Miracle-dz/UniFAR-FTUs huggingface dataset:
Association of Response to Inhaled Nitric Oxide and Duration of Mechanical Ventilation in Pediatric Acute Respiratory Distress Syndrome*

Objectives: Literature regarding appropriate use of inhaled nitric oxide for pediatric acute respiratory distress syndrome is sparse. This study aims to determine if positive response to inhaled nitric oxide is associated with decreased mortality and duration of mechanical ventilation in pediatric acute respiratory distress syndrome. Design: Retrospective cohort study. Setting: Large pediatric academic medical center. Patients or Subjects: One hundred sixty-one children with pediatric acute respiratory distress syndrome and inhaled nitric oxide exposure for greater than or equal to 1 hour within 3 days of pediatric acute respiratory distress syndrome onset. Interventions: Patients with greater than or equal to 20% improvement in oxygenation index or oxygen saturation index by 6 hours after inhaled nitric oxide initiation were classified as “responders. ” Measurements and Main Results: Oxygenation index, oxygen saturation index, and ventilator settings were evaluated prior to inhaled nitric oxide initiation and 1, 6, 12, and 24 hours following inhaled nitric oxide initiation. Primary outcomes were mortality and duration of mechanical ventilation. Baseline characteristics, including severity of illness, were similar between responders and nonresponders. Univariate analysis showed no difference in mortality between responders and nonresponders (21% vs 21%; p = 0.999). Ventilator days were significantly lower in responders (10 vs 16; p < 0.001). Competing risk regression (competing risk of death) confirmed association between inhaled nitric oxide response and successful extubation (subdistribution hazard ratio = 2.11; 95% CI, 1.41–3.17; p < 0.001). Response to inhaled nitric oxide was associated with decreased utilization of high-frequency oscillatory ventilation and extracorporeal membrane oxygenation and lower hospital charges (difference in medians of $424,000). Conclusions: Positive response to inhaled nitric oxide was associated with fewer ventilator days, without change in mortality, potentially via reduced use of high-frequency oscillatory ventilation and extracorporeal membrane oxygenation. Future studies of inhaled nitric oxide for pediatric acute respiratory distress syndrome should stratify based on oxygenation response, given the association with favorable outcomes.
The Adaptor Protein CD2AP Is a Coordinator of Neurotrophin Signaling-Mediated Axon Arbor Plasticity

Growth of intact axons of noninjured neurons, often termed collateral sprouting, contributes to both adaptive and pathological plasticity in the adult nervous system, but the intracellular factors controlling this growth are largely unknown. An automated functional assay of genes regulated in sensory neurons from the rat in vivo spared dermatome model of collateral sprouting identified the adaptor protein CD2-associated protein (CD2AP; human CMS) as a positive regulator of axon growth. In non-neuronal cells, CD2AP, like other adaptor proteins, functions to selectively control the spatial/temporal assembly of multiprotein complexes that transmit intracellular signals. Although CD2AP polymorphisms are associated with increased risk of late-onset Alzheimer's disease, its role in axon growth is unknown. Assessments of neurite arbor structure in vitro revealed CD2AP overexpression, and siRNA-mediated knockdown, modulated (1) neurite length, (2) neurite complexity, and (3) growth cone filopodia number, in accordance with CD2AP expression levels. We show, for the first time, that CD2AP forms a novel multiprotein complex with the NGF receptor TrkA and the PI3K regulatory subunit p85, with the degree of TrkA:p85 association positively regulated by CD2AP levels. CD2AP also regulates NGF signaling through AKT, but not ERK, and regulates long-range signaling though TrkA+/RAB5+ signaling endosomes. CD2AP mRNA and protein levels were increased in neurons during collateral sprouting but decreased following injury, suggesting that, although typically considered together, these two adult axonal growth processes are fundamentally different. These data position CD2AP as a major intracellular signaling molecule coordinating NGF signaling to regulate collateral sprouting and structural plasticity of intact adult axons. SIGNIFICANCE STATEMENT Growth of noninjured axons in the adult nervous system contributes to adaptive and maladaptive plasticity, and dysfunction of this process may contribute to neurologic pathologies. Functional screening of genes regulated during growth of noninjured axons revealed CD2AP as a positive regulator of axon outgrowth. A novel association of CD2AP with TrkA and p85 suggests a distinct intracellular signaling pathway regulating growth of noninjured axons. This may also represent a novel mechanism of generating specificity in multifunctional NGF signaling. Divergent regulation of CD2AP in different axon growth conditions suggests that separate mechanisms exist for different modes of axon growth. CD2AP is the first signaling molecule associated with adult sensory axonal collateral sprouting, and this association may offer new insights for NGF/TrkA-related Alzheimer's disease mechanisms.
Sex Differences in Behavioral Reactions to Provocation of Anger

