tbuckley/cabot-search huggingface dataset:
P<scp>hysiological</scp>C<scp>ontrol of</scp>I<scp>mmune</scp>R<scp>esponse and</scp>I<scp>nflammatory</scp>T<scp>issue</scp>D<scp>amage by</scp>H<scp>ypoxia</scp>-I<scp>nducible</scp>F<scp>actors and</scp>A<scp>denosine</scp>A<sub>2A</sub>R<scp>eceptors</scp>
Authors: Michail V. Sitkovsky, Dmitriy Lukashev, Sergey Apasov, Hidefumi Kojima, Masahiro Koshiba, Charles Caldwell, Akio Ohta, Manfred Thiel
Journal: Annual Review of Immunology (2004)

Immune cell-mediated destruction of pathogens may result in excessive collateral damage to normal tissues, and the failure to control activated immune cells may cause immunopathologies. The search for physiological mechanisms that downregulate activated immune cells has revealed a critical role for extracellular adenosine and for immunosuppressive A2A adenosine receptors in protecting tissue from inflammatory damage. Tissue damage-associated deep hypoxia, hypoxia-inducible factors, and hypoxia-induced accumulation of adenosine may represent one of the most fundamental and immediate tissue-protecting mechanisms, with adenosine A2A receptors triggering "OFF" signals in activated immune cells. In these regulatory mechanisms, oxygen deprivation and extracellular adenosine accumulation serve as "reporters," while A2A adenosine receptors serve as "sensors" of excessive tissue damage. The A2A receptor-triggered generation of intracellular cAMP then inhibits activated immune cells in a delayed negative feedback manner to prevent additional tissue damage. Targeting A2A adenosine receptors may have important clinical applications.
Neisseria meningitidis Urethritis
Authors: Marcia A. Miller
Journal: JAMA (1979)

FOR years, the sine qua non of gonococcal infection in the male patient has been a thick, purulent urethral discharge and evidence of Gramnegative intracellular diplococci on smear examination. Indeed, these findings are used for presumptively diagnosing gonorrhea in males. Similarly for the female patient, an oxidase-positive colony that shows Gram-negative diplococci by microscopic examination is often accepted as a gonococcus without further investigation. As early as 1939, attention was drawn to microorganisms that could invalidate the diagnosis of gonorrhea by the smear method. DeBord<sup>1</sup>indicated such for<i>Mima polymorpha (Moraxella osloensis)</i>, and in 1942 Carpenter and Charles<sup>2</sup>reported the isolation of<i>Neisseria meningitidis</i>from gonococcal-like discharge in seven male patients. Little attention has been paid to<i>N meningitidis</i>until recent years. Since 1971, there have been reports of 80 patients in whom<i>N</i><i>meningitidis</i>was isolated from the urethra, cervix, or anal canal.<sup>3,4</sup> This article reports
Upper airway function and arousability to ventilatory challenge in slow wave versus stage 2 sleep in obstructive sleep apnoea
Authors: R. Ratnavadivel, D. Stadler, S. Windler, J. Bradley, D. Paul, R. D. McEvoy, P. G. Catcheside
Journal: Thorax (2009)

