighbor trace distances and point out that our indicator might be useful also in other contexts such as for the many-body localization transition.


Analysis of ras gene mutations and methylation state in human leukemias.
We have screened a large series of primary human leukemias for activating point mutations at codons 12, 13 and 61 of the N-ras and K-ras proto-oncogenes and at codons 12 and 61 of the H-ras proto-oncogene by using panels of oligonucleotide probes in conjunction with polymerase chain reaction gene amplification. 13 of 64 (20%) acute lymphoblastic leukemia cases had ras gene mutations mostly involving N-ras codon 12/13, G-A (gly-asp) transitions. Consistent with previous studies, a comparable pattern and frequency of ras mutation was found amongst 45 cases of acute myeloid leukemia and myelodysplasia. By contrast, of 30 cases of mature B cell chronic lymphocytic leukemia, only one in terminal prolymphocytoid transformation harboured an activated ras gene. These patterns of mutation did not correlate with ras gene methylation state, a finding not obviously compatible with differential gene accessibility being an important determinant of ras gene mutation patterns in leukemogenesis. Our data suggest that activated ras is more important in tumourigenesis of immature than mature lymphocyte progenitors whilst similar mechanisms associated with aetiology and/or target cell susceptibility probably underlie the similar patterns of ras gene mutations seen in acute leukemias of both myeloid and lymphoid cell lineages.


Trembler as a Mouse Model of CMT1A?
The Trembler mouse suffers from a dominantly inherited autosomal mutation that results in an abnormal myelination of the peripheral nervous system. Biochemical studies have shown that dysmyelination is the primary event, demyelination being a late-occurring process. The expression of myelin protein genes has been studied. The steady-state levels for PMP22 mRNA represent 10 and 5% of normal values in the nerves of heterozygous and homozygous Trembler, respectively. This is due to a reduced expression of the specific transcript driven by the promoter 1 of the PMP22 gene. Collective results indicate that Trembler dysmyelination is not necessarily the consequence of a large accumulation of the mutated PMP22 protein. Moreover, it appears that the situation in the Trembler is different from that encountered in most CMT1A patients, where an increased PMP22 gene dosage is responsible for the disease. Therefore, the Trembler mutant is perhaps not an ideal model for this human neuropathy.


Stellar encounters as the origin of distant Solar System objects in highly eccentric orbits.
The Kuiper belt extends from the orbit of Neptune at 30 au to an abrupt outer edge about 50 au from the Sun. Beyond the edge is a sparse population of objects with large orbital eccentricities. Neptune shapes the dynamics of most Kuiper belt objects, but the recently discovered planet 2003 VB12 (Sedna) has an eccentric orbit with a perihelion distance of 70 au, far beyond Neptune's gravitational influence. Although influences from passing stars could have created the Kuiper belt's outer edge and could have scattered objects into large, eccentric orbits, no model currently explains the properties of Sedna. Here we show that a passing star probably scattered Sedna from the Kuiper belt into its observed orbit. The likelihood that a planet at 60-80 au can be scattered into Sedna's orbit is about 50 per cent; this estimate depends critically on the geometry of the fly-by. Even more interesting is the approximately 10 per cent chance that Sedna was captured from the outer disk of the passing star. Most captures have very high inclination orbits; detection of such objects would confirm the presence of extrasolar planets in our own Solar System.


ACR and EULAR improvement criteria have comparable validity in rheumatoid arthritis trials. American College of Rheumatology European League of Associations for Rheumatology.
We compared the validity of the American College of Rheumatology (ACR) and the European League of Associations for Rheumatology (EULAR) definitions of response in rheumatoid arthritis (RA) clinical trials. US: ACR and EULAR improvement criteria were calculated in 7 large randomized RA clinical trials. The discriminant validity of the response criteria between treatment groups was studied using the Mantel-Haenszel chi-squared value. To compare both sets of criteria the chi-squared ratio was determined for each trial. Europe: In 2 large randomized RA clinical trials, ACR and EULAR criteria were calculated, once with extensive and once with 28 joint counts. The classification of patients with these 4 criteria were compared with each other using cross tables. We further studied the difference in response between treatment groups per trial, the association of response with patient and investigator assessment of improvement, and the association of response with radiological progression. US: The chi-squared ratio for most trials was close to 1. There was no clear pattern suggesting that the discriminant validity of the ACR criteria was stronger than the discriminant validity of the EULAR definition of response or vice versa. Europe: Conflicting results between ACR and EULAR were present in only 3% of patients in both trials. The discriminant validity of all 4 criteria (ACR and EULAR with reduced and extensive joint counts) was comparable. All criteria were related with the overall assessment of improvement by both investigator and patient. The association with radiographic progression was comparable for EULAR and ACR improvement criteria. There is a high level of agreement between ACR and EULAR improvement classification, and their validity is equivalent. The discriminating potential of the criteria between treatment groups is comparable, as is the association with patient's and investigator's overall assessment and with radiographic progression.