The purpose of this study was to examine sex differences in behavioral reactions to provocation of anger. In a field study, 72 subjects recorded all anger-arousing incidents for a 2-wk. period. Physical and Verbal Antagonism were found in more reports by men while Passive Consent was noted in more reports by women. For a laboratory study, 101 subjects responded to self-report scales of behavioral responses after exposure to an insulting letter. No sex differences were noted in subjects' self-reports of behavioral reactions. Variations in design are brought to bear in interpreting the findings.
VEGF Potentiates GD3-Mediated Immunosuppression by Human Ovarian Cancer Cells

Purpose: Natural killer T (NKT) cells are important mediators of antitumor immune responses. We have previously shown that ovarian cancers shed the ganglioside GD3, which inhibits NKT-cell activation. Ovarian cancers also secrete high levels of VEGF. In this study, we sought to test the hypothesis that VEGF production by ovarian cancers suppresses NKT-cell–mediated antitumor responses. Experimental Design: To investigate the effects of VEGF on CD1d-mediated NKT-cell activation, a conditioned media model was established, wherein the supernatants from ovarian cancer cell lines (OV-CAR-3 and SK-OV-3) were used to treat CD1d-expressing antigen-presenting cells (APC) and cocultured with NKT hybridomas. Ovarian cancer–associated VEGF was inhibited by treatment with bevacizumab and genistein; conditioned medium was collected, and CD1d-mediated NKT-cell responses were assayed by ELISA. Results: Ovarian cancer tissue and ascites contain lymphocytic infiltrates, suggesting that immune cells traffic to tumors, but are then inhibited by immunosuppressive molecules within the tumor microenvironment. OV-CAR-3 and SK-OV-3 cell lines produce high levels of VEGF and GD3. Pretreatment of APCs with ascites or conditioned medium from OV-CAR-3 and SK-OV-3 blocked CD1d-mediated NKT-cell activation. Inhibition of VEGF resulted in a concomitant reduction in GD3 levels and restoration of NKT-cell responses. Conclusions: We found that VEGF inhibition restores NKT-cell function in an in vitro ovarian cancer model. These studies suggest that the combination of immune modulation with antiangiogenic treatment has therapeutic potential in ovarian cancer. Clin Cancer Res; 22(16); 4249–58. ©2016 AACR.
Understanding, Implementing and Exploiting Agility and Leanness

The latter part of the 20th century saw the lean production paradigm positively impact many market sectors ranging from automotive through to construction. In particular, there is much evidence to suggest that level scheduling combined with the elimination of muda has successfully delivered a wide range of products to those markets where cost is the primary order winning criteria. However, there are many other volatile markets where the order winner is availability, which has led to the emergence of the agile paradigm typified by "quick response" and similar initiatives. Nevertheless, lean and agile are not mutually exclusive paradigms and may be married to advantage as is shown in the lighting industry case study. The outcome of our review of the characteristics of "lean" and "agile" supply is the proposition of a model for enabling change to the agile enterprise. This incorporates the three levels of principles, programmes and actions. We conclude by showing that the model encompasses the major factors executed within the case study, which covers agility throughout the product introduction process and product delivery process. It appears to be a feature of the successful implementation of agility that it is an organisation-wide shift in culture and cannot be restricted to just a few activities.
HLA‐G has a concentration‐dependent effect on the generation of an allo‐CTL response

