Plasma and Salivary Non-Urate Total Antioxidant Capacity Does Not Depend on Dietary Vitamin C, E, or β-Carotene Intake in Older Subjects.
The native Total Antioxidant Capacity (TAC) of plasma and saliva is generally determined by uric acid (UA). Several studies have assessed the impact of habitual dietary antioxidative vitamin intake on TAC, but it remains unknown whether it influences Non-Urate Total Antioxidant Capacity (Nu-TAC), i.e., TAC after enzymatic UA elimination. The purpose of this study was to assess whether the intake of antioxidative vitamins C, E, and β-carotene, provided with usual daily food rations, affects plasma and salivary Nu-TAC. The study involved 56 older subjects (aged 66.9 ± 4.3 years), divided into two age- and sex-matched groups: group 1 (n = 28), with lower combined vitamin C, E, and β-carotene intake, and group 2 (n = 28), with higher intake. A 24 h dietary recall was obtained from each individual. Nu-TAC was assessed simultaneously with two methods in plasma (Ferric Reducing Ability of Plasma—Nu-FRAP, 2.2-diphenyl-1-picryl-hydrazyl—Nu-DPPH) and in saliva (Nu-FRAS and Nu-DPPHS test). No differences were found in the Nu-TAC parameters between the groups, either in plasma (Nu-FRAP, Nu-DPPH) or in saliva (Nu-FRAS, Nu-DPPHS) (p > 0.05). No plasma or salivary Nu-TAC indices correlated with dietary vitamin C, E, or β-carotene intake or with other nutrients. Habitual, not extra-supplemented dietary intake does not significantly affect plasma or salivary Nu-TAC.


Functionality of HDL: antioxidation and detoxifying effects.
High-density lipoproteins (HDL) are complexes of multiple talents, some of which have only recently been recognised but all of which are under active investigation. Clinical interest initially arose from their amply demonstrated role in atherosclerotic disease with their consequent designation as a major cardiovascular disease (CVD) risk factor. However, interest is no longer confined to vascular tissues, with the reports of impacts of the lipoprotein on pancreatic, renal and nervous tissues, amongst other possible targets. The ever-widening scope of HDL talents also encompasses environmental hazards, including infectious agents and environmental toxins. In almost all cases, HDL would appear to have a beneficial impact on health. It raises the intriguing question of whether these various talents emanate from a basic ancestral function to protect the cell.The following chapter will illustrate and review our current understanding of some of the functions attributed to HDL. The first section will look at the antioxidative functions of HDL and possible mechanisms that are involved. The second section will focus specifically on paraoxonase-1 (PON1), which appears to bridge the divide between the two HDL functions discussed herein. This will lead into the final section dealing with HDL as a detoxifying agent protecting against exposure to environmental pathogens and other toxins.


A Year of Infection in the Intensive Care Unit: Prospective Whole Genome Sequencing of Bacterial Clinical Isolates Reveals Cryptic Transmissions and Novel Microbiota.
Bacterial whole genome sequencing holds promise as a disruptive technology in clinical microbiology, but it has not yet been applied systematically or comprehensively within a clinical context. Here, over the course of one year, we performed prospective collection and whole genome sequencing of nearly all bacterial isolates obtained from a tertiary care hospital's intensive care units (ICUs). This unbiased collection of 1,229 bacterial genomes from 391 patients enables detailed exploration of several features of clinical pathogens. A sizable fraction of isolates identified as clinically relevant corresponded to previously undescribed species: 12% of isolates assigned a species-level classification by conventional methods actually qualified as distinct, novel genomospecies on the basis of genomic similarity. Pan-genome analysis of the most frequently encountered pathogens in the collection revealed substantial variation in pan-genome size (1,420 to 20,432 genes) and the rate of gene discovery (1 to 152 genes per isolate sequenced). Surprisingly, although potential nosocomial transmission of actively surveilled pathogens was rare, 8.7% of isolates belonged to genomically related clonal lineages that were present among multiple patients, usually with overlapping hospital admissions, and were associated with clinically significant infection in 62% of patients from which they were recovered. Multi-patient clonal lineages were particularly evident in the neonatal care unit, where seven separate Staphylococcus epidermidis clonal lineages were identified, including one lineage associated with bacteremia in 5/9 neonates. Our study highlights key differences in the information made available by conventional microbiological practices versus whole genome sequencing, and motivates the further integration of microbial genome sequencing into routine clinical care.


Bottlenose dolphins exchange signature whistles when meeting at sea.
The bottlenose dolphin, Tursiops truncatus, is one of very few animals that, through vocal learning, can invent novel acoustic signals and copy whistles of conspecifics. Furthermore, receivers can extract identity information from the invented part of whistles. In captivity, dolphins use such signature whistles while separated from the rest of their group. However, little is known about how they use them at sea. If signature whistles are the main vehicle to transmit identity information, then dolphins should exchange these whistles in contexts where groups or individuals join. We used passive acoustic localization during focal boat follows to observe signature whistle use in the wild. We found that stereotypic whistle exchanges occurred primarily when groups of dolphins met and joined at sea. A sequence analysis verified that most of the whistles used during joins were signature whistles. Whistle matching or copying was not observed in any of the joins. The data show that signature whistle exchanges are a significant part of a greeting sequence that allows dolphins to identify conspecifics when encountering them in the wild.


Relational versus structural goals prioritize different social information.
People gather information about others along a few fundamental dimensions; their current goals determine which dimensions they most need to know. As proponents of competing social-evaluation models, we sought to study the dimensions that perceivers spontaneously prioritize when gathering information about unknown social groups. Because priorities depend on functions, having relational goals (e.g., deciding whether and how to interact with a group) versus structural goals (e.g., getting an overview of society) should moderate dimensional priorities. Various candidate dimensions could differentiate perceivers' impressions of social groups. For example, the Stereotype Content model argues that people evaluate others in terms of their Warmth (i.e., their Sociability and Morality) and Competence (i.e., their Ability and Assertiveness). Alternatively, the Agency-Beliefs-Communion (ABC) model proposes conservative-progressive Beliefs. Five studies (N = 2,268) found that participants consistently prioritized learning about targets' Warmth. However, goal moderated priority: When participants had a relational goal, such as an unknown group increasing in their neighborhood, they showed more interest in targets' Sociability, a facet of Warmth. When participants had a structural goal, such as an unknown group increasing in their nation, they showed more interest in the groups' Beliefs, as well as increased interest in Competence-related facets. Diverse methods reveal interest in all dimensions, reconciling discrepancies among social-evaluation models by identifying how relational versus structural goals differentiate priorities of the fundamental dimensions proposed by current models. Results have implications for fundamental dimensions of social cognition, more generally. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Internet Use, Risk Awareness, and Demographic Characteristics Associated With Engagement in Preventive Behaviors and Testing: Cross-Sectional Survey on COVID-19 in the United States.
During the coronavirus disease (COVID-19) pandemic, engagement in preventive behaviors and getting tested for the virus play a crucial role in protecting people from contracting the new coronavirus. This study aims to examine how internet use, risk awareness, and demographic characteristics are associated with engagement in preventative behaviors and testing during the COVID-19 pandemic in the United States. A cross-sectional survey was conducted on Amazon Mechanical Turk from April 10, 2020, to April 14, 2020. Participants' internet use (in terms of the extent of receiving information pertaining to COVID-19), risk awareness (whether any immediate family members, close friends or relatives, or people in local communities tested positive for COVID-19), demographics (sex, age, ethnicity, income, education level, marital status, and employment status), as well as their engagement in preventative behaviors and testing were assessed. Our data included 979 valid responses from the United States. Participants who received more COVID-19-related health information online reported more frequent effort to engage in all types of preventive behaviors: wearing a facemask in public (odds ratio [OR] 1.55, 95% CI 1.34-1.79, P<.001), washing hands (OR 1.58, 95% CI 1.35-1.85, P<.001), covering nose and mouth when sneezing and coughing (OR 1.78, 95% CI 1.52-2.10, P<.001), keeping social distance with others (OR 1.41, 95% CI 1.21-1.65, P<.001), staying home (OR 1.40, 95% CI 1.20-1.62, P<.001), avoiding using public transportation (OR 1.57, 95% CI 1.32-1.88, P<.001), and cleaning frequently used surfaces (OR 1.55, 95% CI 1.34-1.79, P<.001). Compared with participants who did not have positive cases in their social circles, those who had immediate family members (OR 1.48, 95% CI 8.28-26.44, P<.001) or close friends and relatives (OR 2.52, 95% CI 1.58-4.03, P<.001) who tested positive were more likely to get tested. Participants' sex, age, ethnicity, marital status, and employment status were also associated with preventive behaviors and testing. Our findings revealed that the extent of receiving COVID-19-related information online, risk awareness, and demographic characteristics including sex, ethnicity, age, marital status, and employment status are key factors associated with US residents' engagement in various preventive behaviors and testing for COVID-19.


Measles, mumps and rubella vs diphtheria-tetanus-acellular-pertussis-inactivated-polio-Haemophilus influenzae type b as the most recent vaccine and risk of early 'childhood asthma'.
Live vaccines may have beneficial non-specific effects. We tested whether the live measles, mumps and rubella (MMR) vaccine compared with the non-live diphtheria-tetanus-acellular-pertussis-inactivated-polio-Haemophilus influenzae type b (DTaP-IPV-Hib) vaccine as the most recent vaccine was associated with less childhood asthma and fewer acute hospital contacts for childhood asthma among boys and girls. This study is a nationwide register-based cohort study of 338 761 Danish children born between 1999 and 2006. We compared (i) the incidence of first-registered childhood asthma based on hospital contacts and drug prescriptions and (ii) the incidence of severe asthma defined as acute hospital contacts for childhood asthma between the ages of 15 and 48 months among children whose last received vaccine was three doses of DTaP-IPV-Hib and then MMR with children whose last received vaccine was three doses of DTaP-IPV-Hib. For boys, following the recommended vaccine schedule of MMR after DTaP-IPV-Hib3 compared with DTaP-IPV-Hib3 as the last received vaccine, MMR was associated with 8.1 (95% confidence interval 3.9-12.3) fewer childhood asthma cases per 1000 boys, corresponding to 10% (5-15%) reduction in the cumulative incidence of childhood asthma. MMR, when given last, was also associated with 16.3 (95% confidence interval 12.7-20.0) fewer acute hospital admissions for childhood asthma per 1000 boys, corresponding to a 27% (22-31%) reduction in the cumulative incidence. No associations were seen for girls. MMR may have a protective effect against childhood asthma for boys. This calls for an understanding of whether non-specific effects of vaccines can be used to optimize our vaccine programmes.