Incidence and risk factors of cerebral sinovenous thrombosis in infants.
To describe the incidence of term and preterm neonatal cerebral sinovenous thrombosis (CSVT) and identify perinatal risk factors. This was a national capture-recapture calculation-corrected surveillance and nested case-control study. Infants born preterm and at term with magnetic resonance imaging-confirmed neonatal CSVT were identified by surveillance in all paediatric hospitals in Germany (2015-2017). Incidence was corrected for underreporting using a capture-recapture method in one federal state and then extrapolated nationwide. We reviewed PubMed for comparisons with previously reported incidence estimators. We used a population-based perinatal database for quality assurance to select four controls per case and applied univariate and multivariable regression for risk factor analysis. Fifty-one newborn infants (34 males, 17 females; 14 born preterm) with neonatal CSVT were reported in the 3-year period. The incidence of term and preterm neonatal CSVT was 6.6 (95% confidence interval [CI] 4.4-8.7) per 100 000 live births. Median age at time of confirmation of the diagnosis was 9.95 days (range 0-39d). In the univariate analysis, male sex, preterm birth, hypoxia and related indicators (umbilical artery pH <7.1; 5-minute Apgar score <7; intubation/mask ventilation; perinatal asphyxia), operative vaginal delivery, emergency Caesarean section, and pathological fetal Doppler sonography were associated (p<0.05) with neonatal CSVT. Multivariable regression yielded hypoxia (odds ratio=20.3; 95% CI 8.1-50.8) as the independent risk factor. Incidence of neonatal CSVT was within the range of other population-based studies. The results suggest that hypoxia is an important perinatal risk factor for the aetiology of neonatal CSVT.


Langerhans' cell population studies with OKT6 and HLA-DR monoclonal antibodies in vitiligo patients treated with oral phenylalanine loading and UVA irradiation.
In vitiligo patients, treated with oral phenylalanine loading combined with UVA irradiation (Phe-UVA), Langerhans' cells (LC) were counted in pigmented and depigmented skin. The LC, which were labelled with OKT6 and HLA-DR monoclonal antibodies, were expressed per linear mm epidermis. Before treatment the number of OKT6(+) cells was significantly increased in vitiliginous skin especially in the basal layer. Under treatment the number went down and was comparable to normal skin. When using HLA-DR labelling the number of LC increased in vitiliginous skin which had been treated with Phe-UVA. The influence of Phe-UVA on the shift of LC subpopulations is discussed.


Comparison of trace elements in tissue of beaver (Castor canadensis) and local vegetation from a rural region of southern Ontario, Canada.
Beavers have been analyzed in several studies examining trace elements (TEs) in wildlife; however, most of these studies were undertaken in areas with known environmental pollutants. To understand and quantify natural enrichments of TEs in beaver tissue, samples of kidney, liver, muscle from 28 animals were compared with bark from 40 species of trees and shrubs, from the same, uncontaminated watershed. Pearson correlation and factor analysis show that conservative, lithophile elements such as Al, Ga, Th, and Y, all surrogates for mineral dust particles, explain 61% of the variation in the bark data. In contrast, Cd, Co, Cu, Mn, Mo, Ni, Rb, Se, Sr, and Tl in bark are independent of Al, and therefore most likely occur in non-mineral forms. Comparing tissue concentrations of beaver and bark, the organs are enriched in micronutrients such as Cu, Fe, Mo, Se, and Zn, but also non-essential, benign elements such as Cs and Rb, and potentially toxic elements such as Cd and Tl. Thus, the elements most enriched in beaver organs are those that apparently occur in biological form in the plant tissue. The elements enriched in these animals, relative to bark, appear to offer the most promise for monitoring environmental contamination by TEs using beavers. The majority of TEs of environmental relevance are most abundant in beaver kidney. However, monitoring studies must consider the variation in TE concentrations in beaver tissue, including those due to sex and age. Also, due consideration must be given to background concentrations of TEs in the vegetation composing the diet of the animals. The natural enrichment in the case of elements such as Cd, in beaver tissue relative to bark, is profound. These data establish critical baseline values for TEs in beavers in an unpolluted environment, thereby allowing for their use as model organisms in tracking how heavy metal pollutants may affect wildlife.