Human leucocyte antigen (HLA) ‐G is expressed on trophoblast cells during pregnancy, suggesting a role in protection of the semiallogeneic fetus. Published data suggest that HLA‐G protects a cell against natural killer cell lysis. It has been hypothesized that HLA‐G may also protect the fetus by preventing allo‐cytotoxic T lymphocyte (CTL) responses. To test this hypothesis, we assayed the effects of various concentrations of purified HLA‐G on CTL response in a mixed lymphocyte culture (MLC) system. We found that concentrations ≥ 0·1 µg/ml of HLA‐G suppressed the allo‐CTL response by 30–100% over the control, but, paradoxically, concentrations of 0·01–0·05 µg/ml of HLA‐G augmented the allo‐CTL response by 25–50% over the control. Concentrations ≤ 0·001 µg/ml HLA‐G had no effect. Addition of HLA‐G to preprimed allo‐CTL effector cells did not affect their killing ability. Allo‐CTL suppressive doses of HLA‐G induced a T helper type 2 (Th2) cytokine response, whereas allo‐CTL‐enhancing doses of HLA‐G induced a Th1‐type cytokine response. HLA‐G purified from first‐trimester placenta does not affect allo‐proliferative responses nor does it alter the percentage of CD4+ or CD8+ T cells in MLCs. These findings support a potential role for HLA‐G‐mediated suppression of allo‐CTL formation in normal pregnancies. In addition, the effects observed at lower concentrations of HLA‐G may have interesting implications for the condition of pre‐eclampsia in which concentrations of this HLA class I molecule are reduced.
Negligent care and malpractice claiming behavior in Utah and Colorado.

BACKGROUND Previous studies relating the incidence of negligent medical care to malpractice lawsuits in the United States may not be generalizable. These studies are based on data from 2 of the most populous states (California and New York), collected more than a decade ago, during volatile periods in the history of malpractice litigation. OBJECTIVES The study objectives were (1) to calculate how frequently negligent and nonnegligent management of patients in Utah and Colorado in 1992 led to malpractice claims and (2) to understand the characteristics of victims of negligent care who do not or cannot obtain compensation for their injuries from the medical malpractice system. DESIGN We linked medical malpractice claims data from Utah and Colorado with clinical data from a review of 14,700 medical records. We then analyzed characteristics of claimants and nonclaimants using evidence from their medical records about whether they had experienced a negligent adverse event. MEASURES The study measures were negligent adverse events and medical malpractice claims. RESULTS Eighteen patients from our study sample filed claims: 14 were made in the absence of discernible negligence and 10 were made in the absence of any adverse event. Of the patients who suffered negligent injury in our study sample, 97% did not sue. Compared with patients who did sue for negligence occurring in 1992, these nonclaimants were more likely to be Medicare recipients (odds ratio [OR], 3.5; 95% CI [CI], 1.3 to 9.6), Medicaid recipients (OR, 3.6; 95% CI, 1.4 to 9.0), > or =75 years of age (OR, 7.0; 95% CI, 1.7 to 29.6), and low income earners (OR, 1.9; 95% CI, 0.9 to 4.2) and to have suffered minor disability as a result of their injury (OR, 6.3; 95% CI, 2.7 to 14.9). CONCLUSIONS The poor correlation between medical negligence and malpractice claims that was present in New York in 1984 is also present in Utah and Colorado in 1992. Paradoxically, the incidence of negligent adverse events exceeds the incidence of malpractice claims but when a physician is sued, there is a high probability that it will be for rendering nonnegligent care. The elderly and the poor are particularly likely to be among those who suffer negligence and do not sue, perhaps because their socioeconomic status inhibits opportunities to secure legal representation.
Gamma Interferon Stimulates Rat Alveolar Macrophages To Kill Pneumocystis carinii byl-Arginine- and Tumor Necrosis Factor-Dependent Mechanisms

ABSTRACT Pneumocystis carinii pneumonia remains a serious complication for immunocompromised patients. In the present study,P. carinii organisms interacted with gamma interferon (IFN-γ)-stimulated alveolar macrophages (AMs) to activate thel-arginine-dependent cytocidal pathway involving reactive nitrogen intermediates (RNI) that were assayed as nitrite (NO2−). Unstimulated cultures of AMs produced negligible quantities of RNI. Addition of P. cariniiorganisms to IFN-γ-primed AMs resulted in greatly enhanced production of RNI. NO2− levels increased from 0.8 ± 0.4 to 11.1 ± 3.8 μM as early as 6 h after P. carinii organisms were incubated with IFN-γ-stimulated AMs and to 35.1 ± 8.9 μM after a 24-h incubation, a near-maximum level. High levels of NO2− were produced by AMs primed with as little as 10 U of IFN-γ per ml in the presence ofP. carinii, and a 20-fold increase in IFN-γ concentration resulted in only a further 65% increase in NO2− production. RNI-dependent killing ofP. carinii was demonstrated by both a 51Cr release assay and a [35S]methionine pulse immunoprecipitation assay. Addition of either monoclonal tumor necrosis factor alpha (TNF-α) neutralizing antibody or 200 μMNG-monomethyl-l-arginine (l-NGMMA), a competitive inhibitor of the l-arginine-dependent pathway, significantly decreased NO2− production and reduced P. carinii killing. TNF-α alone had no effect on P. carinii viability. These results suggest that (i) the specific interaction of P. carinii organisms with IFN-γ-primed AMs triggers the production of RNI, (ii) RNI are toxic to P. carinii, and (iii) TNF-α likely plays a central role in mediating P. carinii killing by IFN-γ-stimulated AMs.
Dietary intake and physical activity levels of children attending Australian childcare services.