[Effect of different supplies of vitamin E on biochemical changes in T-2 mycotoxicosis in rats].
Maintainance of rats within 3 months on a ration with low content of vitamin E (6 mg/kg as compared with 100 mg/kg in control) did not alter distinctly the enzymatic activity in mitochondria, lysosomes and the activity of the enzymes, metabolizing xenobiotics as well as did not affect the permeability of lysosomal and plasmatic membranes. In subacute T-2 mycotoxicosis of rats kept on control ration the following alterations were noted: decrease in activity of lysosomal enzymes, aniline hydroxylase, carboxyl esterase and in content of cytochrome P-450 in liver tissue simultaneously with two-fold activation of epoxide hydrolase and UDP-glucuronosyl transferase; decrease in non-sedimented activity of lysosomal enzymes; decrease in activity of alkaline phosphatase and of lysosomal enzymes in blood serum. After administration of the toxin into vitamin E deficient rats, its effect was increased, hemorrhagic syndrome was distinctly developed, permeability of lysosomal and plasmatic membranes was increased. Subnormal consumption of vitamin E appears to cause destabilization of biological membranes structure, which is manifested under conditions of stress.


The cost-effectiveness of prenatal carrier screening for cystic fibrosis.
To evaluate the economic consequences of routinely offering cystic fibrosis-carrier screening to pregnant white women under 35 years of age. Decision analysis was used to evaluate the health outcomes and medical costs of a screening program from the health care payer's perspective. Probabilities were taken from the literature; cost data were based on consultations with laboratory and hospital administrators. Sensitivity analysis was performed for key assumptions. If the test acceptance rate were 78% and the screening test identified 85% of carriers, a prenatal cystic fibrosis-carrier screening program would identify slightly more than half of the high-risk pregnancies in the population. For a cohort of one million pregnant women, it would cost $83 million. If the proportion of couples choosing abortion were 30% and the lifetime cost of medical care for cystic fibrosis were $243,650, the program would save $12 million in averted costs of medical care for cystic fibrosis, for a net cost of $71 million. Even after accounting for the savings in averted medical care for cystic fibrosis, the cost per high-risk pregnancy identified would be $82,000; the cost per unwanted cystic fibrosis birth averted would be $1.4 million. Results were sensitive to the cost and sensitivity of the screening test, but relatively insensitive to the test acceptance rate and therapeutic abortion rates between 50-100% among pregnancies identified with cystic fibrosis. A prenatal cystic fibrosis-carrier screening program would not save the health care payer money under most assumptions, but may be justified if the benefit of the early information provided to expectant parents is judged worth the cost.


Revealing microbial species diversity using sequence capture by hybridization.
Targeting small parts of the 16S rDNA phylogenetic marker by metabarcoding reveals microorganisms of interest but cannot achieve a taxonomic resolution at the species level, precluding further precise characterizations. To identify species behind operational taxonomic units (OTUs) of interest, even in the rare biosphere, we developed an innovative strategy using gene capture by hybridization. From three OTU sequences detected upon polyphenol supplementation and belonging to the rare biosphere of the human gut microbiota, we revealed 59 nearly full-length 16S rRNA genes, highlighting high bacterial diversity hidden behind OTUs while evidencing novel taxa. Inside each OTU, revealed 16S rDNA sequences could be highly distant from each other with similarities down to 85 %. We identified one new family belonging to the order Clostridiales, 39 new genera and 52 novel species. Related bacteria potentially involved in polyphenol degradation have also been identified through genome mining and our results suggest that the human gut microbiota could be much more diverse than previously thought.


Metabolism of indole-3-acetic acid in Arabidopsis.
The metabolism of indole-3-acetic acid (IAA) was investigated in 14-d-old Arabidopsis plants grown in liquid culture. After ruling out metabolites formed as an effect of nonsterile conditions, high-level feeding, and spontaneous interconversions, a simple metabolic pattern emerged. Oxindole-3-acetic acid (OxIAA), OxIAA conjugated to a hexose moiety via the carboxyl group, and the conjugates indole-3-acetyl aspartic acid (IAAsp) and indole-3-acetyl glutamate (IAGlu) were identified by mass spectrometry as primary products of IAA fed to the plants. Refeeding experiments demonstrated that none of these conjugates could be hydrolyzed back to IAA to any measurable extent at this developmental stage. IAAsp was further oxidized, especially when high levels of IAA were fed into the system, yielding OxIAAsp and OH-IAAsp. This contrasted with the metabolic fate of IAGlu, since that conjugate was not further metabolized. At IAA concentrations below 0.5 microM, most of the supplied IAA was metabolized via the OxIAA pathway, whereas only a minor portion was conjugated. However, increasing the IAA concentrations to 5 microM drastically altered the metabolic pattern, with marked induction of conjugation to IAAsp and IAGlu. This investigation used concentrations for feeding experiments that were near endogenous levels, showing that the metabolic pathways controlling the IAA pool size in Arabidopsis are limited and, therefore, make good targets for mutant screens provided that precautions are taken to avoid inducing artificial metabolism.


High density spectral beam combination with spatial chirp precompensation.
A method for spectral combination of lasers with extremely high spectral density is introduced, enabling greater than 80% and theoretically approaching 100% spectral density utilization with no degradation in beam quality. Experiments demonstrating the utility of our method are described, cumulating in a demonstration of a compact, packaged laser with photonic-crystal-fiber-rod amplifiers at 0.5-MW peak power and 0.15-nm wavelength spacing. Our method is potentially scalable to many 100's of channels within the gain bandwidth of high average power or peak power rare earth doped fiber lasers at any wavelength in a compact footprint and uses only reflective optics and gratings.


Beamforming Through Regularized Inverse Problems in Ultrasound Medical Imaging.
Beamforming (BF) in ultrasound (US) imaging has significant impact on the quality of the final image, controlling its resolution and contrast. Despite its low spatial resolution and contrast, delay-and-sum (DAS) is still extensively used nowadays in clinical applications, due to its real-time capabilities. The most common alternatives are minimum variance (MV) method and its variants, which overcome the drawbacks of DAS, at the cost of higher computational complexity that limits its utilization in real-time applications. In this paper, we propose to perform BF in US imaging through a regularized inverse problem based on a linear model relating the reflected echoes to the signal to be recovered. Our approach presents two major advantages: 1) its flexibility in the choice of statistical assumptions on the signal to be beamformed (Laplacian and Gaussian statistics are tested herein) and 2) its robustness to a reduced number of pulse emissions. The proposed framework is flexible and allows for choosing the right tradeoff between noise suppression and sharpness of the resulted image. We illustrate the performance of our approach on both simulated and experimental data, with in vivo examples of carotid and thyroid. Compared with DAS, MV, and two other recently published BF techniques, our method offers better spatial resolution, respectively contrast, when using Laplacian and Gaussian priors.


Microbial responses to warming enhance soil carbon loss following translocation across a tropical forest elevation gradient.
Tropical soils contain huge carbon stocks, which climate warming is projected to reduce by stimulating organic matter decomposition, creating a positive feedback that will promote further warming. Models predict that the loss of carbon from warming soils will be mediated by microbial physiology, but no empirical data are available on the response of soil carbon and microbial physiology to warming in tropical forests, which dominate the terrestrial carbon cycle. Here we show that warming caused a considerable loss of soil carbon that was enhanced by associated changes in microbial physiology. By translocating soils across a 3000 m elevation gradient in tropical forest, equivalent to a temperature change of ± 15 °C, we found that soil carbon declined over 5 years by 4% in response to each 1 °C increase in temperature. The total loss of carbon was related to its original quantity and lability, and was enhanced by changes in microbial physiology including increased microbial carbon-use-efficiency, shifts in community composition towards microbial taxa associated with warmer temperatures, and increased activity of hydrolytic enzymes. These findings suggest that microbial feedbacks will cause considerable loss of carbon from tropical forest soils in response to predicted climatic warming this century.


Neck circumference as an anthropometric measure of obesity in diabetics.
Obesity is a risk factor for type 2 diabetes mellitus. Insulin resistance is associated with visceral subcutaneous fat content. Neck circumference (NC) is a marker of upper body subcutaneous adipose tissue distribution. The aim of this study is to compare NC in diabetics and non-diabetics and to correlate NC with other anthropometric measures. A cross-sectional study was conducted in 350 type 2 diabetics and 350 non-diabetics of >30 years of age. Anthropometric parameters like body mass index (BMI), waist circumference (WC), hip circumference, and NC were measured. Independent t-test and Pearson's correlation were the tests of significance done to analyze quantitative data. There was positive correlation of NC, BMI, and index of central obesity. The NC in diabetics was significantly higher than in non-diabetics (P < 0.001). NC >36 cm in diabetics and >37 cm in non-diabetics was the best cutoff value to determine subjects with central obesity. The findings indicated that NC may be used both in clinical practice and in epidemiologic studies as a straightforward and reliable index. It is an economical easy to use test with less consumption of time and correlates well with other standard anthropometric parameters.


Effect of the structure of bone morphogenetic protein carriers on ectopic bone regeneration.
To study the effect of the shape of carriers on bone regeneration, two biodegradable polymeric materials, a polyglycolide (PGA) nonwoven fabric and a gelatin hydrogel, were used as carriers of recombinant human bone morphogenetic protein-2 (rhBMP-2). The PGA nonwoven fabric was made from PGA fibers of 20 microm diameter without using any binders while the gelatin hydrogel was prepared by cross-linking of gelatin in aqueous solution with glutaraldehyde to a water content of 95% when swollen with water. Following impregnation of rhBMP-2, the carriers of disk type were implanted into the Wistar rat thigh muscle. The induction of ectopic bone formation from the rhBMP-2-impregnated carriers was evaluated by Softex and histologic observation after staining the explanted tissue with alizarin red S stain to identify calcium deposition. Both of the biodegradable polymeric carriers containing 10 microg of rhBMP-2 induced ectopic bone formation after 2 weeks of implantation but not at the first week after implantation. A remarkable finding was a difference in the macroscopic morphology between the ectopic bones induced by the PGA nonwoven fabric and the gelatin hydrogel. The PGA nonwoven fabric containing rhBMP-2 induced ectopic bone formation inside of the carrier, whereas the gelatin hydrogel formed bone at the periphery of the carrier.


