tbuckley/cabot-search huggingface dataset:
TRPA1 is a major oxidant sensor in murine airway sensory neurons
Authors: Bret F. Bessac, Michael Sivula, Christian A. von Hehn, Jasmine Escalera, Lauren Cohn, Sven-Eric Jordt
Journal: Journal of Clinical Investigation (2008)

Sensory neurons in the airways are finely tuned to respond to reactive chemicals threatening airway function and integrity. Nasal trigeminal nerve endings are particularly sensitive to oxidants formed in polluted air and during oxidative stress as well as to chlorine, which is frequently released in industrial and domestic accidents. Oxidant activation of airway neurons induces respiratory depression, nasal obstruction, sneezing, cough, and pain. While normally protective, chemosensory airway reflexes can provoke severe complications in patients affected by inflammatory airway conditions like rhinitis and asthma. Here, we showed that both hypochlorite, the oxidizing mediator of chlorine, and hydrogen peroxide, a reactive oxygen species, activated Ca(2+) influx and membrane currents in an oxidant-sensitive subpopulation of chemosensory neurons. These responses were absent in neurons from mice lacking TRPA1, an ion channel of the transient receptor potential (TRP) gene family. TRPA1 channels were strongly activated by hypochlorite and hydrogen peroxide in primary sensory neurons and heterologous cells. In tests of respiratory function, Trpa1(-/-) mice displayed profound deficiencies in hypochlorite- and hydrogen peroxide-induced respiratory depression as well as decreased oxidant-induced pain behavior. Our results indicate that TRPA1 is an oxidant sensor in sensory neurons, initiating neuronal excitation and subsequent physiological responses in vitro and in vivo.
Inhibitors of the Arachidonic Acid Pathway and Peroxisome Proliferator–Activated Receptor Ligands Have Superadditive Effects on Lung Cancer Growth Inhibition
Authors: Ingalill Avis, Alfredo Martínez, Jordi Tauler, Enrique Zudaire, Anatoly Mayburd, Raed Abu-Ghazaleh, Frank Ondrey, James L. Mulshine
Journal: Cancer Research (2005)

Abstract Arachidonic acid (AA) metabolizing enzymes and peroxisome proliferator–activated receptors (PPARs) have been shown to regulate the growth of epithelial cells. We have previously reported that exposure to the 5-lipoxygenase activating protein–directed inhibitor MK886 but not the cyclooxygenase inhibitor, indomethacin, reduced growth, increased apoptosis, and up-regulated PPARα and γ expression in breast cancer cell lines. In the present study, we explore approaches to maximizing the proapoptotic effects of PPARγ on lung cancer cell lines. Non–small-cell cancer cell line A549 revealed dose-dependent PPARγ reporter activity after treatment with MK886. The addition of indomethacin in combination with MK886 further increases reporter activity. We also show increased growth inhibition and up-regulation of apoptosis after exposure to MK886 alone, or in combination with indomethacin and the PPAR ligand, 15-deoxy-Δ12,14-prostaglandin J2 compared with single drug exposures on the adenocarcinoma cell line A549 and small-cell cancer cell lines H345, N417, and H510. Real-time PCR analyses showed increased PPAR mRNA and retinoid X receptor (RXR)α mRNA expression after exposure to MK886 and indomethacin in a time-dependent fashion. The results suggest that the principal proapoptotic effect of these drugs may be mediated through the known antiproliferative effects of the PPARγ-RXR interaction. We therefore explored a three-drug approach to attempt to maximize this effect. The combination of low-dose MK886, ciglitazone, and 13-cis-retinoic acid interacted at least in a superadditive fashion to inhibit the growth of lung cancer cell lines A549 and H1299, suggesting that targeting PPARγ and AA action is a promising approach to lung cancer growth with a favorable therapeutic index.
The p65 subunit of NF-κB binds to PGC-1α, linking inflammation and metabolic disturbances in cardiac cells
Authors: David Álvarez-Guardia, Xavier Palomer, Teresa Coll, Mercy M. Davidson, Tung O. Chan, Arthur M. Feldman, Juan C. Laguna, Manuel Vázquez-Carrera
Journal: Cardiovascular Research (2010)

