Self-determination theory interventions versus usual care in people with diabetes: a protocol for a systematic review with meta-analysis and trial sequential analysis.
Existing self-management and behavioural interventions for diabetes vary widely in their content, and their sustained long-term effectiveness is uncertain. Autonomy supporting interventions may be a prerequisite to achieve 'real life' patient engagement and more long-term improvement through shared decision-making and collaborative goal setting. Autonomy supportive interventions aim to promote that the person with diabetes' motivation is autonomous meaning that the person strives for goals they themselves truly believe in and value. This is the goal of self-determination theory and guided self-determination interventions. Self-determination theory has been reviewed but without assessing both benefits and harms and accounting for the risk of random errors using trial sequential analysis. The guided self-determination has not yet been systematically reviewed. The aim of this protocol is to investigate the benefits and harms of self-determination theory-based interventions versus usual care in adults with diabetes. We will conduct the systematic review following The Cochrane Collaboration guidelines. This protocol is reported according to the PRISMA checklist. A comprehensive search will be undertaken in the CENTRAL, MEDLINE, EMBASE, LILACS, PsycINFO, SCI-EXPANDED, CINAHL, SSCI, CPCI-S and CPCI-SSH to identify relevant trials. We will include randomised clinical trials assessing interventions theoretically based on guided self-determination or self-determination theory provided face-to-face or digitally by any healthcare professional in any setting. The primary outcomes will be quality of life, mortality, and serious adverse events. The secondary will be diabetes distress, depressive symptoms and adverse events not considered serious. Exploratory outcomes will be glycated haemoglobin and motivation. Outcomes will be assessed at the end of the intervention and at maximum follow-up. The analyses will be performed using Stata version 16 and trial sequential analysis. Two authors will independently screen, extract data from and perform risk of bias assessment of included studies using the Cochrane risk of bias tool. Certainty of the evidence will be assessed by GRADE. Self-determination theory interventions aim to promote a more autonomous patient engagement and are commonly used. It is therefore needed to evaluate the benefit and harms according to existing trials. PROSPERO CRD42020181144.


Cardiac hemodynamics are linked with structural and functional features of brain aging: the age, gene/environment susceptibility (AGES)-Reykjavik Study.
Advanced heart failure is linked with structural and functional alterations in the brain. It is unclear whether a graded decrease in cardiac function puts older subjects at risk for brain aging. We investigated the association between cardiac hemodynamics and features of brain aging in community-dwelling older subjects. With data from a sub-study (n=931 subjects, mean age 75.9 years, 47.7% male) of the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, we investigated the association of MRI measures of cardiac hemodynamics, including left ventricular stroke volume (LVSV) and cardiac output (CO) to brain characteristics. In multivariable analyses, each 10 mL lower LVSV was associated with 4.4 mL (95% CI 1.9 to 6.9) lower total parenchymal brain volume (TBV) and 3.7 mL (95% CI 1.8 to 5.7) lower gray matter volume (GMV). Likewise, each unit (L/min) lower CO was associated with 3.9 mL (95% CI 0.4 to 7.4) lower TBV and 3.9 mL (95% CI 0.4 to 7.4) lower GMV. Lower LVSV was associated with worse performance in processing speed (P=0.043) and executive function (P<0.001). Lower CO was associated with worse performance in processing speed (P=0.015) and executive function (P=0.003). Each 10 mL lower LVSV and each unit lower CO associated with a higher risk of mild cognitive impairment or dementia (odds ratio: 1.24, 95% CI 0.99 to 1.57 and odds ratio: 1.40, 95% CI 0.99 to 2.00, respectively). A graded decrease in cardiac functioning is associated with features of brain aging. Older persons with cardiac or cognitive signs and symptoms may have both cardiac and cerebral diseases and should be evaluated accordingly.


Lung cancer early detection and health disparities: the intersection of epigenetics and ethnicity.
Lung cancer is the most prominent cause of cancer-related mortality. Significant disparities in incidence and outcome characterize the disease's manifestations among ethnically and racially diverse populations. Complete surgical resection is the most effective curative treatment. However, success relies on early tumor detection. The National Lung Cancer Screening trial showed that lung cancer related mortality can be reduced by the use of low-dose CT (LDCT) screening. However, this test is plagued by a high false positive rate of 97% and the device itself is limited to designated cancer centers due to its expense and size. This restriction makes it difficult for underserved groups to access LDCT screening, the current standard of care. Highly sensitive and specific epigenetic DNA methylation-based biomarkers have the potential to work independently or in conjunction with LDCT screening to identify early-stage tumors. These tests could reduce unnecessary invasive confirmatory diagnostic tests and their associated morbidity and mortality. These tests also have the opportunity to bring lung cancer screening to the community thereby reducing unequal accessibility. However, epigenetic alterations are closely linked to the interplay between hereditary and environmental factors such as diet, lifestyle, ethnic ancestry, toxin exposure, residential segregation, and disparate community support structures. Despite this, the overwhelming number of early detection DNA methylation biomarker studies to date have either failed to control for ethnicity or have employed heavily Caucasian-biased patient cohorts. This review seeks to summarize the literature related to the early detection of lung cancer through molecular biomarkers among different ethnicities. Ethnical specific epigenetic biomarkers have the potential to be the first step towards an accessible, available personalized medicine approach to cancer through liquid biopsy.


Factors influencing the use of tocilizumab as monotherapy in patients with rheumatoid arthritis in a real-life setting: results at 1 year of the ACT-SOLO study.
Using a biologic disease-modifying antirheumatic drug (bDMARD) as monotherapy in clinical practice for patients with rheumatoid arthritis (RA) is common and recognised by health authorities although current guidelines recommend to combine them with conventional synthetic (cs)DMARDs. This study mainly aimed to search for real-life factors influencing the use of tocilizumab as MONO or in combination (COMBO). In this non-interventional, prospective, national, multicentre study, data were collected every 3 months over a 12-month period in RA patients starting tocilizumab. The proportion of monotherapy patients was described, together with significant explicative factors. Among the 577 analysed patients recruited from January 2012 to August 2013 (228 monotherapy patients; 40%), 79% were women, mean RA duration was 11±9 years, previous RA treatments included bDMARDs and csDMARDs in 75% of cases and mean Disease Activity Score 28 joints-Erythrocyte Sedimentation Rate (DAS28-ESR) was 5.2±1.3 at inclusion. Explicative factors for monotherapy were at least 65 years (OR=1.47, p=0.0485), no methotrexate within the two last years (OR=5.96, p<0.0001), past severe infection (OR=1.99, p=0.0272) and higher baseline DAS28-ESR (OR=1.22, p=0.0086). Regarding clinical results (DAS28-ESR, Clinical Disease Activity Index (CDAI) and Simple Disease Activity Index (SDAI) low disease activity and remission; ACR20/50/70 and European League Against Rheumatism (EULAR) response; Health Assessment Questionnaire Disability Index (HAQ-DI) score), no relevant differences between monotherapy and combination patients were observed at 1 year. A total of 23 tocilizumab-treated patients (4%) experienced serious infections; no new safety signals were noted with no differences between groups. ACT-SOLO confirms the high proportion of RA patients receiving tocilizumab as MONO in clinical practice. The study also showed that clinical results at 1 year were similar between MONO and COMBO patients in a real-life setting. NCT01474291.


Surface properties of magnetite in high temperature aqueous electrolyte solutions: A review.
Deposits and scales formed on heat transfer surfaces in power plant water/steam circuits have a significant negative impact on plant reliability, availability and performance, causing tremendous economic consequences and subsequent increases in electricity cost. Consequently, the improvement of the understanding of deposition mechanisms on power generating surfaces is defined as a high priority in the power industry. The deposits consist principally of iron oxides, which are steel corrosion products and usually present in colloidal form. Magnetite (Fe3O4) is the predominant and most abundant compound found in water/steam cycles of all types of power plants. The crucial factor that governs the deposition process and influences the deposition rate of magnetite is the electrostatic interaction between the metal wall surfaces and the suspended colloidal particles. However, there is scarcity of data on magnetite surface properties at elevated temperatures due to difficulties in their experimental measurement. In this paper a generalized overview of existing experimental data on surface characteristics of magnetite at high temperatures is presented with particular emphasis on possible application in the power industry. A thorough analysis of experimental techniques, mathematical models and results has been performed and directions for future investigations have been considered. The state-of-the-art assessment showed that for the characterization of magnetite/aqueous electrolyte solution interface at high temperatures acid-base potentiometric titrations and electrophoresis were the most beneficial and dependable techniques which yielded results up to 290 and 200°C, respectively. Mass titrations provided data on magnetite surface charge up to 320°C, however, this technique is highly sensitive to the minor concentrations of impurities present on the surface of particle. Generally, fairly good correlation between the isoelectric point (pHiep) and point of zero charge (pHpzc) values has been obtained. All obtained results showed that the surface of magnetite particles is negatively charged in typical high temperature thermal power plant water, which indicates the low probability of aggregation and deposition on plant metal surfaces. The results also gave strong evidence on decline of pHiep and pHpzc with temperature in the same manner as neutral pH of water. The thermodynamic parameters of magnetite surface protonation reactions were in good agreement with each other and obtained using one site/two pK and mainly one site/one pK model. All collected data provided evidences for interaction between particles, probability of deposition and eventual attachment to the steel surface at various pH and temperatures and can serve as a foundation for future surface studies aimed at optimizing plant performances and reducing of magnetite deposition. In future works it would be indispensable to provide the surface experimental data for extended temperature ranges, typical solution chemistries and metal surfaces of power plant structural components and thus obtain entire set of results useful in modeling the surface behavior and control of deposition process in power reactors and thermal plant circuits. Moreover, the acquired results will be applicable and greatly valuable to all other types of power plants, industrial facilities and technological processes using the high temperature water medium.


The Temporal Relationship Between Exercise, Recovery Processes, and Changes in Performance.
Physiological and psychological demands during training and competition generate fatigue and reduce an athlete's sport-specific performance capacity. The magnitude of this decrement depends on several characteristics of the exercise stimulus (eg, type, duration, and intensity), as well as on individual characteristics (eg, fitness, profile, and fatigue resistance). As such, the time required to fully recover is proportional to the level of fatigue, and the consequences of exercise-induced fatigue are manifold. Whatever the purpose of the ensuing exercise session (ie, training or competition), it is crucial to understand the importance of optimizing the period between exercise bouts in order to speed up the regenerative processes and facilitate recovery or set the next stimulus at the optimal time point. This implies having a fairly precise understanding of the fatigue mechanisms that contribute to the performance decrement. Failing to respect an athlete's recovery needs may lead to an excessive accumulation of fatigue and potentially "nonfunctional overreaching" or to maladaptive training. Although research in this area recently increased, considerations regarding the specific time frames for different physiological mechanisms in relation to exercise-induced fatigue are still missing. Furthermore, recommendations on the timing and dosing of recovery based on these time frames are limited. Therefore, the aim of this article is to describe time courses of recovery in relation to the exercise type and on different physiological levels. This summary supports coaches, athletes, and scientists in their decision-making process by considering the relationship of exercise type, physiology, and recovery.