Patients with obstructive sleep apnoea (OSA) have reduced event rates during slow wave sleep (SWS) compared with stage 2 sleep. To explore this phenomenon, ventilatory and arousal timing responses to partial and complete airflow obstruction during SWS versus stage 2 sleep were examined.Ten patients, mean+/-SD apnoea-hypopnoea index (AHI) 49.7+/-16.5 events/h with reduced OSA frequency during SWS (SWS AHI 18.9+/-14.0 events/h) slept with an epiglottic pressure catheter and nasal mask/pneumotachograph. Patients underwent rapid continuous positive airway pressure (CPAP) dialdowns to three subtherapeutic levels and brief airway occlusions in random order.Post-dialdown, there were marked reductions in peak flow and minute ventilation, and progressive increases in inspiratory effort (p<0.001), but with limited ventilatory recovery and no differences between sleep stages. CPAP versus peak flow relationships on the third and second to last breath pre-arousal were not different between sleep stages. Arousals occurred later and post-dialdown arousal probability was lower during SWS compared with stage 2 sleep, Cox hazard ratio (95% CI) 0.65 (0.48 to 0.88), p=0.006. During SWS occlusions, time to arousal (mean+/-SEM) was prolonged (23.0+/-2.6 vs 17.1+/-1.7 s, p=0.02). Inspiratory effort developed more rapidly (-1.0+/-0.2 vs -0.6+/-0.1 cm H(2)O/s, p=0.019) and was more negative (-28.7+/-2.7 vs -20.3+/-1.6 cm H(2)O, p<0.001) on the breath preceding arousal.Except for a heightened ventilatory drive response during airway occlusion, airway function and ventilatory compensation to ventilatory challenge appear to be similar, but with consistently and substantially delayed arousal responses, in SWS versus stage 2 sleep.
A Novel Approach Using DNA-Repair–Deficient Chicken DT40 Cell Lines for Screening and Characterizing the Genotoxicity of Environmental Contaminants
Authors: Kyunghee Ji, Toshiaki Kogame, Kyungho Choi, Xin Wang, Jinyoung Lee, Yoshihito Taniguchi, Shunichi Takeda
Journal: Environmental Health Perspectives (2009)

BackgroundMany bacterial or mammalian cell-based test systems, such as the Ames test, chromosomal aberration assays, or gene mutation assays, are commonly used in developed countries to detect the genotoxicity of industrial chemicals. However, the specificity is generally limited and the sensitivity is not sufficiently high. In addition, most assays cannot provide information on mechanisms of genotoxicity of a given chemical.ObjectivesWe aimed to establish a sensitive and fast screening method that is also capable of characterizing mechanisms of genotoxicity.MethodsWe developed a novel bioassay employing gene-disrupted clones of the chicken DT40 B-lymphocyte line, which are designed to be deficient in several specific DNA repair pathways. Genotoxic chemicals can delay cellular proliferation in DNA-repair–deficient clones more significantly than in wild-type cells by interfering with DNA replication, thereby inducing DNA damage. In addition, we verified the validity of this assay by analyzing the genotoxicity of γ-rays, ultraviolet (UV) light, and sodium metaarsenite (NaAsO2). We also characterized DNA lesions induced by NaAsO2.ResultsGenotoxicity of given stressors was successfully screened based on a comparison of proliferation kinetics between wild-type and DNA-repair–deficient mutants in 48 hr. We also found that NaAsO2 apparently induces at least two types of damage: chromosomal breaks and UV photoproduct-like DNA lesions.ConclusionThis bioassay is a reliable and sensitive screening tool for environmental mutagens as well as for further characterizing the nature of detected genotoxicity.
Hyperhomocysteinemia Induces Renal Hemodynamic Dysfunction
Authors: Patricia A. Fischer, Graciela N. Dominguez, Luis A. Cuniberti, Vero[Combining Acute Accent]nica Martinez, Jose[Combining Acute Accent] P. Werba, Agusti[Combining Acute Accent]n J. Ramirez, Lucas D. Masnatta
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Hyperhomocysteinemia is associated with endothelial dysfunction, although the underlying mechanism is unknown. Previous studies have shown that nitric oxide (NO) plays an important role in the regulation of systemic and renal hemodynamics. This study investigated whether hyperhomocysteinemia induces renal oxidative stress and promotes renal dysfunction involving disturbances of the NO-pathway in Wistar rats. During 8 wk, control (C) and hyperhomocysteinemic (HYC) groups had free access to tap water and homocysteine-thiolactone (HTL, 50 mg/kg per d), respectively. At 8 wk, plasma homocysteine concentration, renal superoxide anion (O2τ), nitrotyrosine, and nitrite+nitrate levels, and renal function were measured. To assess NO involvement, the responses to L-Arginine (L-Arg, 300 mg/kg) and NG-nitro-L-arginine-methyl-ester (L-NAME, 20 μg/kg per min for 60 min) were analyzed. The HYC group showed higher homocysteine concentration (7.6 ± 1.7 versus 4.9 ± 1.0 μmol/L; P < 0.001), (O2τ; production (157.92 ± 74.46 versus 91.17 ± 29.03 cpm · 103/mg protein), and nitrite+nitrate levels (33.4 ± 5.1 versus 11.7 ± 4.3 μmol/mg protein; P < 0.001) than the control group. Western blot analyses showed a nitrotyrosine mass 46% higher in the HYC group than in the controls. Furthermore, the HYC group showed lower GFR, renal plasma flow (RPF), and higher renal vascular resistance (RVR) than the controls. After L-Arg administration, the responses of GFR, RPF, and RVR were attenuated by 36%, 40%, and 50%, respectively; after L-NAME, the responses of RPF and RVR were exaggerated by 79% and 112%, respectively. This suggests a reduced NO bioavailability to produce vasodilation and an enhanced sensitivity to NO inhibition. In conclusion, hyperhomocysteinemia induces oxidative stress, NO inactivation, and renal dysfunction involving disturbances on the NO-pathway. E-Mail: [email protected]
Homoisoflavanone prevents mast cell activation and allergic responses by inhibition of <scp>S</scp>yk signaling pathway
Authors: Y. S. Lee, S. Hur, T.‐Y. Kim
Journal: Allergy (2014)

