tbuckley/cabot-search huggingface dataset:
Resolving lung injury: a new role for Tregs in controlling the innate immune response
Authors: Anthony Pietropaoli, Steve N. Georas
Journal: Journal of Clinical Investigation (2009)

Inflammation-associated lung injury is a major cause of morbidity and mortality for patients in intensive care units. Although the cellular and molecular events that initiate lung inflammation are now well understood, the mechanisms that promote its resolution remain poorly defined. In this issue of the JCI, D’Alessio et al. show in a mouse model that recovery from acute lung injury is not simply a passive process, but involves Tregs in an active resolution program (see the related article beginning on page 2898).
Linkage of neutrophil serine proteases and decreased surfactant protein-A (SP-A) levels in inflammatory lung disease
Authors: F Rubio
Journal: Thorax (2004)

<b>Background:</b> In patients with cystic fibrosis (CF) neutrophils are recruited in excess to the airways yet pathogens are not cleared and the patients suffer from chronic infections. Recent studies have shown a deficiency in airway fluids from patients with CF and other inflammatory pulmonary conditions of surfactant protein A (SP-A), a pattern recognition molecule that facilitates uptake of microbes by macrophages and neutrophils. <b>Methods:</b> In vitro simulations were used to test the hypothesis that decreased SP-A levels in CF might be the result of degradation by neutrophil serine proteases. <b>Results:</b> Very low levels of the neutrophil granule serine proteases cathepsin G, elastase, and proteinase-3 rapidly degraded pure SP-A when tested in buffered saline. The order of potency was cathepsin G&gt;elastase&gt;proteinase-3. The addition of cathepsin G or elastase to normal bronchoalveolar lavage (BAL) fluid caused a dose dependent degradation of endogenous native SP-A. Cathepsin G and elastase were present in the BAL fluid from many patients with CF. Simple incubation of protease positive BAL fluid from patients with CF caused a time dependent degradation of added SP-A or, where present, endogenous SP-A. The degradation of SP-A by protease(s) in BAL fluid of patients with CF was abrogated by diisopropylfluorophosphate and monocyte/neutrophil elastase inhibitor. <b>Conclusions:</b> The findings strongly suggest that the neutrophil serine proteases cathepsin G and/or elastase and/or proteinase-3 contribute to degradation of SP-A and thereby diminish innate pulmonary antimicrobial defence.
Misuse of Drugs Act 1971.
Authors: S Bradshaw
Journal: BMJ (1971)

Uses of Allopuninol SIR,-With reference to your excellent leading article (23 October, p. 185), I would raise two points.Having followed up a series of gouty patients for 20 years, first on uricosurics and then on allopurinol, I have no doubt in stating that the urinary complications while using the uricosuric drugs make allopurinol the preferable method of treat- ment in any case where it is decided to start long-term treatment.Secondly, from a follow-up of 50 cases, now for over five years,' the dangers of long-term treatment seem to be minimal.Moreover, the return to statu quo on gradually ceasing treatment with allopurinol in the least severe cases is much less rapid than on discontinuing the uricosuric agents.-Iam, etc.,
Length-dependent calcium inotropism in cat papillary muscle.
Authors: L L Huntsman, D K Stewart
Journal: Circulation Research (1977)

We studied changes in the relationship of isometric developed force to muscle length when extracellular calcium concentration was altered in isolated cat papillary muscles. In two series of experiments at temperatures of 30 degrees C and 32 degrees C, and rates of 12 and 30 beats/min, 21 muscles were exposed to calcium concentrations of 1.125, 2.25 and 4.5 mM. Muscle lengths were varied between 80% and 100% of the length at which maximum developed force occurred (Lmax). Peak developed force and the time from stimulus to peak were measured. The data indicate that force is not altered proportionately at all lengths when calcium concentration is changed. Rather, we found that a substantially greater modification of force occurs at short lengths than at long lengths. Similarly, the time to peak force increases with length at a rate which is more than 4 times greater at the low calcium concentration than it is at the high concentration. Small but consistent shifts of Lmax also are seen. We observed that Lmax is longer when inotropic changes reduce force and shorter when force is increased. These results indicate that the inotropic effect of extracellular calcium concentration changes is dependent on muscle length.
Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection
Authors: R A M Breen
Journal: Thorax (2004)

