Miracle-dz/UniFAR-FTUs huggingface dataset:
Protease-Activated Receptor-2 Activation Induces Acute Lung Inflammation by Neuropeptide-Dependent Mechanisms 1

Protease-activated receptors (PARs) and tachykinin-immunoreactive fibers are located in the lung as sentries to respond to a variety of pathological stimuli. The effects of PAR activation on the lung have not been adequately studied. We report on the effects of instilling PAR-activating peptides (PAR-APs, including PAR1-, PAR2-, and PAR4-AP) into the lungs of ventilated or spontaneously breathing mice. PAR2-AP, but not PAR1-AP or PAR4-AP, caused a sharp increase in lung endothelial and epithelial permeability to protein, extravascular lung water, and airway tone. No responses to PAR2-AP were detected in PAR2 knockout mice. In bronchoalveolar lavage, PAR2 activation caused 8- and 5-fold increase in MIP-2 and substance P levels, respectively, and a 12-fold increase in the number of neutrophils. Ablation of sensory neurons (by capsaicin) markedly decreased the PAR2-mediated airway constriction, and virtually abolished PAR2-mediated pulmonary inflammation and edema, as did blockade of NK1 or NK2 receptors. Thus, PAR2 activation in the lung induces airway constriction, lung inflammation, and protein-rich pulmonary edema. These effects were either partly or completely neuropeptide dependent, suggesting that PAR2 can cause lung inflammation by a neurogenic mechanism.
Staff Needs When Working in Secure Forensic Child and Adolescent Mental Health

ABSTRACT There is increasing recognition regarding the psychological impact of working in demanding healthcare settings. However, little empirical research has been conducted, especially within a child and adolescent setting. This study investigates the needs of staff working with adolescents in a secure forensic psychiatric environment. Semistructured interviews were conducted with 13 staff members within a secure forensic unit for adolescents with mental health problems. The interviews were analyzed using interpretative phenomenological analysis. Participants encountered varying experiences, both positive and negative. The dominant themes identified from the analysis were risk of isolation, meaningful contact, openness, safety, control and structure, staff relationships, and complex task. Staff faced numerous challenges such as negotiating complex relationships with management, other staff, and the young people while in a complex working environment. Various levels of support are required to manage the challenges placed on them, including both individual and group support.
Risk of thrombosis associated with oral contraceptives of women from 97 families with inherited thrombophilia: high risk of thrombosis in carriers of the G20210A mutation of the prothrombin gene.

BACKGROUND AND OBJECTIVES Oral contraceptives (OC) and inherited thrombophilia are well-known risk factors associated with venous thromboembolism (VTE). However, there are only few studies on the risk of VTE in women with inherited thrombophilia who use oral contraceptives. DESIGN AND METHODS We performed a retrospective family cohort study of 325 women belonging to 97 families with inherited thrombophilia, including antithrombin, protein S and C deficiencies, the factor V Leiden mutation (FVL) and the G20210A mutation of the prothrombin gene (PT20210A) to determine the risk of VTE associated with OC intake. RESULTS For carriers of the PT20210A mutation, the risk of VTE in OC users was 3-fold higher (95% CI 1.3-6.8) than that in non-carriers. Carriers of FVL mutation taking OC showed an OR of 1.4 (95% CI 0.6-3.3), indicating a tendency to increase the risk of VTE. INTERPRETATION AND CONCLUSIONS Because of the high prevalence of the PT20210A (6.5%) and FVL (2%) mutations in the general Spanish population and the increased risk of VTE associated with OC intake, genetic screening for these mutations should be considered in potential OC users belonging to families with thrombophilia.
Cellular Origins of Endogenous Amino Acids Released into the Extracellular Fluid of the Rat Striatum During Severe Insulin‐Induced Hypoglycemia

