tbuckley/cabot-search huggingface dataset:
The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia–reperfusion injury
Authors: Øystein Sandanger, Trine Ranheim, Leif Erik Vinge, Marte Bliksøen, Katrine Alfsnes, Alexandra V. Finsen, Christen P. Dahl, Erik T. Askevold, Geir Florholmen, Geir Christensen, Katherine A. Fitzgerald, Egil Lien, Guro Valen, Terje Espevik, Pål Aukrust, Arne Yndestad
Journal: Cardiovascular Research (2013)

Nucleotide-binding oligomerization domain-Like Receptor with a Pyrin domain 3 (NLRP3) is considered necessary for initiating a profound sterile inflammatory response. NLRP3 forms multi-protein complexes with Apoptosis-associated Speck-like protein containing a Caspase recruitment domain (ASC) and Caspase-1, which activate pro-interleukin-1β (IL-1β) and pro-IL-18. The role of NLRP3 in cardiac cells is not known. Thus, we investigated the expression and function of NLRP3 during myocardial ischaemia.Myocardial infarction (MI) was induced in adult C57BL/6 mice and Wistar rats by ligation of the coronary artery. A marked increase in NLRP3, IL-1β, and IL-18 mRNA expression was found in the left ventricle after MI, primarily located to myocardial fibroblasts. In vitro studies in cells from adult mice showed that myocardial fibroblasts released IL-1β and IL-18 when primed with lipopolysaccharide and subsequently exposed to the danger signal adenosine triphosphate, a molecule released after tissue damage during MI. When hearts were isolated from NLRP3-deficient mice, perfused and subjected to global ischaemia and reperfusion, a marked improvement of cardiac function and reduction of hypoxic damage was found compared with wild-type hearts. This was not observed in ASC-deficient hearts, potentially reflecting a protective role of other ASC-dependent inflammasomes or inflammasome-independent effects of NLRP3.This study shows that the NLRP3 inflammasome is up-regulated in myocardial fibroblasts post-MI, and may be a significant contributor to infarct size development during ischaemia-reperfusion.
Nerves and Personal Power. Some Principles of Psychology as Applied to Conduct and Health.
Journal: JAMA (1922)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
A RANDOMISED PLACEBO CONTROLLED TRIAL TO COMPARE THE EFFECTS OF TWO DOSAGES OF OMEGA-3 PUFA ON EXERCISE-INDUCED BRONCHOCONSTRICTION (EIB)
Authors: NC Williams, K Hunter, MA Johnson, GR Sharpe
Journal: British Journal of Sports Medicine (2013)