It has been suggested that deterioration of tuberculosis (TB) during appropriate treatment, termed a paradoxical reaction (PR), is more common and severe in HIV positive individuals on highly active antiretroviral therapy (HAART).A study was undertaken to determine the frequency of PR and its associated features in a population of HIV+TB+ patients and a similar sized group of HIV-TB+ individuals.PR occurred in 28% of 50 HIV+TB+ patients and 10% of 50 HIV-TB+ patients. Disseminated TB was present in eight of 13 HIV+TB+ patients and four of five HIV-TB+ patients with PR. In 28 HIV+TB+ patients starting HAART, PR was significantly associated with commencing HAART within 6 weeks of starting antituberculosis treatment (p = 0.03) and was more common in those with disseminated TB (p = 0.09). No association was found between development of PR and baseline CD4 count or CD4 response to HAART.PR is common in HIV infected and uninfected individuals with TB. Early introduction of HAART and the presence of disseminated TB appear to be important in co-infected patients.
Delivery of genes into the CF airway
Authors: Deborah R Gill, Stephen C Hyde
Journal: Thorax (2014)

Gene therapy was suggested as a potential treatment for cystic fibrosis (CF), even before the identification of the <i>CFTR</i> gene. Initial enthusiasm has been tempered as it became apparent that reintroduction of the <i>CFTR</i> gene into the cells of the lung is more difficult than anticipated. Here, we review the major gene delivery vectors evaluated clinically, and suggest that advances in either plasmid DNA design and/or hybrid lentivirus biology may finally facilitate lung gene transfer with efficiencies sufficient for CF gene therapy to offer clinical benefit.
Randomized Trial of Continuous Subcutaneous Delivery of Exenatide by ITCA 650 Versus Twice-Daily Exenatide Injections in Metformin-Treated Type 2 Diabetes
Authors: Robert R. Henry, Julio Rosenstock, Douglas K. Logan, Thomas R. Alessi, Kenneth Luskey, Michelle A. Baron
Journal: Diabetes Care (2013)

To evaluate ITCA 650, a continuous subcutaneous miniature osmotic pump delivery system of exenatide versus twice-daily exenatide injections (Ex-BID) in subjects with type 2 diabetes.We conducted a randomized, two-stage, 24-week, open-label, phase 2 study in type 2 diabetes inadequately controlled with metformin. Stage I: 155 subjects were randomized to 20 or 40 μg/day of ITCA 650 or Ex-BID 5 → 10 μg. Stage II: 131 subjects were rerandomized to 20, 40, 60, or 80 μg/day of ITCA 650. Change from baseline for HbA1c, weight, and fasting plasma glucose were evaluated at weeks 12 and 24.HbA1c was significantly lower in all groups after 12 and 24 weeks. Stage I: mean change in HbA1c from a mean baseline of 7.9-8.0% was -0.98, -0.95, and -0.72% for the 20 and 40 μg/day ITCA 650 and Ex-BID groups, respectively, with 63, 65, and 50% of subjects achieving HbA1c levels ≤ 7% (P < 0.05). Stage II: significant (P < 0.05) reductions in HbA1c (≈ 1.4% from baseline) were achieved with 60 and 80 μg/day ITCA 650, and 86 and 78% of subjects achieved HbA1c ≤ 7% at 24 weeks; respectively. Weight was reduced by 2.8-3.7 kg (P < 0.05) at 24 weeks in all except the 20 → 20 μg/day group. ITCA 650 was well tolerated; nausea was lower and transient with 20 μg/day relative to Ex-BID; and 60 μg/day had the best profile of tolerability and HbA1c lowering.ITCA 650 significantly reduced HbA1c and weight and was well tolerated. The 20 → 60 μg/day regimen was considered the best dose for further examination in phase 3.
Angiotensin II Increases Pax-2 Expression in Fetal Kidney Cells Via the AT2 Receptor
Authors: Shao-Ling Zhang, Babak Moini, Julie R. Ingelfinger
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Although both the renin angiotensin system (RAS) and the paired homeobox 2 gene (Pax-2) seem critically important in renal organogenesis, whether and how they might interact has not been addressed. The present study asked whether a link between the RAS and Pax-2 exists in fetal renal cells, speculating that such an interaction, if present, might influence renal development. Embryonic kidney explants and embryonic renal cells (mouse late embryonic mesenchymal epithelial cells [MK4] and mouse early embryonic mesenchymal fibroblasts [MK3]) were used. Pax-2 protein and Pax-2 mRNA were detected by immunofluorescence, Western blot, reverse transcription–PCR, and real-time PCR. Angiotensin II (AngII) upregulated Pax-2 protein and Pax-2 mRNA expression via the AngII type 2 (AT2) receptor in MK4 but not in MK3 cells. The stimulatory effect of AngII on Pax-2 gene expression could be blocked by PD123319 (AT2 inhibitor), AG 490 (a specific Janus kinase 2 inhibitor), and genistein (a tyrosine kinase inhibitor) but not by losartan (AT1 inhibitor), SB203580 (specific p38 mitogen-activated protein kinase inhibitor), PD98059 (specific MEK inhibitor), SP600125 (JNK inhibitor), and diphenyleneiodonium chloride (an NADPH oxidase inhibitor). Moreover, embryonic kidney explants in culture confirmed that AngII upregulates Pax-2 gene expression via the AT2 receptor. These studies demonstrate that the stimulatory effect of AngII on Pax-2 gene expression is mediated, at least in part, via the Janus kinase 2/signal transducers and activators of transcription signaling transduction pathway, suggesting that RAS and Pax-2 interactions may be important in renal development.
Foxp3 <sup>+</sup> CD4 <sup>+</sup> T Cells Improve Healing After Myocardial Infarction by Modulating Monocyte/Macrophage Differentiation
Authors: Johannes Weirather, Ulrich D.W. Hofmann, Niklas Beyersdorf, Gustavo C. Ramos, Benjamin Vogel, Anna Frey, Georg Ertl, Thomas Kerkau, Stefan Frantz
Journal: Circulation Research (2014)