A comparison of flow cytometry and immunohistochemistry in human colorectal cancers.
In human colorectal cancer it has been reported that some tumours lack the HLA-ABC antigens. This has been interpreted as reflecting tumour escape from the immune system. Earlier data have been obtained by immunohistochemistry. In this study, we compared the expression of HLA-ABC, HLA-DR, CD80 (B7-1) and CD54 (ICAM-1) in 20 tumours using both a conventional immunohistochemistry two-layer technique and multiparameter flow cytometry, gating on an epithelial cell marker. Colorectal cancer tissue used in flow cytometry was dissociated with collagenase, deoxyribonuclease and hyaluronidase. The intensity of expression of HLA-ABC, HLA-DR and CD80 was unaffected by the enzymes, but CD54 was decreased by 30%. The reproducibility of flow cytometry was good. Microscopy of sections revealed that about 5% of each tumour sample consisted of normal epithelium, but even after correction for this, flow cytometry was superior to immunohistochemistry in 33 out of 80 cases, and showed that tumours described as HLA-ABC negative by immunohistochemistry were in fact weakly positive for HLA-ABC. We conclude that flow cytometry and immunohistochemistry are complementary, and that flow cytometry is superior to immunohistochemistry for detecting antigens/epitopes present in low amounts.


Assembly and architecture of invertebrate cytoplasmic intermediate filaments reconcile features of vertebrate cytoplasmic and nuclear lamin-type intermediate filaments.
The two major intermediate filament (IF) proteins from the esophagus epithelium of the snail Helix pomatia and the two major IF proteins from muscle tissue of the nematode Ascaris suum were investigated under a variety of assembly conditions. The lowest-order complexes from each of the four protostomic invertebrate (p-INV) IF proteins are parallel, unstaggered dimers involving two-stranded alpha-helical coiled coil formation of their approximately 350 amino acid residue central rod domain (i.e. long-rod). In the electron microscope these are readily recognized by their distinct approximately 56 nm long rod with two globular domains (i.e. representing the non-helical carboxy-terminal tail domain of the p-INV IF proteins) attached at one end, closely resembling vertebrate lamin dimers. The next-higher-order oligomers are tetramers, which are easily recognized by their two pairs of globular tail domains attached at either end of a approximately 72 nm long central rod portion. According to their size and shape, these tetramers are built from two dimers associated laterally in an antiparallel, approximately half-staggered fashion via the amino-terminal halves of their rod domains. This is similar to the NN-type tetramers found as the most abundant oligomer species in all types of vertebrate cytoplasmic IF proteins, which contain a approximately 310 amino acid residue central rod domain (i.e. short-rod). As a first step toward filament formation, the p-INV IF tetramers anneal longitudinally into protofilaments by antiparallel CC-type association of the carboxy-terminal halves of their dimer rods. The next step involves radial growth, occurring initially through lateral association of two four-chain protofilaments into octameric subfibrils, which then further associate into mature, full-width filaments. Head-to-tail polymers of dimers and paracrystalline fibers commonly observed with vertebrate lamins were only rarely seen with p-INV IF proteins. The globular domains residing at the carboxy-terminal end of p-INV IF dimers were studding the surface of the filaments at regular, approximately 24.5 nm intervals, thereby giving them a "beaded" appearance with an axial periodicity of about 24.5 nm, which is approximately 3 nm longer than the corresponding approximately 21.5 nm repeat pattern exhibited by short-rod vertebrate IFs.


Serum periostin in smokers and never smokers with asthma.
Elevated serum periostin is associated with airway eosinophilia and may predict response to therapies targeting Th2 inflammation. Smoking in asthma is generally associated with non-eosinophilic airway inflammation and corticosteroid insensitivity. We determined the effect of smoking status on serum periostin in asthma. Serum periostin (ELISA; Aviscera Bioscience) was measured in 107 patients with stable asthma of different disease severity and 45 healthy controls. The effects on serum periostin of clinical indices including smoking status and of inflammatory biomarkers including sputum eosinophil count were analysed. Serum periostin was measured before and after two weeks of oral corticosteroids in a separate group of 33 non-smokers and smokers with stable asthma. Serum periostin (median [IQR], ng/mL) was reduced in smokers with asthma compared to never smokers with asthma; 9 (9, 307) versus 233 (34, 1108) respectively, p = 0.017. Periostin was not influenced by disease severity (p = 0.786) or atopic status (p = 0.144). There was a weak correlation between serum periostin and sputum eosinophil count in smokers with asthma (r = 0.315, p = 0.020). The proportion of patients with an elevated serum periostin concentration was greater in never smokers with asthma compared to smokers with asthma [65% versus 39% respectively, p = 0.003]. Oral steroid treatment reduced serum periostin (p = 0.030) in non-smokers with asthma. Despite lower median serum periostin concentrations in smokers with asthma compared to never smokers with asthma, approximately forty percent of this group had a high level. The potential value of a raised serum periostin concentration in predicting a beneficial response to therapies targeting Th2 inflammation in smokers with asthma requires to be investigated.


Quantifying exposure of wild bumblebees to mixtures of agrochemicals in agricultural and urban landscapes.
The increased use of pesticides has caused concern over the possible direct association of exposure to combinations of these compounds with bee health problems. There is growing proof that bees are regularly exposed to mixtures of agrochemicals, but most research has been focused on managed bees living in farmland, whereas little is known about exposure of wild bees, both in farmland and urban habitats. To determine exposure of wild bumblebees to pesticides in agricultural and urban environments through the season, specimens of five different species were collected from farms and ornamental urban gardens in three sampling periods. Five neonicotinoid insecticides, thirteen fungicides and a pesticide synergist were analysed in each of the specimens collected. In total, 61% of the 150 individuals tested had detectable levels of at least one of the compounds, with boscalid being the most frequently detected (35%), followed by tebuconazole (27%), spiroxamine (19%), carbendazim (11%), epoxiconazole (8%), imidacloprid (7%), metconazole (7%) and thiamethoxam (6%). Quantifiable concentrations ranged from 0.17 to 54.4 ng/g (bee body weight) for individual pesticides. From all the bees where pesticides were detected, the majority (71%) had more than one compound, with a maximum of seven pesticides detected in one specimen. Concentrations and detection frequencies were higher in bees collected from farmland compared to urban sites, and pesticide concentrations decreased through the season. Overall, our results show that wild bumblebees are exposed to multiple pesticides when foraging in agricultural and urban landscapes. Such mixtures are detected in bee tissues not just during the crop flowering period, but also later in the season. Therefore, contact with these combinations of active compounds might be more prolonged in time and widespread in the environment than previously assumed. These findings may help to direct future research and pesticide regulation strategies to promote the conservation of wild bee populations.


Retrograde Amnesia from Conditioned Competing Responses.
If electroconvulsive shock is given immediately after a learning trial, retrograde amnesia for that response occurs. The usual interpretation of such amnesia states that a neural engram, after a learning trial, requires a certain amount of time to consolidate, and electroconvulsive shock interferes with this consolidation, producing amnesia. Four studies are summarized which indicate that convulsive shock serves as an unconditioned stimulus producing a convulsive response, that takes precedence over other behavior, and part of which becomes conditioned to stimuli in the learning situation. The convulsive response competes with, and replaces, the previous response, resulting in the appearance of amnesia.


[Early and late results and problems of coronary artery bypass grafting in patients over 80-year-old].
This study evaluated the validity of coronary artery bypass grafting (CABG) in patients over 80-year-old investigating the early and late result, patient's opinion to the surgery, and change of activities of daily living scale. From July 1993 to September 2002, consecutive 94 patients over 80-year-old were performed CABG in our institution. The group consisted of 43 female patients, and mean age of 82.6 years. Of these patients, 36 were operated conventional CABG (CABG group) and 58 patients were operated with off-pump CABG (OPCAB) group. There were no significant differences between 2 groups in preoperative characteristics except for anemia and hypertension. Operative results, including mortality, number of distal anastomoses, operative time had no significant differences between 2 groups. But maximum CK-MB fraction was higher in CABG group. There were 4 operative deaths, indicating operative mortality was 4.3%. Late results showed overall survival rate at 3 years was 81.1% and cardiac event free survival rate at 3 years was 88.8%. Questionnaire revealed over 80% patients were satisfied with the surgery but less than 40% patients felt activities of daily living (ADL) scale was improved. Operative results of CABG in octogenarians were satisfied, but more efforts to remain patient's high ADL were mandatory.


Protein secretion in Pseudomonas aeruginosa: the xcpA gene encodes an integral inner membrane protein homologous to Klebsiella pneumoniae secretion function protein PulO.
xcp mutations have pleiotropic effects on the secretion of proteins in Pseudomonas aeruginosa PAO. The nucleotide sequence of a 1.2-kb DNA fragment that complements the xcp-1 mutation has been determined. Sequence analysis shows the xcpA gene product to be a 31.8-kDa polypeptide, with a highly hydrophobic character. This is consistent with a localization in the cytoplasmic membrane in P. aeruginosa, determined after specific expression of the xcpA gene under control of the T7 phi 10 promoter. A very strong homology was found between XcpA and PulO, a membrane protein required for pullulanase secretion in Klebsiella pneumoniae. This suggests the existence of a signal sequence-dependent secretion process common to these two unrelated gram-negative bacteria.


Alcohol-related violence defined by ultimate goals: a qualitative analysis of the features of three different types of violence by intoxicated young male offenders.
Based upon a functional approach to understanding aggression, we aimed to identify the occurrence of and to describe the features of three types of alcohol-related violence defined a priori by ultimate goals: (1) violence in pursuit of nonsocial profit-based goals, (2) violence in pursuit of social dominance goals, and (3) violence as defence in response to threat. A sample of 149 young men with offences of violence that were alcohol related was interviewed. Cases were classified and detailed information from the first ten cases in each class (N=30) was subjected to thematic analysis. Intoxicated violence in pursuit of nonsocial profit-based goals was opportunistic and motivated by the desire for more alcohol or drugs. Violence, in these cases, although serious, appeared to be brief. Intoxicated violence in pursuit of social dominance goals was typically precipitated by past or current insult or injury, and was accompanied by strong anger and an adrenaline rush. Attacks were ferocious, and robbing the victim was not uncommon, perhaps to inflict additional humiliation. Feelings of pride and satisfaction were typical and expressions of remorse were uncommon. Regarding intoxicated violence as defence in response to threat, attacks were often expected, and in some cases the respondent made a pre-emptive strike. Weapon use was common in this group. Fear was experienced, but so too was anger. Feelings of excitement were not reported and remorse was common. Further validation of these types is warranted, and the potential implications of these findings for prevention and treatment are discussed.