Genotypic abundance of carotenoids and polyphenolics in the hull of field pea (Pisum sativum L.).
Consumption of pulse crops, including field pea, is considered effective for a healthy diet. Hulls (seed coats) play an important role for protection of the cotyledon and embryo, but also as mediating positive effects on health outcomes. The biochemical attributes of field pea hulls were thus assessed to determine the occurrence of specific phytochemicals and their genotypic variability. Sequestered bioproducts in mature hulls predominantly consisted of trans-lutein and chlorophylls a and b. Trace amounts of other carotenoid and pheophytin metabolites were identified. In developing hulls, violaxanthin, neoxanthin, lutein, zeaxanthin, chlorophylls a and b and β-carotene were detected. Genotypic differences in the accumulation of lutein and chlorophylls a and b were observed over years and locations. Polyphenolics and hydroxybenzoic acids were detected in the 'dun' and 'maple' field pea types-the only genotypes to have pigmented hulls. Unextractable patches of condensed tannin influenced the visual uniformity of the maple and dun genotypes, CDC Rocket and CDC Dundurn. Within the yellow and green market classes, carotenoid and chlorophyll accumulation was consistent. Green cotyledon varieties sequestered higher concentrations of lutein than the yellow cotyledon varieties. Maple and dun types were more variable, reflective of different selection criteria. The occurrence of flavonoid-related compounds was correlated only with pigmented seed coat genotypes. The dietary potential of the chlorophylls and carotenoids that accumulated in the hulls split from the green and yellow field pea types is discussed as a value-added prospect in food supplements.


[Surgical treatment in peptic ulcer hemorrhage].
For the last 8 years the results of the surgical treatment of 124 patients have been studied in order to get more exact indications for the surgical treatment of gastroduodenal ulcerous hemorrhages. The conservative therapy was found to be effective in the first degree of severity of hemorrhage. The second and third degree are often followed by recurrent hemorrhages which speaks for the early surgical treatment.


Biochemical resolving power of fluorescence lifetime imaging: untangling the roles of the instrument response function and photon-statistics.
A deeper understanding of spatial resolution has led to innovations in microscopy and the disruption of biomedical research, as with super-resolution microscopy. To foster similar advances in time-resolved and spectral imaging, we have previously introduced the concept of 'biochemical resolving power' in fluorescence microscopy. Here, we apply those concepts to investigate how the instrument response function (IRF), sampling conditions, and photon-statistics limit the biochemical resolution of fluorescence lifetime microscopy. Using Fisher information analysis and Monte Carlo simulations, we reveal the complex dependencies between photon-statistics and the IRF, permitting us to quantify resolution limits that have been poorly understood (e.g., the minimum resolvable decay time for a given width of the IRF and photon-statistics) or previously underappreciated (e.g., optimization of the IRF for biochemical detection). With this work, we unravel common misunderstandings on the role of the IRF and provide theoretical insights with significant practical implications on the design and use of time-resolved instrumentation.


[The microsurgical decompression of the accessory nerve in spasmodic torticollis].
Microsurgical decompression of the accessory nerve was conducted in 10 patients with spasmodic torticollis (tonic and tonic-clonic forms). Compression of the roots of the accessory nerve of the posterior inferior cerebellar and the vertebral arteries was discovered. Decompression was accomplished by division of the arachnoid adhesions, anastomosis with sensory roots of C1 and C2, and placing a layer of muscular tissue between the nerve and the vessel. The results of treatment of spasmodic torticollis are analysed and the efficacy of neurovascular decompression is emphasized.


Broad-scale informed consent: A survey of the CTSA landscape.
Research opportunities associated with the proliferation of the electronic health record (EHR), big data initiatives, and innovative approaches to trial design can present challenges for obtaining and documenting informed consent. Broad-scale informed consent (a term used herein to describe institutional models, rather than the Common Rule's strict regulatory definition for "broad consent") may facilitate the use of existing data and samples and speed the pace of research by minimizing barriers to consent. We explored the use of broad-scale informed consent within the Clinical Translational Science Award (CTSA) Program Network. We surveyed CTSA Hubs concerning policies, practices, experiences, and needs within three domains of broad-scale informed consent: (1) participant recontact; (2) biospecimens; and (3) clinical data sharing. Of 61 CTSA Hubs surveyed, 37 (61%) indicated ongoing work related to at least 1 domain of broad-scale informed consent; 18 Hubs (30%) reported work in all 3 domains. The EHR predominated as the implementation system across all three domains. Research and IT leadership and the Institutional Review Board were most commonly endorsed as institutional drivers, while systems/technical issues and impact on clinical workflow were the most commonly reported barriers. While survey results indicate considerable variability in the implementation of broad-scale informed consent across the CTSA consortium, it is clear that all CTSA Hubs are actively considering policy and process related to these concepts. Next steps cluster within three areas: training and workforce development, streamlined policies and templates, and implementation strategies that facilitate integration into clinical workflow.


Couplons in rat atria form distinct subgroups defined by their molecular partners.
Standard local control theory, which describes Ca(2+) release during excitation-contraction coupling (ECC), assumes that all ryanodine receptor 2 (RyR2) complexes are equivalent. Findings from our laboratory have called this assumption into question. Specifically, we have shown that the RyR2 complexes in ventricular myocytes are different, depending on their location within the cell. This has led us to hypothesize that similar differences occur within the rat atrial cell. To test this hypothesis, we have triple-labelled enzymatically isolated fixed myocytes to examine the distribution and colocalization of RyR2, calsequestrin (Casq), voltage-gated Ca(2+) channels (Ca(v)1.2), the sodium-calcium exchanger (Ncx) and caveolin-3 (Cav3). A number of different surface RyR2 populations were identified, and one of these groups, in which RyR2, Ca(v)1.2 and Ncx colocalized, might provide the structural basis for 'eager' sites of Ca(2+) release in atria. A small percentage of the dyads containing RyR2 and Ca(v)1.2 were colocalized with Cav3, and therefore could be influenced by the signalling molecules it anchors. The majority of the RyR2 clusters were tightly linked to Ca(v)1.2, and, whereas some were coupled to both Ca 1.2 and Ncx, none were with Ncx alone. This suggests that Ca(v)1.2-mediated Ca(2+) -induced Ca(2+) release is the primary method of ECC. The two molecules studied that were found in the interior of atrial cells, RyR2 and Casq, showed significantly less colocalization and a reduced nearest-neighbour distance in the interior, compared with the surface of the cell. These differences might result in a higher excitability for RyR2 in the interior of the cells, facilitating the spread of excitation from the periphery to the centre. We also present morphometric data for all of the molecules studied, as well as for those colocalizations found to be significant.


Systematic analysis of pleiotropy in C. elegans early embryogenesis.
Pleiotropy refers to the phenomenon in which a single gene controls several distinct, and seemingly unrelated, phenotypic effects. We use C. elegans early embryogenesis as a model to conduct systematic studies of pleiotropy. We analyze high-throughput RNA interference (RNAi) data from C. elegans and identify "phenotypic signatures", which are sets of cellular defects indicative of certain biological functions. By matching phenotypic profiles to our identified signatures, we assign genes with complex phenotypic profiles to multiple functional classes. Overall, we observe that pleiotropy occurs extensively among genes involved in early embryogenesis, and a small proportion of these genes are highly pleiotropic. We hypothesize that genes involved in early embryogenesis are organized into partially overlapping functional modules, and that pleiotropic genes represent "connectors" between these modules. In support of this hypothesis, we find that highly pleiotropic genes tend to reside in central positions in protein-protein interaction networks, suggesting that pleiotropic genes act as connecting points between different protein complexes or pathways.


High plasma adenosine levels in overweight/obese pregnant women.
We aim to investigate whether overweight/obese pregnant women have elevated plasma levels of adenosine associated with increased consumption of high-calorie food. Sixty women were included. They were divided into lean (n = 23 and n = 12) or overweight/obese (n = 7 and n = 18) non-pregnant and pregnant women, respectively. Clinical records and maternal blood samples were collected after informed consent. A self-reported dietary questionnaire was also completed. Plasma adenosine levels were determined with high-performance liquid chromatography. Biochemical parameters, including glucose, total protein, and lipid profile, were determined using standard colorimetric assays. Adenosine levels were higher in pregnant women than in non-pregnant women (18.7 ± 1.6 vs 10.8 ± 1.3 nM/μg protein, respectively, p < 0.0001). Overweight/obese pregnant women (21.9 ± 2.5 nM/μg protein) exhibited higher adenosine levels than lean pregnant (14.5 ± 1.0 nM/μg protein, p = 0.04) or non-pregnant women (11.7 ± 1.5 nM/μg protein, p = 0.0005). Also, pregnant women with elevated weight gain exhibited higher (26.2 ± 3.7 nM/μg protein) adenosine levels than those with adequate weight gain (14.9 ± 1.4 nM/μg protein, p = 0.03). These differences were not statistically significant compared with those of pregnant women with reduced weight gain (17.4 ± 2.1 nM/μg protein, p = 0.053). Body mass index and adenosine only in pregnant women were positively correlated (r = 0.39, p = 0.02). While, polyunsaturated fatty acid (PUFA) consumption was negatively correlated with plasma adenosine levels only in non-pregnant women (r = -0.33, p = 0.03). Pregnancy is associated with high plasma adenosine levels, which are further elevated in pregnant women who are overweight/obese. High PUFA intake might reduce plasma adenosine levels in non-pregnant women.


p53 has a direct apoptogenic role at the mitochondria.
p53 induces apoptosis by target gene regulation and transcription-independent signaling. However, a mechanism for the latter was unknown. We recently reported that a fraction of induced p53 translocates to the mitochondria of apoptosing tumor cells. Targeting p53 to mitochondria is sufficient to launch apoptosis. Here, we provide evidence that p53 translocation to the mitochondria occurs in vivo in irradiated thymocytes. Further, we show that the p53 protein can directly induce permeabilization of the outer mitochondrial membrane by forming complexes with the protective BclXL and Bcl2 proteins, resulting in cytochrome c release. p53 binds to BclXL via its DNA binding domain. We probe the significance of mitochondrial p53 and show that tumor-derived transactivation-deficient mutants of p53 concomitantly lose the ability to interact with BclXL and promote cytochrome c release. This opens the possibility that mutations might represent "double-hits" by abrogating the transcriptional and mitochondrial apoptotic activity of p53.