AIM The primary aim of this study was to describe the dietary intake and physical activity levels of children while attending childcare. METHODS A cross-sectional study was conducted with 18 centre-based childcare services in the Hunter region of New South Wales, Australia. Childcare service characteristics were assessed via telephone interview. Child dietary intake and physical activity levels were assessed during a one-day observation conducted at participating childcare services using previously validated tools. RESULTS Children consumed a mean of 0.2 serves of vegetables, 0.7 serves of fruit, 1.4 serves of grain (cereal) foods, 0.1 serves of lean meat and poultry, fish, eggs, nuts and seeds and legumes/beans, 0.6 serves of milk, yoghurt, cheese and alternatives, and 0.7 serves of discretionary foods during attendance at childcare. Of all child physical activity counts, 48.6% were classified as 'sedentary', and 22.3% classified as 'very active'. Bivariate analyses indicated that children attending services located in rural areas consumed significantly more serves of vegetables (0.3 serves (SD 0.7) vs 0.1 serves (SD 0.2), P = 0.05). Multivariate analyses indicated that services with large child enrolments had a significantly greater proportion of child counts classified as 'very active' (23.6% of child counts (95% CI 1.6, 29.5) vs 14.9% of child counts (95% CI 9.1, 20.6), P = 0.007). CONCLUSIONS There is considerable scope to improve the diet and activity behaviours of children during attendance at childcare. Future research is needed to identify effective strategies to best support childcare services in implementing policies and practices to improve such behaviours in children.
Serum levels of excitatory amino acids, serine, glycine, histidine, threonine, taurine, alanine and arginine in treatment‐resistant depression: modulation by treatment with antidepressants and prediction of clinical responsivity

Previous research has revealed that major depression is accompanied by disorders in excitatory amino acids, e.g. glutamate and aspartate, and alterations in serum levels of other amino acids, e.g. serine, glycine and taurine. The aim of the present study was to examine serum levels of aspartate, asparagine, glutamate, glutamine, serine, glycine, threonine, histidine, alanine, taurine and arginine in major depression patients with treatment‐resistant depression (TRD). No significant differences in the serum concentrations of any of the above amino acids could be found between patients with and without TRD and normal controls. Non‐responders to treatment with antidepressants during a period of 5 weeks were characterized by significantly lower serum levels of aspartate, asparagine, serine, threonine and taurine. A 5‐week period of treatment with antidepressants significantly reduced the serum levels of aspartate, glutamate and taurine, and significantly increased the serum concentrations of glutamine. The results suggest that alterations in serum levels of aspartate, asparagine, serine, threonine and taurine may predict the subsequent response to treatment with antidepressants, and that the latter may modulate serum levels of excitatory amino acids and taurine.
Validity of questionnaire self-reports on computer, mouse and keyboard usage during a four-week period

Objective: To examine the validity and potential biases in self-reports of computer, mouse and keyboard usage times, compared with objective recordings. Methods: A study population of 1211 people was asked in a questionnaire to estimate the average time they had worked with computer, mouse and keyboard during the past four working weeks. During the same period, a software program recorded these activities objectively. The study was part of a one-year follow-up study from 2000–1 of musculoskeletal outcomes among Danish computer workers. Results: Self-reports on computer, mouse and keyboard usage times were positively associated with objectively measured activity, but the validity was low. Self-reports explained only between a quarter and a third of the variance of objectively measured activity, and were even lower for one measure (keyboard time). Self-reports overestimated usage times. Overestimation was large at low levels and declined with increasing levels of objectively measured activity. Mouse usage time proportion was an exception with a near 1:1 relation. Variability in objectively measured activity, arm pain, gender and age influenced self-reports in a systematic way, but the effects were modest and sometimes in different directions. Conclusion: Self-reported durations of computer activities are positively associated with objective measures but they are quite inaccurate. Studies using self-reports to establish relations between computer work times and musculoskeletal pain could be biased and lead to falsely increased or decreased risk estimates.
Mechanisms of Initiation and Termination Reactions in Conjugative DNA Processing