Carcinogenesis and lung cancer: 70 years of progress and more to come.
This commentary celebrates the 40th year of Carcinogenesis, spanning 1980-2020 with a focus on lung cancer. For lung cancer, these 40 years come toward the end of a century of scientific inquiry that began with descriptions of this highly fatal malignancy and that closes with emphasis on molecular processes and genomics. This commentary gives a historical perspective of lung cancer research as well as a look into the questions that remain to be addressed. Over the 20th century and into the first two decades of the 21st, a series of issues have more or less sequentially been the focus of epidemiological investigation of lung cancer, as questions have been answered and methodologies have evolved. These questions began with whether an epidemic was occurring and continue now with exploration of causal mechanisms and molecular risk predictors. With tobacco smoking firmly established decades ago as a cause of lung cancer, the evidence has long been sufficient to motivate tobacco prevention and control. There is unfinished business as tobacco smoking remains widespread and the industry continues to market new, addicting, products.


Heterogeneity in intratumor distribution of p53 mutations in human prostate cancer.
Prostatic carcinoma from 65 patients have been examined for the occurrence of point mutations in the p53 tumor suppressor gene locus within the region of exons 5 to 8. Overall, only a small fraction of tumors (12.3%) was found to contain p53 mutations. No significant correlation was detected between the presence of the mutant gene and either tumor volume or histopathological grade. However, metastatic prostatic tumors are found to display a higher percentage (21.4%) of p53 mutations compared with primary adenocarcinomas (9.8%). Analysis of the topographical distribution of the p53 mutant genotype revealed two remarkable findings. First, multifocal tumors within a prostate appear to differ in harboring the mutant gene, and second, evidence is obtained for intratumor heterogeneity in the distribution of the mutant p53 allele. Together these findings appear to explain, at least in part, why there has been a wide discrepancy in the reported detection frequency of p53 mutations in prostate cancer specimens. It appears that the outcome of mutation analysis would depend not only on which tumors but also which regions of the tumors are included in the study. Furthermore, the observed heterogeneous topographical distribution of the mutation, if confirmed to be unique to prostate cancer, may have important implications in the understanding of the biology of prostate carcinogenesis.


Unveiling Medin Folding and Dimerization Dynamics and Conformations via Atomistic Discrete Molecular Dynamics Simulations.
Medin is a principal component of localized amyloid found in the vasculature of individuals over 50 years old. Its amyloid aggregation has been linked to endothelial dysfunction and vascular inflammation, contributing to the pathogenesis of various vascular diseases. Despite its significance, the structures of the medin monomer, oligomer, and fibril remain elusive, and the dynamic processes of medin aggregation are not fully understood. In this study, we comprehensively investigated the medin folding and dimerization dynamics and conformations using atomistic discrete molecular dynamics simulations. Our simulation results suggested that the folding initiation of the medin involved the formation of β-sheets around medin30-41 and medin42-50, with subsequent capping of other segments to their β-sheet edges. Medin monomers typically consisted of three or four β-strands, along with a dynamic N-terminal helix. Two isolated medin peptides readily aggregated into a β-sheet-rich dimer, displaying a strong aggregation propensity. Dimerization of medin not only enhanced the β-sheet conformations but also led to the formation of β-barrel oligomers. The aggregation tendencies of medin1-18 and medin19-29 were relatively weak. However, the segments of medin30-41 and medin42-50 played a crucial role as they primarily formed a β-sheet core and facilitated medin1-18 and medin19-29 to form intra- and interpeptide β-sheets. The findings highlight the critical role of the medin30-41 and medin42-50 regions in stabilizing the monomer structure and driving the medin amyloid aggregation. These regions could potentially serve as promising targets for designing antiamyloid inhibitors against amyloid aggregation of medin. Additionally, our study provides a full picture of the monomer conformations and dimerization dynamics for medin, which will help better understand the pathology of medin aggregation.


Reflecting on motivations: How reasons to publish affect research behaviour in astronomy.
Recent research in the field of reflexive metrics, which analyses the effects of the use of performance indicators on scientific conduct, has studied the emergence and consequences of evaluation gaps in science. The concept of evaluation gaps captures potential discrepancies between what researchers value about their research, in particular research quality, and what metrics measure. In the language of rational choice theory, an evaluation gap persists if motivational factors arising out of the internal component of an actor's situation are incongruent with those arising out of the external components. The aim of this research is therefore to study and compare autonomous and controlled motivations to become an astronomer, to do research in astronomy and to publish scientific papers. This study is based on a comprehensive quantitative survey of academic and non-academic astronomers worldwide with 3509 responses. By employing verified instruments to measure perceived publication pressure, distributive & procedural justice, overcommitment to work and observation of scientific misconduct, this paper also investigates how these different motivational factors affect research output and behaviour. I find evidence for an evaluation gap and that controlled motivational factors arising from evaluation procedures based on publication record drives up publication pressure, which, in turn, was found to increase the likelihood of perceived frequency of misbehaviour.


Intranuclear membranous inclusions in oocytes of a viviparous teleost (Xiphophorus helleri).
Intranuclear inclusions were observed in oocytes of Xiphophorus helleri during prophase I. In osmium-fixed leptotene nuclei, the inclusions were made up of groups of membrane-limited vesicles or tubules with pale contents, situated near the inner nuclear membrane with which some of them exhibited apparent continuities. In zygotene nuclei, larger vesicles also appeared bounded by two or three membranes and containing tubules apparently invaginated from their walls. In pachytene-dictyate nuclei most vesicular bodies had a wall formed by stratified membranes, or were entirely made up of membranous whorls. In glutaraldehyde-osmium fixed material some of these myeline-like bodies showed a peculiar arrangement, consisting of concentric bands each containing thick inner dense lamellae 2-0-3-0 nm thick and a 5-0 nm outer lamella. It is suggested that these inclusion bodies arise from the inner nuclear membrane of oocytes when cells start to grow intensely during prophase I. The bodies seem to become more complex at late prophase, probably by association of individual vesicles and the occurrence of multiple membrane invaginations, which may be related to active metabolic phenomena taking place at this stage in oocytes.


Evaluation of the antimutagenic, antigenotoxic, and antioxidant activities of Eriobotrya japonica leaves.
The leaves of Eriobotrya japonica (Thunb.) Lindl. (Rosaceae) are used in traditional medicine to treat inflammatory diseases. However, information about the antigenotoxic and antioxidant properties of its leaves remains to be elucidated. The objective of this work was to evaluate the mutagenic/antimutagenic, genotoxic/antigenotoxic, and antioxidant potentials of aqueous and total oligomers flavonoid (TOF) extracts from E. japonica. The mutagenic/antimutagenic and genotoxic/antigenotoxic potentials of extracts (50, 250, and 500 µg/plate) were evaluated, respectively, by the Ames test with 48 h incubation and the SOS chromotest test with 2 h incubation. The antioxidant capacity of these extracts (ranging from 50 to 700 µg/mL) was tested using xanthine/xanthine oxidase and the deoxyribose assays. Eriobotrya japonica extracts showed neither mutagenic nor genotoxic effect. The highest protective effect against methyl methanesulfonate and 2-aminoanthracene was obtained in the presence of aqueous extract, with IC50 values of 80 and 140 µg/plate, respectively, against S. typhimurium TA104. Moreover, this extract (500 µg/plate) was also able to reduce significantly the genotoxicity induced by nitrofurantoin and aflatoxin B1 with IC50 values of 140 and 240 µg/assay, respectively. Likewise, aqueous and TOF extracts inhibited xanthine oxidase and superoxide anion formation with IC50 values ranging from 45 to 95 and from 70 to 90 µg/mL, respectively. However, TOF extract is more efficient in inhibiting hydroxyl radical and chelating iron ion with IC50 values of 140 and 400 µg/mL, respectively, when compared with the aqueous extract. Eriobotrya japonica prevents the genotoxicity of some carcinogenic substances probably thanks to its antioxidant capacities.


Activity of Von Willebrand factor and levels of VWF-cleaving protease (ADAMTS13) in preterm and full term neonates.
Von Willebrand Factor (VWF) has a central role in primary hemostasis. Its biological activity is related to the size of VWF multimers, spontaneously binding to platelets and inducing circulating microthrombi formation. This process is down-regulated by the VWF cleaving protease ADAMTS13 (A Disintegrin and Metalloprotease with ThromboSpondin motif). To date, information regarding the levels of ADAMTS13 in neonates and preterm infants is scarce. Our aim was to study ADAMTS13, VWF antigen (Ag) and Ristocetin cofactor (RiCof) activity in neonates and evaluate potential correlations with perinatal complications. Our cohort consisted of 128 (48/128: born preterm) neonates, born in Sheba Medical Center and followed until hospital discharge. Control group consisted of 20 healthy adults. As expected, a significant elevation of VWF:Ag was observed in preterm and term infants compared to adults. VWF:Ag levels were highest in full term infants (Median 129.0 IQR 33.8) and lowest in adults (Median 119.0 IQR 58.5) (p<0.05), and RiCoF levels in neonates were higher than in adults. ADAMTS13 was significantly (p<0.05) higher in preterm babies in comparison to full term and adult controls. Neonates that underwent stressful conditions or experienced vascular complications such as IUGR, ROP, NEC, had lower levels of ADAMTS13 in our study. Further studies are required to validate and asses potential significance of these findings.


Evaluation of new biomarkers of stress in saliva of sheep.
Some routine handling procedures can produce stress in farm animals, and an adequate control of these stressors is important to avoid the negative effects on animal health and production. The measurement of biomarkers in saliva can be a suitable tool for the evaluation and control of stress. In this report, lipase, butyrylcholinesterase (BChE), total esterase (TEA) and adenosine deaminase (ADA) activities in the saliva of sheep were evaluated as biomarkers of stress. For this purpose, they were measured after inducing stress by facing a dog (experiment 1) and shearing (experiment 2), and comparing them to other stress salivary biomarkers such as α-amylase (sAA) and cortisol, as well as heart rate (HR). Each analyte was measured at the basal time, and during and just after the end of the stressful stimulus, and at various times for the first hour after the period of stress induction. Values were compared with those obtained from a control group. Lipase was the only analyte that showed significant changes between the stress and the control group in both experiments. Although TEA and ADA increased after stress, no significant differences were seen compared with the control group. Lipase was correlated highly with sAA and HR, in experiment 1; and correlated moderately with cortisol and HR in experiment 2. Lipase showed the greatest percentage increase after the stressful stimuli and less overlap with the control group in the two experiments. From the results of this study it can be concluded that lipase, TEA, BChE and ADA are enzymes present in the saliva of sheep and that they can be measured by using simple and fast colorimetric methods. Further studies should be undertaken with regard to the possible application of lipase as a biomarker of stress in sheep.