Delivery of Topical Drugs to the Olfactory Cleft.
Olfactory dysfunction affects approximately 20% of the population globally, with incidence increasing over the age of 60. The pathophysiology is complex, not yet fully understood, and depends on many factors, including the underlying cause. Despite this, the present literature on olfaction is limited due to significant heterogeneity in methodological approaches. This has resulted in limited effective treatments available for olfactory dysfunction. Medications for olfactory dysfunction can be administered locally (directly to the olfactory epithelium) or systemically (orally or intravenously). Currently, there are various methods for local drug delivery to the olfactory epithelium (nasal drops, nasal sprays, atomisers, pressured meter-dosed inhalers, rinses, and exhalation delivery systems). The aims of this review are to summarise the different methods of drug delivery to the olfactory cleft, evaluate the current literature to assess which method is the most effective in delivering drugs to the olfactory epithelium, and review the medications currently available to treat olfactory dysfunction topically. Going forward, further research is required to better establish effective methods of drug delivery to the olfactory epithelium to treat smell disorders.


Associations Between Physician Empathy, Physician Characteristics, and Standardized Measures of Patient Experience.
To identify correlates of physician empathy and determine whether physician empathy is related to standardized measures of patient experience. Demographic, professional, and empathy data were collected during 2013-2015 from Cleveland Clinic Health System physicians prior to participation in mandatory communication skills training. Empathy was assessed using the Jefferson Scale of Empathy. Data were also collected for seven measures (six provider communication items and overall provider rating) from the visit-specific and 12-month Consumer Assessment of Healthcare Providers and Systems Clinician and Group (CG-CAHPS) surveys. Associations between empathy and provider characteristics were assessed by linear regression, ANOVA, or a nonparametric equivalent. Significant predictors were included in a multivariable linear regression model. Correlations between empathy and CG-CAHPS scores were assessed using Spearman rank correlation coefficients. In bivariable analysis (n = 847 physicians), female sex (P < .001), specialty (P < .01), outpatient practice setting (P < .05), and DO degree (P < .05) were associated with higher empathy scores. In multivariable analysis, female sex (P < .001) and four specialties (obstetrics-gynecology, pediatrics, psychiatry, and thoracic surgery; all P < .05) were significantly associated with higher empathy scores. Of the seven CG-CAHPS measures, scores on five for the 583 physicians with visit-specific data and on three for the 277 physicians with 12-month data were positively correlated with empathy. Specialty and sex were independently associated with physician empathy. Empathy was correlated with higher scores on multiple CG-CAHPS items, suggesting improving physician empathy might play a role in improving patient experience.


Genome-Wide Association Analysis Reveals Loci and Candidate Genes Involved in Fiber Quality Traits Under Multiple Field Environments in Cotton (Gossypium hirsutum).
Fiber length, fiber strength, and fiber micronaire are the main fiber quality parameters in cotton. Thus, mining the elite and stable loci/alleles related to fiber quality traits and elucidating the relationship between the two may accelerate genetic improvement of fiber quality in cotton. Here, genome-wide association analysis (GWAS) was performed for fiber quality parameters based on phenotypic data, and 56,010 high-quality single nucleotide polymorphisms (SNPs) using 242 upland cotton accessions under 12 field environments were obtained. Phenotypic analysis exhibited that fiber length (FL) had a positive correlation with fiber strength (FS) and had a negative correlation with fiber micronaire (Mic). Genetic analysis also indicated that FL, FS, and Mic had high heritability of more than 80%. A total of 67 stable quantitative trait loci (QTLs) were identified through GWAS analysis, including 31 for FL, 21 for FS, and 22 for Mic. Of them, three pairs homologous QTLs were detected between A and D subgenomes, and seven co-located QTLs with two fiber quality parameters were found. Compared with the reported QTLs, 34 co-located with previous studies, and 33 were newly revealed. Integrated with transcriptome analysis, we selected 256, 244, and 149 candidate genes for FL, FS, and Mic, respectively. Gene Ontology (GO) analysis showed that most of the genes located in QTLs interval of the three fiber quality traits were involved in sugar biosynthesis, sugar metabolism, microtubule, and cytoskeleton organization, which played crucial roles in fiber development. Through correlation analysis between haplotypes and phenotypes, three genes (GH_A05G1494, GH_D11G3097, and GH_A05G1082) predominately expressed in fiber development stages were indicated to be potentially responsible for FL, FS, and Mic, respectively. The GH_A05G1494 encoded a protein containing SGS-domain, which is related to tubulin-binding and ubiquitin-protein ligase binding. The GH_D11G3097 encoded 20S proteasome beta subunit G1, and was involved in the ubiquitin-dependent protein catabolic process. The GH_A05G1082 encoded RAN binding protein 1 with a molecular function of GTPase activator activity. These results provide new insights and candidate loci/genes for the improvement of fiber quality in cotton.


Deterministic Switching of the Growth Direction of Self-Catalyzed GaAs Nanowires.
The typical vapor-liquid-solid growth of nanowires is restricted to a vertical one-dimensional geometry, while there is a broad interest for more complex structures in the context of electronics and photonics applications. Controllable switching of the nanowire growth direction opens up new horizons in the bottom-up engineering of self-assembled nanostructures, for example, to fabricate interconnected nanowires used for quantum transport measurements. In this work, we demonstrate a robust and highly controllable method for deterministic switching of the growth direction of self-catalyzed GaAs nanowires. The method is based on the modification of the droplet-nanowire interface in the annealing stage without any fluxes and subsequent growth in the horizontal direction by a twin-mediated mechanism with indications of a novel type of interface oscillations. A 100% yield of switching the nanowire growth direction from vertical to horizontal is achieved by systematically optimizing the growth parameters. A kinetic model describing the competition of different interface structures is introduced to explain the switching mechanism and the related nanowire geometries. The model also predicts that the growth of similar structures is possible for all vapor-liquid-solid nanowires with commonly observed truncated facets at the growth interface.


Adult respiratory distress syndrome complicating severely uncontrolled diabetes mellitus: report of nine cases and a review of the literature.
We report the occurrence of the adult respiratory distress syndrome (ARDS) in association with uncontrolled diabetes in nine patients. In reviewing the literature we found nine similar cases reported in little over a decade. In most cases no condition known to precipitate ARDS was discovered. The evidence suggests that the severely uncontrolled diabetic state in some way may initiate pathologic events leading to the capillary leak of ARDS. This description of the association of these two entities not commonly recognized as occurring simultaneously has important clinical implications: the entity should be anticipated in uncontrolled diabetic patients who present with acidosis, hypotension, hypothermia, and/or coma. The clinical or radiologic diagnosis of pneumonia or fluid overload should not be made in the uncontrolled diabetic patient in the absence of unequivocal evidence of infection or congestive heart failure. The development of dyspnea, hypoxemia, rales, or infiltrates in the otherwise routine resuscitation of these patients should lead the clinician to suspect the development of ARDS. Prompt invasive monitoring in these cases is indicated to aid in their management and may help to improve survival. We found calculation of the A-a gradient to be useful in patients with uncontrolled diabetes. Although not necessarily predictive, widened gradients were the earliest detectable abnormality found in all patients who developed ARDS.


Molecular structures, conformational analysis, and preferential modes of binding of 3-aroyl-2-arylbenzo[b]thiophene estrogen receptor ligands: LY117018 and aryl azide photoaffinity labeling analogs.
Structural and computational modeling studies were performed on the antiestrogen LY117018 (3) and two photoaffinity labeling analogs, in which an azide replaces the basic ether side chain (methyl ether tetrafluoro azide 7 and its protio analog 8). These studies were undertaken in order to determine the conformational preferences of these compounds and to propose favorable orientational modes for their binding to the estrogen receptor. In the crystallographic studies, we found that, unlike tetrafluoro azide 7, which adopts a face-to-face stacking of the p-hydroxyphenyl and benzoyl groups in the solid state, the pendant rings in the corresponding protio analog 8 are found in a predominantly offset pi-stacked array. In LY117018, which has an ether on the benzoyl ring, stacking of the pendant rings does not occur in the crystal structure; it assumes a T-shape, with the benzoyl group oriented perpendicular to the benzo[b]thiophene nucleus. In modeling studies, analogs of LY117018, 7, and 8 were subjected to a conformational grid search by molecular mechanics, and for each compound, three low-energy conformers (and their atropisomers) were obtained. These conformers were further geometry optimized by semiempirical molecular orbital calculations. For each compound, one of the three minimum-energy conformers is quite similar to the solid-state geometry. The computational structure of the tetrafluoro azide showed the greatest stacking between the benzoyl group and the p-methoxyphenyl ring, but less stacking than was observed in the crystallographic structure. The orientational preferences of these benzo[b]thiophene ligands with the estrogen receptor were analyzed with the receptor volume mapping technique, a method based on the correspondence of the hydroxyl groups and the volume that the benzo[b]thiophene compound shares with a composite molecular volume of high-affinity estradiol-type ligands (the receptor excluded volume, RExV). If the benzo[b]thiophene nucleus is overlapped with the steroid AB rings, the best overlap with the RExV is achieved, but there is poor correspondence of the hydroxyl groups. An orientation and conformation in which the benzoyl group of the 3-benzoyl-2-aryl-benzo[b]thiophenes occupies a 7 alpha-like position relative to the steroid produces both ample volume overlap with the RExV and close approximation of the hydroxyl groups and is presented as the putative bioactive conformation.


Cellular Model of Colon Cancer Progression Reveals Signatures of mRNAs, miRNA, lncRNAs, and Epigenetic Modifications Associated with Metastasis.
Here, we developed and comprehensively characterized a cellular model of colon cancer progression consisting of four defined derivatives of a colon cancer cell line that resulted from consecutive epithelial-mesenchymal and mesenchymal-epithelial transitions (EMT/MET) and phenotypically recapitulate the metastatic cascade. Initial EMT was induced by prolonged exposure to IL6, a cytokine also generated by the tumor-stroma. Genome-wide characterization of transcriptional (mRNA, miRNA, and lncRNA) and epigenetic (DNA methylation, H3K4me3, H3K79me3, and H3K27me3 histone modifications) profiles of the cell derivatives, combined with correlative analyses of expression, methylation, and clinical data from the TCGA-COAD database gave insights into the molecular basis of their phenotypic changes. The signatures characterizing invasive, mesenchymal-like cell states as well as the metastases-derived epithelial-like state showed significant association with metastasis, positive nodal status, and poor survival of colon cancer patients. Global hypomethylation of gene-regulatory regions was observed during tumor progression, with the lowest degree of methylation present in cells isolated from metastases. Upregulation of an axon-guidance-related gene signature was the most significant feature of metastatic tumor cells and was also found in primary tumors from colon cancer patients with distant metastases. Furthermore, the microRNAs miR-99a, miR-100, and miR-125b showed elevated expression in mesenchymal-like cells, associated with poor survival, and promoted migration and invasion. Finally, elevated expression of H19 lncRNA due to promoter demethylation was observed in cells isolated from metastases and was associated with poor survival of colon cancer patients. In the future, our results may be further exploited for the discovery and evaluation of novel metastasis-associated mechanisms and biomarkers. Cancer Res; 77(8); 1854-67. ©2017 AACR.


