tbuckley/cabot-search huggingface dataset:
Transcriptome-Based Network Analysis Reveals a Spectrum Model of Human Macrophage Activation
Authors: Jia Xue, Susanne V. Schmidt, Jil Sander, Astrid Draffehn, Wolfgang Krebs, Inga Quester, Dominic De Nardo, Trupti D. Gohel, Martina Emde, Lisa Schmidleithner, Hariharasudan Ganesan, Andrea Nino-Castro, Michael R. Mallmann, Larisa Labzin, Heidi Theis, Michael Kraut, Marc Beyer, Eicke Latz, Tom C. Freeman, Thomas Ulas, Joachim L. Schultze
Journal: Immunity (2014)

Highlights•Macrophages react with specific transcriptional programming upon distinct signals•Activation by TNF, PGE2, and P3C activates a STAT4-associated transcriptional program•NFKB1, JUNB, and CREB1 are central transcription factors of macrophage activation•Inflammatory signatures are lost in alveolar macrophages from COPD patientsSummaryMacrophage activation is associated with profound transcriptional reprogramming. Although much progress has been made in the understanding of macrophage activation, polarization, and function, the transcriptional programs regulating these processes remain poorly characterized. We stimulated human macrophages with diverse activation signals, acquiring a data set of 299 macrophage transcriptomes. Analysis of this data set revealed a spectrum of macrophage activation states extending the current M1 versus M2-polarization model. Network analyses identified central transcriptional regulators associated with all macrophage activation complemented by regulators related to stimulus-specific programs. Applying these transcriptional programs to human alveolar macrophages from smokers and patients with chronic obstructive pulmonary disease (COPD) revealed an unexpected loss of inflammatory signatures in COPD patients. Finally, by integrating murine data from the ImmGen project we propose a refined, activation-independent core signature for human and murine macrophages. This resource serves as a framework for future research into regulation of macrophage activation in health and disease.Graphical abstract
Challenges and approaches for the development of safer immunomodulatory biologics
Authors: Jean G. Sathish, Swaminathan Sethu, Marie-Christine Bielsky, Lolke de Haan, Neil S. French, Karthik Govindappa, James Green, Christopher E. M. Griffiths, Stephen Holgate, David Jones, Ian Kimber, Jonathan Moggs, Dean J. Naisbitt, Munir Pirmohamed, Gabriele Reichmann, Jennifer Sims, Meena Subramanyam, Marque D. Todd, Jan Willem Van Der Laan, Richard J. Weaver, B. Kevin Park
Journal: Nature Reviews Drug Discovery (2013)
Inflammatory cells and cellular activation in the lower respiratory tract in Churg-Strauss syndrome
Authors: A. Schnabel, E. Csernok, J. Braun, W. L Gross
Journal: Thorax (1999)