An exaggerated or persistent inflammatory activation after myocardial infarction (MI) leads to maladaptive healing and subsequent remodeling of the left ventricle. Foxp3(+) CD4(+) regulatory T cells (Treg cells) contribute to inflammation resolution. Therefore, Treg cells might influence cardiac healing post-MI.Our aim was to study the functional role of Treg cells in wound healing post-MI in a mouse model of permanent left coronary artery ligation.Using a model of genetic Treg-cell ablation (Foxp3(DTR) mice), we depleted the Treg-cell compartment before MI induction, resulting in aggravated cardiac inflammation and deteriorated clinical outcome. Mechanistically, Treg-cell depletion was associated with M1-like macrophage polarization, characterized by decreased expression of inflammation-resolving and healing-promoting factors. The phenotype of exacerbated cardiac inflammation and outcome in Treg-cell-ablated mice could be confirmed in a mouse model of anti-CD25 monoclonal antibody-mediated depletion. In contrast, therapeutic Treg-cell activation by superagonistic anti-CD28 monoclonal antibody administration 2 days after MI led to improved healing and survival. Compared with control animals, CD28-SA-treated mice showed increased collagen de novo expression within the scar, correlating with decreased rates of left ventricular ruptures. Therapeutic Treg-cell activation induced an M2-like macrophage differentiation within the healing myocardium, associated with myofibroblast activation and increased expression of monocyte/macrophage-derived proteins fostering wound healing.Our data indicate that Treg cells beneficially influence wound healing after MI by modulating monocyte/macrophage differentiation. Moreover, therapeutic activation of Treg cells constitutes a novel approach to improve healing post-MI.
Malignant mimicry—a 17-year-old with abdominal pain and weight loss
Authors: Sheena Mankodi, Katie Planche, Jennifer Watkins, Charles Murray
Journal: Gut (2012)

A 17-year-old woman of Afro-Caribbean origin presented with a 1 month history of abdominal pain associated with vomiting and weight loss. Symptoms had gradually become more frequent and persistent. She had previously been well and had no previous hospital attendances or illnesses.

Vital signs and physical examination was normal with the exception of tenderness in the epigastrium on palpation.

Initial bloods tests revealed the following abnormalities only; platelets 520, alkaline phosphatase 169, C-reactive protein 73, international normalised ratio 1.3.

An x-ray of her chest was abnormal with bilateral reticular nodular shadowing and CT of her chest, abdomen and pelvis showed multiple ill-defined spiculated nodules …
Immediate and delayed effects of nitrogen dioxide exposure at an ambient level on bronchial responsiveness to histamine in subjects with asthma
Authors: V Strand, P Salomonsson, J Lundahl, G Bylin
Journal: European Respiratory Journal (1996)