Nuclear factor-kappaB (NF-kappaB) is a transcription factor induced by a wide range of stimuli, including hyperglycaemia and pro-inflammatory cytokines. It is associated with cardiac hypertrophy and heart failure. It was previously reported that the NF-kappaB-mediated inhibition of proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) might explain the shift in glucose metabolism during cardiac pathological processes induced by pro-inflammatory stimuli, although the specific mechanisms remain to be elucidated. We addressed the specific mechanisms by which exposure to tumour necrosis factor-alpha (TNF-alpha) results in PGC-1alpha down-regulation in cardiac cells and, as a consequence, in the metabolic dysregulation that underlies heart dysfunction and failure.By using coimmunoprecipitation studies, we report for the first time that the p65 subunit of NF-kappaB is constitutively bound to PGC-1alpha in human cardiac cells and also in mouse heart, and that NF-kappaB activation by TNF-alpha exposure increases this binding. Overexpression and gene silencing analyses demonstrated that the main factor limiting the degree of this association is p65, because only the modulation of this protein modified the physical interaction. Our data show that the increased physical interaction between p65 and PGC-1alpha after NF-kappaB activation is responsible for the reduction in PGC-1alpha expression and subsequent dysregulation of glucose oxidation.On the basis of these data, we propose that p65 directly represses PGC-1alpha activity in cardiac cells, thereby leading to a reduction in pyruvate dehydrogenase kinase 4 (PDK4) expression and the subsequent increase in glucose oxidation observed during the proinflammatory state.
Regulation of Methionine Adenosyltransferase in Normal Diploid and Simian Virus 40-Transformed Human Fibroblasts&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: S J Jacobsen, R M Hoffman, R W Erbe
Journal: JNCI Journal of the National Cancer Institute (1980)

Methionine adenosyltransferase activity in normal diploid and simian virus 40 (SV40)-transformed human fibroblasts increased severalfold when cell monolayers were cultured in medium deficient in L-methionine. This increase in methionine adenosyltransferase activity required RNA and protein syntheses and probably represented a derepression of the enzyme's biosynthesis. Furthermore, studies with RNA synthesis inhibitors suggested that the regulation of this enzyme activity in human fibroblasts involved posttranscriptional mechanisms. The inclusion of homocysteine thiolactone, a metabolic precursor of methionine, in the methionine-deficient medium inhibited the derepression in normal human fibroblasts but augmented the derepression in fully transformed fibroblasts. These differences in derepression patterns thus appeared related to altered metabolism of homocysteine and/or methionine in SV40-transformed human fibroblasts and as such may serve as a transformation marker in SV40-transformed cells.
Involvement of T44 molecules in an antigen-independent pathway of T cell activation. Analysis of the correlations to the T cell antigen-receptor complex.
Authors: A Moretta, G Pantaleo, M Lopez-Botet, L Moretta
Journal: The Journal of Experimental Medicine (1985)