Selective granulocyte/monocyte apheresis in the treatment of HIV-infected patients: short-term and long-term effects on immunological and virological parameters.
CD4 T cells constitute the major cellular target of HIV infection and, in the natural evolution of the disease, are gradually lost, leading to severe immunodeficiency. Highly active antiretroviral therapy (HAART) is generally effective in reducing HIV replication to undetectable levels and allows the recovery of CD4 T cells in the majority of patients treated. However, some sanctuaries of HIV replication persist even after years of effective HAART and are responsible for the rebound of viral replication when treatment is interrupted. Monocytes/macrophages are also infectable by HIV and are less susceptible to its cytopathic effects compared to CD4 T cells. Replication-competent HIV DNA is detectable in peripheral monocytes of patients under HAART. These cells may therefore contribute to the maintenance of HIV replication during treatment. In addition, both monocytes and granulocytes are abnormally activated during HIV infection and this results in overproduction of some pro-inflammatory cytokines, among them TNF-alpha. For these reasons we tested whether the renewal of the pool of circulating monocytes and granulocytes by selective apheresis (G1 apheresis) could influence some key immunological and virological parameters in HAART-treated patients. The results showed that treatment with G1 apheresis without discontinuation of HAART results in an accelerated immune reconstitution with sustained increases in CD4 T cell counts in those patients who respond virologically to HAART. G1 apheresis is also followed by a strong reduction of TNF-alpha and a reduction of cells bearing integrated HIV DNA. Taken together, the results indicate that G1 apheresis could be used to improve the immunological and virological response to HAART.


Alternatively spliced variants of Gallus gallus TNFRSF23 are expressed in the ovary and differentially regulated by cell signaling pathways.
As a result of searching recently available chicken (ch) expressed sequence tag databases, a new Tumor Necrosis Factor Receptor Super Family (TNFRSF) member with similarity to the murine (m) TNFRSF23 decoy receptor (DcR) has been identified. However, by comparison with the mTNFRSF23, there exist at least two splice variants of chTNFRSF23, one of which includes an intracellular death domain (TNFRSF23.v1) characteristic of death receptors, and the other with a truncated cytoplasmic domain of a DcR (named TNFRSF23.v2). These two splice variants of chTNFRSF23 display differential patterns of mRNA expression across various hen tissues, with the highest levels observed within reproductive tissues. More specifically, TNFRSF23.v1 is most highly expressed in preovulatory follicle granulosa cells in the ovary, whereas TNFRSF23.v2 mRNA is found at highest levels in ovarian stromal tissue. Primary culture experiments with granulosa cells determined that expression of TNFRSF23.v1 mRNA was decreased by protein kinase A signaling and enhanced by transforming growth factor (TGF) alpha treatment. Interestingly, TGFbeta1 and signaling via protein kinase C also enhanced levels of TNFRSF23.v1 expression but only in undifferentiated granulosa cells from prehierarchal follicles. Based on patterns of mRNA expression and its endocrine/paracrine regulation, we predict that ovarian chTNFRSF23 represents a modulator of granulosa cell survival and/or differentiation. Finally, the characterization of these receptor variants is of considerable interest from an evolutionary perspective in that they provide additional evidence to support a continuing divergence of TNFRSF members throughout vertebrate evolution.


A double-blind controlled trial of high dose methylprednisolone in patients with multiple sclerosis: 2. Laboratory results.
Laboratory measurements were compared in paired samples from 50 patients included in a double-blind placebo controlled trial of methylprednisolone in the treatment of multiple sclerosis. Cerebrospinal fluid total cell count, IgG and C9 indices, and percentage of peripheral blood OKT8 positive cells were abnormal at entry and returned closer to the normal range after active than placebo treatment, but the differences were not statistically significant. The percentage of peripheral blood OKT4 positive cells was normal at entry as was the amplitude of visual evoked potentials, whereas their latency was prolonged; these measurements were each uninfluenced by methylprednisolone. Corticosteroids might act merely by influencing oedema, but the laboratory results suggest that methylprednisolone affects immunological events which underly rapid onset and recovery of symptoms in patients with multiple sclerosis; additional forms of treatment are needed to maintain these clinical and immunological effects.