CD11b(+) Mononuclear Cells Mitigate Hyperoxia-Induced Lung Injury in Neonatal Mice.
Bronchopulmonary dysplasia (BPD) is a common consequence of life-saving interventions for infants born with immature lungs. Resident tissue myeloid cells regulate lung pathology, but their role in BPD is poorly understood. To determine the role of lung interstitial myeloid cells in neonatal responses to lung injury, we exposed newborn mice to hyperoxia, a neonatal mouse lung injury model with features of human BPD. In newborn mice raised in normoxia, we identified a CD45(+) F4/80(+) CD11b(+), Ly6G(lo-int) CD71(+) population of cells in lungs of neonatal mice present in significantly greater percentages than in adult mice. In response to hyperoxia, surface marker and gene expression in whole lung macrophages/monocytes was biased to an alternatively activated phenotype. Partial depletion of these CD11b(+) mononuclear cells using CD11b-diphtheria toxin (DT) receptor transgenic mice resulted in 60% mortality by 40 hours of hyperoxia exposure with more severe lung injury, perivascular edema, and alveolar hemorrhage compared with DT-treated CD11b-DT receptor-negative controls, which displayed no mortality. These results identify an antiinflammatory population of CD11b(+) mononuclear cells that are protective in hyperoxia-induced neonatal lung injury in mice, and suggest that enhancing their beneficial functions may be a treatment strategy in infants at risk for BPD.


Reactivity of anomeric 1alpha- and 1beta-pentofuranosyl azide derivatives in ammonia chemical ionization.
Electron impact (EI), fast atom bombardment (FAB) and ammonia chemical ionization [CI(NH3)] mass spectrometry were applied with the aim of differentiating between the anomeric 1alpha- and 1beta-azidopentofuranosyl derivatives. Calculated ammonium affinities [AA(M)] and proton affinities [PA(M)] show that beta-anomers have higher affinities for H+ and NH4+ ions than alpha-azides. Protonated molecules, obtained by CI(NH3) of azidofuranosyl derivatives, lose HN3 giving abundant furanosyl (S+) ions. Ammonia solvation of MH+ ions competes with the previous reaction producing the [SNHN2NH3]+ ion, a competitive product to the ammonium-attached [SN3NH4]+ ion. The fragmentation pathways of the stable and metastable [MNH4]+, MH+ ions, and several other important fragment ions, were determined using mass analyzed ion kinetic energy spectrometry (MIKES). The abundance of the [SN3NH4]+ and/or [SNHN2NH3]+ ions was found to correlate inversely with the exothermicity of ammonia solvation of the MH+ ion. The abundance of the fragment ions [SNHNH3]+, [SNH3]+ and SNH+ in some examples correlates with the exothermicity of the corresponding [MNH4]+ and MH+ parent ion formation. The fragment ions SNH3+ and SNHNH3+ can be formed, at least in part, in the ammonia solvation reaction of the S+ and SNH+ ions taking place within the high-pressure region of the CI ion source.


COVID-19 and chronic diabetes: the perfect storm for reactivation tuberculosis?: a case series.
The coronavirus disease 2019 pandemic is predicted to have a net negative effect on tuberculosis control, with an estimated excess of 6.3 million tuberculosis cases and 1.4 million deaths by 2025. Programmatic issues such as the lockdown of tuberculosis services affect all patients, while biosocial factors have a differential impact on an individual's risk for tuberculosis or adverse tuberculosis outcomes. We report three Hispanic cases of incident tuberculosis (two males, 43 and 44 years old; one female, 49 years old) after resolution of coronavirus disease episodes. Coincidentally, all cases shared a common risk factor: a chronic history poorly controlled diabetes. Our findings alert to the threat posed by the synergy between coronavirus disease and diabetes, on tuberculosis reactivation. In medium- to high-risk settings for tuberculosis, we recommend implementation of routine screening for latent tuberculosis infection in these cases, and preventive tuberculosis treatment in those who are positive.


Hexacyano Ferrate (III) Reduction by Electron Transfer Induced by Plasmonic Catalysis on Gold Nanoparticles.
Redox reactions are of great importance in environmental catalysis. Gold nanoparticles (Au-NPs) have attracted much attention because of their catalytic activity and their localized surface plasmon resonance (LSPR). In the present study, we investigated, in detail, the reduction of ferricyanide (III) ion into a ferrocyanide (II) ion catalyzed by spherical gold nanoparticles of two different sizes, 15 nm and 30 nm, and excited at their LSPR band. Experiments were conducted in the presence (or absence) of sodium thiosulfate. This catalysis is enhanced in the presence of Au- NPs under visible light excitation. This reduction also takes place even without sodium thiosulfate. Our results demonstrate the implication of hot electrons in this reduction.


Canonical and Non-Canonical Roles of GRK2 in Lymphocytes.
G protein-coupled receptor kinase 2 (GRK2) is emerging as a key integrative signaling node in a variety of biological processes ranging from cell growth and proliferation to migration and chemotaxis. As such, GRK2 is now implicated as playing a role in the molecular pathogenesis of a broad group of diseases including heart failure, cancer, depression, neurodegenerative disease, and others. In addition to its long-known canonical role in the phosphorylation and desensitization of G protein-coupled receptors (GPCRs), recent studies have shown that GRK2 also modulates a diverse array of other molecular processes via newly identified GRK2 kinase substrates and via a growing number of protein-protein interaction binding partners. GRK2 belongs to the 7-member GRK family. It is a multidomain protein containing a specific N-terminal region (referred to as αN), followed by a regulator of G protein signaling homology (RH) domain, an AGC (Protein kinase A, G, C serine/threonine kinase family) kinase domain, and a C-terminal pleckstrin homology (PH) domain. GPCRs mediate the activity of many regulators of the immune system such as chemokines and leukotrienes, and thus GRK proteins may play key roles in modulating the lymphocyte response to these factors. As one of the predominant GRK family members expressed in immune cells, GRK2's canonical and noncanonical actions play an especially significant role in normal immune cell function as well as in the development and progression of disorders of the immune system. This review summarizes our current state of knowledge of the roles of GRK2 in lymphocytes. We highlight the diverse functions of GRK2 and discuss how ongoing investigation of GRK2 in lymphocytes may inform the development of new therapies for diseases associated with lymphocyte dysregulation.


Global gene expression profiling of human lung epithelial cells after exposure to nanosilver.
The toxic effects of silver nanoparticles (AgNPs) on cells are well established, but only limited studies on the effect of AgNPs and silver ions on the cellular transcriptome have been performed. In this study, the effect of AgNPs on the gene expression in the human lung epithelial cell line A549 exposed to 12.1 µg/ml AgNPs (EC20) for 24 and 48h was compared with the response to control and silver ion (Ag(+)) treated cells (1.3 µg/ml) using microarray analysis. Twenty-four hours to AgNP altered the regulation of more than 1000 genes (more than twofold regulation), whereas considerably fewer genes responded to Ag(+) (133 genes). The upregulated genes included members of the metallothionein, heat shock protein, and histone families. As expected from the induction of meta l lothionein and heat shock protein genes, Ag(+) and AgNP treatment resulted in intracellular production of reactive oxygen species but did not induce apoptosis or necrosis at the concentrations used in this study. In addition, the exposure to AgNPs influenced the cell cycle and led to an arrest in the G2/M phase as shown by cell cycle studies by flow cytometry and microscopy. In conclusion, although the transcriptional response to Ag(+) exposure was highly related to the response caused by AgNPs, our findings suggest that AgNPs, due to their particulate form, affect exposed cells in a more complex way.


Interaction of culture-derived macrophages with the fibroblast-binding domain of fibronectin is a necessary but inefficient signal for fibronectin enhancement of CR1-mediated phagocytosis.
Human plasma fibronectin (Fn) enhances ingestion of opsonized particles through its interaction with phagocytic cells. To better characterize the site or sites on Fn responsible for this effect, we subjected Fn to limited proteolytic cleavage by chymotrypsin and used affinity and gel filtration chromatography to isolate a 110,000 dalton cell-binding fragment, a 60,000 dalton fragment that bound both heparin and gelatin, and 50,000 and 45,000 dalton fragments that bound to gelatin but not heparin. The cell-binding fragment mediated adhesion and spreading of fibroblasts on glass slides, whereas the heparin-gelatin and gelatin-binding fragments failed to cause fibroblast spreading. At high concentrations, the cell-binding fragment doubled phagocytosis of C4b-coated sheep erythrocytes by human monocyte-derived macrophages, whereas equal concentrations of the other fragments had minimal enhancing effect on phagocytosis. Interestingly, the effect of the cell-binding fragment on CR1-mediated phagocytosis was always less than the effect of intact Fn, even when a 40-fold higher molar concentration of the cell-binding fragment was used. Fab of a monoclonal anti-Fn, HFn 7.1, which recognizes the 110,000 dalton cell-binding fragment of Fn and inhibits fibroblast binding, blocked enhancement of CR1-mediated phagocytosis by intact Fn. Fab of Fn 8, a monoclonal anti-Fn that binds the heparin-gelatin-binding fragment, failed to inhibit the Fn effect. These data suggest that interaction of the macrophage with the cell-binding domain of Fn is critical for the Fn effect on CR1-mediated phagocytosis. In addition, there may be other domains of the Fn molecule that have a role in augmenting the Fn-phagocyte interaction.