Differences in destruction of cysts of pathogenic and nonpathogenic Naegleria and Acanthamoeba by chlorine.
The destructive action of chlorine on the pathogenic Naegleria fowleri and Acanthamoeba culbertsoni, the nonpathogenic N. gruberi, and an avirulent Acanthamoeba isolate was investigated. N fowleri is somewhat more sensitive to chlorine than N. gruberi, whereas the two Acanthamoeba strains are very resistant. This study yields information needed for the destruction of amoebic cysts in drinking water and swimming pools. It also gives some explanation for the occurence of Acanthamoeba strains in these waters.


Environmental enrichment restores memory functioning in mice with impaired IL-1 signaling via reinstatement of long-term potentiation and spine size enlargement.
Environmental enrichment (EE) was found to facilitate memory functioning and neural plasticity in normal and neurologically impaired animals. However, the ability of this manipulation to rescue memory and its biological substrate in animals with specific genetically based deficits in these functions has not been extensively studied. In the present study, we investigated the effects of EE in two mouse models of impaired memory functioning and plasticity. Previous research demonstrated that mice with a deletion of the receptor for the cytokine interleukin-1 (IL-1rKO), and mice with CNS-specific transgenic over-expression of the IL-1 receptor antagonist (IL-1raTG) display impaired hippocampal memory and long-term potentiation (LTP). We report here a corrective effect of EE on spatial and contextual memory in IL-1rKO and IL-1raTG mice and reveal two mechanisms for this beneficial effect: Concomitantly with their disturbed memory functioning, LTP in IL-1rKO mice that were raised in a regular environment is impaired, and their dendritic spine size is reduced. Both of these impairments were corrected by environmental enrichment. No deficiencies in neurogenesis or hippocampal BDNF and vascular endothelial growth factor secretion were found in IL-1rKO mice that were raised in a regular environment, and both of these variables were increased to a similar degree in enriched IL-1rKO and wild-type mice. These findings suggest that exposure to an enriched environment may be beneficial for individuals with impaired learning and memory related to genetic impairments of IL-1 signaling (and possibly other genetic causes), by reversing impairments in dentate gyrus LTP and spine size and by promoting neurogenesis and trophic factors secretion.


Cross-Cultural Perspectives on Self-Change in Close Relationships: Evidence From Hong Kong Chinese and European Americans.
Three studies examined cultural perceptions of self-change in romantic relationships. In Study 1 (N = 191), Chinese participants perceived hypothetical couples who changed for the sake of the relationship to have better relationship quality than couples who did not, compared to European American participants. In Study 2 (N = 396), Chinese individuals in a dating relationship were more likely to perceive that they had changed in the relationship, and self-change was a stronger predictor of relationship quality for them than for American dating individuals. In Study 3 (N = 115 dyads), Chinese married couples perceived greater self-change, and their perceived self-change was due in part to higher endorsement of dutiful adjustment beliefs than American couples. Self-change was a stronger predictor of relationship quality for Chinese married couples than American couples. Our studies provide support for cultural differences in the role of self-change in romantic relationships, which have implications for partner regulation and relationship counseling across cultures.


Triamidetriamine bearing macrobicyclic and macrotricyclic ligands: potential applications in the development of copper-64 radiopharmaceuticals.
A versatile and straightforward synthetic approach is described for the preparation of triamide bearing analogues of sarcophagine hexaazamacrobicyclic cage ligands without the need for a templating metal ion. Reaction of 1,1,1-tris(aminoethyl)ethane (tame) with 3 equiv of 2-chloroacetyl chloride, yields the tris(α-chloroamide) synthetic intermediate 6, which when treated with either 1,1,1-tris(aminoethyl)ethane or 1,4,7-triazacyclononane furnished two novel triamidetriamine cryptand ligands (7 and 8 respectively). The Co(III) and Cu(II) complexes of cryptand 7 were prepared; however, cryptand 8 could not be metalated. The cryptands and the Co(III) complex 9 have been characterized by elemental analysis, (1)H and (13)C NMR spectroscopy, and X-ray crystallography. These studies confirm that the Co(III) complex 9 adopts an octahedral geometry with three facial deprotonated amido-donors and three facial amine donor groups. The Cu(II) complex 10 was characterized by elemental analysis, single crystal X-ray crystallography, cyclic voltammetry, and UV-visible absorption spectroscopy. In contrast to the Co(III) complex (9), the Cu(II) center adopts a square planar coordination geometry, with two amine and two deprotonated amido donor groups. Compound 10 exhibited a quasi-reversible, one-electron oxidation, which is assigned to the Cu(2+/3+) redox couple. These cryptands represent interesting ligands for radiopharmaceutical applications, and 7 has been labeled with (64)Cu to give (64)Cu-10. This complex showed good stability when subjected to L-cysteine challenge whereas low levels of decomplexation were evident in the presence of L-histidine.


Health professional perceptions of communicating with adolescents and young adults about bone cancer clinical trial participation.
Low recruitment of adolescents and young adults in cancer clinical trials is widely reported and may be linked to limited improvements in survival. Research to date does not adequately explain all underlying reasons for poor trial accrual. This paper reports health professional perceptions of communicating with adolescents and young adults with bone sarcoma about clinical trial participation. This study used narrative inquiry. Findings are reported from thematic analysis of in-depth interviews with 18 multidisciplinary health professionals working in a supra-regional bone and soft tissue sarcoma centre. Participants described professional expertise, the development of specialist knowledge and skills and strategies used to develop trusting relationships with adolescents and young adults with bone sarcoma. These factors were perceived to facilitate communication about clinical trial participation. Emergent themes were having credibility through expertise of the team, developing specialist communication skills through reflection on practice, having inclusive approaches to education and training about clinical trials, individual communication styles used to form trusting relationships, using a patient-centred approach to connect with adolescents and young adults, creating time needed to form trusting relationships and effective team working. We aligned findings of this study with characteristics of patient-physician trust and provide a basis for transferable recommendations. Our findings can be used to inform the development of age-specific, specialist communication skills and highlight health professional education needs about clinical trials. Additional research is needed to explore which elements of team working optimise improved clinical trial participation, in what contexts and why.


[Regulation of liver cysteine proteinases during macrophagal stimulation and depression].
The lysosomal pathway of intracellular protein degradation involves the cooperative action of proteinases, among which cysteine proteinases cathepsin B and cathepsin L are particularly important. The hypothesis that the abnormal ratio of proteinases/proteinase inhibitors (i.e. higher activities of proteinases and lower activities of their inhibitors) results in uncontrolled proteolysis and cellular dysfunctions has been experimentally tested. Cathepsin B was used as a marker of macrophagal lysosomes and cathepsin L was employed as a marker of hepatocytic lysosomes. Zymosan stimulation of macrophages was shown to induce increased secretion of macrophagal lysosomal enzymes into blood during early zymosan administration, followed by higher rates of phagocytosis and labilization of lysosomes both of macrophages and hepatocytes labilization. Macrophagal depression induced by gadolinium chloride in rats was also accompanied by increased secretion of acid hydrolases into blood and labilization of macrophageal lysosomes, which reflects the lysosomotropic properties of the agent. Gadolinium chloride prevented zymosan stimulation of macrophages in the liver, but not in the spleen and lung. A new approach is proposed to evaluate the functional activity of hepatocytic lysosomes by the marker lysosomal enzymes of macrophages (cathepsin B) and hepatocytes (cathepsin L). Possible modes of regulation of endogenous proteinases are considered with special emphasis on the protective function of endogenous proteinase inhibitors secreted by macrophages simultaneously with cathepsin B and other cysteine proteinases.


Fluorescence properties of Neurospora tyrosinase.
Some structural properties of Neurospora tyrosinase have been studied by fluorescence spectroscopy. The emission spectra observed for oxy-, deoxy-, met- and apo-tyrosinase and the Co2+-substituted form are indicative of a protein containing buried tryptophan residues. By using acrylamide and iodide, part of the emission is quenched, indicating heterogeneity in the tryptophan environment. Upon binding of Cu2+ or Co2+ to apo-tyrosinase, a marked decrease of the tryptophan quantum yield is observed. A further decrease in emission intensity results from the binding of molecular O2 to the deoxy form. The fluorescent probe 8-anilinonaphthalene-1-sulphonate binds to tyrosinase only when the metal ions are removed. Reconstitution of apo-tyrosinase with Cu2+ completely displaces the probe, suggesting that 8-anilinonaphthalene-1-sulphonate binds to apo-tyrosinase at the active site. The fluorescence properties of Neurospora tyrosinase are compared with those of haemocyanin.


Heterologous expression and coupling of G protein-gated inwardly rectifying K+ channels in adult rat sympathetic neurons.
1. G protein-gated inwardly rectifying K+ (GIRK) channels were heterologously expressed in rat superior cervical ganglion (SCG) neurons by intranuclear microinjection. The properties of GIRK channels and their coupling to native receptors were characterized using the whole-cell patch-clamp technique. 2. Following coinjection of either GIRK1-2 or GIRK1-4 cDNA, application of noradrenaline (NA) produced large inwardly rectifying K+ currents. Injection of cDNA encoding individual GIRK subunits produced only small and inconsistent NA-activated inward currents. Current arising from the native expression of GIRK channels in SCG neurons was not observed. 3. NA-mediated activation of GIRK channels was abolished by pertussis toxin (PTX) pretreatment, indicating coupling via G proteins of the Gi/Go subfamily. Conversely, vasoactive intestinal peptide (VIP) activated GIRK channel currents via a cholera toxin-sensitive pathway suggesting coupling through Galphas. Pretreatment of neurons with PTX caused a significant increase in amplitude of the VIP-mediated GIRK channel currents when compared with untreated cells. 4. Application of adenosine, prostaglandin E2 and somatostatin resulted in activation of GIRK channel currents. Activation of m1 muscarinic acetylcholine receptors (i.e. application of oxotremorine M to PTX-treated neurons) failed to elicit overt GIRK channel currents. 5. GIRK channel overexpression decreased basal Ca2+ channel facilitation significantly when compared with uninjected neurons. Furthermore, the NA-mediated inhibition of Ca2+ channels was significantly attenuated. 6. In summary, the ability to heterologously express GIRK channels in adult sympathetic neurons allows the experimental alteration of receptor-G protein-effector stoichiometry. Such studies may increase our understanding of the mechanisms underlying ion channel modulation by G proteins in a neuronal environment.