Abstract Background Mast cells play important roles in allergic inflammatory responses because they produce leukotrienes ( LT s), prostaglandins ( PG s), and a variety of inflammatory cytokines. Thus, pharmacological interventions for allergies have focused on inhibiting mast cell activation. Homoisoflavanone ( HIF ), isolated from C remastra appendiculata Makino, has anti‐angiogenic activities; however, its effects on allergic reactions have not been determined. The aim of this study was to assess the inhibitory effects of HIF on mast cell activation, which is critical for anti‐allergic reaction and the underlying mechanisms. Methods Enzyme‐linked immunosorbent assays, quantitative real‐time PCR , western blot analyses, and degranulation assay were performed to measure pro‐inflammatory and allergic mediators in PMA /A23187‐ or IgE/antigen‐stimulated mouse bone marrow‐derived mast cells ( BMMC s), HMC ‐1, RBL ‐1, or human PBMC ‐derived mast cells treated with or without HIF . The anti‐allergic effects of HIF were determined in mouse models using dinitrophenol‐immunoglobulin E‐induced passive cutaneous anaphylaxis ( PCA ) and compound 48/80‐induced ear swelling. Results Homoisoflavanone down‐regulated PGD 2 , LTB 4 , and LTC 4 production and inhibited the production of pro‐inflammatory cytokines, such as interleukin‐6 and tumor necrosis factor‐α in PMA /A23187‐ or IgE/antigen‐stimulated mast cells. The molecular mechanisms by which HIF caused these inhibitory effects were determined to be the inactivation of spleen tyrosine kinase (Syk) signaling and the concurrent suppression of cPLA 2 . HIF inhibited IgE‐mediated PCA and compound 48/80‐induced ear swelling in mouse. Conclusions Homoisoflavanone inhibited mast cell activation through the suppression of Syk pathway together with the inhibition of cPLA 2 . Thus, it might be a good candidate molecule for allergic diseases.
Correlation of airway obstruction and patient-reported endpoints in clinical studies
Authors: S. Shingo, J. Zhang, T.F. Reiss
Journal: European Respiratory Journal (2001)