Treatment of EIB often involves drug interventions, but long-term use may cause systemic side effects (Dahl, Respir Med 2006;8:1307–1317). Supplementing the diet of EIB sufferers with fish oil rich in omega-3 (ω-3) polyunsaturated fatty acids (PUFA) improved post-exercise lung function and reduced systemic markers of inflammation and the need for bronchodilator use (Mickleborough et al . Am J Respir Crit Care Med 2003;168:1181–1189; Mickleborough et al . Chest 2006;129:39–49). However, these studies used high dosages of ω-3 PUFA (5–6 g · day −1 ), so we examined (and report preliminary data for) the effects of two different dosages of ω-3 PUFA on EIB in asthmatics. Six physically active EIB positive (≥ −10%ΔFEV 1 after eucapnic voluntary hyperventilation, EVH) males and 6 (age and activity matched) non-EIB males (CTRL) volunteered for the randomised, double-blind placebo (PLA) controlled crossover study. Subjects completed (in a counterbalanced fashion) three 21 day experimental conditions: (A) HIGH dose: 6.2 g·day −1 ω-3 PUFA (3.7 g EPA, 2.5 g DHA) (B) HALF dose 3.1 g·day −1 (1.8 g EPA, 1.3 g DHA) and (C) PLA (medium chain triglyceride). EIB response to EVH was assessed on days 0 and 21, with a 14 day washout period between conditions. For CTRLs, FEV 1 was not different after EVH within or between conditions. In the EIB group, the %ΔFEV 1 at 6-min post-EVH was improved equally after HIGH and HALF, both being better than PLA ( P &lt;0.05): at day 21 the %ΔFEV 1 6 min post-EVH was −32±20% (PLA), −21±18% (HIGH), and −19±18% (HALF). From day 0 to 21, %ΔFEV 1 at 6 min post-EVH showed 38±16% and 36±21% improvements for HIGH and HALF respectively and PLA showed no change (−6±19%) ( P&gt; 0.05). These data suggest that lower dosages (3.1 g·day −1 ) of ω-3 PUFA are as effective in aiding the treatment of EIB as high (6.2 g·day −1 ) dosages.
Activation of PI3K Signaling in Merkel Cell Carcinoma
Authors: Valentina Nardi, Youngchul Song, Juan A. Santamaria-Barria, Arjola K. Cosper, Quynh Lam, Anthony C. Faber, Genevieve M. Boland, Beow Y. Yeap, Kristin Bergethon, Vanessa L. Scialabba, Hensin Tsao, Jeffrey Settleman, David P. Ryan, Darrell R. Borger, Atul K. Bhan, Mai P. Hoang, Anthony J. Iafrate, James C. Cusack, Jeffrey A. Engelman, Dora Dias-Santagata
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine tumor, often metastatic at presentation, for which current chemotherapeutic regimens are largely ineffective. As its pathogenesis is still unknown, we hypothesized that deregulation of signaling pathways commonly activated in cancer may contribute to MCC tumorigenesis and may provide insights into targeted therapy approaches for this malignancy. Experimental Design: We retrospectively profiled 60 primary MCC samples using a SNaPshot-based tumor genotyping assay to screen for common mutations in 13 cancer genes. Results: We identified mutations in 9 (15%) MCC primary tumors, including mutations in TP53 (3 of 60) and activating mutations in the PIK3CA gene (6 of 60). Sanger sequencing of the primary MCC tumors detected one additional PIK3CA mutation (R19K) that had not been previously described in cancer. Merkel cell polyoma virus (MCPyV) was detected in 38 (66%) MCC cases and patients with MCPyV-positive cancers showed a trend toward better survival. With one exception, the presence of MCPyV and activating mutations in PIK3CA appeared mutually exclusive. We observed that signaling through the PI3K/pAKT pathway was active in one MCPyV-positive and in all MCPyV-negative MCC cell lines, as evidenced by AKT phosphorylation. Importantly, the presence of a PIK3CA-activating mutation was associated with sensitivity to treatment with ZST474, a specific phosphoinositide 3-kinase (PI3K) inhibitor, and to NVP-BEZ235, a dual PI3K/mTOR inhibitor, targeted agents under active clinical development. Conclusions: PI3K pathway activation may drive tumorigenesis in a subset of MCC and screening these tumors for PIK3CA mutations could help identify patients who may respond to treatment with PI3K pathway inhibitors. Clin Cancer Res; 18(5); 1227–36. ©2012 AACR.
Ruxolitinib: The First FDA Approved Therapy for the Treatment of Myelofibrosis
Authors: John Mascarenhas, Ronald Hoffman
Journal: Clinical Cancer Research (2012)

The BCR-ABL1-negative myeloproliferative neoplasms (e.g., essential thrombocythemia, polycythemia vera, and primary myelofibrosis) are a group of heterogeneous hematologic malignancies that involve a clonal proliferation of hematopoietic stem cells. Thrombosis, bleeding, and transformation to acute leukemia reduce the overall survival of patients with myelofibrosis, a disease typified by progressive splenomegaly and disease-related symptoms such as fatigue, pruritus, and bony pains. Hematopoietic stem cell transplant offers the only potential for cure in a minority of eligible patients, leaving a serious unmet need for improved therapies. Recent advances in our understanding of the pathogenetic mechanisms underlying these diseases have led to an explosion of clinical trials evaluating novel therapies. The discovery of an activating mutation in the Janus-activated kinase 2 (JAK2) gene provided a therapeutic target to downregulate this activated signaling pathway, which influences the phenotype of these diseases. Ruxolitinib (Jakafi; Incyte) is a small-molecule inhibitor of JAK1/2 that has proved to be effective at reducing splenomegaly and ameliorating symptoms in myeloproliferative neoplasms. Based on the results of 2 pivotal randomized phase III clinical trials, ruxolitinib has become the first therapeutic to be approved by the U.S. Food and Drug Administration for treatment of patients with myelofibrosis. Ruxolitinib offers a well-tolerated oral therapeutic option for patients with myelofibrosis with symptomatic splenomegaly and debilitating disease-related symptoms, but it does not seem to be effective at eliminating the underlying hematological malignancy.
P255 The Effects of Hypoxia on Neutrophil Degranulation
Authors: K Hoenderdos, L Porter, S Alam, N Mc Govern, C Fiddler, J Skepper, ER Chilvers, AM Condliffe
Journal: Thorax (2012)