The time-kinetics of NO2 induced effects on bronchial responsiveness are poorly known as most observations have been made shortly after exposure. The aim of this study was to measure nonspecific bronchial responsiveness, lung function and inflammatory markers at different times after NO2 exposure in asthmatics. Nineteen subjects with mild asthma were exposed to either purified air or 488 micrograms.m-3 (0.26 ppm) NO2 for 30 min during intermittent exercise. Airway responsiveness to histamine, specific airway resistance (sRaw) and thoracic gas volume (TGV) were measured 30 min, 5 h, 27 h and 7 days after exposure. Peripheral blood inflammatory mediators and the expression of an adhesion molecule, (Mac1) on granulocytes, were analysed 30 min and 27 h after exposure. Bronchial responsiveness to histamine was significantly increased 5 h after NO2 exposure when compared to air (median provocative dose of histamine required to cause 100% increase of sRaw ((PDsRaw,100%) 110 micrograms after NO2 exposure vs 203 micrograms on air). There was a tendency for an increase after 30 min, which was nonsignificant (median PDsRaw,100% 100 vs 153 micrograms). NO2 exposure did not affect sRaw, but TGV was significantly reduced after exposure. We found an increased expression of Mac-1 on granulocytes 30 min after NO2 exposure when compared to pre-exposure values. No effect was seen on tryptase, eosinophil cationic protein (ECP), or myeloperoxidase (MPO). These results suggest that exposure to an ambient level of NO2 causes a delayed effect on bronchial responsiveness in asthmatics. The increased expression of an adhesion molecule in peripheral blood may indicate a NO2-induced priming of human granulocytes.
Formoterol protects against platelet-activating factor-induced effects in asthma
Authors: J. Gabrijelcic, A. Casas, R.A. Rabinovich, J. Roca, J.A. Barberà, K.F. Chung, R. Rodríguez-Roisin
Journal: European Respiratory Journal (2003)

Platelet-activating factor (PAF) is an inflammatory mediator that provokes neutropaenia, bronchoconstriction and gas exchange defects due to exudation of bulk plasma within the airways. While the inhibitory effects of short-acting β 2 ‐agonists on PAF‐induced disturbances have been consistently shown, those of long-acting β 2 ‐agonists are less convincing. To further explore the mechanisms involved in PAF challenge in asthma, 12 patients (forced expiratory volume in one second, 90±4% predicted) were investigated 2 h after inhaled formoterol (18 µg), in a double-blind, placebo-controlled, crossover design following PAF (18 µg) inhalation. Compared with the placebo, at 5 min, premedication with formoterol reduced PAF-induced cough and dyspnoea, and attenuated increased respiratory system resistance (by 67%) and arterial deoxygenation (by 50%). Likewise, ventilation-perfusion ( V ′ A / Q ′) inequality improved, as reflected by the dispersion of pulmonary blood flow (by 63%) and an overall index of V ′ A / Q ′ heterogeneity (by 71%). In contrast, PAF-induced facial flushing, neutropaenia and subsequent rebound neutrophilia remained unchanged. The improvement in gas exchange abnormalities shown after platelet-activating factor in patients with asthma pretreated with formoterol at the recommended clinical dose may reflect, in addition to its class effects, an anti-exudative effect of formoterol in the airways.
Rapid Identification of Candida albicans Septicemia in Man by Gas-Liquid Chromatography
Authors: Geraldine G. Miller, Michael W. Witwer, Abraham I. Braude, Charles E. Davis
Journal: Journal of Clinical Investigation (1974)

Gas-liquid chromatography (GLC) was used to study normal serum and serum from patients with septicemia caused by a variety of bacteria and by Candida albicans. The gas chromatograms of seven sera from six patients with septicemia due to C. albicans were found to be significantly and reproducibly different from those of normal sera. Chromatograms of serum from 19 bacteremic patients were indistinguishable from normals. The major peaks present in chromatograms of normal sera were identified by GLC and mass spectroscopy as the methyl esters of palmitic, oleic, linoleic, and stearic acids. In addition to these peaks, serum from patients with candidemia contained abnormal peaks that were also present in cultures of C. albicans grown in normal serum and in washed C. albicans harvested from cultures in yeast nitrogen base broth. Chromatograms from 11 cases of mucosal candidates differed little from normal and were easily distinguished from those of fungemia patients. Chromatograms of serum from two of four patients with deep-invasive candidiasis were indistinguishable from those of fungemia and reverted to normal after infections were eradicated.
Total body and exchangeable potassium in chronic airways obstruction: a controversial area?
Authors: K Boddy, D L Davies, A D Howie, M M Madkour, M E Mahaffy, A I Pack
Journal: Thorax (1978)