Is the Virtual Reality Fundamentals of Arthroscopic Surgery Training Program a Valid Platform for Resident Arthroscopy Training?
Training in arthroscopy is associated with a steep learning curve for trainees and bears risks for patients. Virtual reality (VR) arthroscopy simulation platforms seek to overcome this and to provide a safe environment for surgical learners. The Fundamentals of Arthroscopic Surgery Training (FAST) program is one such platform. It is currently not known whether the VR FAST program can be employed as a useful teaching or examination tool to assess the basic arthroscopic skills of surgical trainees. (1) Does the VR FAST program differentiate among novice, intermediate, and expert arthroscopists? (2) Does ambidextrous performance in the VR FAST program correlate with arthroscopic experience? We prospectively recruited orthopaedic interns (novices), residents (intermediates), and fellows and attendings (experts) to complete the VR FAST program over a 1-year period from four major orthopaedic training programs on a voluntary basis. Sixty-six of 156 invited orthopaedic surgeons participated: 26 of 50 novices (16 men and 10 women), 27 of 65 intermediates (20 men and seven women), and 13 of 41 experts (10 men and three women). Surgeons of any arthroscopic experience were included, with only those with prior experience on the VR FAST program being excluded. The program consists of eight modules: three basic camera modules (Image Centering, Horizon Control, and Telescoping), three advanced camera modules (Periscoping, Trace the Line, and Trace the Curve), and two instrumented bimanual-dexterity modules (Probe Triangulation and Gather the Stars). Time taken to complete each task and measures of economy of movement (camera and instrument path length, camera alignment) were used as measures of arthroscopic experience. Every participant completed the modules using their dominant and nondominant hands. Equality in proficiency in completing the tasks using the dominant and nondominant hands were determined to be measures of arthroscopic experience. Due to the large number of outcome variables, only p values < 0.01 were considered to be statistically significant. Six of eight VR FAST modules did not discriminate among novice, intermediate, and expert arthroscopy participants. However, two did, and the ones that were most effective at distinguishing participants by level of experience were the Periscoping and Gather the Stars modules. For the Periscoping module using the dominant hand, novices required longer to complete the task with a median time of 231 seconds (IQR 149 to 358) and longer camera path length median of 191 cm (IQR 128 to 273) compared with intermediates who needed 127 seconds (IQR 106 to 233) and 125 cm (IQR 92 to 159) and experts who needed 121 seconds (IQR 93 to 157) and 119 cm (IQR 90 to 134) (p = 0.001 and p = 0.003, respectively). When using the nondominant hand, novices took longer to complete the task with a median time of 231 seconds (IQR 170 to 350) and longer camera path length 204 cm (IQR 169 to 273) compared with intermediates who required 132 seconds (IQR 97 to 162) and 111 cm (IQR 88 to 143) and experts who needed 119 seconds (IQR 104 to 183) and 120 cm (IQR 108 to 166) (p < 0.001 and p < 0.001, respectively). For the Gather the Stars module using the nondominant hand, only the novices needed longer to complete the task at a median of 131 seconds (IQR 112 to 157) and needed a longer grasper path length of 290 cm (IQR 254 to 332) compared with intermediates who needed 84 seconds (IQR 72 to 119) and 232 cm (IQR 195 to 254) and experts who needed 98 seconds (IQR 87 to 107) and 244 cm (IQR 215 to 287) (p < 0.001 and p = 0.001, respectively). Six of eight VR FAST modules did not demonstrate construct validity, and we found no correlation between arthroscopic experience and ambidextrous performance. Two modules demonstrated construct validity; however, refinement and expansion of the modules is needed with further validation in large prospective trials so that pass-fail thresholds can be set for use in high-stakes examinations. Most VR FAST modules were not discriminatory; however, they can form essential conceptual and procedural building blocks in an arthroscopic curriculum that are beneficial for novices when developing key psychomotor skills. In their present format, however, they are unsuitable for assessing arthroscopic proficiency.


Localization of a carboxylic residue possibly involved in the inhibition of vacuolar H+-pyrophosphatase by N, N'-dicyclohexylcarbodi-imide.
A vacuolar H(+)-pyrophosphatase (EC 184.108.40.206) that catalyses PP(i) hydrolysis and the electrogenic translocation of protons from the cytosol to the vacuole lumen, was purified from etiolated hypocotyls of mung bean seedlings (Vigna radiata L.). Group-specific modification was used to identify a carboxylic residue involved in the inhibition of vacuolar H(+)-pyrophosphatase. Carbodi-imides, such as N,N'-dicyclohexylcarbodi-imide (DCCD) and 1-ethyl-3-(3-dimethylamino-propyl)carbodi-imide, and Woodward's reagent K caused a progressive decline in the enzymic activity of vacuolar H(+)-pyrophosphatase in a time- and concentration-dependent manner. The stoichiometry of labelling of the vacuolar H(+)-pyrophosphatase by [(14)C]DCCD determined that DCCD modifies one carboxylic residue per subunit of the enzyme. Protection studies suggest that the DCCD-reactive carboxylic residue resides at or near the substrate-binding site. Furthermore, peptide mapping analysis reveals that Asp(283), located in the putative loop V of a tentative topological model of vacuolar H(+)-pyrophosphatase on the cytosolic side, was labelled by radioactive [(14)C]DCCD. Cytosolic loop V contains both DCCD-sensitive Asp(283) and a conserved motif sequence, rendering it a candidate for the catalytic site of vacuolar H(+)-pyrophosphatase. A topological picture of the active domain of vacuolar H(+)-pyrophosphatase is tentatively proposed.


Probucol attenuates high glucose-induced Müller cell damage through enhancing the Nrf2/p62 signaling pathway.
This study investigated the protective effect of probucol on Müller cells exposed to high glucose conditions and examined potential mechanisms of action. Primary human retinal Müller cells were incubated with high glucose (HG, 35 mM) in the present or absence of different concentrations of probucol for 24 h. Cell viability was determined using the CCK-8 method. Mitochondrial membrane potential (MMP) was measured using JC-1 staining and cell cycle by flow cytometry. The expression of nuclear factor E2-related factor 2 (Nrf2), glutamate-cysteine ligase catalytic subunit, and p62 was quantified using quantitative polymerase chain reaction and western blot. We found that HG inhibited cell proliferation, arrested cell cycle, and increased MMP in human Müller cells. Probucol activated the Nrf2/p62 pathway and upregulated the anti-apoptotic protein, Bcl2, and attenuated HG-mediated damage in Müller cells. Our results suggest that probucol may protect Müller cells from HG-induced damage through enhancing the Nrf2/p62 signaling pathway.


Invaded grassland communities have altered stability-maintenance mechanisms but equal stability compared to native communities.
Theory predicts that stability should increase with diversity via several mechanisms. We tested predictions in a 5-year experiment that compared low-diversity exotic to high-diversity native plant mixtures under two irrigation treatments. The study included both wet and dry years. Variation in biomass across years (CV) was 50% lower in mixtures than monocultures of both native and exotic species. Growth among species was more asynchronous and overyielding values were greater during and after a drought in native than exotic mixtures. Mean-variance slopes indicated strong portfolio effects in both community types, but the intercept was higher for exotics than for natives, suggesting that exotics were inherently more variable than native species. However, this failed to result in higher CV's in exotic communities because species that heavily dominated plots tended to have lower than expected variance. Results indicate that diversity-stability mechanisms are altered in invaded systems compared to native ones they replaced.


[Photo-emissions of nucleic acids and related compounds in the 120--250 nm region].
Photoemission of thin films of uracil, citosine, timine, adenine, quanine, DNA, RNA, nucleosides, nucleotides in the spectral region 125-250 nm is investigated. Photoemission work functions are determined, their values are in the interval of 5.7-6.1 ev. The dependence of photoemission efficiency on wave length for uracil, timine, DNA, RNA are measured. The results of this work with earlier data on luminescence yields are discussed. Possibility of radiation recombination process for wave lengths shorter than 160 nm is suggested.


Endemic work-related febrile respiratory illness among construction workers.
Construction workers building Denver International Airport (DIA) reported work-related respiratory and flulike symptoms of several months duration. We performed a cross-sectional interview study of 495 randomly selected DIA workers from six contractors in comparison with preplacement workers. We defined cases as workers with two work-attributed lower respiratory symptoms and one work-attributed systemic symptom. Case rates were significantly higher among DIA workers (34%) compared with those who had never worked at DIA (2%). Risk factors for illness included exposure to fireproofing (OR, 4.21; 95% CI, 1.95-9.08), work in tunnels and adjoining areas (OR, 3.07; 95% CI, 1.84-5.12), length of DIA employment (OR, 0.65; 95% CI, 0.46-0.92), and preexisting bronchitis (OR, 2.43; 95% CI, 1.17-5.05). Our industrial hygiene investigation revealed alkaline dust (pH 11) present at a worksite associated with elevated risk of illness, and we identified airborne Penicillium mold widely distributed indoors at DIA. Clinical evaluation of 26 self-identified symptomatic DIA employees, including bronchoalveolar lavage and biopsy in 10, revealed work-related asthma in three workers and histologic evidence of chronic bronchitis in four who had never smoked. We concluded that future investigations of endemic work-related febrile respiratory illness among construction workers should evaluate its association with indoor exposure to dusts from alkaline fireproofing, Penicillium mold, mycotoxins, and bacterial bioaerosols.


Statistical problems in assessing the true value of new in vitro diagnostic tests, with special reference to the chemiluminescent assay (CLA, MAST).
By virtue of familiarity and usage over many years, diagnostic tests may become established and be regarded as infallible "Gold Standards". In the case of allergic disease no test except perhaps allergen challenge can ever precisely reflect the clinical disease at the actual site of the allergic reaction. Thus when a new test is introduced there are no fixed values available for statistical comparison when directly comparing established tests with more recent additions. This is illustrated by many articles comparing the new multiple allergosorbent test system (CLA, MAST) which is a chemiluminescent assay, to other previously established tests. The major reports on CLA in the diagnosis of allergy are here discussed and summarized. Most trials have compared the accuracy of CLA with clinical history, with the skin prick test (SPT), the universally used in vivo method, or with RAST, the most common in vitro diagnostic method. CLA performed similarly to SPT and most CLA and RAST results matched; nevertheless in statistical analyses the problems of comparing diagnostic methods without a Gold Standard against which to judge become obvious-if two fallible methods disagree, which is correct? These statistical problems are discussed as well as other difficulties, such as the impact of the use of different allergen sources and the differing prevalence of allergies in the various test populations analysed.


ZEB1 imposes a temporary stage-dependent inhibition of muscle gene expression and differentiation via CtBP-mediated transcriptional repression.
Skeletal muscle development is orchestrated by the myogenic regulatory factor MyoD, whose activity is blocked in myoblasts by proteins preventing its nuclear translocation and/or binding to G/C-centered E-boxes in target genes. Recent evidence indicates that muscle gene expression is also regulated at the cis level by differential affinity for DNA between MyoD and other E-box binding proteins during myogenesis. MyoD binds to G/C-centered E-boxes, enriched in muscle differentiation genes, in myotubes but not in myoblasts. Here, we used cell-based and in vivo Drosophila, Xenopus laevis, and mouse models to show that ZEB1, a G/C-centered E-box binding transcriptional repressor, imposes a temporary stage-dependent inhibition of muscle gene expression and differentiation via CtBP-mediated transcriptional repression. We found that, contrary to MyoD, ZEB1 binds to G/C-centered E-boxes in muscle differentiation genes at the myoblast stage but not in myotubes. Its knockdown results in precocious expression of muscle differentiation genes and acceleration of myotube formation. Inhibition of muscle genes by ZEB1 occurs via transcriptional repression and involves recruitment of the CtBP corepressor. Lastly, we show that the pattern of gene expression associated with muscle differentiation is accelerated in ZEB1(-/-) mouse embryos. These results set ZEB1 as an important regulator of the temporal pattern of gene expression controlling muscle differentiation.