Prior studies indicate that the 9.3 monoclonal antibody (mAb) which defines a 44 kD T lineage-specific glycoprotein (T44) enhances the proliferative response of peripheral blood T lymphocytes to phytohemagglutinin (PHA) or allogeneic cells. The T44 molecule was expressed in both resting and activated T lymphocytes and in a subset of thymocytes, as assessed by indirect immunofluorescence and flow cytofluorometry. In view of the potential importance of T44 in T cell activation, we investigated the ability of the 9.3 (anti-T44) antibody to stimulate peripheral blood T lymphocytes under culture conditions giving optimal proliferative responses to anti-T3 mAb. Like UCHT1 (anti-T3) mAb, the 9.3 (anti-T44 mAb) promoted strong proliferative responses of purified T cells, provided that adherent cells were added to the culture. Maximal proliferation in response to 9.3 antibody was consistently detected at day 5 (at day 3 with anti-T3 or PHA). Moreover, triggering of T lymphocytes with 9.3 antibody (in the presence of adherent cells) resulted in strong IL-2 production that peaked at 48 h. Analysis of the physical and functional relationship between the T44 molecule and other molecules involved in T cell activation, including the clonotypically restricted Ti and the monomorphic T3 or T11 molecules, was carried out on a mutagenized jurkat T leukemia cell line. This mutant, termed JA3 (surface phenotype: T11+, T3+, 3A1+, T4-, T8-, DR-, Tac-, 4F2+, T44+) produced large amounts of IL-2 upon stimulation with PHA, anti-T3, or anticlonotypic mAb in conjunction with phorbol myristate acetate (or adherent cells). The molecules precipitated by anti-T44 mAb from 125I-labeled JA3 cells appeared as a diffuse band of Mr 40-45,000 under reducing conditions; under nonreducing conditions, a prominent band of Mr 80-85,000 was observed, while the Mr 40-45,000 band was greatly reduced. Thus, T44 molecules in both reducing and nonreducing conditions had relative molecular weights similar to that of molecules carrying clonotypic (Ti) determinants. In addition, like anti-Ti or anti-T3 mAb, anti-T44 antibody induced JA3 cells to produce large amounts of IL-2 in the presence of phorbol myristate acetate. Other similarities between T44 and molecules carrying clonotypic structures included the susceptibility to antibody-induced modulation and the late reexpression (72 h) at the cell surface after modulation. Taken together, these experiments suggest that anti-T44 mAb might recognize a monomorphic determinant of the T cell receptor molecule or be physically or functionally linked to the T3-Ti complex.(ABSTRACT TRUNCATED AT 400 WORDS)
Hepatic methotrexate content and progression of hepatic fibrosis: preliminary findings.
Authors: M J Ahern, S Kevat, W Hill, P J Hayball, H Harley, P D Hall
Journal: Annals of the Rheumatic Diseases (1991)

<h3>Abstract</h3> Visceral leishmaniasis (VL) is a fatal disease and a growing public health problem in East Africa, where Ethiopia has one of the highest VL burdens. The largest focus of VL in Ethiopia is driven by high prevalence in migrant agricultural workers and associated with a high rate of co-infection with HIV. This co-infection makes VL more difficult to treat successfully, and is associated with a high rate of relapse, with VL/HIV patients frequently experiencing many relapses of VL before succumbing to this infection. We present genome-wide data on <i>Leishmania donovani</i> isolates from a longitudinal study of cohorts of VL and VL/HIV patients reporting to a single clinic in Ethiopia. Extensive clinical data allows us to investigate the influence of co-infection and relapse on the populations of parasites infecting these patients. We find that the same parasite population is responsible for both VL and VL/HIV infections, and that in most cases, disease relapse is caused by recrudescence of the population of parasites that caused primary VL. Complex, multi-clonal infections are present in both primary and relapse cases, but the infrapopulation of parasites within a patient loses genetic diversity between primary disease presentation and subsequent relapses, presumably due to a population bottleneck induced by treatment. These data suggest that VL/HIV relapses are not caused by genetically distinct parasite infections, nor by re-infection. Treatment of VL does not lead to sterile cure, and in VL/HIV the infecting parasites are able to re-establish after clinically successful treatment, leading to repeated relapse of VL. <h3>Importance</h3> Visceral leishmaniasis (VL) is the second largest cause of deaths due to parasite infections, and a growing problem in East Africa. In Ethiopia, it is particularly associated with migrant workers moving from non-endemic regions for seasonal agricultural work, and frequently found as a co-infection with HIV, which leads to frequent VL relapse following treatment. Insight into the process of relapsing in these patients is thus key to controlling the VL epidemic in Ethiopia. We show that there is little genetic differentiation between the parasites infecting HIV positive and HIV negative VL patients. Moreover, we provide evidence that relapses are caused by the initially infecting parasite population, and that treatment induces a loss of genetic diversity in this population. We propose that restoring functioning immunity and improving anti-parasitic treatment may be key in breaking the cycle of relapsing VL in VL/HIV patients.
Dietary Salt Intake and Blood Pressure
Authors: Robert A. Holden
Journal: JAMA (1983)