Potassium deficiency is an important complication in the treatment of heart disease. However, there is a serious dichotomy in the literature. Severe potassium depletion has been reported in this condition when exchangeable potassium was measured whereas normal levels or marginal depletion were found in measurements of total body potassium. To clarify this situation, simultaneous measurements of total body potassium by whole-body counting, and of exchangeable potassium by isotope dilution using 43K, were made in 10 male subjects with established airways obstruction. Sequential determinations showed that exchangeable potassium increased up to 68 hours after administration, and values obtained at only 24 hours would have been a substantial underestimate. In this group of subjects neither total body nor exchangeable potassium at 48 hours was significantly different from the expected normal value.
Traceable Self‐Assembly of Laser‐Triggered Cyanine‐Based Micelle for Synergistic Therapeutic Effect
Authors: Yuan‐I Chen, Cheng‐Liang Peng, Pei‐Chi Lee, Ming‐Hsien Tsai, Chun‐Yen Lin, Ying‐Hsia Shih, Min‐Feng Wei, Tsai‐Yueh Luo, Ming‐Jium Shieh
Journal: Advanced Healthcare Materials (2015)

To track nanocarriers, many researches adopt nanocarriers labeled with radiotracers or encapsulating near-infrared fluorescence (NIRF) dye. In this study, novel amphiphilic copolymers, methoxy poly(ethylene glycol) (mPEG)-cyanine-poly(ε-caprolactone) (PCL) (mPEG-Cy-PCL) are synthesized. mPEG-Cy-PCL are capable of performing NIRF imaging, photothermal therapy (PTT) on cancer cells and self-assembly nanocarriers. Cy-based micelles can encapsulate doxorubicin (Doxo@Cy-micelle) and achieve NIRF image-guided drug delivery. Doxo@Cy-micelles are nanosized micelles enhancing the accumulation of Doxo in tumor sites and decreasing side effects. Doxo@Cy-micelles exhibit an excellent PTT and synergistic chemotherapy of cancer via laser-triggered release of Doxo from micelles, eventually resulting in decreased cancer recurrence rates. The results show that Cy-based micelles are excellent nanocarriers for NIRF imaging and synergistic photothermal-chemotherapy of cancer.
Rapid desensitization of neonatal rat liver beta-adrenergic receptors. A role for beta-adrenergic receptor kinase.
Authors: I García-Higuera, F Mayor
Journal: Journal of Clinical Investigation (1994)

Exposure of beta-adrenergic receptors (BAR) to agonists often leads to a rapid loss of receptor responsiveness. The proposed mechanisms of such rapid receptor desensitization include receptor phosphorylation by either cAMP-dependent protein kinase or the specific beta-adrenergic receptor kinase (BARK), leading to functional uncoupling from adenylyl cyclase and sequestration of the receptors away from the cell surface. To evaluate the physiological role of such mechanisms, we have investigated whether rapid regulation of BAR occurs in the neonatal rat liver immediately after birth, a physiological situation characterized by a dramatic but transient increase in plasma catecholamines. We have detected a rapid, transient uncoupling of liver plasma membrane BARs from adenylyl cyclase (corresponding to a desensitization of approximately 45%) within the first minutes of extrauterine life, followed by a transient sequestration of approximately 40% of the BARs away from the plasma membrane. In agreement with such pattern of desensitization, we have detected (by enzymatic and immunological assays) rapid changes in BARK specific activity in different neonatal rat liver subcellular fractions that take place within the same time frame of BAR uncoupling and sequestration. Our results provide new evidence on the potential role of BAR desensitization mechanisms in vivo and suggest that they are involved in modulating catecholamines actions at the moment of birth. Furthermore, our data indicate that in addition to its suggested role as a rapid modulator of adrenergic receptor function at synapse, rapid BARK-mediated receptor regulation may have functional relevance in other tissues in response to high circulating or local levels of agonists.
A multicenter phase II study incorporating high-dose rituximab and liposomal doxorubicin into the CODOX-M/IVAC regimen for untreated Burkitt's lymphoma
Authors: A.M. Evens, K.R. Carson, J. Kolesar, C. Nabhan, I. Helenowski, N. Islam, B. Jovanovic, P.M. Barr, P.F. Caimi, S.A. Gregory, L.I. Gordon
Journal: Annals of Oncology (2013)
Psychiatric Opinion Regarding Abortion: Preliminary Report of a Survey
Authors: RALPH M. CROWLEY, ROBERT W. LAIDLAW
Journal: American Journal of Psychiatry (1967)

A survey of the opinions of psychiatrists regarding indications for interruption of pregnancy showed that over four-fifths of those responding favored liberalization of the legally permitted bases for interruption of pregnancy. In addition, letters and comments revealed an intense interest in the matter, not only in regard to the welfare and interests of the individual woman but also in regard to the welfare and interests of the child-to-be and that of the community to which both mother and child look for support. Canadian and foreign psychiatrists differed little from their U. S. colleagues.