[Internet and videogame addiction: a review].
With the introduction of the new technologies to our daily lives, the Internet and electronic games have become widely and unrestrictedly used tools and one of the major global phenomena in the last decade. Several investigations have attested the benefits from such resources; however, their healthy, adaptive use progressively gave place to their abuse and the lack of control, which have severely impacted on the daily life of millions of users. The objective of this study was to systematically review the articles looking into Internet and electronic games addiction in the general population. We intend, therefore, to evaluate the progression of these concepts in the course of the last decade, as well as contributing to better understand this condition and its comorbidities. A systematic literature review was conducted by means of MedLine, Lilacs, SciELO, and Cochrane using the following terms as a parameter: "Internet addiction", "pathological internet use", "internet abuse", "videogame" , "computer games" and "electronic games". The electronic search was done up to December 2007. Studies conducted in distinct countries still indicate very different prevalence rates; this is probably due to the absence of consensus and the use of diverse names, which brings about the adoption of distinct diagnostic criteria. Many patients reporting abusive use and dependence show significant consequences to their professional, academic (school), social and family lives. Further investigations are needed to determine whether this abusive Internet and electronic game use should be understood as one of the newest psychiatric classifications of the 21st century or just substrates of other disorders.


Sudden rate drop intervention rate level in patients with new 'clarity' pacemakers and carotid sinus syndrome.
In patients in whom syncopal episodes are mainly caused by occasional drops in heart rate, Sudden Rate Drop intervention feature intends to provide high rate intervention pacing. New Vitatron Medical B.V. pacemaker system Clarity DDDR, provides AN option FOR recognizing Sudden Rate Drop and responding by intervention pacing until it detects the recovering. In patients with carotid sinus syndrome it is possible to provoke this situation BY sinus carotidus massage. We have implanted 10 of these devices in our center, 2 of which in patients with hypersensitive carotid sinus syndrome. In both patients, we activated sudden rate drop intervention on DDD mode pacing and applied protocol for testing the necessary level of Sudden Rate Drop Intervention Rate. Both patients gave their informed consent to be submitted to this testing. Pacemaker software assumes rate intervention level of 110 bpm. We tested our patients for rate levels of 90 and 110 bpm. Massaging the carotid sinus during 5 seconds, we provoked Sudden Rate Drop Intervention 10 times, in each patient, 5 times at intervention rate of 90 and 5 times at 110 bpm. Patients were unaware of the programmed intervention rate and were merely expected to report any different sensations experienced during the testing. In all 20 tests, pacemaker responded to sudden rate drop elicited by carotid sinus massage (100%), which was verified by selected event recordings. After the massage, neither of the patients registered any sensations at sudden rate drop intervention rate level of 90 bpm in a total od 10 tests (100%), while 8 out of 10 massages at 110 bpm intervention rate provoked palpitations (80%). On the grounds of this testing, we concluded that lowering of Sudden Rate Drop Intervention Rate Level from 110 BPM to 90 BPM does not affect the reliability of system reaction, but changes patient's awareness of heart beats. As a final conclusion, it should be said that basic prerogatives of a pacing system: safety and efficacy with minimal energy consumption, and in this case, quality of life option that a patients practically does not feel intervention when it occurs, are all met.


Pixel labeling by supervised probabilistic relaxation.
A simple modification to existing probabilistic relaxation procedures is suggested which allows the information contained in initial labels to exert an influence on the direction of relaxation throughout the process. In this manner, the initial labels assume more importance than with conventional algorithms and are used in combination with the outcome of relaxation at each iteration to produce a cooperative estimate of the correct label for a particular object. Pixel labeling examples are presented which show the performance that can be obtained with the modified algorithm. The procedure is readily generalized to allow other data to influence the process.


[Specific activity and molecular forms of NAD-kinase in Neurospora crassa ontogeny].
The specific activity and molecular forms of NAD-kinase during ontogenesis of Neurospora crassa were investigated. The specific activity of the enzyme increased drastically at critical stages of fungal development, i.e. during conidia germination and during transition from the logarithmic to stationary growth stage, reaching 85 nmole NADP/hr/mg protein. By polyacrylamide gel electrophoresis four forms of NAD-kinase were revealed that had the following molecular masses: I-338,000, II-306,000, III-229,000, and IV-203,000. The vegetative mycelium contained predominantly form III, and conidia showed a high content of high-molecular-weight forms I and II.


Roles of Efflux Pumps from Different Superfamilies in the Surface-Associated Motility and Virulence of Acinetobacter baumannii ATCC 17978.
Although the relationship between Acinetobacter baumannii efflux pumps and antimicrobial resistance is well documented, less is known about the involvement of these proteins in the pathogenicity of this nosocomial pathogen. In previous work, we identified the AbaQ major facilitator superfamily (MFS) efflux pump and demonstrated its participation in the motility and virulence of A. baumannii In the present study, we examined the role in these processes of A. baumannii transporters belonging to different superfamilies of efflux pumps. Genes encoding known or putative permeases belonging to efflux pump superfamilies other than the MFS were selected, and the corresponding knockouts were constructed. The antimicrobial susceptibilities of these mutants were consistent with previously reported data. In mutants of A. baumannii strain ATCC 17978 carrying inactivated genes encoding the efflux pumps A1S_2736 (resistance nodulation division [RND]), A1S_3371 (multidrug and toxic compound extrusion [MATE]), and A1S_0710 (small multidrug resistance [SMR]), as well as the newly described ATP-binding cassette (ABC) permeases A1S_1242 and A1S_2622, both surface-associated motility and virulence were reduced compared to the parental strain. However, inactivation of the genes encoding the known ABC permeases A1S_0536 and A1S_1535, the newly identified putative ABC permeases A1S_0027 and A1S_1057, or the proteobacterial antimicrobial compound efflux (PACE) transporters A1S_1503 and A1S_2063 had no effects on bacterial motility or virulence. Our results demonstrate the involvement of antimicrobial transporters belonging at least to five of the six known efflux pump superfamilies in both surface-associated motility and virulence in A. baumannii ATCC 17978.


Probing the safety of medications in the frail elderly: evidence from a randomized clinical trial of sertraline and venlafaxine in depressed nursing home residents.
In nursing home residents and other frail elderly patients, old age and potential drug-drug and drug-disease interactions may affect the relative safety and efficacy of medications. The purpose of this study was to examine the efficacy and tolerability of venlafaxine and sertraline for the treatment of depression among nursing home residents. The study was a 10-week randomized, double-blind, controlled trial of venlafaxine (doses up to 150 mg/day) versus sertraline (doses up to 100 mg/day) among 52 elderly nursing home residents with a DSM-IV depressive disorder and, at most, moderate dementia. The primary measure of outcome was the Hamilton Rating Scale for Depression (HAM-D). Adverse events were monitored and recorded systematically during the trial. Twelve subjects were discontinued due to serious adverse events (SAE), 5 were discontinued due to other significant side effects, and 2 withdrew consent. Tolerability estimated by the time to termination was lower for venlafaxine than sertraline for serious adverse events (log rank statistic = 5.28, p =.022), for serious adverse events or side effects (log rank statistic = 8.08, p =.005), or for serious adverse events, side effects, or withdrawal of consent (log rank statistic = 10.04, p =.002). Mean (SD) HAM-D scores at baseline were 20.2 (3.4) for sertraline and 20.3 (3.7) for venlafaxine; intent-to-treat endpoint HAM-D scores were 12.2 (5.1) and 15.7 (6.2) (F = 3.45; p =.069). There were no differences in categorical responses for the intent-to-treat sample or completers. In this frail elderly population, venlafaxine was less well tolerated and, possibly, less safe than sertraline without evidence for an increase in efficacy. This unexpected finding demonstrates the need for systematic research on the safety of drugs in the frail elderly.


Experimental anti-GBM disease as a tool for studying spontaneous lupus nephritis.
Lupus nephritis is an immune-mediated disease, where antibodies and T cells both play pathogenic roles. Since spontaneous lupus nephritis in mouse models takes 6-12 months to manifest, there is an urgent need for a mouse model that can be used to delineate the pathogenic processes that lead to immune nephritis, over a quicker time frame. We propose that the experimental anti-glomerular basement membrane (GBM) disease model might be a suitable tool for uncovering some of the molecular steps underlying lupus nephritis. This article reviews the current evidence that supports the use of the experimental anti-GBM nephritis model for studying spontaneous lupus nephritis. Importantly, out of about 25 different molecules that have been specifically examined in the experimental anti-GBM model and also spontaneous lupus nephritis, all influence both diseases concordantly, suggesting that the experimental model might be a useful tool for unraveling the molecular basis of spontaneous lupus nephritis. This has important clinical implications, both from the perspective of genetic susceptibility as well as clinical therapeutics.


Mitigating nitrogen pollution with under-sown legume-grass cover crop mixtures in winter cereals.
Nitrogen (N) pollution from N inputs to agricultural soils contributes to widespread eutrophication and global climate change. One period susceptible to N losses is between winter grain harvest in summer and corn planting in spring in a corn (Zea mays L.)-soybean [Glycine max (L.) Merr.]-winter grain rotation. Cover crops used to immobilize N during this period often depend on tillage, which can exacerbate N losses. Therefore, we evaluated whether reduced-till cover crops could decrease nitrate (NO3 - ) leaching and nitrous oxide (N2 O) emissions during this period. We tested this strategy in a cropping systems experiment on a 4-ha plot in central Pennsylvania over 2 yr. This experiment compared a clover (Trifolium pratense L.)-timothy (Phleum pratense L.) cover crop no-till underseeded into a standing spelt crop with a vetch (Vicia villosa Roth)-triticale (× Triticosecale Wittm. ex A. Camus) cover crop established with tillage after spelt harvest. These systems were compared based on fortnightly N2 O emissions using static chambers (n = 4 per six sample dates) and potential NO3 - leaching using anion resin bags (n = 4 per system per year). Reduced-till cover crops minimized peak N2 O emissions during the fall compared with tilled cover crops. However, reduced-till cover crops did not decrease potentially leachable NO3 - relative to tilled cover crops despite decreases in soil inorganic N. Cover crop N isotopes revealed that clover N may have mineralized and leached over the winter. Our results suggest that reduced-till cover crops can decrease N2 O emissions to mitigate the climate impact of agriculture but that winter-hardy cover crops should be chosen to mitigate leaching.