To obtain insight into the mechanisms of tissue injury in lung disease due to Churg-Strauss syndrome (CSS), the bronchoalveolar lavage (BAL) cell profile and the levels in the BAL fluid of cell products released by activated eosinophils and neutrophils were assessed.Thirteen patients with active progressive CSS (n = 7) or CSS in partial remission (n = 6) underwent clinical staging and bronchoalveolar lavage. The levels of eosinophil cationic protein (ECP), myeloperoxidase (MPO), and peroxidase activity in the BAL fluid were determined and the results were compared with those of 19 patients with pulmonary active Wegener's granulomatosis (WG) and nine control subjects.In patients with progressive CSS the BAL cell profile was dominated by eosinophils, neutrophil elevation being the exception. The eosinophilia was associated with high ECP levels (4.39 ng/ml and 0. 40 ng/ml in the two CSS groups compared with unmeasurable values in the controls). Individual patients with highly active CSS also had raised MPO levels, comparable to the levels in the most active WG patients. Peroxidase activity in the BAL fluid was 1.26 U/ml and 0. 10 U/ml in the two groups of patients with CSS and 0.20 U/ml in the controls. Pulmonary disease in patients with WG was characterised by an extensive increase in MPO (0.30 ng/ml versus 0.13 ng/ml in the controls) together with high peroxidase activity in the BAL fluid (4. 37 U/ml), but only a small increase in ECP levels was seen. No correlation was found between the ECP and MPO levels in patients with CSS which suggests that eosinophil and neutrophil activation vary independently of each other.These findings suggest that, in addition to eosinophil activation, neutrophil activation is an important feature in some patients with highly active CSS. The balance of neutrophil and eosinophil involvement appears to be variable and this may be one explanation for the individually variable treatment requirements of patients with CSS.
Ventilation-Induced Chemokine and Cytokine Release Is Associated with Activation of Nuclear Factor- κ B and Is Blocked by Steroids
Authors: HEINZ-DIETER HELD, SILKE BOETTCHER, LUTZ HAMANN, STEFAN UHLIG
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Recent clinical trials have shown that the survival of patients with acute respiratory distress syndrome (ARDS) is improved by ventilation with reduced volumes. These studies suggested that overinflation of the lungs causes overactivation of the immune system. The present study investigated the hypothesis that ventilation with increased tidal volumes results in early responses similar to those caused by stimulation with one of the major risk factors for ARDS: bacterial lipopolysaccharide (LPS). We therefore compared the effects of ventilation (-10 cm H2O or -25 cm H2O end-inspiratory pressure) and LPS (50 microg/ml) on nuclear factor (NF)-kappaB activation, chemokine release, and cytokine release in isolated perfused lungs obtained from BALB/C mice. We found that both LPS and ventilation with -25 cm H2O (overventilation; OV) caused translocation of NF-kappaB, which was abolished by pretreatment with the steroid dexamethasone. Furthermore, both treatments resulted in similar increases in perfusate levels of alpha-chemokines (macrophage inflammatory protein; [MIP]-2; KC), beta-chemokines (macrophage chemotactic protein-1; MIP-1alpha), and cytokines (tumor necrosis factor-alpha, interleukin-6), which were largely prevented by dexamethasone pretreatment. In LPS-resistant C3H/HeJ mice, only OV, and not LPS, caused translocation of NF-kappaB and release of MIP-2. We conclude that OV evokes early inflammatory responses similar to those evoked by LPS (i.e., NF-kappaB translocation and release of proinflammatory mediators). The NF-kappaB translocation elicited by OV appears to be independent of Toll-like receptor 4 and not due to LPS contamination introduced by the ventilator. Our data further suggest that steroids might be considered as a subsidiary treatment during artificial mechanical ventilation.
Screening for Prostate Cancer With the Prostate-Specific Antigen Test
Authors: Julia H. Hayes, Michael J. Barry
Journal: JAMA (2014)

Prostate cancer screening with the prostate-specific antigen (PSA) test remains controversial.To review evidence from randomized trials and related modeling studies examining the effect of PSA screening vs no screening on prostate cancer-specific mortality and to suggest an approach balancing potential benefits and harms.MEDLINE, EMBASE, and the Cochrane Register of Controlled Trials were searched from January 1, 2010, to April 3, 2013, for PSA screening trials to update a previous systematic review. Another search was performed in EMBASE and MEDLINE to identify modeling studies extending the results of the 2 large randomized trials identified. The American Heart Association Evidence-Based Scoring System was used to rate level of evidence.Two trials-the Prostate, Lung, Colorectal and Ovarian (PLCO) screening trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC)-dominate the evidence regarding PSA screening. The former trial demonstrated an increase in cancer incidence in the screening group (relative risk [RR], 1.12; 95% CI, 1.07-1.17) but no cancer-specific mortality benefit to PSA screening after 13-year follow-up (RR, 1.09; 95% CI, 0.87-1.36). The ERSPC demonstrated an increase in cancer incidence with screening (RR, 1.63; 95% CI, 1.57-1.69) and an improvement in the risk of prostate cancer-specific death after 11 years (RR, 0.79; 95% CI, 0.68-0.91). The ERSPC documented that 37 additional men needed to receive a diagnosis through screening for every 1 fewer prostate cancer death after 11 years of follow-up among men aged 55 to 69 years (level B evidence for prostate cancer mortality reduction). Harms associated with screening include false-positive results and complications of biopsy and treatment. Modeling studies suggest that this high ratio of additional men receiving diagnoses to prostate cancer deaths prevented will decrease during a longer follow-up (level B evidence).Available evidence favors clinician discussion of the pros and cons of PSA screening with average-risk men aged 55 to 69 years. Only men who express a definite preference for screening should have PSA testing. Other strategies to mitigate the potential harms of screening include considering biennial screening, a higher PSA threshold for biopsy, and conservative therapy for men receiving a new diagnosis of prostate cancer.
Role of reactive oxygen species in cocaine-induced cardiac dysfunction
Authors: F Moritz
Journal: Cardiovascular Research (2003)