Abstract: The effect of severe insulin‐induced hypoglycemia on the extracellular levels of endogenous amino acids in the rat striatum was examined using the brain microdialysis technique. A characteristic pattern of alterations consisting of a 9–12‐fold increase in aspartate (Asp), and more moderate increases in glutamate (Glu), taurine (Tau), and γ‐aminobutyric acid (GABA), was noted following cessation of electroencephalographic activity (isoelectricity). Glutamine (Gln) levels were reduced both during and after the isoelectric period and there was a delayed increase in extracellular phosphoethanolamine (PEA) content. The effects of decortication and excitotoxin lesions on the severe hypoglycemia‐evoked efflux of endogenous amino acids in the striatum were also examined. Decortication reduced the release of Glu and Asp both 1 week and 1 month post‐lesion. The efflux of other neuroactive amino acids was not affected significantly. In contrast, GABA, Tau, and PEA efflux was attenuated in kainate‐lesioned striata. Glu and Asp release was also reduced under these conditions, and a smaller decrease in extracellular Gln was noted. These data suggest that GABA, Glu, and Asp are released primarily from their transmitter pools during severe hypoglycemia. The releasable pools of Tau and PEA appear to be located in kainate‐sensitive striatal neurons. The significance of these results is discussed with regard to the excitotoxic theory of hypoglyce‐mic cell death.
[TNF-alpha secretion by human macrophage-like cells in response to wear particles and its modification by drugs].

UNLABELLED Tumour necrosis factor (TNF) is considered to be the initiator protein of particle disease leading to aseptic loosening of endoprostheses. The aim of the present study was to investigate the TNF response of the macrophage-like cells (MLC) to the periprosthetic particles typically found during revision surgery. For this purpose, particles of polyethylene (PE), pure titanium (Ti), chromium (Cr), cobalt (Co), alumina ceramic (Al2O3) and zirconium dioxide (ZrO2) were used. Additionally, the therapeutic effect of non-steroidal and steroidal drugs, biphosphonates and pentoxyfylline on PE particles was investigated with the aim of differentiating drugs with, from those without, a positive effect on aseptic loosening. METHOD In an established macrophage model (Rader et al. 1999), THP1 cells (human monocytic cell line) were differentiated over a period of five days in the presence of vitamin D3 and GM-CSF in macrophage-like cells (MLC). To obtain a TNF profile of the different materials, 10(6) MLC were incubated with each of a range of different particle concentrations. For drug testing purposes 80 x 10(8) PE particles, which evoked a maximum TNF response, were applied together with increasing drug concentrations in the same manner. The supernatant was then investigated for TNF secretion using ELISA. RESULTS It was found that the greatest TNF response was provoked by Co and PE particles, and was 25 and 23 times as high, respectively, in comparison with control. The smallest TNF secretion was seen with Al2O3 (4 x control) and ZrO2 (5 x control). At the recommended dose, non-steroidal anti-inflammatory drugs (NSAIDs) produced no decrease in TNF secretion. The biphosphonates, etidronate and ibendronate significantly reduced the TNF response of the PE-stimulated macrophages (by 1/7 and 1/5, respectively). Therapeutic doses of pentoxyfylline also led to a decrease of 1/5 in maximum TNF release. CONCLUSION Ceramic articulating surfaces are superior to metal/metal or PE/PE matings in terms of the biological effects of their wear particles. At therapeutic doses, NSAIDs have no beneficial effect on the process of aseptic loosening. Certain biphosphonates and pentoxyfylline have a positive effect on aseptic loosening.
Influence of Consumer Complaints Handling On Consumer Satisfaction in Dairy Milk Processors in Kenya

The purpose of this study was to assess the influence of consumer complaints handling on consumer satisfaction in dairy milk processors in Kenya. The study population was 384 consumers from 15 major supermarkets chains in Kenya. Primary data was sought from consumers of processed dairy milk using a semi-structured self-administered questionnaire employing a mixed methods research design. Descriptive and regression analysis and regression analysis were conducted with the help of SPSS software. Majority of the respondents disagreed that their complaints were handled so well to their expectation. Respondents also disagreed that merchandisers were receptive to their complaints as consumers to their satisfaction. The results showed a weak positive relationship between complaints handling and consumer satisfaction. The beta value of the computed (composite index) scores of consumers’ complaints handling was 0.027 with a t-test value of 1.026 and significance level of 0.306. Dairy milk processors in Kenya had poor consumer complaints handling mechanisms. However this seemed to have no reduction in consumer satisfaction in the products in question. The study recommended that dairy milk processors in Kenya had poor consumer complaints handling mechanisms.
Molecular and Biochemical Characterization of Ambler Class A Extended-Spectrum β-Lactamase CGA-1 from Chryseobacterium gleum