Interactions of a cationic antimicrobial (ε-polylysine) with an anionic biopolymer (pectin): an isothermal titration calorimetry, microelectrophoresis, and turbidity study.
ε-Polylysine (ε-PL) is a food-grade cationic antimicrobial that is highly effective against a range of food pathogens and spoilage organisms. In compositionally complex environments, like those found in most foods and beverages, the antimicrobial activity of cationic ε-PL is likely to be impacted by its interactions with anionic components. The purpose of this study was to characterize the interactions between cationic ε-polylysine and an anionic biopolymer (high methoxyl pectin, HMP) using isothermal titration calorimetry (ITC), microelectrophoresis (ME), and turbidity measurements. ITC and ME measurements indicated that ε-PL bound to pectin, while turbidity measurements indicated that the complexes formed could be either soluble or insoluble depending on solution composition. Ionic strength and pH were also shown to affect the interactions significantly, highlighting their electrostatic origin. This study demonstrates that ε-PL can form either soluble or insoluble complexes with anionic biopolymers depending on the composition of the system. Our study provides basic knowledge that will facilitate the more rational application of ε-PL in complex food systems.


Psoas Muscle Density Evaluated by Chest CT and Long-Term Mortality in COPD Patients.
Poor muscle quality in COPD patients relates to exercise intolerance and mortality. Muscle quality can be estimated on computed tomography (CT) by estimating psoas density (PsD). We tested the hypothesis that PsD is lower in COPD patients than in controls and relates to all-cause mortality. At baseline, PsD was measured using axial low-dose chest CT images in 220 COPD patients, 80% men, who were 65±8 years old with mild to severe airflow limitation and in a control group of 58 subjects matched by age, sex, body mass index (BMI) and body surface area (BSA). COPD patients were prospectively followed for 76.5 (48-119) months. Anthropometrics, smoking history, BMI, dyspnoea, lung function, exercise capacity, BODE index and exacerbations history were recorded. Cox proportional risk analysis determined the factors more strongly associated with long-term mortality. PsD was lower in COPD patients than in controls (40.5 vs 42.5, p=0.045). During the follow-up, 54 (24.5%) deaths occurred in the COPD group. PsD as well as age, sex, pack-year history, FEV1%, 6MWD, mMRC, BODE index, were independently associated with mortality. Multivariate analysis showed that age (HR 1.06; 95% CI 1.02-1.12, p=0.006) and CT-assessed PsD (HR 0.97; 95%CI 0.94-0.99, p=0.023) were the variables independently associated with all-cause mortality. In COPD patients with mild to severe airflow limitation, chest CT-assessed psoas muscle density was lower than in matched controls and independently associated with long-term mortality. Muscle quality using the easy to evaluate psoas muscle density from chest CT may provide clinicians with important prognostic information in COPD.


C16 hydroxylation of 3beta-hydroxy-delta5-steroids during the early neonatal period.
Temporal changes of the serum levels of 16-hydroxypregnenolone (3beta,16alpha-dihydroxy-5-pregnen-20-one) 3-sulfate (16-OH-Preg S) and 16-hydroxydehydroepiandrosterone (3beta,16alpha-dihydroxy-5-androsten-17-one) 3-sulfate (16-OH-DHEA S) were investigated by analyzing the levels of their precursor steroids, pregnenolone (3beta-hydroxy-5-pregnen-20-one) 3-sulfate (Preg S) and dehydroepiandrosterone (3beta-hydroxy-5-androsten-17-one) 3-sulfate (DHEA S), respectively, in the early neonatal period. The serum levels of these steroids were measured by GC-MS in full-term (gestational age: 37-41 weeks), pre-term (gestational age: 28-36 weeks) and extremely immature (gestational age: 24-27 weeks) infants. The changes in 16-hydroxysteroid production were also investigated by analyzing the ratios of the serum levels of 16-OH-Preg S and Preg S (16-OH-Preg S/Preg S ratio), and 16-OH-DHEA S and DHEA S (16-OH-DHEA S/DHEA S ratio). It was confirmed that the 16-hydroxylation of DHEA S and Preg S increased after birth, and the 16-OH-Preg S/Preg S ratio in full-term infants was significantly higher than in pre-term and extremely immature infants at days 0, 1-6 and 7-13. On the other hand, there were no significant differences between the 16-OH-DHEA S/DHEA S ratios of the three groups at days 0, 1-6 or 7-13. The mechanism of differences in the 16-hydroxylation of Preg S and DHEA S is also discussed.


Regulatory network of Escherichia coli: consistency between literature knowledge and microarray profiles.
The transcriptional network of Escherichia coli may well be the most complete experimentally characterized network of a single cell. A rule-based approach was built to assess the degree of consistency between whole-genome microarray experiments in different experimental conditions and the accumulated knowledge in the literature compiled in RegulonDB, a data base of transcriptional regulation and operon organization in E. coli. We observed a high and statistical significant level of consistency, ranging from 70%-87%. When effector metabolites of regulatory proteins are not considered in the prediction of the active or inactive state of the regulators, consistency falls by up to 40%. Similarly, consistency decreases when rules for multiple regulatory interactions are altered or when "on" and "off" entries were assigned randomly. We modified the initial state of regulators and evaluated the propagation of errors in the network that do not correlate linearly with the connectivity of regulators. We interpret this deviation mainly as a result of the existence of redundant regulatory interactions. Consistency evaluation opens a new space of dialogue between theory and experiment, as the consequences of different assumptions can be evaluated and compared.


Transcriptomic Analysis of Retinal Gene in Experimental Retinal Detachment Rats and Exploration of S100A9 and TLR4 in Human Vitreous.
To screen for the differentially expressed genes in experimental retinal detachment rats, and to explore the expression of S100 calcium-binding protein A9 and Toll-like receptor 4 in the vitreous of rhegmatogenous retinal detachment patients. Three rats of experimental retinal detachment and three normal rats were enrolled in the study. Transcriptomics (RNAseq) sequencing technology was used to screen differentially expressed genes in the retinas of the experimental retinal detachment group and the normal group. The selected differentially expressed genes for gene ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis were performed. In addition, the vitreous of 15 patients with rhegmatogenous retinal detachment and six patients with the control group were collected. The expressions of S100 calcium-binding protein A9 and Toll-like receptor 4 were detected by Elisa, and the differences in expression levels were analyzed statistically. A total of 198 differentially expressed genes were screened by RNAseq sequencing, including 118 upregulated genes and 80 downregulated genes. Kyoto Encyclopedia of Genes and Genomes analysis confirmed that the most enriched pathway was the mitogen-activated protein kinase signaling pathway. Compared to the normal group, the expressions of suppressor of cytokine signaling-3, Storkhead box-2, S100 calcium-binding protein A9, Spi-1 proto-oncogene, phosphodiesterase 1B, and kinesin-light chain 1 mRNA in the retinas of the experimental retinal detachment rats were up-regulated, and the expressions of Max interacting protein 1 and the voltage-gated sodium 1 were down-regulated. Compared to the control group, the expressions of S100 calcium-binding protein A9 and Toll-like receptor 4 were upregulated by Elisa in the vitreous humor of rhegmatogenous retinal detachment patients with a statistically significant difference (p all <.05). The differentially expressed genes of experimental retinal detachment rats were suppressor of cytokine signaling-3, Storkhead box-2, S100 calcium-binding protein A9, Spi-1 proto-oncogene, phosphodiesterase 1B, kinesin-light chain 1, Max interacting protein 1, voltage-gated sodium 1, etc. The differences of S100 calcium-binding protein A9 and Toll-like receptor 4 expressions between the rhegmatogenous retinal detachment patients and the control group were statistically significant, indicating that they may play a potential role in the inflammatory process of rhegmatogenous retinal detachment.


Risk assessment analysis for maternal autoantibody-related autism (MAR-ASD): a subtype of autism.
The incidence of autism spectrum disorder (ASD) has been rising, however ASD-risk biomarkers remain lacking. We previously identified the presence of maternal autoantibodies to fetal brain proteins specific to ASD, now termed maternal autoantibody-related (MAR) ASD. The current study aimed to create and validate a serological assay to identify ASD-specific maternal autoantibody patterns of reactivity against eight previously identified proteins (CRMP1, CRMP2, GDA, NSE, LDHA, LDHB, STIP1, and YBOX) that are highly expressed in developing brain, and determine the relationship of these reactivity patterns with ASD outcome severity. We used plasma from mothers of children diagnosed with ASD (n = 450) and from typically developing children (TD, n = 342) to develop an ELISA test for each of the protein antigens. We then determined patterns of reactivity a highly significant association with ASD, and discovered several patterns that were ASD-specific (18% in the training set and 10% in the validation set vs. 0% TD). The three main patterns associated with MAR ASD are CRMP1 + GDA (ASD% = 4.2 vs. TD% = 0, OR 31.04, p = <0.0001), CRMP1 + CRMP2 (ASD% = 3.6 vs. TD% = 0, OR 26.08, p = 0.0005) and NSE + STIP1 (ASD% = 3.1 vs. TD% = 0, OR 22.82, p = 0.0001). Additionally, we found that maternal autoantibody reactivity to CRMP1 significantly increases the odds of a child having a higher Autism Diagnostic Observation Schedule (ADOS) severity score (OR 2.3; 95% CI: 1.358-3.987, p = 0.0021). This is the first report that uses machine learning subgroup discovery to identify with 100% accuracy MAR ASD-specific patterns as potential biomarkers of risk for a subset of up to 18% of ASD cases in this study population.


Prototypical phosphine complexes of antimony(III).
Complexes of the generic formula [Cln(PR3)mSb]((3-n)+) (n = 1, 2, 3, or 4 and m = 1 or 2) have been prepared featuring [ClSb](2+), [Cl2Sb](1+), Cl3Sb, or [Cl4Sb](1-) as acceptors with one or two phosphine ligands {PMe3, PPh3, PCy3 (Cy = C6H11)}. The solid-state structures of the complexes reveal foundational features that define the coordination chemistry of a lone pair bearing stibine acceptor site. The experimental observations are interpreted with dispersion-corrected density functional theory calculations to develop an understanding of the bonding and structural diversity.