Tissues such as the skin and intestinal epithelium experience physiological hypoxia whereas pathological hypoxia occurs at inflammatory sites. Neutrophils are recruited to infective/inflamed areas and are thus required to operate under low oxygen tensions. We have shown previously that hypoxia delays neutrophil apoptosis (JEM 2005; 201:105) and impairs bacterial killing (J Immunol 2011; 186:453) and have now studied the effect of hypoxia on the release of histotoxic neutrophil proteases. Neutrophils isolated from healthy volunteers were subjected to normoxia or hypoxia (3 kPa). Superoxide anion release was measured by the reduction of cytochrome. C Elastase release was quantified by the cleavage of labelled elastin. Hypoxic incubation for 4 hours resulted in a 3- fold reduction in superoxide anion release from cells stimulated with GM-CSF and fMLP. In contrast, elastase release from the azurophilic granules was augmented almost 3-fold under hypoxia. The release of MMP-9 and lactoferrin was similarly up-regulated, suggesting a more generalised increase in degranulation under hypoxia. In addition to this electron microscopy showed that hypoxia induced a more activated phenotype (e.g. increased membrane ruffling and cell spreading). We show that hypoxia can induce a more destructive neutrophil phenotype, with enhanced degranulation and release of potentially histotoxic proteases, impaired bacterial killing, and delayed apoptosis. These data suggest that hypoxia aversively affects neutrophil function and may augment neutrophil mediated tissue destruction.
Hepatic Transferrin Receptors in Hereditary Hemochromatosis
Authors: M. Lombard, W. Vogel, A. Bomford, R. Williams, R. Sciot, J. J. Van Den Ord, V. J. Desmet, G. Gerken, M. Manns, G. Ramadori, K.-H. Meyer zum Büschenfelde, I. Ghadiminejad, H. Baum, Şinasi Özsoylu
Journal: Hepatology (1988)
Efficacy of an Antihypertensive Agent
Authors: F. Gilbert McMahon
Journal: JAMA (1975)

In a double-blind evaluation, the efficacy of a combination of methyldopa with hydrochlorothiazide was compared with that of its components, methyldopa and hydrochlorothiazide. The combination was found to be more efficacious than either of its components. It reduced the arithmetic mean of the pressures of all patients from 170/116 to 133/95 mm Hg in four weeks. Despite the greater effect of the combination, side effects were mild.
Revealing signaling pathway deregulation by using gene expression signatures and regulatory motif analysis
Authors: Yingchun Liu, Markus Ringnér
Journal: Genome biology (2007)

Abstract Gene expression signatures consisting of tens to hundreds of genes have been found to be informative for different biological states. Recently, many computational methods have been proposed for biological interpretation of such signatures. However, there is a lack of methods for identifying cell signaling pathways whose deregulation results in an observed expression signature. We present a strategy for identifying such signaling pathways and evaluate the strategy using six human and mouse gene expression signatures.
Relation between creatinine and uric acid excretion.
Authors: Y Nishida
Journal: Annals of the Rheumatic Diseases (1992)

The relation between creatinine and uric acid metabolism was analysed in 77 male patients with primary gout and 62 healthy male subjects. Significant positive correlations between 24 hour urinary creatinine and uric acid excretion were shown in both groups. The mean urinary creatinine and uric acid excretions in the patients with gout were significantly increased as compared with those of normal male controls. These results suggest that there is a close correlation between creatinine and uric acid synthesis. In addition, it seems that accelerated uric acid synthesis seen in some patients with gout is due to increased creatinine synthesis.
Advanced Access
Authors: Mark Murray, Donald M Berwick
Journal: JAMA (2003)