ABSTRACT Antibiotic susceptibility testing by disk diffusion of a Chryseobacterium gleum isolate, strain CIP 103039, showed a typical synergy image between clavulanic acid and expanded-spectrum cephalosporins. Shotgun cloning gave a recombinant plasmid in Escherichia coli that produced a β-lactamase, CGA-1, with a pI value of 8.9 that conferred resistance to most penicillins (except ureidopenicillins) and narrow-spectrum cephalosporins and an intermediate susceptibility to expanded-spectrum cephalosporins and aztreonam. The CGA-1 amino acid sequence shared only 60% amino acid identity with CME-1 and CME-2 from Chryseobacterium meningosepticum, the most closely related β-lactamases. CGA-1 was very likely chromosome encoded. It is a novel member of the PER subgroup of Ambler class A β-lactamases (Bush functional group 2be).
Pharmacotherapy of dry eye

Introduction: Based on data from the largest studies of dry eye to date – the Women's Health Study (WHS) and the Physicians' Health Study (PHS) – and other studies, it has been estimated that about 3.23 million women and 1.68 million men, for a total of 4.91 million Americans aged ≥ 50 years, have dry eye. Tens of millions more have less severe symptoms and probably a more episodic manifestation of the disease that is notable only during contact with some adverse contributing factor(s), such as low humidity or contact lens wear. Dry eye disease is a common yet frequently under-recognized public health problem whose etiology and management challenge clinicians and researchers involved in this field. Areas covered: Advances in the understanding of the disease have been made over the past 10 years in areas of epidemiology, pathogenesis, clinical manifestation, and possible therapy. Historical aspects and recent information in relation to the use of artificial tear substitutes and anti-inflammatory agents in dry eye disease, including topical cyclosporin and corticosteroids, autologous serum, tetracyclines and systemic immunosuppressants, are covered in this review. The reader will gain insight into the recent views on the pharmacological menu of treatments for dry eyes following the recommendations of the 2007 International Dry Eye Workshop. Expert opinion: Dry eye is a visually disabling disease, the treatment of which needs tailoring according to the type and severity of dry eye disease.
Autosomal recessive distal renal tubular acidosis caused by G701D mutation of anion exchanger 1 gene.

Anion exchanger 1 (AE1 or band 3), encoded by the AE1 or SLC4A1 gene, regulates chloride-bicarbonate exchange in erythrocytes and alpha-intercalated cells of the distal nephron. Defects of AE1 at the basolateral membrane of alpha-intercalated cells may result in the failure of hydrogen ion secretion at the apical membrane, leading to distal renal tubular acidosis (dRTA). Abnormalities of the AE1 gene were previously reported to be associated with autosomal dominant dRTA. However, recent studies of Thai dRTA families have shown that mutations in this gene result in autosomal recessive (AR) dRTA, giving rise to the postulation that AE1 gene mutations causing AR dRTA might be found commonly in Thai pediatric patients with dRTA. We performed a study of the AE1 gene using DNA linkage, polymerase chain reaction single-strand conformation polymorphism, restriction endonuclease HpaII digestion, and DNA sequence analyses in eight families involving 12 Thai children with dRTA, shown by abnormal urinary acidification using a short acid-loading test, as well as among their family members. Seven patients with dRTA from five families had the same homozygous missense G701D mutation of the AE1 gene. Their parents or siblings heterozygous for the AE1 G701D mutation were clinically normal and did not have abnormal urinary acidification, although a heterozygous sibling in one family had abnormal urinary acidification. Results of this and previous studies show that a homozygous AE1 G701D mutation causes AR dRTA and is a common molecular defect among Thai pediatric patients with dRTA.
Depressive symptoms in community-dwelling older adults receiving opioid therapy for chronic pain.