Early chest radiography and CT in the diagnosis, management and outcome of invasive pulmonary aspergillosis.
We report the chest radiographic and CT findings in 21 immunocompromised patients with invasive pulmonary aspergillosis (IPA) and describe the outcome when the early diagnosis was linked to treatment with liposomal amphotericin B. Chest radiographs and CT examinations were analyzed retrospectively in 53 consecutive neutropenic patients with suspected early IPA. Twenty-one of 244 patients admitted for chemotherapy of hematologic malignancy fulfilled the definition for IPA - incidence of 8.6%. The incidence of normal and non-specific chest radiographic findings was high (29% and 71%, respectively) during the early stages of IPA. The CT halo sign was seen in 20 of the 21 patients (95%), and occurred within 5 days of neutropenic fever that was unresponsive to antibiotics in 5 patients. Crescent signs or cavitations were seen in 7 patients (33%). Treatment with liposomal amphotericin B was associated with an attributable mortality of 9.5%. Two patients died from IPA having a high fungal burden. Early chest CT in neutropenic patients at risk for IPA is an important diagnostic and management tool and should be included in the investigative protocol even when chest radiographs are normal or non-specific.


Efficient targeted gene disruption in the soma and germ line of the frog Xenopus tropicalis using engineered zinc-finger nucleases.
The frog Xenopus, an important research organism in cell and developmental biology, currently lacks tools for targeted mutagenesis. Here, we address this problem by genome editing with zinc-finger nucleases (ZFNs). ZFNs directed against an eGFP transgene in Xenopus tropicalis induced mutations consistent with nonhomologous end joining at the target site, resulting in mosaic loss of the fluorescence phenotype at high frequencies. ZFNs directed against the noggin gene produced tadpoles and adult animals carrying up to 47% disrupted alleles, and founder animals yielded progeny carrying insertions and deletions in the noggin gene with no indication of off-target effects. Furthermore, functional tests demonstrated an allelic series of activity between three germ-line mutant alleles. Because ZFNs can be designed against any locus, our data provide a generally applicable protocol for gene disruption in Xenopus.


Emotional response to healthier foods: Influence of culture and health consciousness.
Sugar, salt, and fat content in processed products are important concerns for consumers. Hence, alternative "healthy" versions of conventional foods such as chocolate, potato chips, and yogurt are offered. This work aimed to define the emotional response of consumers from different cultural backgrounds (Spain vs. Brazil) evoked by healthier versions of conventional products and the relationship between hedonic responses and health consciousness. A total of 186 Brazilian and 152 Spanish consumers participated in this online cross-cultural study. Participants answered a Health Consciousness Questionnaire and an emotional check-all-that-applies questionnaire using picture stimuli of conventional chocolate, potato chips, and yogurt and their healthier versions with less sugar, salt, and fat content, respectively. The Brazilians' emotional responses were more diverse for all stimuli compared to the Spaniards'. However, participants from both cultures rated an average of "slightly agree" on the health consciousness scale; a higher level of consumption, liking, and willingness to buy; and a higher frequency of positive emotional terms for the stimuli of conventional products compared to their healthier versions. A higher frequency of evocation of "active" is strongly associated with higher levels of health consciousness. Strategic actions by the food industry and government must consider cultural, emotional, and health-conscious factors to encourage the consumption of healthier foods. PRACTICAL APPLICATION: Food manufacturers can use the information obtained from this study to create healthier versions of their products that appeal to consumers' emotional responses and health consciousness levels. The findings can assist in designing strategic actions to promote healthier food consumption by emphasizing the benefits of healthier food choices and making them more appealing to consumers. The methodology employed in this study can also be applied to further studies aimed to assess emotional responses to food stimuli across different cultures.