To establish the correlation among asthma efficacy parameters over a long period, data from over 1500 patients in two one-year asthma clinical trials with montelukast, a Cys-LT 1 antagonist, were analysed. Airway obstruction measurements, forced expiratory volume in one second (FEV 1 ) and peak expiratory flow (PEF), were measured at clinic visits. Patients recorded daytime symptom score, “as-needed” β-agonist use, and PEF on a daily basis. Relationships among these parameters at baseline and during the one-year treatment period were established by correlation analyses. Multiple correlations between the airway obstruction (FEV 1 and PEF) and patient-reported measurements were evaluated by canonical correlation analysis. Pairwise correlations of the efficacy parameters over a one-year time period were stable. Canonical correlation between the airway obstruction and patient-reported asthma efficacy endpoints was low, indicating that each category of endpoints measures a distinctively different aspect of the disease. It appears that at least one endpoint from each category should be used in asthma clinical studies.
PI3-kinase activation is critical for host barrier permissiveness to <i>Listeria monocytogenes</i>
Authors: Grégoire Gessain, Yu-Huan Tsai, Laetitia Travier, Matteo Bonazzi, Solène Grayo, Pascale Cossart, Caroline Charlier, Olivier Disson, Marc Lecuit
Journal: The Journal of Experimental Medicine (2015)

Invasion of nonphagocytic cells, a critical property of Listeria monocytogenes (Lm) that enables it to cross host barriers, is mediated by the interaction of two bacterial surface proteins, InlA and InlB, with their respective receptors E-cadherin and c-Met. Although InlA–E-cadherin interaction is necessary and sufficient for Lm crossing of the intestinal barrier, both InlA and InlB are required for Lm crossing of the placental barrier. The mechanisms underlying these differences are unknown. Phosphoinositide 3-kinase (PI3-K) is involved in both InlA- and InlB-dependent pathways. Indeed, InlA-dependent entry requires PI3-K activity but does not activate it, whereas InlB–c-Met interaction activates PI3-K. We show that Lm intestinal target cells exhibit a constitutive PI3-K activity, rendering InlB dispensable for InlA-dependent Lm intestinal barrier crossing. In contrast, the placental barrier does not exhibit constitutive PI3-K activity, making InlB necessary for InlA-dependent Lm placental invasion. Here, we provide the molecular explanation for the respective contributions of InlA and InlB to Lm host barrier invasion, and reveal the critical role of InlB in rendering cells permissive to InlA-mediated invasion. This study shows that PI3-K activity is critical to host barrier permissiveness to microbes, and that pathogens exploit both similarities and differences of host barriers to disseminate.
Human Epidermal Growth Factor Enhances Healing of Diabetic Foot Ulcers
Authors: Man Wo Tsang, Wan Keung R. Wong, Chi Sang Hung, Kwok-Man Lai, Wegin Tang, Elaine Y.N. Cheung, Grace Kam, Leo Leung, Chi Wai Chan, Chung Min Chu, Edward K.H. Lam
Journal: Diabetes Care (2003)