Delay of care is a persistent and undesirable feature of current health care systems. Although delay seems to be inevitable and linked to resource limitations, it often is neither. Rather, it is usually the result of unplanned, irrational scheduling and resource allocation. Application of queuing theory and principles of industrial engineering, adapted appropriately to clinical settings, can reduce delay substantially, even in small practices, without requiring additional resources. One model, sometimes referred to as advanced access, has increasingly been shown to reduce waiting times in primary care. The core principle of advanced access is that patients calling to schedule a physician visit are offered an appointment the same day. Advanced access is not sustainable if patient demand for appointments is permanently greater than physician capacity to offer appointments. Six elements of advanced access are important in its application balancing supply and demand, reducing backlog, reducing the variety of appointment types, developing contingency plans for unusual circumstances, working to adjust demand profiles, and increasing the availability of bottleneck resources. Although these principles are powerful, they are counter to deeply held beliefs and established practices in health care organizations. Adopting these principles requires strong leadership investment and support.
Malaria Blood Stage Suppression of Liver Stage Immunity by Dendritic Cells
Authors: Carlos Ocaña-Morgner, Maria M. Mota, Ana Rodriguez
Journal: The Journal of Experimental Medicine (2003)

Malaria starts with Plasmodium sporozoites infection of the host's liver, where development into blood stage parasites occurs. It is not clear why natural infections do not induce protection against the initial liver stage and generate low CD8+ T cell responses. Using a rodent malaria model, we show that Plasmodium blood stage infection suppresses CD8+ T cell immune responses that were induced against the initial liver stage. Blood stage Plasmodium affects dendritic cell (DC) functions, inhibiting maturation and the capacity to initiate immune responses and inverting the interleukin (IL)-12/IL-10 secretion pattern. The interaction of blood stage parasites with DCs induces the secretion of soluble factors that inhibit the activation of CD8+ T cells in vitro and the suppression of protective CD8+ T cell responses against the liver stage in vivo. We propose that blood stage infection induces DCs to suppress CD8+ T cell responses in natural malaria infections. This evasion mechanism leaves the host unprotected against reinfection by inhibiting the immune response against the initial liver stage of the disease.
A longitudinal analysis of pulmonary function in rats during a 12 month cigarette smoke exposure
Authors: JL Wright, JP Sun, S Vedal
Journal: European Respiratory Journal (1997)

We wanted to examine the longitudinal effects of chronic cigarette smoke exposure, and to determine whether the chronic alterations in pulmonary function induced by long-term cigarette smoke exposure in an animal model could be predicted by initial or early alterations in function. A group of Sprague Dawley rats was exposed to the smoke of 7 cigarettes x day(-1) for 5 days x week(-1) during a total period of 12 months. Lung volume, flow-volume curves and pressure-volume curves were recorded at baseline, and after 2, 4, 8 and 12 months of smoke exposure. A control group of rats was subjected to the same regimen of testing, but was not exposed to smoke. Thirteen rats completed the study in the smoke-exposed group and seven rats in the control group. We found that chronic exposure to cigarette smoke produced early abnormalities in pulmonary function, with the forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio showing an acceleration of ageing effect, particularly between 4 and 8 months of exposure. In this model, although the two groups had significantly different airflow after 12 months, the initial values in each group were remarkably similar, and we could not identify any pulmonary function test which had predictive value. We conclude that longitudinal studies of cigarette smoke exposure in this rat model allow better characterization of the nature and time course of the effects of smoking on the lung.
Cerebellum and Nonmotor Function
Authors: Peter L. Strick, Richard P. Dum, Julie A. Fiez
Journal: Annual Review of Neuroscience (2009)