Donor-Recipient Story in Allogeneic Hematopoietic Stem Cell Transplantation.
Patients with a variety of blood, immune, and metabolic disorders may require an allogeneic hematopoietic stem cell transplant as part of their treatment. However, over 70% of these patients do not have a matched sibling donor and require an alternative donor, such as a matched unrelated donor. We present a multi-part story of a Canadian stem cell recipient who underwent transplantation for treatment of refractory chronic myelogenous leukemia, and the matched unrelated donor who saved his life. The story segments feature excerpts from interviews with the donor and the recipient, along with representative images of both storytellers. The excerpts were optimized for publication on social media and were arranged to build a story arc that parallels the journey of the donor and recipient together. This donor-recipient story may serve as a resource to help raise awareness about stem cell donation and to encourage eligible individuals to register as donors. The story is one of several developed by Why We Swab, a library of stories in stem cell donation in Canada (Facebook, Twitter, and Instagram; @WhyWeSwab) to support the recruitment of committed unrelated donors.


Subchondral fracture following arthroscopic knee surgery. A series of eight cases.
Osteonecrosis has been reported as a rare complication of arthroscopic knee surgery, with the diagnosis based on radiographic findings associated with recurrent or worsening clinical symptoms. The term osteonecrosis has been applied to this clinical entity despite a lack of pathologic evidence to support the diagnosis. The purpose of this study was to document the pathologic changes involved in this rare process. Patients who had undergone an arthroscopic procedure followed by a total knee replacement within two years were eligible for the study. Inclusion criteria included pre-arthroscopy magnetic resonance imaging findings consistent with a meniscal tear with otherwise normal bone morphology followed by a provisional diagnosis of post-arthroscopy osteonecrosis based on subsequent imaging studies. Patients were excluded if a laser-assisted device had been utilized during the arthroscopy. Seven patients (eight knees) with an average age of sixty-four years met the criteria and were included in the study group. All patients had undergone an arthroscopic medial meniscectomy, and two also had had a chondroplasty, with use of a mechanical shaver. Seven of the post-arthroscopy lesions involved the medial femoral condyle, and one lesion involved the medial tibial plateau. Pathologic analysis revealed a subchondral fracture with callus formation, indicated by the presence of woven bone, in all cases. Four patients had essentially intact articular cartilage overlying the lesion, which was characterized by disruption of the trabecular architecture indicative of subchondral bone fracture. The other four patients had an isolated osteochondral defect with reparative tissue within the base of the defect. Only two knees had localized evidence of osteonecrosis, which appeared to be secondary to the fracture. This study provides pathologic evidence supporting the concept that subchondral fracture, and not osteonecrosis, is the major event in this rare complication following arthroscopy. Further investigation into the etiology of this condition is warranted.


Combined management of intracranial arteriovenous malformations with embolization and gamma knife radiosurgery: comparative evaluation of the long-term results.
Volume reduction of large AVMs attained with endovascular embolization can be potentially helpful for their subsequent radiosurgical management. The objective of the present retrospective analysis was comparative evaluation of the long-term outcome after GKR for intracranial AVM performed with and without initial embolization of the nidus. The long-term outcome in 15 patients with intracranial AVM treated with initial embolization and subsequent GKR was evaluated and compared with the series of 237 patients treated during the same period solely with GKR. All patients were followed at least 2 years after radiosurgery. Mean reductions of the nidus volume and score of the radiosurgery-based grading system for AVMs after embolization constituted 6.9 +/- 2.4 mL and 0.7 +/- 0.2, respectively (P < .001). Complete obliteration of the nidus after GKR was marked in 10 cases (67%). It was attained in 9 (90%) of 10 AVMs with postembolization nidus volume less than 12 mL, and in 1 (20%) of 5 with postembolization nidus volume more than 12 mL (P < .05). Delayed cyst formation was met once (7%). Obliteration and long-term morbidity rates did not differ significantly in patients treated with and without preradiosurgical nidus embolization, whereas nidus volume was seemingly larger in the former cohort. Combined management with embolization and GKR may be effective for selected cases of large intracranial AVM. Radiosurgery preceded by partial nidus embolization does not associate with increased rate of long-term complications.


Generation of high-quality higher-order Laguerre-Gaussian beams using liquid-crystal-on-silicon spatial light modulators.
We report on the high-quality holographic generation of higher-order Laguerre-Gaussian (LG) beams using a liquid-crystal-on-silicon spatial light modulator. The effects of the input beam pattern on the output LG beam quality are investigated in detail through theoretical discussions and experiments. Correlation analyses between observed beam patterns and theoretical mode profiles reveal that higher beam quality is achieved for output LG beams generated from a top-hat input beam than from a Gaussian input beam.