Somatic mutations in cerebral cortical malformations.
Although there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the optimal techniques to detect somatic mosaicism have not been systematically evaluated. Using a customized panel of known and candidate genes associated with brain malformations, we applied targeted high-coverage sequencing (depth, ≥200×) to leukocyte-derived DNA samples from 158 persons with brain malformations, including the double-cortex syndrome (subcortical band heterotopia, 30 persons), polymicrogyria with megalencephaly (20), periventricular nodular heterotopia (61), and pachygyria (47). We validated candidate mutations with the use of Sanger sequencing and, for variants present at unequal read depths, subcloning followed by colony sequencing. Validated, causal mutations were found in 27 persons (17%; range, 10 to 30% for each phenotype). Mutations were somatic in 8 of the 27 (30%), predominantly in persons with the double-cortex syndrome (in whom we found mutations in DCX and LIS1), persons with periventricular nodular heterotopia (FLNA), and persons with pachygyria (TUBB2B). Of the somatic mutations we detected, 5 (63%) were undetectable with the use of traditional Sanger sequencing but were validated through subcloning and subsequent sequencing of the subcloned DNA. We found potentially causal mutations in the candidate genes DYNC1H1, KIF5C, and other kinesin genes in persons with pachygyria. Targeted sequencing was found to be useful for detecting somatic mutations in patients with brain malformations. High-coverage sequencing panels provide an important complement to whole-exome and whole-genome sequencing in the evaluation of somatic mutations in neuropsychiatric disease. (Funded by the National Institute of Neurological Disorders and Stroke and others.).


Maturity assessment and maturity models in health care: A multivocal literature review.
The maturity of practices and infrastructure in the health care domain directly impacts the quality and efficiency of health care services. Therefore, various health care administrations (e.g. from hospital management to the nationwide health authority) need to assess and improve their operational maturity. This study aimed to review and classify studies that propose/use maturity assessment or maturity models (MMs) as a vehicle to achieve operational excellence in the health care domain. To achieve this objective, we performed a multivocal literature review (MLR) - a form of systematic review that includes data from the grey literature (e.g. white papers and online documents) in addition to formal, peer-reviewed literature. Based on 101 sources, 80 from peer-reviewed literature and 21 from the grey literature, we identified 68 different MMs on, for example, telemedicine, care pathways and digital imaging. We reviewed them with respect to various aspects, including types of research and contribution, list of MMs proposed/used with their subject areas, elements of maturity/capability and application scope or scale. In the synthesis of empirical benefits of using MMs, two were found to be significant: (a) identifying issues and providing guidance for improvement in health care contexts, and (b) improving efficiency, effectiveness, performance and productivity. This MLR provides an overview of the landscape and serves as an index to the vast body of knowledge in this area. Our review creates an opportunity to cope with the challenges in obtaining an overview of the state-of-the-art and practice, choosing the most suitable models or developing new models with further specialties.


Biology of neuroblastomas in Japan found by screening.
Between June 1983 and December 1990, cytogenetic analysis was performed on 82 neuroblastoma patients, including 41 patients found by mass screening. The N-myc copy number was determined in 77 of the 82 patients. Patients were classified into three groups: patients found by mass screening (group A) (n = 41), patients found clinically who were under 12 months of age (group B) (n = 12), and patients found clinically who were over 12 months of age (group C) (n = 29). All patients in group A had hyperdiploid (H-2n) or near-triploid (3n) karyotypes; they were all completely free of tumor for 4-84 months after diagnosis, although one patient relapsed and attained complete remission again. Among those in group B, one patient with a stage 4 tumor had a near-diploid Karyotype (2n) and N-myc amplification, and died 18 months after diagnosis. Another patient aged 2 days with a stage 4S tumor had near-diploid karyotype and N-myc amplification, and died 9 months after diagnosis. Tumors in the remaining 18 patients in group B had hyperdiploid or near-triploid karyotypes, they lacked N-myc amplification, and the patients were free of tumor for 12-89 months after diagnosis. All patients in group C except two have near-diploid or hypotetraploid karyotypes, and 21 of 29 patients died within 18 months. One 13-month-old patient (classified in stage 2) and another 7-year-old patient (stage 2) had near-triploid karyotypes and were alive at 74 and 72 months, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


[Production of immobilized SalI and PvuII restrictase preparations].
Conditions for the immobilization of specific endonucleases Sal I and Pvu II on BrCN-activated Sepharose 4B have been selected. Some physico-chemical properties of the preparations of immobilized restrictases Sal I and Pvu II have been characterized. The specific and general activity values of the preparations thus obtained have been established. The immobilized enzymes have been used for the multiple restriction of the DNA of phage lambda and the DNA of Neisseria meningitidis.


Factors associated with osteonecrosis of the jaw among bisphosphonate users.
Bisphosphonates are medications that impact bone reformation by inhibiting osteoclast function. Osteonecrosis of the jaw has been reported among patients receiving these medications. It is unclear if the risk factors associated with osteonecrosis of the jaw among cancer patients taking bisphosphonates also are possible risk factors among patients receiving these medications for other indications. A systematic review search strategy was used to identify cases of osteonecrosis of the jaw among patients taking bisphosphonates for an indication other than cancer to identify potential contributing factors. Data were analyzed according to previous models to develop a more expanded model that may explain possible mechanisms for the development of osteonecrosis of the jaw among patients without cancer. Ninety-nine cases of osteonecrosis of the jaw were identified among patients who were prescribed a bisphosphonate for an indication other than cancer. These cases included 85 osteoporosis patients, 10 patients with Paget's disease, 2 patients with rheumatoid arthritis, 1 patient with diabetes, and 1 patient with maxillary fibrous dysplasia. The mean age was 69.4 years, 87.3% were female, and 83.3% were receiving oral, but not intravenous, bisphosphonates. Of the 63 patients reporting dental care information, 88.9% had a dental procedure before the onset of osteonecrosis of the jaw. Of all cases providing medical information, 71% were taking at least one medication that affects bone turnover in addition to the bisphosphonate, and 81.3% reported additional underlying health conditions. The case details suggest a multiplicity of factors associated with this condition and provide the foundation for a model outlining the potential mechanism for the development of osteonecrosis of the jaw among patients taking bisphosphonates for an indication other than cancer.


Human homeostasis in high-latitude environment.
Profound changes occur in human metabolism in high-latitude environments under the action of climatic, industrial, and social factors. These changes involve protein, fat, carbohydrate, vitamin, and macro and microelement metabolism. This allowed us to state that "a polar metabolic type" is formed in the Arctic and Antarctic regions. The most pronounced alterations are found in energy metabolism. They can be characterized as "the change-over from carbohydrate-type metabolism to the lipid one." Metabolic changes are reflected in the chemical composition of internal medium (blood) of the human organism and its homeostasis. However, homeostasis in high-latitude environments depends not only on natural, but also on various conditioning factors, in particular, prolonged emotional stress and inactual nutritional pattern. These two factors exert a pronounced effect on adaptive changes in human metabolism and its homeostasis. Both factors often act concurrently and result in sustained and persistent changes of homeostasis, which lead directly to obesity and development of endocrine and cardiovascular pathology. This is observed not only for newcomers, but also for the indigenous population of the Asian North.


Assessment of uvulopalatopharyngoplasty for the treatment of sleep apnea syndrome.
Uvulopalatopharyngoplasty (UPPP) consists in the surgical removal of the uvula, part of the muscular portion of the soft palate and redundant palatal and pillar mucosa, and the tonsils. Since 1981, UPPP has been proposed for the treatment of sleep apnea syndrome. Polysomnographic studies have shown that in about half of the patients submitted to UPPP there is a 50% or greater reduction in apnea index. Attempts to identify presurgically those patients more likely to benefit from UPPP have yielded inconsistent results. Limited retrospective follow-up data suggest that UPPP does not modify the increased mortality associated with moderate and severe sleep apnea syndrome. Patients submitted to UPPP report subjective improvement, irrespective of the objective polysomnographic postsurgical results. It is suggested that polysomnographic evaluation of UPPP results should be mandatory; that any patient with 20 or more apnea/hypopneas per hour of sleep or sleep fragmentation after UPPP should be considered a treatment failure and be offered alternative therapy; and that UPPP should be performed only as part of prospective clinical trials including long-term follow-up.


Association of Sleep Characteristics With Nocturnal Hypertension and Nondipping Blood Pressure in the CARDIA Study.
Background Sleep characteristics and disorders are associated with higher blood pressure (BP) when measured in the clinic setting. Methods and Results We tested whether self-reported sleep characteristics and likelihood of obstructive sleep apnea (OSA) were associated with nocturnal hypertension and nondipping systolic BP (SBP) among participants in the CARDIA (Coronary Artery Risk Development in Young Adults) study who completed 24-hour ambulatory BP monitoring during the year 30 examination. Likelihood of OSA was determined using the STOP-Bang questionnaire. Global sleep quality, habitual sleep duration, sleep efficiency, and midsleep time were obtained from the Pittsburgh Sleep Quality Index. Nocturnal hypertension was defined as mean asleep SBP ≥120 mm Hg or diastolic BP ≥70 mm Hg. Nondipping SBP was defined as a decline in awake-to-asleep SBP <10%. Among 702 participants, the prevalence of nocturnal hypertension and nondipping SBP was 41.3% and 32.5%, respectively. After multivariable adjustment including cardiovascular risk factors, the prevalence ratios (PRs) for nocturnal hypertension and nondipping SBP associated with high versus low likelihood of OSA were 1.32 (95% CI, 1.00-1.75) and 1.31 (95% CI, 1.02-1.68), respectively. The association between likelihood of OSA and nocturnal hypertension was stronger for white participants (PR: 2.09; 95% CI, 1.23-3.48) compared with black participants (PR: 1.11; 95% CI, 0.79-1.56). The PR for nondipping SBP associated with a 1-hour later midsleep time was 0.92 (95% CI, 0.85-0.99). Global sleep quality, habitual sleep duration, and sleep efficiency were not associated with either nocturnal hypertension or nondipping SBP. Conclusions These findings suggest that addressing OSA risk and sleep timing in a clinical trial may improve BP during sleep.