Contractility alterations and LV hypertrophy after chronic cocaine administration have been shown to be accompanied by an increase in oxidative stress. This study was carried out to investigate whether the production of reactive oxygen species is an early event of primary importance in cocaine-induced myocardial injury or simply occurs as a consequence of the ventricular dysfunction itself.After 2 days of cocaine administration to rats, no differences were observed in echocardiographic parameters between the cocaine-treated group and the control group. However, an increase in oxidative stress in the myocardium was indicated by an increase in lipid peroxidation (+35%, cocaine vs. control), an increase in antioxidant enzymes (catalase +110%, glutathione peroxidase +40% and superoxide dismutase +38%) and of NADPH-driven superoxide production (assessed by chemiluminescence). Furthermore, higher gp91phox and p22phox mRNA expression, measured by quantitative real-time RT-PCR, was found in the cocaine group. On day 8, cocaine administration induced a cardiac dysfunction, characterized by a decrease in cardiac index (-30%, cocaine vs. controls) and left ventricular (LV) fractional shortening (-23%, cocaine vs. controls). This LV dysfunction was prevented by antioxidant treatment (100 mg/kg/day vitamin C and 100 U/kg/day vitamin E). Moreover, in these animals, antioxidant treatment decreased lipid peroxides and decreased the activity of NADPH oxidase, associated with the downregulation of gp91phox.These data indicate that cocaine administration induces early NADPH-driven O2-. release which may play an important role in the development and progression of the LV dysfunction observed after chronic cocaine abuse.
Getting real about invariants
Authors: Alan Costall, Giulia Parovel, Michele Sinico
Journal: Behavioral and Brain Sciences (2001)

Stoffregen &amp; Bardy argue that unimodal invariants do not exist, and that only “amodal” invariants are possible. But they confuse two separate issues. Amodal invariants, we argue, do indeed exist to specify features of the environment, but not even an amodal invariant, in isolation, could specify their “presence” or “reality.”
Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation
Authors: Taylor H. Schreiber, Dietlinde Wolf, Matthew S. Tsai, Jackie Chirinos, Vadim V. Deyev, Louis Gonzalez, Thomas R. Malek, Robert B. Levy, Eckhard R. Podack
Journal: Journal of Clinical Investigation (2010)