A Lipidomic Analysis of Docosahexaenoic Acid (22:6, ω3) Mediated Attenuation of Western Diet Induced Nonalcoholic Steatohepatitis in Male Ldlr -/- Mice.
Nonalcoholic fatty liver disease (NAFLD) is a major public health problem worldwide. NAFLD ranges in severity from benign steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and primary hepatocellular cancer (HCC). Obesity and type 2 diabetes mellitus (T2DM) are strongly associated with NAFLD, and the western diet (WD) is a major contributor to the onset and progression of these chronic diseases. Our aim was to use a lipidomic approach to identify potential lipid mediators of diet-induced NASH. We previously used a preclinical mouse (low density lipoprotein receptor null mouse, Ldlr -/-) model to assess transcriptomic mechanisms linked to WD-induced NASH and docosahexaenoic acid (DHA, 22:6, ω3)-mediated remission of NASH. This report used livers from the previous study to carry out ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and high-performance liquid chromatography coupled with dynamic multi-reaction monitoring (HPLC-dMRM) to assess the impact of the WD and DHA on hepatic membrane lipid and oxylipin composition, respectively. Feeding mice the WD increased hepatic saturated and monounsaturated fatty acids and arachidonic acid (ARA, 20:4, ω6) in membrane lipids and suppressed ω3 polyunsaturated fatty acids (PUFA) in membrane lipids and ω3 PUFA-derived anti-inflammatory oxylipins. Supplementing the WD with DHA lowered hepatic ARA in membrane lipids and ARA-derived oxylipins and significantly increased hepatic DHA and its metabolites in membrane lipids, as well as C20-22 ω3 PUFA-derived oxylipins. NASH markers of inflammation and fibrosis were inversely associated with hepatic C20-22 ω3 PUFA-derived Cyp2C- and Cyp2J-generated anti-inflammatory oxylipins (false discovery rate adjusted p-value; q ≤ 0.026). Our findings suggest that dietary DHA promoted partial remission of WD-induced NASH, at least in part, by lowering hepatic pro-inflammatory oxylipins derived from ARA and increasing hepatic anti-inflammatory oxylipins derived from C20-22 ω3 PUFA.


[Prognostic value of x-ray computed tomography in acute pancreatitis: contribution of the injection of intravenous contrast media].
Thirty seven patients suffering from acute pancreatitis were explored using contrast-enhanced computed tomography (CT). The authors found a good concordance between the extension of the lesions on the initial CT examination, prognostic criteria on admission and the course of the disease. In addition, a new prognostic CT sign was reported in the early phase of parenchymal contrast perfusion, i.e. the lack of contrast-enhancement in a limited portion of the pancreas. This sign was present in 8 patients, all with severe clinical symptoms. These 8 patients showed the highest morbidity rate in the series with abscess-type complications occurring in all, compared with 24 p. 100 among the 29 other patients who did not exhibit this CT sign. Moreover, these 8 patients showed the highest mortality rate (25 p. 100 compared with 3.5 p. 100 among the other patients). An histological analysis of partial pancreatectomy specimens was performed in 7 out of the 8 patients. Devitalized pancreatic tissue, at the site of the parenchymal abnormalities on CT scan, was found in all cases. One false negative case was reported. Contrast-enhanced CT scan seems to be the most reliable method for diagnosing pancreatic necrosis during acute severe pancreatitis. It appears to be an useful prognostic predictor of morbidity. It can improve the outcome of the disease by depicting and guiding needle aspiration of a fluid collection, and/or surgery in case of clinical findings suggesting abscess formation.