Amelioration of Ochratoxin A-induced immunotoxic effects by silymarin and Vitamin E in White Leghorn cockerels.
Silymarin (SL) is the bioactive extract of the plant Silybum marianum and Vitamin E (VE) is an important anti-oxidant. The present study was designed to evaluate potential ameliorative effects of SL and VE against Ochratoxin A (OTA)-induced immunotoxic effects in White Leghorn cockerels. One day-old birds were divided into 12 groups (20 birds/group) and fed basal diets amended with OTA (1.0 or 2.0 mg/kg) alone or in combination with SL (10 g/kg) and/or VE (200 mg/kg) for 42 days. Immunological in situ responses, including antibody formation against sheep red blood cells (7 and 14 days after both primary and booster injections), lymphoproliferative responses to avian tuberculin (30 days of age), and mononuclear phagocytic system function (i.e. by clearance of injected carbon particles) assay (42 days of age), were assessed. Results suggested that silymarin and Vitamin E alone or in combination ameliorated the immunotoxic effects induced by 1.0 mg OTA/kg but could not significantly impact on the effect from ingestion of 2.0 mg OTA/kg. The results of the present study suggested that both SL and VE possess an ability to ameliorate OTA-induced immunotoxicity in chicks. However, it remains to be determined whether/what SL:OTA or VE:OTA ratios are required to assure such mitigation of OTA-induced immunotoxicities.


Painful intraorbital meningiomas.
Three cases are reported of meningioma involving the orbital apex presenting with either progressive or episodic retroocular pain. In two cases pain was steroid responsive and in one of these patients this led to an initial diagnosis of orbital pseudotumour. Pain preceded visual loss and other symptoms by many months and these cases illustrate the importance of full investigation and where necessary surgical exploration in cases of apparent orbital inflammatory disease with an atypical or progressive course.


Hydrochlorothiazide use is strongly associated with risk of lip cancer.
The diuretic hydrochlorothiazide is amongst the most frequently prescribed drugs in the United States and Western Europe, but there is suggestive evidence that hydrochlorothiazide use increases the risk of lip cancer. To study the association between use of hydrochlorothiazide and squamous cell carcinoma of the lip. We conducted a case-control study using Danish nationwide registry data. From the Cancer Registry (2004-2012), we identified 633 case patients with squamous cell carcinoma (SCC) of the lip and matched them to 63 067 population controls using a risk-set sampling strategy. Hydrochlorothiazide use (1995-2012) was obtained from the Prescription Registry and defined according to cumulative use. Applying conditional logistic regression, we calculated odds ratios (ORs) for SCC lip cancer associated with hydrochlorothiazide use, adjusting for predefined potential confounders obtained from demographic, prescription and patient registries. Ever-use of hydrochlorothiazide was associated with an adjusted OR for SCC lip cancer of 2.1 (95% confidence interval (CI): 1.7-2.6), increasing to 3.9 (95%CI: 3.0-4.9) for high use (≥25 000 mg). There was a clear dose-response effect (P < 0.001), with the highest cumulative dose category of hydrochlorothiazide (≥100 000 mg) presenting an OR of 7.7 (95%CI: 5.7-10.5). No association with lip cancer was seen with use of other diuretics or nondiuretic antihypertensives. Assuming causality, we estimated that 11% of the SCC lip cancer cases could be attributed to hydrochlorothiazide use. Hydrochlorothiazide use is strongly associated with an increased risk of lip cancer.


A Case Report of Disseminated Canine Histiocytic Sarcoma in Trinidad and Tobago.
Ocular histiocytic sarcomas (as a presenting part of disseminated histiocytic sarcoma) are not commonly diagnosed. A 10-year-old female intact Rottweiler presented to the School of Veterinary Medicine, Trinidad with buphthalmia and pain in the left eye. The cornea of the left eye appeared diffusely opaque with a conjunctival mucopurulent ocular discharge. A thorough ophthalmic assessment identified an intraocular proliferative tumor to which a unilateral enucleation was performed, however the animal died soon after. Post mortem examination and light microscopy revealed that the intraocular lesion with visceral macro-metastases was in fact a histiocytic sarcoma. Further to this, immune-phenotyping was performed to confirm the diagnosis of disseminated histiocytic sarcoma. This is the first time such a tumor has been diagnosed in Trinidad and Tobago.


THE FORMATION OF MILK SUGAR : THE IN VITRO SYNTHESIS OF LACTOSE BY ACTIVE MAMMARY GLAND PREPARATIONS.
1. The mammary glands of rats in the height of lactation were frozen in situ, removed, and dried in the vacuum in the frozen state. 2. The dried gland, added to pig serum, pig serum plus glucose, pig serum plus galactose, and pig serum plus lactose, then incubated at 37.5 degrees C., yielded a synthesis of non-fermentable, reducing material. 3. The dried gland added to glucose solution alone and incubated at 37.5 degrees C. yielded a synthesis of a non-fermentable reducing disaccharide, having a reaction velocity of reduction resembling that of pure lactose. 4. There is a "short time" storage of some forms of lactose precursor in the active mammary gland. This precursor is non-reducing but becomes available and reducing when the gland is placed in a solution containing glucose.


[Nova-T and Copper-T in a 5 years' comparison].
A multi-centre randomized comparative study for five years was conducted on the efficacy of the Nova-T and the copper-T-200 intra-uterine contraceptive devices. A total of 1865 insertions during the last days of menstruation or a few days following menstruation or immediately following a therapeutic abortion (in 322 women) was performed. The cumulative total Pearl-Index during the five years of the study was 0.8 for the Nova-T and 2.0 for the copper-T-200. The pregnancy rate for the Nova-T was lower than for the copper-T-200 in each country, each age group and each parity group. The copper-T was expelled most frequently in the youngest age group and most rarely in the oldest age group. Evaluated by the expulsion rate, the retention of the Nova-T was not influenced by age and much less influenced by parity than the retention of the copper-T. Because of the small diameter of the insertion tube, there were no problems with the insertion of the Nova-T. The removal of the Nova-T was easy and uncomplicated. In our study, the fertility returned unencumbered irrespective of a wearing time of the device for more or less than two years. The results show, that the Nova-T is an excellent device for intra-uterine contraception.


Temperature-sensitive mutants of vaccinia virus. I. Isolation and preliminary characterization.
Fifty-seven temperature-sensitive (ts) mutants of a neurotropic variant of vaccinia virus were obtained. A comparison of the effectiveness of 6 different mutagens showed that in in vivo experiments nitrosomethylurea induced 10%, nitrosoguanidine 8%, and bromodeoxyuridine 2.5% ts mutants. In vitro, at the same degree of inactivation, UV irradiation, hydroxylamine and nitrous acid induced 2.5% ts mutants. Out of 49 mutants studied, 27 had a DNA+ phenotype, 19 a DNA+/-and 3 a DNA- phenotype. Under permissive conditions, two thirds of all the mutants tested formed thermolabile virions. In experiments on genetic recombination, the recombination frequency between different pairs was from 2.8 to 57%. Seven of the mutants were plotted on the virus genetic map in a certain sequence.


Determination of Nurses' Knowledge Levels on Skin Tears: A Cross-sectional Study.
To determine nurses' knowledge level about skin tears (STs). This cross-sectional study included 346 nurses working in acute care hospitals in Turkey who completed web- or paper-based surveys in September and October 2021. Researchers used the Skin Tear Knowledge Assessment Instrument, which consists of 20 questions across six domains, to assess nurses' level of ST knowledge. The mean age of the nurses was 33.67 (SD, 8.88) years, 80.6% were women, and 73.7% had an undergraduate degree. Nurses' mean number of correct answers on the Skin Tear Knowledge Assessment Instrument was 9.33 (SD, 2.83) of 20 (46.66% [SD, 14.14%]). The mean numbers of correct answers by domain were as follows: etiology, 1.34 (SD, 0.84) of 3; classification and observation, 2.21 (SD, 1.00) of 4; risk assessment, 1.01 (SD, 0.68) of 2; prevention, 2.68 (SD, 1.23) of 6; treatment, 1.66 (SD, 1.05) of 4; and specific patient groups, 0.74 (SD, 0.44) of 1. Significant associations were found among the nurses' ST knowledge scores and whether they had graduated from a nursing program (P = .005), their working years (P = .002), their working unit (P < .001), and whether they provided care to patients with STs (P = .027). Nurses' level of knowledge of the etiology, classification, risk assessment, prevention, and treatment of STs was low. The authors recommend including more information about STs in basic nursing education, in-service training, and certificate programs to increase nurses' ST knowledge.


Performance heuristics for GR(1) synthesis and related algorithms.
Reactive synthesis for the GR(1) fragment of LTL has been implemented and studied in many works. In this work we present and evaluate a list of heuristics to potentially reduce running times for GR(1) synthesis and related algorithms. The list includes several heuristics for controlled predecessor computation and BDDs, early detection of fixed-points and unrealizability, fixed-point recycling, and several heuristics for unrealizable core computations. We have implemented the heuristics and integrated them in our synthesis environment Spectra Tools, a set of tools for writing specifications and running synthesis and related analyses. We evaluate the presented heuristics on SYNTECH15, a total of 78 specifications of 6 autonomous Lego robots, on SYNTECH17, a total of 149 specifications of 5 autonomous Lego robots, all written by 3rd year undergraduate computer science students in two project classes we have taught, as well as on benchmarks from the literature. The evaluation investigates not only the potential of the suggested heuristics to improve computation times, but also the difference between existing benchmarks and the robot's specifications in terms of the effectiveness of the heuristics. Our evaluation shows positive results for the application of all the heuristics together, which get more significant for specifications with slower original running times. It also shows differences in effectiveness when applied to different sets of specifications. Furthermore, a comparison between Spectra, with all the presented heuristics, and two existing tools, RATSY and Slugs, over two well-known benchmarks, shows that Spectra outperforms both on most of the specifications; the larger the specification, the faster Spectra becomes relative to the two other tools.


Increased production of 4 kDa amyloid beta peptide in serum deprived human primary neuron cultures: possible involvement of apoptosis.
The etiology of the amyloid beta peptide in sporadic Alzheimer's disease (AD) is not known. Amyloid beta peptide (A beta), a proteolytic product of the amyloid precursor protein (APP), is deposited in the senile plaques and cerebrovascular tissues of individuals with either sporadic or familial AD (FAD). Increased A beta production from mutant APPs in FAD fosters the hypothesis that overexpression of A beta plays a primary role in the pathogenesis of AD. The absence of APP mutations in sporadic AD which displays identical pathological features than FAD such as synapse and neuronal loss, senile plaques and neurofibrillary tangles, suggests other causes for overexpression and/or deposition of A beta. To investigate the effect of neuronal death on APP metabolism and A beta secretion, human primary neuron cultures were induced to undergo apoptosis by serum deprivation. Serum deprived neurons display shrunken and rounded morphology, contain condensed chromatine and fragmented DNA, which are characteristic of apoptosis. In serum deprived neurons, metabolism of APP through the nonamyloidogenic secretory pathway is decreased to 20% from 40% in control cultures whereas 4kDa A beta is increased three- to fourfold. The results suggest that human neurons undergoing apoptosis generate excess A beta and indicates a possible mechanism for increased A beta in the absence of APP mutations.