Does the cerebellum influence nonmotor behavior? Recent anatomical studies demonstrate that the output of the cerebellum targets multiple nonmotor areas in the prefrontal and posterior parietal cortex, as well as the cortical motor areas. The projections to different cortical areas originate from distinct output channels within the cerebellar nuclei. The cerebral cortical area that is the main target of each output channel is a major source of input to the channel. Thus, a closed-loop circuit represents the major architectural unit of cerebro-cerebellar interactions. The outputs of these loops provide the cerebellum with the anatomical substrate to influence the control of movement and cognition. Neuroimaging and neuropsychological data supply compelling support for this view. The range of tasks associated with cerebellar activation is remarkable and includes tasks designed to assess attention, executive control, language, working memory, learning, pain, emotion, and addiction. These data, along with the revelations about cerebro-cerebellar circuitry, provide a new framework for exploring the contribution of the cerebellum to diverse aspects of behavior.
US Supreme Court's exoneration of the Affordable Care Act
Authors: R. Steinbrook
Journal: BMJ (2015)

Survives second major constitutional challenge and may finally be here to stay

Having survived its second major US Supreme Court challenge in three years, the Affordable Care Act, popularly known as “Obamacare,” is very likely to remain in effect after President Barack Obama leaves office in 2017 and may yet become a lasting and important part of the social safety net in the United States, like Medicare and Social Security.

In a 6-3 decision issued on 25 June 2015, the Supreme Court ruled constitutional the federal government’s ability to subsidize eligible people on lower and middle incomes to buy health insurance on the federal marketplace.1 Writing for the majority, Chief Justice John Roberts bluntly stated: “Congress passed the Affordable Care Act to improve health insurance markets, not to destroy them.” Abolishing the subsidies on the federal health insurance exchanges, which would have the effect of decreasing the number of people with health insurance, “could well push a State’s individual insurance market into a death spiral. It is implausible that Congress meant the Act to operate in this manner.”1

The Supreme Court rejected the first constitutional challenge to the Patient Protection and Affordable …
Depressive Symptoms and Severity of Illness in Multiple Sclerosis: Epidemiologic Study of a Large Community Sample
Authors: Lydia Chwastiak, Dawn M Ehde, Laura E Gibbons, Mark Sullivan, James D Bowen, George H Kraft
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: Previous research has shown high prevalence rates of depression in multiple sclerosis patients seen in specialty clinics. The relationships among depressive symptoms and severity, duration, and course of multiple sclerosis are controversial. METHOD: A survey was mailed to members of the Multiple Sclerosis Association of King County (Wash.). Of the 1,374 eligible participants, 739 returned the survey, a response rate of 53.8%. Data about demographic characteristics, employment, and duration and course of multiple sclerosis were collected. Severity of multiple sclerosis was determined by the Expanded Disability Status Scale, self-report version. Severity of depressive symptoms was evaluated with the Center for Epidemiologic Studies Depression Scale (CES-D Scale). Analysis of covariance was used to compare mean CES-D Scale scores across categories of multiple sclerosis, and logistic regression was used to identify variables associated with clinically significant depression. RESULTS: Clinically significant depressive symptoms (CES-D Scale score ≥16) were found in 41.8% of the subjects, and 29.1% of the subjects had moderate to severe depression (score ≥21). Subjects with advanced multiple sclerosis were much more likely to experience clinically significant depressive symptoms than subjects with minimal disease. Shorter duration of multiple sclerosis was associated with a greater likelihood of significant depressive symptoms, but the pattern of illness progression was not. CONCLUSIONS: In this large community sample, the severity of multiple sclerosis was more strongly associated with depressive symptoms than was pattern of illness. Clinicians should evaluate depression in patients with recent diagnoses of multiple sclerosis, major changes in functioning, or limited social support.
Host defences to Burkitt tumour.
Authors: V. A. Ngu
Journal: BMJ (1967)

Psoriasis of Scalp-Williams et al.BEJDI2N'IWJLR 345 psoriasis of the scalp.Patients found it cosmetically superior to ointments and creams, and the preparation was effective compared with the inert base.NOTE.-Since this work began Hagerman (1965) has reported the successful use of an alcoholic solution of triamcinolone in psoriasis of the scalp.The preparation he used contained salicylic acid and benzalkonium chloride in addition to the steroid, and his patients used an occlusive dressing on the head at night REFmEREcEs