Substitution of conserved residues within the active site alters the cleavage religation equilibrium of DNA topoisomerase I.
Eukaryotic DNA topoisomerase I (Top1p) catalyzes the relaxation of supercoiled DNA and constitutes the cellular target of camptothecin (CPT). Mutation of conserved residues in close proximity to the active site tyrosine (Tyr(727) of yeast Top1p) alters the DNA cleavage religation equilibrium, inducing drug-independent cell lethality. Previous studies indicates that yeast Top1T722Ap and Top1N726Hp cytotoxicity results from elevated levels of covalent enzyme-DNA intermediates. Here we show that Top1T722Ap acts as a CPT mimetic by exhibiting reduced rates of DNA religation, whereas increased Top1N726Hp.DNA complexes result from elevated DNA binding and cleavage. We also report that the combination of the T722A and N726H mutations in a single protein potentiates the cytotoxic action of the enzyme beyond that induced by co-expression of the single mutants. Moreover, the addition of CPT to cells expressing the double top1T722A/N726H mutant did not enhance cell lethality. Thus, independent alterations in DNA cleavage and religation contribute to the lethal phenotype. The formation of distinct cytotoxic lesions was also evidenced by the different responses induced by low levels of these self-poisoning enzymes in isogenic strains defective for the Rad9 DNA damage checkpoint, processive DNA replication, or ubiquitin-mediated proteolysis. Substitution of Asn(726) with Phe or Tyr also produces self-poisoning enzymes, implicating stacking interactions in the increased kinetics of DNA cleavage by Top1N726Hp and Top1N726Fp. In contrast, replacing the amide side chain of Asn(726) with Gln renders Top1N726Qp resistant to CPT, suggesting that the orientation of the amide within the active site is critical for effective CPT binding.


[Postvaccinal dysentery immunity studied on the model of ligated loop of the small intestine of rabbits].
Chemical (detergent) antigens administered intraintestinally or intravenously to rabbits were applied to reproduce postvaccinal immunity to experimental shigellosis. There was noted an increase of the antibody level in the serum, an intensification of its preventive proerties, and the absence of dilatation of the isolated loops of the small intestine after the administration of the corresponding dysentery culture. Oral immunization of rabbits with the detergent antigen sorbed on ionexchange resin also led to immunity.


Empowering Our People: Syndemic Moderators and Effects of a Culturally Adapted, Evidence-Based Intervention for Sexual Risk Reduction among Native Americans with Binge Substance Use.
Native American (NA) communities are disproportionately affected by the intersecting, synergistic epidemics of sexually transmitted infections (STIs) and substance use. Targeted approaches to addressing these syndemics are critical given the relative scarcity of mental health and behavioral specialists in NA communities. We conducted a series of moderation analyses using data from a randomized controlled trial of the EMPWR (Educate, Motivate, Protect, Wellness, Respect) intervention for reducing sexual risk behaviors, culturally adapted for NA adults with recent binge substance use living on rural reservations. We considered several potential moderators and substance use and sexual risk outcomes at 6- and 12-months post-baseline. Three hundred and one people participated in the study. Age, marital status, educational attainment, employment, and depressive symptoms were differentially associated with intervention effects. EMPWR could be strengthened with the incorporation of additional skills-building related to condom use negotiation with casual partners. For individuals with lower educational attainment or without employment, additional supports and approaches to intervention may be needed. Importantly, this study did not identify intersecting sexual risk and substance use behaviors as moderators of EMPWR effectiveness, suggesting that NA adults with varying levels of risk behavior may be equally likely to benefit from this intervention.


Purification of bovine striatal dopamine D-2 receptor by affinity chromatography.
Bovine striatal dopamine D-2 receptor has been purified approximately 2000-fold by affinity chromatography. The receptor, solubilized with cholic acid and sodium chloride, was adsorbed on haloperidol-linked Sepharose CL-6B and eluted with spiroperidol. The adsorption of receptor to the affinity matrix was biospecific as preincubation of the solubilized preparation with D-2 receptor agonists or antagonists blocked retention of receptor. The process also displayed stereoselectivity with respect to (+)- and (-)-butaclamol. Nondopaminergic agents such as mianserin and propranolol failed to exhibit any effect on the adsorption process. Elution of the receptor was also biospecific, as dopaminergic drugs were most effective (spiroperidol greater than haloperidol greater than dopamine) in eluting the bound receptor; whereas other agents, e.g. propranolol, mianserin, and acetic acid, were only slightly effective. One-cycle affinity purification resulted in a recovery of 12% of the original membrane-bound dopamine D-2 receptor with a specific activity of 169,600 fmol/mg of protein as assayed with [3H]spiroperidol binding. The order of potency of D-2 agonists (N-propylnorapomorphine greater than NO434 greater than apomorphine greater than dopamine) and antagonists (spiroperidol greater than (+)-butaclamol greater than domperidone) with the purified preparation was found to be similar to that of the solubilized dopamine D-2 receptor.