OBJECTIVE—To study the healing effect of recombinant human epidermal growth factor (hEGF) on diabetic foot ulcers. RESEARCH DESIGN AND METHODS—A total of 127 consecutive patients were screened and 61 diabetic subjects were recruited into this double-blind randomized controlled study. Predetermined criteria were used for diagnosis and classification of the diabetic wound. The patients were randomized into three groups. All patients attended our Diabetes Ambulatory Care Center every other week for joint consultation with the diabetologist and the podiatrist. Group 1 (control) was treated with Actovegin 5% cream (Actovegin), group 2 with Actovegin plus 0.02% (wt/wt) hEGF, and group 3 with Actovegin plus 0.04% (wt/wt) hEGF. The study end point was the complete closure of the wound. Failure to heal was arbitrarily defined as incomplete healing after 12 weeks. RESULTS—Final data were obtained from 61 patients randomly assigned into three groups. The mean ages of the patients, wound sizes, wound duration, metabolic measurements, and comorbidities were comparable within groups, except that group 3 had more female patients. Mean follow-up for the patients was 24 weeks. Data were cutoff at 12 weeks, and results were analyzed by intention to treat. After 12 weeks, in group 1 (control) eight patients had complete healing, two patients underwent toe amputation, and nine had nonhealing ulcers. In group 2 (0.02% [wt/wt] hEGF) 12 patients experienced wound healing, 2 had toe amputations, and 7 had nonhealing ulcers. Some 20 of 21 patients in group 3 (0.04% [wt/wt] hEGF) showed complete wound healing. Healing rates were 42.10, 57.14, and 95% for the control, 0.02% (wt/wt) hEGF, and 0.04% (wt/wt) hEGF groups, respectively. Kaplan-Meier survival analysis suggested that application of cream with 0.04% (wt/wt) hEGF caused more ulcers to heal by 12 weeks and increased the rate of healing compared with the other treatments (log-rank test, P = 0.0003). CONCLUSIONS—Our data support the contention that application of hEGF-containing cream, in addition to good foot care from a multidisciplinary team, significantly enhances diabetic foot ulcer wound healing and reduces the healing time.
Selective Degradation of Host MicroRNAs by an Intergenic HCMV Noncoding RNA Accelerates Virus Production
Authors: Sanghyun Lee, Jaewon Song, Sungchul Kim, Jongkyu Kim, Yujin Hong, Youngkyun Kim, Donghyun Kim, Daehyun Baek, Kwangseog Ahn
Journal: Cell Host & Microbe (2013)
The Hippo Pathway Is Activated and Is a Causal Mechanism for Adipogenesis in Arrhythmogenic Cardiomyopathy
Authors: Suet Nee Chen, Priyatansh Gurha, Raffaella Lombardi, Alessandra Ruggiero, James T. Willerson, A.J. Marian
Journal: Circulation Research (2013)

Rationale: Mutations in the intercalated disc proteins, such as plakophilin 2 (PKP2), cause arrhythmogenic cardiomyopathy (AC). AC is characterized by the replacement of cardiac myocytes by fibro-adipocytes, cardiac dysfunction, arrhythmias, and sudden death. Objective: To delineate the molecular pathogenesis of AC. Methods and Results: Localization and levels of selected intercalated disc proteins, including signaling molecules, were markedly reduced in human hearts with AC. Altered protein constituents of intercalated discs were associated with activation of the upstream Hippo molecules in the human hearts, in Nkx2.5-Cre:Dsp W/F and Myh6:Jup mouse models of AC, and in the PKP2 knockdown HL-1 myocytes (HL-1 PKP2:shRNA ). Level of active protein kinase C-α isoform, which requires PKP2 for activity, was reduced. In contrast, neurofibromin 2 (or Merlin), a molecule upstream of the Hippo pathway and that is inactivated by protein kinase C-α isoform, was activated. Consequently, the downstream Hippo molecules mammalian STE20-like protein kinases 1/2 (MST1/2), large tumor suppressor kinases 1/2 (LATS1/2), and Yes-associated protein (YAP) (the latter is the effector of the pathway) were phosphorylated. Coimmunoprecipitation detected binding of phosphorylated YAP, phosphorylated β-catenin, and junction protein plakoglobin (the latter translocated from the junction). RNA sequencing, transcript quantitative polymerase chain reaction, and reporter assays showed suppressed activity of SV40 transcriptional enhancer factor domain (TEAD) and transcription factor 7-like 2 (TCF7L2), which are transcription factors of the Hippo and the canonical Wnt signaling, respectively. In contrast, adipogenesis was enhanced. Simultaneous knockdown of Lats1/2 , molecules upstream to YAP, rescued inactivation of YAP and β-catenin and adipogenesis in the HL-1 PKP2:shRNA myocytes. Conclusions: Molecular remodeling of the intercalated discs leads to pathogenic activation of the Hippo pathway, suppression of the canonical Wnt signaling, and enhanced adipogenesis in AC. The findings offer novel mechanisms for the pathogenesis of AC.
Role of bronchoalveolar lavage in the evaluation of interstitial pneumonitis in recipients of bone marrow transplants.
Authors: H J Milburn, H G Prentice, R M du Bois
Journal: Thorax (1987)