OBJECTIVE The purpose of the study was to identify factors associated with depressive symptoms in community-dwelling older adults receiving prescription opioids for chronic pain. DESIGN This was a cross-sectional research design. A survey was used to gather demographic information, pain severity, health status, and factors associated with depressive symptoms. SETTING Eleven outpatient clinics affiliated with the Baltimore Veterans Affairs Medical Center and the University of Maryland Medical System were included. PARTICIPANTS One hundred sixty-three older adults receiving opioid medications for chronic pain were recruited. OUTCOME MEASURES Depressive symptoms were assessed via the Center for Epidemiologic Studies Depression Scale-10 (CESD-10). RESULTS Univariate, bivariate, and ordinary least square (OLS) regression analyses were conducted to identify frequencies and to address the research questions. Nearly 40 percent of the elderly opioid therapy patients had depressive symptoms on the CESD-10. Bivariate analysis revealed that higher levels of pain severity were related to higher levels of depressive symptoms. OLS regression analysis revealed four risk factors significantly associated with higher depressive symptoms: higher pain severity, lower levels of functional status, lower levels of spirituality, and lower levels of social support. Age, gender, living alone, and perception of health status were not significantly associated with depressive symptoms. CONCLUSIONS Depression is an underdiagnosed, treatable pain comorbidity that should be evaluated in older patients receiving opioid therapy. Undertreated depression in chronic pain patients receiving opioid medications may explain suboptimal improvement in pain and functional status despite increasing opioid dosage.
A case-crossover analysis of out-of-hospital coronary deaths and air pollution in Rome, Italy.

RATIONALE Out-of-hospital coronary heart disease death is a major public health problem, but the association with air pollution is not well understood. OBJECTIVES We evaluated the association between daily ambient air pollution levels (particle number concentration [PNC]--a proxy for ultrafine particles [diameter < 0.1 microm], mass of particles with diameter less than 10 microm [PM10]; CO, NO2, and O3) and the occurrence of fatal, nonhospitalized coronary events. METHODS Subjects were 5,144 out-of-hospital fatalities (410-414, International Classification of Diseases-9; 1998-2000) who had been residents of Rome. Hospitalizations during the 3 yr before death were considered to identify comorbidities (e.g., diabetes, hypertension, heart failure, dysrhythmia, chronic obstructive pulmonary disease). Statistical analyses were performed using a case-crossover design. MEASUREMENTS AND MAIN RESULTS The association with out-of-hospital coronary deaths was statistically significant for PNC, PM10, and CO. Air pollution on the day of death had the strongest effect (e.g., 7.6% increase [95% confidence interval, 2.0-13.6%]) for an interquartile range of PNC, 27,790 particles/cm3. The 65-74- and 75+-yr age groups were at higher risk than the 35-64-yr age group, and there was a suggestion of effect modification for people with hypertension and chronic obstructive pulmonary disease. CONCLUSIONS Air pollutants originating from combustion processes, including ultrafine particles, are related to fatal, nonhospitalized coronary events. The effect is stronger among people over 65 years of age, but is not limited to a group with a specific comorbidity.
STELLAR AND GASEOUS NUCLEAR DISKS OBSERVED IN NEARBY (U)LIRGs

We present near-infrared integral field spectroscopy of the central kiloparsec of 17 nearby luminous and ultra-luminous infrared galaxies undergoing major mergers. These observations were taken with OSIRIS assisted by the Keck I and II Adaptive Optics systems, providing spatial resolutions of a few tens of parsecs. The resulting kinematic maps reveal gas disks in at least 16 out of 19 nuclei and stellar disks in 11 out of 11 nuclei observed in these galaxy merger systems. In our late-stages mergers, these disks are young (stellar ages <30 Myr) and likely formed as gas disks that became unstable to star formation during the merger. On average, these disks have effective radii of a few hundred parsecs, masses between 108 and 1010 M☉, and v/σ between 1 and 5. These disks are similar to those created in high-resolution hydrodynamical simulations of gas-rich galaxy mergers, and favor short coalescence times for binary black holes. The few galaxies in our sample in earlier stages of mergers have disks that are larger (reff ∼ 200–1800 pc) and are likely remnants of the galactic disks that have not yet been completely disrupted by the merger.
Theoretical model for glomerular filtration of charged solutes.