TNF receptor superfamily member 25 (TNFRSF25; also known as DR3, and referred to herein as TNFR25) is constitutively and highly expressed by CD4+FoxP3+ Tregs. However, its function on these cells has not been determined. Here we used a TNFR25-specific agonistic monoclonal antibody, 4C12, to study the effects of TNFR25 signaling on Tregs in vivo in mice. Signaling through TNFR25 induced rapid and selective expansion of preexisting Tregs in vivo such that they became 30%–35% of all CD4+ T cells in the peripheral blood within 4 days. TNFR25-induced Treg proliferation was dependent upon TCR engagement with MHC class II, IL-2 receptor, and Akt signaling, but not upon costimulation by CD80 or CD86; it was unaffected by rapamycin. TNFR25-expanded Tregs remained highly suppressive ex vivo, and Tregs expanded by TNFR25 in vivo were protective against allergic lung inflammation, a mouse model for asthma, by reversing the ratio of effector T cells to Tregs in the lung, suppressing IL-13 and Th2 cytokine production, and blocking eosinophil exudation into bronchoalveolar fluid. Our studies define what we believe to be a novel mechanism for Treg control and important functions for TNFR25 in regulating autoaggression that balance its known role in enhancing autoimmunity.
Effects of Thyroparathyroidectomy, Exogenous Calcium, and Short-Term Calcitriol Therapy on the Growth Plate in Renal Failure
Authors: Cheryl P. Sanchez, Yu-Zhu He
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Several factors have been implicated in the development of adynamic bone, including the use of calcium-containing phosphate binding agents, aggressive calcitriol therapy, and parathyroidectomy. To evaluate the effects of these interventions on the growth plate, weanling rats underwent sham nephrectomy (Control, n = 10) and 5/6 nephrectomy (Nx). In the nephrectomized group, animals underwent (a) thyroparathyroidectomy (Nx-TPTX, n = 7), (b) received exogenous calcium (Nx-Calcium, n = 10), (c) received short-term calcitriol therapy (Nx-D, n = 10), or (d) nephrectomized control (Nx-Control, n = 10). Higher serum calcium and lower PTH levels were demonstrated in Nx-Calcium and Nx-D animals. A decline in growth was demonstrated in Nx-Calcium and Nx-TPTX accompanied by shorter tibial lengths. The width of the growth plate was wider in Nx-Calcium animals due to an increase in the width of the hypertrophic zone and a decrease in the proliferative zone; these changes were accompanied by an impairment of chondroclastic resorption, lower gelatinase B/MMP-9 activity, decline in insulin-like growth factor-I (IGF-I) receptor, and lower histone-4 mRNA expression. Such findings in the growth plate, may partially contribute to the diminution of growth in these animals. Although growth was impaired in the Nx-TPTX animals, there were no significant changes demonstrated in the growth plate cartilage. Histone-4 transcripts, IGF-I receptor expression, and histochemical staining for chondroclasts were decreased in Nx-D animals. Thus, treatments used in the management of secondary hyperparathyroidism in renal failure have diverse effects on the growth plate of the young skeleton, and concurrent use of these interventions needs further evaluation. E-mail: [email protected]
Unified Ultrasonographic Diagnostic Criteria for Polycystic Kidney Disease
Authors: Franck A. Belibi, Charles L. Edelstein
Journal: Journal of the American Society of Nephrology (2008)

Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening hereditary disease in the United States, occurring in approximately one in every 400 to 1000 live births.1 ADPKD accounts for approximately 5 to 10% of end-stage renal failure in the United States requiring dialysis and renal transplantation.2 ADPKD is characterized by progressive enlargement of cyst-filled kidneys, severely affecting those who inherit one of the known genes that cause the disease. Mutations in PKD1, located on chromosome 16, are associated with a higher prevalence (85% of cases), earlier clinical presentation, and higher morbidity and mortality. Less profoundly affected individuals with mutations in PKD2, located on chromosome 4, account for the remaining 15% of cases.3 In patients with PKD2 mutations, end-stage kidney disease occurs on average 20 yr later than with PKD1 mutations (mean age 74 versus 54 yr).3 In a study previously reported in JASN , PKD1 kidneys were significantly larger and had more cysts than PKD2 kidneys, although the rate of cyst growth was not different between PKD1 and PKD2 kidneys.4

On the basis of effectiveness, cost, and safety, ultrasound is the most commonly used imaging modality to make the diagnosis of ADPKD. Magnetic resonance imaging and computed tomography scanning are used for research purposes, and no reported studies have compared ultrasound with other imaging modalities for the diagnosis of ADPKD. ADPKD is suspected when patients present with symptoms related to the large kidneys associated with hypertension, flank pain or hematuria, palpable kidneys or liver, or subarachnoid hemorrhage. ADPKD is also diagnosed incidentally when an abdominal ultrasound is performed for …
Students should spend part of training in rural hospitals
Authors: Bryan Christie
Journal: BMJ (2005)

Medical students and junior doctors should receive some of their training in rural and remote hospitals to help produce more doctors suitable to work in such areas. This is one of many ideas to emerge from an initiative organised by the Royal College of Physicians of Edinburgh that examines the sustainability of healthcare provision in Scotland's outlying areas.