Performance of QuantiFERON-TB Gold Plus for detection of latent tuberculosis infection in pregnant women living in a tuberculosis- and HIV-endemic setting.
We evaluated the performance of QuantiFERON-TB Gold Plus (QFT-Plus), which includes two Mycobacterium tuberculosis antigen formulations (TB1 and TB2), for detection of latent tuberculosis infection during pregnancy. Eight-hundred-twenty-nine Ethiopian pregnant women (5.9% HIV-positive) were tested with QFT-Plus, with bacteriological sputum analysis performed for women with clinically suspected tuberculosis and HIV-positive women irrespective of clinical presentation. QFT-Plus read-out was categorized according to the conventional cut-off (0.35 IU/ml) for both antigen formulations. In addition, we analysed the distribution of QFT-Plus results within a borderline zone (0.20-0.70 IU/ml), and interferon-γ response in relation to HIV infection and gestational age. Two-hundred-seventy-seven women (33%) were QFT-Plus-positive (HIV-positive 16/49 [33%]; HIV-negative 261/780 [33%]). There was a strong agreement between the two antigen formulations (κ = 0.92), with discordant results in 29 cases (3.5%). Whereas discordant QFT-Plus results were rare in pregnancy, several results with both TB1 and TB2 within the borderline range were observed (11/49 [22%] vs. 43/780 [5.5%] in HIV-positive and HIV-negative women, respectively; p<0.0001). HIV-positive women had lower absolute interferon-γ levels (TB1: 0.47 vs. 2.16 IU/ml; p<0.001, TB2: 0.49 vs. 2.24 IU/ml, p<0.001, considering results ≥0.20 IU/ml) compared to HIV-negative women. QFT-Plus-positive women who submitted samples at later stages of pregnancy had lower mitogen- (p<0.001) but higher TB-antigen-specific (p = 0.031 for TB1, p = 0.061 for TB2) interferon-γ response. Considering their lower capacity to produce TB-specific interferon-γ, a lower cut-off level for defining QFT-Plus-positivity may be considered in HIV-positive pregnant women.


Benefit of adjuvant chemotherapy after resection of stage II (T1-2N1M0) non-small cell lung cancer in elderly patients.
We evaluated the use and efficacy of adjuvant chemotherapy after resection of T1-2N1M0 non-small cell lung cancer (NSCLC) in elderly patients. Factors associated with the use of adjuvant chemotherapy in patients older than 65 years of age who underwent surgical resection of T1-2N1M0 NSCLC without induction chemotherapy or radiation in the Surveillance, Epidemiology, and End Results-Medicare database from 1992 to 2006 were assessed using a multivariable logistic regression model that included treatment, patient, tumor, and census tract characteristics. Overall survival (OS) was analyzed using the Kaplan-Meier approach and inverse probability weight-adjusted Cox proportional hazard models. Overall, 2,781 patients who underwent surgical resection as the initial treatment for T1-2N1M0 NSCLC and survived at least 31 days after surgery were identified, with adjuvant chemotherapy given to 784 patients (28.2 %). Factors that predicted adjuvant chemotherapy use were younger age and higher T status. The 5-year OS was significantly better for patients who received adjuvant chemotherapy compared with patients not given adjuvant chemotherapy: 35.8 % (95 % confidence interval [CI] 31.9-39.6) vs. 28.0 % (95 % CI 25.9-30.0) (p = 0.008). In the inverse probability weight-adjusted Cox proportional hazard regression model, adjuvant chemotherapy use predicted significantly improved survival (hazard ratio 0.84; 95 % CI 0.76-0.92; p = 0.0002). Adjuvant chemotherapy after resection of T1-2N1M0 NSCLC is associated with significantly improved survival in patients older than 65 years. These data can be used to provide elderly patients with realistic expectations of the potential benefits when considering adjuvant chemotherapy in this setting.


Phytoestrogens and Mycoestrogens Induce Signature Structure Dynamics Changes on Estrogen Receptor α.
Endocrine disrupters include a broad spectrum of chemicals such as industrial chemicals, natural estrogens and androgens, synthetic estrogens and androgens. Phytoestrogens are widely present in diet and food supplements; mycoestrogens are frequently found in grains. As human beings and animals are commonly exposed to phytoestrogens and mycoestrogens in diet and environment, it is important to understand the potential beneficial or hazardous effects of estrogenic compounds. Many bioassays have been established to study the binding of estrogenic compounds with estrogen receptor (ER) and provided rich data in the literature. However, limited assays can offer structure information with regard to the ligand/ER complex. Our current study surveys the global structure dynamics changes for ERα ligand binding domain (LBD) when phytoestrogens and mycoestrogens bind. The assay is based on the structure dynamics information probed by hydrogen deuterium exchange mass spectrometry and offers a unique viewpoint to elucidate the mechanism how phytoestrogens and mycoestrogens interact with estrogen receptor. The cluster analysis based on the hydrogen deuterium exchange (HDX) assay data reveals a unique pattern when phytoestrogens and mycoestrogens bind with ERα LBD compared to that of estradiol and synthetic estrogen modulators. Our study highlights that structure dynamics could play an important role in the structure function relationship when endocrine disrupters interact with estrogen receptors.


Expression profiles and functional analyses of Wnt-related genes in human joint disorders.
Rheumatoid arthritis (RA) and osteoarthritis (OA) are joint disorders that cause major public health problems. Previous studies of the etiology of RA and OA have implicated Wnt genes, although the exact nature of their involvement remains unclear. To further clarify the relationship between RA, OA, and the Wnt gene family, gene expression analyses were performed on articular cartilage, bone, and synovial tissues in knee joints taken from RA, OA, and nor-mal/control patients. Cytokine assays were also performed in cells transfected with Wnt-7b, a member of the gene family most closely linked to RA and OA. Of the human Wnt genes, real-time PCR analysis revealed significant up-regulation of Wnt-7b in OA cartilage and RA synovium. In situ hybridization and immunohistochemistry also revealed that Wnt-7b was present in articular cartilage, bone, and synovium of RA samples and in osteophytes, articular cartilage, bone marrow, and synovium of OA samples. The levels of the cytokines tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 were significantly increased in RA synovium and Wnt-7b-transfected normal synovial cells when compared with normal samples. These results point to the potential involvement of Wnt signaling in the pathobiology of both RA and OA.


What Could "Fair Allocation" during the Covid-19 Crisis Possibly Mean in Sub-Saharan Africa?
The Covid-19 pandemic has sparked rapid and voluminous production of bioethics commentary in popular media and academic publications. Many of the discussions are new twists on an old theme: how to fairly allocate scarce medical resources, such as ventilators and intensive care unit beds. In this essay, we do not add another allocation scheme to the growing pile, partly out of appreciation that such schemes should be products of inclusive and transparent community engagement and partly out of recognition of their limited utility for physicians working in the field. Instead, we make the more modest claim that context matters when making such decisions and, more specifically, that recommendations from high-income countries about fair allocation during Covid-19 should not be cut and pasted into low-income settings. We offer a few examples of why seemingly universal, well-intentioned ethical recommendations could have adverse consequences if unreflectively applied in sub-Saharan Africa.


Adult syringomielia. Classification, pathogenesis and therapeutic approaches.
Syringomyelia is characterized by the presence of cystic cavities inside the spinal cord, with an incidence estimated of 8.4 new cases/year/100 000 people. The cavities are usually located inside the cervical cord, although they can extend upwards and/or downwards. The underlying cause of all types of syringomyelia is an alteration in physiologic cerebrospinal fluid (CSF) flow dynamics. Four different main types may be described in descending order of frequency: associated with Chiari I malformations, associated with vertebral trauma, associated with basilar invagination and associated with hydrocephalus. Conservative treatment is not recommended as the surgical procedure stops the progress of the disease with clinical improvement being the rule. Early surgical treatment is highly recommended before the establishment of gross neurological deficits occurs. Treatment is urged in case of clinical deterioration or when the follow-up MRI studies show increase in size and extension of the syringomyelic cavity. The first step in the surgical treatment is a precise diagnosis of its etiology to direct the treatment to the underlying cause. Treatment directed to normalize CSF flow homeostasis should be case tailored. Surgical measures that aim to reconstruct the continuity of the subarachnoid space at the site of the block are the first treatment option. Shunting is advocated when reestablishment of the pathways proves impossible or as a second procedure.


Blood Nicotine Predicts the Behavioral Economic Abuse Liability of Reduced-Nicotine Cigarettes.
Cigarette smoking continues to be a major health concern and remains the leading preventable cause of death in the US. Recent efforts have been made to determine the potential health and policy benefits of reducing nicotine in combustible cigarettes. The degree to which changes in blood nicotine relate to measures of the abuse liability of reduced-nicotine cigarettes is unknown. The current study examined the relation between blood nicotine and behavioral economic demand measures of cigarettes differing in nicotine content. Using a within-subject design, participants smoked a single cigarette during each experimental session. Cigarettes included the participant's usual-brand cigarette and SPECTRUM investigational cigarette differing in nicotine level (mg of nicotine to g of tobacco; 15.8 mg/g, 5.2 mg/g, 2.4 mg/g, 1.3 mg/g, and 0.4 mg/g). During each session, blood was collected at multiple timepoints and behavioral economic demand was assessed. Nonlinear mixed-effects models were used to estimate differences in derived intensity (Q0) and change in elasticity (α). Measures of blood nicotine decreased in an orderly fashion related to nicotine level and significantly predicted change in elasticity (α), but not derived intensity. No differences in demand parameters between the usual brand and 15.8mg/g cigarettes were observed. However, α was significantly higher (lower valuation) for 0.4mg/g than 15.8mg/g cigarettes. The lowest nicotine level (0.4mg/g) corresponded with the lowest abuse liability (α) compared to the full-strength control (15.8mg/g), with the 1.3mg/g level also resulting in low abuse liability. This is the first study examining the relative contributions of nicotine content in cigarettes and blood nicotine levels on the behavioral economic demand abuse liability of cigarettes ranging in nicotine content. Our results suggest blood nicotine and nicotine content both predict behavioral economic demand abuse liability. In addition, our results suggest a nicotine content of 1.3mg/g or lower may be effective at reducing cigarette uptake among first-time (naïve) smokers. Our results largely conform to previous findings suggesting a very low nicotine content cigarette maintains lower abuse liability than full-strength cigarettes.