Previous experimental studies have revealed that for a given molecular size, the glomerular capillary wall restricts the passage of polyanions more than that of neutral macromolecules, and restricts transport of the latter more than that of polycations. We have developed a theoretical model of this charge-selectivity based on the following principal assumptions: a) all ions (tracer macromolecule and univalent cations and anions) obey a modified Nernst-Planck flux expression, including terms for convection and size-selective retardation; b) the capillary wall has a homogeneous distribution of fixed negative charges; and c) Donnan equilibria exist at the surfaces of this "membrane. " To allow specific application of the model we measured electrophoretic mobilities of narrow fractions of dextran sulfate (DS) and diethylaminoethyl dextran (DEAE), and used these to estimate effective molecular charge as a function of molecular size. Based on these measurements and fractional clearance data for DS and DEAE reported previously for the normal Munich-Wistar rat, the capillary wall has an apparent fixed charge concentration of 120--170 meq/liter. The effects of this membrane charge on the filtration of water and on the transcapillary electrical potential difference are also discussed.
Monetary policy and financial shocks in an empirical small open-economy DSGE model

Determine the optimal response of a small open economy's central bank to financial shocks that lead to increases in credit spreads. Increasing credit spreads reduce the efficacy of monetary policy when the central bank is reducing the policy rate to accommodate a lowering in economic activity.Used a DSGE model that incorporates heterogeneous households and financial intermediaries. Financial shocks leads to an increase in non-performing loans, which in turn causes the financial intermediary to increase the spread over the policy rate at which it is willing to lend.The central bank should reduce the policy rate in response to rising credit spreads, however this response is more muted when compared to a closed economy facing a similar shock.
Business Models for Sustainable Finance: The Case Study of Social Impact Bonds

Business models for sustainability (BMfS) are relevant topics on research agendas, given their orientation toward sustainability issues. However, traditional versions of these models are often ill-equipped at solving complex social problems. Cross-sector partnerships for sustainability (CSPfS) have been recognized as a new paradigm that mitigates the failure of traditional models. Impact investing, and social impact bonds (SIBs) in particular, represent an interesting field of research in innovative business models for sustainable finance, even though the literature does not consider SIBs within this broader field. We propose an exploratory study based on qualitative methods aimed at conceptualizing SIBs within the framework of BMfS and understanding how SIB collaboration varies across social sectors and geographical areas. Our study identifies three different models of SIBs characterized by the different degrees of collaboration between actors: (i) SIB as a fully collaborative partnership; (ii) SIB as a low-collaborative partnership; and (iii) SIB as a partially collaborative partnership. Our findings are useful to policy makers and practitioners involved in the SIB design, suggesting that a fully collaborative SIB model may stand a better chance of achieving the expected social impacts.
Receptor-regulated Dynamic S-Nitrosylation of Endothelial Nitric-oxide Synthase in Vascular Endothelial Cells*

The endothelial isoform of nitric-oxide synthase (eNOS) is regulated by a complex pattern of post-translational modifications. In these studies, we show that eNOS is dynamically regulated by S-nitrosylation, the covalent adduction of nitric oxide (NO)-derived nitrosyl groups to the cysteine thiols of proteins. We report that eNOS is tonically S-nitrosylated in resting bovine aortic endothelial cells and that the enzyme undergoes rapid transient denitrosylation after addition of the eNOS agonist, vascular endothelial growth factor. eNOS is thereafter progressively renitrosylated to basal levels. The receptor-mediated decrease in eNOS S-nitrosylation is inversely related to enzyme phosphorylation at Ser1179, a site associated with eNOS activation. We also document that targeting of eNOS to the cell membrane is required for eNOS S-nitrosylation. Acylation-deficient mutant eNOS, which is targeted to the cytosol, does not undergo S-nitrosylation. Using purified eNOS, we show that eNOS S-nitrosylation by exogenous NO donors inhibits enzyme activity and that eNOS inhibition is reversed by denitrosylation. We determine that the cysteines of the zinc-tetrathiolate that comprise the eNOS dimer interface are the targets of S-nitrosylation. Mutation of the zinc-tetrathiolate cysteines eliminates eNOS S-nitrosylation but does not eliminate NO synthase activity, arguing strongly that disruption of the zinc-tetrathiolate does not necessarily lead to eNOS monomerization in vivo. Taken together, these studies suggest that eNOS S-nitrosylation may represent an important mechanism for regulation of NO signaling pathways in the vascular wall.