Dopamine stimulation of active Na and Cl absorption in rabbit ileum: interaction with alpha 2-adrenergic and specific dopamine receptors.
The effects of dopamine on active intestinal ion transport have been evaluated. An epithelial sheet preparation of rabbit ileum was used in vitro with the Ussing chamber-voltage clamp technique. Dopamine, in the presence of 1 mM ascorbic acid, added to the serosal bathing solution caused a dose-dependent decrease in short-circuit current, with a half-maximal effect at 1.2 muM and maximal effect of -50 muA/cm(2) at 50 muM; dopamine decreased the potential difference, and increased the conductance and net Na and net Cl absorption. There was no effect on the residual ion flux. Dopamine did not alter the change in short-circuit current caused by mucosal glucose (10 mM) or serosal theophylline (10 mM). Mucosal dopamine had no effect. The effect of dopamine on short-circuit current was inhibited by the dopamine antagonists haloperidol and domperidone and the alpha(2)-adrenergic antagonist yohimbine; there was no effect of the alpha(1)-antagonist prazosin and the beta-antagonist propranolol. In addition, the alpha(2)-adrenergic agonist clonidine, but not the alpha(1)-agonist methoxamine caused a dose-dependent decrease in short-circuit current. The ileal effects of dopamine did not occur via conversion into norepinephrine or release of norepinephrine from the peripheral nerves since "peripheral sympathectomy" with 6-hydroxydopamine did not alter the dopamine-induced change in ileal short-circuit current. The dopamine effects were not associated with a change in basal ileal cyclic AMP content but were associated with a decrease in total ileal calcium content as measured by atomic absorption spectrometry and as estimated by (45)Ca(++) uptake. The decrease in calcium content could be attributed to a dopamine-induced decrease in (45)Ca(++) influx from the serosal surface. Because of the presence of dopamine in ileal mucosa and these effects on ileal electrolyte transport, it is possible that dopamine may be involved in the physiologic regulation of active intestinal electrolyte absorption.


Prefrontal-temporal circuitry for episodic encoding and subsequent memory.
Humans encounter and form memories for multiple types of experiences that differ in content, novelty, and memorability. Critical for understanding memory is determining (1) how the brain supports the encoding of events with differing content and (2) whether neural regions that are sensitive to novelty also influence whether stimuli will be subsequently remembered. This event-related functional magnetic resonance imaging (fMRI) study crossed content (picture/word), novelty (novel/repeated), and subsequent memory (remembered/forgotten) to examine prefrontal and temporal lobe contributions to encoding. Results revealed three patterns of encoding-related activation in anatomically connected inferior prefrontal and lateral temporal structures that appeared to vary depending on whether visuospatial/visuo-object, phonological/lexical, or semantic attributes were processed. Event content also modulated medial temporal lobe activity; word encoding predominantly activated the left hemisphere, whereas picture encoding activated both hemispheres. Critically, in prefrontal and temporal regions that were modulated by novelty, the magnitude of encoding activation also predicted whether an event would be subsequently remembered. These results suggest that (1) regions that demonstrate a sensitivity to novelty may actively support encoding processes that impact subsequent explicit memory and (2) multiple content-dependent prefrontal-temporal circuits support event encoding. The similarities between prefrontal and lateral temporal encoding responses raise the possibility that prefrontal modulation of posterior cortical representations is central to encoding.


Ternary low-temperature phototherapy nano-systems for the treatment of diabetic wounds.
The physicochemical environment at the sites of chronic diabetic wounds is an ideal habitat for bacteria, which exacerbate the deterioration of the microenvironment at the wound sites and consequently delay wound healing. In recent years, photothermal therapy has been considered an ideal non-antibiotic antimicrobial strategy. However, photothermal therapy alone is prone to cause damage to the body tissues. Herein, a (zeolitic imidazolate framework-8) ZIF-8/(mesoporous polydopamine) MPDA@(deoxyribonuclease I) DNase I ternary nanocomposite system was constructed, which exhibited good antimicrobial and antioxidant properties. Specifically, DNase I was first encapsulated into MPDA nanoparticles (NPs) and then coated with ZIF-8, which rapidly degrades in an acidic bacterial environment, triggering the release of antimicrobial Zn2+ and DNase I, thus enabling low-temperature (∼45 °C) PTT antimicrobial therapy. Meanwhile, the NPs can effectively regulate the oxidative stress environment at the trauma site because of the antioxidant effect of MPDA. Moreover, the experimental results of the diabetic wound infection mouse model showed that the prepared NPs could kill bacteria well and accelerate wound healing. Overall, the phototherapy strategy proposed in this study shows great potential in the treatment of chronically infected wounds.


Ubiquitin and apoptosis in the corpus luteum of the marmoset monkey (Callithrix jacchus).
The polypeptide ubiquitin covalently binds to cytoplasmic proteins and marks them for proteolytic degradation. Ubiquitin is upregulated during apoptosis in some systems. Apoptosis increases during luteolysis but it is not known whether ubiquitin is expressed in regressing corpora lutea. Marmoset ovaries were removed on day 10 of the luteal phase from animals that had received either no treatment, treatment with the PGF2 alpha analogue cloprostenol 24 h earlier, or treatment with the GnRH antagonist antarelix for either 24 or 48 h before ovary collection. Ubiquitin was localized on ovarian sections by immunocytochemistry, and oligonucleosome formation characteristic of apoptosis was examined in isolated corpora lutea by electrophoresis of extracted [32P]DNA. Oligonucleosome formation was low in midluteal corpora lutea on day 10 but increased after induced luteal regression with PGF2 alpha and GnRH antagonist. Nuclear ubiquitin immunoreactivity was found in 1.66 +/- 0.66 steroidogenic cells and cytoplasmic staining was found in 0.4 +/- 0.3 steroidogenic cells (per x 40 field of view) in midluteal phase corpora lutea on day 10. Luteolytic induction with PGF2 alpha significantly increased the number of cells exhibiting cytoplasmic immunoreactivity to 12.24 +/- 1.6 (P < 0.05). Ubiquitin immunoreactivity was not observed after GnRH-induced luteal regression. Apoptotic oligonucleosome formation was found after induced luteal regression with both PGF2 alpha and GnRH antagonist, but ubiquitin upregulation only occurred after PGF2 alpha-induced regression. These results indicate that ubiquitin expression is not specific for luteolysis and is not an indicator of luteal apoptosis, but that the polypeptide does play a role in luteal cellular responses to PGF2 alpha.


Pharmacology and Mechanism of Action of HSK16149, a Selective Ligand of α2δ Subunit of Voltage-Gated Calcium Channel with Analgesic Activity in Animal Models of Chronic Pain.
Chronic pain is a public health problem because current treatments are unsatisfactory with small therapeutic index. Although pregabalin is effective for treating chronic pain, the clinical use is limited because of its side effects. Therefore, improving its therapeutic index is essential. In this study, HSK16149 was found to be a novel ligand of voltage-gated calcium channel (VGCC) α 2 δ subunit. HSK16149 inhibited [3H]gabapentin binding to the α 2 δ subunit and was 23 times more potent than pregabalin. In two rat models of neuropathic pain, the minimum effective dose (MED) of HSK16149 was 10 mg/kg, and the efficacy was similar to that of 30 mg/kg pregabalin. Moreover, the efficacy of HSK16149 could persist up to 24 hours postadministration at 30 mg/kg, whereas the efficacy of pregabalin lasted only for 12 hours at 30 mg/kg in streptozotocin-induced diabetic neuropathy model, indicating that HSK16149 might be a longer-acting drug candidate. HSK16149 could also inhibit mechanical allodynia in intermittent cold stress model and decrease phase II pain behaviors in formalin-induced nociception model. In addition, the locomotor activity test showed that the MED of HSK16149 was similar to that of pregabalin, whereas in the Rotarod test, the MEDs of HSK16149 and pregabalin were 100 and 30 mg/kg, respectively. These findings indicated that HSK16149 might have a better safety profile on the central nervous system. In summary, HSK16149 is a potent ligand of VGCC α 2 δ subunit with a better therapeutic index than pregabalin. Hence, it could be an effective and safe drug candidate for treating chronic pain. SIGNIFICANCE STATEMENT: As a novel potent ligand of voltage-gated calcium channel α 2 δ subunit, HSK16149 has the potential to be an effective and safe drug candidate for the treatment of chronic pain.


Hydrogel-PLGA delivery system prolongs 2-methoxyestradiol-mediated anti-tumor effects in osteosarcoma cells.
Osteosarcoma is a bone tumor that affects children and young adults. 2-Methoxyestradiol (2-ME), a naturally occurring estrogen metabolite, kills osteosarcoma cells, but does not affect normal osteoblasts. In order to effectively target osteosarcoma and improve the therapeutic index of the drug 2-ME, we have encapsulated 2-ME in a composite of oligo-(polyethylene glycol) fumarate (OPF) hydrogel and poly (lactic-co-glycolic acid) (PLGA) microspheres and investigated the effect of polymer composition on 2-ME release kinetics and osteosarcoma cell survival. The in vitro study shows that 2-ME can be released in a controlled manner over 21-days. The initial burst releases observed on day 1 were 50% and 32% for OPF and OPF/PLGA composites, respectively. The extended release kinetics show that 100% of the encapsulated 2-ME is released by day 12 from OPF, whereas the OPF/PLGA composites showed a release of 85% on day 21. 2-ME released from the polymers was biologically active and blocked osteosarcoma cell proliferation in vitro. Also, comparison of 2-ME delivery in osteosarcoma cells in culture, shows that direct treatment has no effect after 3 days, whereas polymer-mediated delivery produces anti-tumor effects that could be sustained for 21 days. These findings show that the OPF and PLGA polymeric system may prove to be useful in controlled and sustained delivery of 2-ME and could be further explored in the treatment of osteosarcoma.


Association between handgrip strength and maximum expiratory flow with site-specific bone mineral density of healthy young adults.
To explore the association of handgrip strength and peak expiratory flow rate with site-specific bone mineral density T scores, and to study the correlation of body mass index and physical activity with the three parameters. The cross-sectional study was conducted in November 2018 at the Combined Military Hospital, Lahore Medical College and Institute of Dentistry, Lahore, Pakistan, and comprised healthy young adults. Data was collected using the international physical activity questionnaire. The subjects were grouped into low, moderate and high categories. Handgrip strength, peak expiratory flow rate, bone mineral density T scores and body mass index were measured for each subject. Data was analysed using SPSS 24. Of the 102 subjects, 52(50.9%) were males and 50(49%) were females. There was a significant difference between the median values for all parameters of males and females (p<0.05). Bone mineral density and physical activity were moderately associated with handgrip strength and peak expiratory flow rate (p<0.05). Body mass index showed a moderate association with bone mineral density (p<0.05). Healthy young adults with better respiratory function and handgrip strength were found to have higher values of site-specific calcaneal bone mineral density. Subjects with higher reported levels of physical activity and a higher body mass index within a healthy range presented with improved values of bone mineral density, handgrip strength and peak expiratory flow rate.