Forty episodes of pneumonitis in 30 recipients of allogeneic bone marrow transplants were investigated by fibreoptic bronchoscopy and bronchoalveolar lavage. A positive diagnosis was made in 32 episodes of pneumonitis (24 patients), giving a diagnostic yield of 80%. In 31 of these the diagnosis was made within 24 hours of bronchoscopy and this enabled the appropriate treatment to be instituted early. Eighteen patients recovered from their primary infection, although two died subsequently of respiratory failure due to postpneumonic lung destruction. Ten patients later developed a second episode of pneumonitis and a diagnosis was made in nine of these. Only three survived a second episode. Bronchoalveolar lavage was well tolerated by all patients and there was no morbidity or mortality that could be directly attributed to the procedure. Bronchoalveolar lavage is a safe and valuable early diagnostic procedure for the investigation of pulmonary complications in patients who have received bone marrow transplants.
Release of α-actin into serum after skeletal muscle damage
Authors: A Martínez-Amat, H Boulaiz, J Prados, J A Marchal, P Padial Puche, O Caba, F Rodríguez-Serrano, A Aránega
Journal: British Journal of Sports Medicine (2005)

The skeletal muscle protein alpha-actin was investigated in the serum of subjects with severe skeletal muscle damage to assess its utility as a reliable and predictive marker of muscle damage.Serum samples were obtained from 33 healthy controls and 33 patients with severe skeletal muscle damage, defined by a total creatine kinase value of >500 IU/l (Rosalki method). Troponin I, troponin T, and myoglobin concentrations were determined by immunoassay and alpha-actin concentrations by Western blot and densitometry.The mean serum concentration of alpha-actin in controls and patients with skeletal muscle damage was 600.9 and 1968.51 ng/ml, respectively, a statistically significant difference. Sera of patients with muscle damage showed higher levels of alpha-actin than of troponin or myoglobin. No significant difference in troponin I levels was observed between the groups.According to these results, alpha-actin was the most significant skeletal muscle damage marker analysed and may be an ideal candidate for the identification of all types of myofibre injury, including sports injuries. Our findings support the use of alpha-actin as a marker alongside other currently used biological proteins.
Asymptomatic Leishmania infantum infections in humans living in endemic and non-endemic areas of Croatia, 2007 to 2009
Authors: K Šiško-Kraljević, A Jerončić, B Mohar, V Punda-Polić
Journal: Eurosurveillance (2013)

The prevalence of asymptomatic leishmaniasis in the general population of Croatia has not been studied to date. To assess the prevalence of Leishmania infantum specific IgG antibodies among immunocompetent residents of Croatia, sera from 2,035 persons (eastern coast of Adriatic Sea, n=1,186; Adriatic islands, n=653; mainland, n=196), were tested by an enzyme immunoassay. A total of 231 (11.4%) persons had anti-Leishmania antibodies. Multivariate analysis revealed that seropositivity was associated with geographic location and age. Residents of coastal areas and islands were significantly more seropositive than mainland residents (odds ratios (OR) 20.37 to 28.51). Moderate to high anti-Leishmania seroprevalence was found throughout the eastern Adriatic coast and islands (4.0% to 22.2%) including the sites previously considered non-endemic. A highly endemic focus was identified in central coastal Dalmatia (seroprevalence 22.2%; OR: 1.72; 95% confidence interval (CI): 1.33-2.22). Regarding age, children aged 0-9 years were the most vulnerable group for asymptomatic Leishmania infection (OR: 2.19; 95% CI: 1.16-4.14).