The advance of specialisation in medicine, together with the fear of …
Preclinical Hemochromatosis in a Population on a High-Iron-Fortified Diet
Authors: K. Sigvard Olsson
Journal: JAMA (1978)

Three hundred forty-seven (96.4%) of all persons aged 30 to 39 years were screened with serum iron and iron binding capacity measurements to determine the incidence of hemochromatosis in a population. No women had signs of iron overload; however, nine men (5%) had persistenly elevated serum iron levels. In four men (2%), increased iron stores was found with a distribution like that in the early stages of hemochromatosis. In combination with recent findings of clinical hemochromatosis at our hospital, this study suggests that this condition is not as rare as has been reported earlier.
Activation of measles virus from silently infected human lymphocytes.
Authors: C J Lucas, J C Ubels-Postma, A Rezee, J M Galama
Journal: The Journal of Experimental Medicine (1978)

Lymphocytes were incubated with measles virus for 4 days in the absence of a lymphocyte stimulating agent. Such nonstimulated lymphocytes, infected with measles virus, did not express the virus antigens that are detectable by cytotoxic antibodies. Approximately 1 out of 5,000, or even fewer, of such lymphocytes produced virus as demonstrated by the infectious center assay; in the supernate only 10--100 infectious viruses per milliliter were detected. No virus structures could be observed by means of an electron microscope. However, such lymphocytes showed no reaction to phytohemagglutinin (PHA) in terms of DNA synthesis in a subsequent culture in the presence of antibodies against measles to prevent spreading of the infection to other cells. Although stimulation by PHA did not result in a significant increase in [3H]thymidine incorporation, measles virus was activated; 32 h after the addition of PHA nearly 80% of the cells were killed by measles virus antibodies and complement. The number of virus-producing cells increased to approximately 1 in 300 or more, and at 72 h the virus titer in the supernate had risen to 10(6) infectious particles per ml. This reactivation of measles virus was still obtained when PHA was added as late as 8 or more days after the initial infection.
Dysbiosis modulates capacity for bile acid modification in the gut microbiomes of patients with inflammatory bowel disease: a mechanism and marker of disease?: Figure 1
Authors: Lesley A Ogilvie, Brian V Jones
Journal: Gut (2012)

The recently published article by Gadaleta and co-workers1 has demonstrated that activation of the bile acid (BA) nuclear receptor, Farnesoid X receptor α (FXR), affords multi-level protection against intestinal inflammation and inflammatory bowel disease (IBD) in mice. Of the numerous avenues of research into IBD diagnosis and treatment that are opened by these findings, the questions posed by Gadaleta and co-workers regarding the contribution of gut bacteria to FXR modulation and aetiology of IBD are of particular significance.

Bacteria resident in the human gastrointestinal tract collectively encode a distributed pathway of BA modification, the products of which are the natural ligands for FXR,2 and there is growing appreciation that this may be a key activity through which the gut microbiota integrates factors relating to diet and mucosal inflammation, to initiate or exacerbate disease.3 These modified BAs display altered binding profiles for BA receptors, with several secondary BAs being among the most potent agonists. Moreover, microbial transformation could also influence BA bioavailability for …
Revealing the Pathogenic and Aging-related Mechanisms of the Enigmatic Idiopathic Pulmonary Fibrosis. An Integral Model
Authors: Moisés Selman, Annie Pardo
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

A growing body of evidence indicates that aberrant activation of alveolar epithelial cells and fibroblasts in an aging lung plays a critical role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, the biopathological processes linking aging with IPF and the mechanisms responsible for the abnormal activation of epithelial cells and fibroblasts have not been elucidated. Many of the hallmarks of aging (e.g., genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, and cellular senescence) have been proposed as essential mechanisms for the development of IPF; however, these disturbances are not restricted to IPF and also occur in other aging-related lung disorders, primarily chronic obstructive pulmonary disease (COPD). Therefore, an unanswered question is why a current/former smoker of about 60 years of age with shorter telomeres, alveolar epithelial senescence, excessive oxidative stress, and mitochondrial dysfunction develops IPF and not COPD; in other words, what makes old lungs specifically susceptible to develop IPF? In this Perspective, we propose an integral model in which the combination of some gene variants and/or gene expression in the aging lung results in the loss of epithelial integrity and consequently in the failure of the alveoli to correctly respond to injury and to face the stress associated with mechanical stretch. Afterward, a distinctive epigenetic "reprogramming" that affects both epithelial cells and fibroblasts provokes, among others, the recapitulation of developmental pathways and the aberrant activation and miscommunication between both cell types, resulting in the exaggerated production and accumulation of extracellular matrix and the subsequent destruction of the lung architecture.