The relaxase (TraI) of plasmid RP4 (IncPα) plays a key role in initiation and termination of transfer DNA replication during conjugative transmission of the plasmid. TraI functions as a DNA strand transferase that cleaves a unique phosphodiester bond at nic of the transfer origin. The cleavage reaction consists in a reversible transesterification that leads to transfer of the 5′ phosphoryl at nic to the hydroxyl group of TraI Tyr-22. Hence, cleavage results in the covalent attachment of TraI to the 5′ terminus of the plasmid strand destined for transfer. To investigate the protein's ability to function in a “second cleavage” reaction proposed to terminate rolling circle mode transfer DNA replication, single-stranded oligonucleotides containing the nic region were immobilized at their 3′ ends on magnetic beads and cleaved by TraI. The resulting covalent TraI-oligonucleotide adducts were active in the joining reaction but unable to cleave oligonucleotides containing an intact nic region, indicating that second cleavage probably requires a TraI dimer, since a monomer is insufficient. The covalently attached oligonucleotide determines the affinity of the relaxase for the 3′ terminus of the T-strand. To further the biochemical characterization of TraI-catalyzed reactions, we used specific TraI mutants, showing that amino acid residues in each relaxase motif are involved in substrate binding. To uncouple substrate binding and cleaving-joining, we applied partially biotinylated TraI mutant proteins that were immobilized to magnetic beads. Using this approach we could demonstrate that tight DNA substrate binding and cleaving-joining are independent processes. Enhanced topoisomerase activity of some TraI mutants was correlated with low specific substrate binding affinity in conjunction with high cleaving-joining activity.
Evidence that benzo(a)anthracene 3,4-diol-1,2-epoxide is an ultimate carcinogen on mouse skin.

Abstract Benzo(a)anthracene (BA) and several benzo-ring derivatives of BA were tested for their tumor-initiating activity on mouse skin. A single topical application of 0.1 to 2.0 µmol of hydrocarbon was followed 7 days later by twiceweekly applications of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate for 20 weeks. Comparisons of the percentage of mice with papillomas and the number of papillomas observed per mouse indicated that both diastereomeric 3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo(a)anthracenes, in which the epoxide oxygen is either cis (diol-epoxide 1) or trans (diol-epoxide 2) to the benzylic 4-hydroxyl group, were 10- to 40-fold more tumorigenic (papillomas/mouse) than was the parent hydrocarbon, benzo(a)anthracene. Diol-epoxide 2 was 2- to 3-fold more tumorigenic than was diol-epoxide 1 after 20 weeks of promotion. The immediate metabolic precursor of the 3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo(a)anthracenes, trans-3,4-dihydroxy-3,4-dihydrobenzo(a)anthracene, had intermediate tumorigenic activity compared to diol-epoxide 1 and diol-epoxide 2 and was approximately 20-fold more tumorigenic (papillomas/mouse) than was BA. Resolution of racemic trans-3,4-dihydroxy-3,4-dihydrobenzo(a)anthracene into the (-)- and (+)-enantiomers and assignment of their absolute stereochemistry revealed that the (-)-(3R,4R) isomer was at least 5-fold more active as a tumor initiator than was the (+)-(3S,4S) isomer. 1,2-Dihydrobenzo(a)anthracene and 3,4-dihydrobenzo(a)anthracene were also tested for tumorigenic activity. 3,4-Dihydrobenzo(a)anthracene was the most potent tumorigenic compound used in this study. 1,2-Dihydrobenzo(a)anthracene was a very weak tumor initiator, with activity comparable to BA. These results support the concept that a diol-epoxide in which the epoxide on a saturated, angular benzo ring forms part of a “bay region” of the hydrocarbon is a prime candidate for an ultimate carcinogenic metabolite of the hydrocarbon. In the case of BA, this metabolite is either or both of the diastereomeric 3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo(a)anthracenes.