With an index for dietary salt use designed to provide a semiquantitative estimate of salt intake, we have found that in a sample representative of the 2.1 million adults in Connecticut, the mean BP of those at the 90th percentile or higher of salt intake differs by a quantitatively insignificant amount from the mean BP of those at the tenth percentile or lower of salt intake. When we examined the obese (body mass index, 90th percentile or higher) separately, similar results were obtained. These findings indicate that it is unlikely dietary salt intake has a clinically significant effect on BP in the majority of individuals in a large defined population, but do not exclude the possibility of a clinically significant effect in a small subgroup of salt-sensitive individuals.
Maternal or Infant Antiretroviral Drugs to Reduce HIV-1 Transmission
Authors: Charles S. Chasela, Michael G. Hudgens, Denise J. Jamieson, Dumbani Kayira, Mina C. Hosseinipour, Athena P. Kourtis, Francis Martinson, Gerald Tegha, Rodney J. Knight, Yusuf I. Ahmed, Deborah D. Kamwendo, Irving F. Hoffman, Sascha R. Ellington, Zebrone Kacheche, Alice Soko, Jeffrey B. Wiener, Susan A. Fiscus, Peter Kazembe, Innocent A. Mofolo, Maggie Chigwenembe, Dorothy S. Sichali, Charles M. van der Horst
Journal: New England Journal of Medicine (2010)

We evaluated the efficacy of a maternal triple-drug antiretroviral regimen or infant nevirapine prophylaxis for 28 weeks during breast-feeding to reduce postnatal transmission of human immunodeficiency virus type 1 (HIV-1) in Malawi.We randomly assigned 2369 HIV-1-positive, breast-feeding mothers with a CD4+ lymphocyte count of at least 250 cells per cubic millimeter and their infants to receive a maternal antiretroviral regimen, infant nevirapine, or no extended postnatal antiretroviral regimen (control group). All mothers and infants received perinatal prophylaxis with single-dose nevirapine and 1 week of zidovudine plus lamivudine. We used the Kaplan-Meier method to estimate the cumulative risk of HIV-1 transmission or death by 28 weeks among infants who were HIV-1-negative 2 weeks after birth. Rates were compared with the use of the log-rank test.Among mother-infant pairs, 5.0% of infants were HIV-1-positive at 2 weeks of life. The estimated risk of HIV-1 transmission between 2 and 28 weeks was higher in the control group (5.7%) than in either the maternal-regimen group (2.9%, P=0.009) or the infant-regimen group (1.7%, P<0.001). The estimated risk of infant HIV-1 infection or death between 2 and 28 weeks was 7.0% in the control group, 4.1% in the maternal-regimen group (P=0.02), and 2.6% in the infant-regimen group (P<0.001). The proportion of women with neutropenia was higher among those receiving the antiretroviral regimen (6.2%) than among those in either the nevirapine group (2.6%) or the control group (2.3%). Among infants receiving nevirapine, 1.9% had a hypersensitivity reaction.The use of either a maternal antiretroviral regimen or infant nevirapine for 28 weeks was effective in reducing HIV-1 transmission during breast-feeding. (ClinicalTrials.gov number, NCT00164736.)
Validation of Interstitial Fluid Continuous Glucose Monitoring in Cystic Fibrosis
Authors: Lee Dobson, Christopher D. Sheldon, Andrew T. Hattersley
Journal: Diabetes Care (2003)

Diabetes is a complication of cystic fibrosis (CF) that is of growing clinical importance. The recognition of diabetes complications in CF subjects (1) has emphasized the need for more accurate monitoring of glycemia. This is complicated by the many factors affecting glycemia in CF subjects, ranging from the consequences of malabsorption to the caloric burden of supplemental nutrition, as well as the metabolic effects of infection and drugs (2). The recent introduction of devices that provide a continuous glucose profile has revealed clinically relevant excursions in glycemia previously overlooked by conventional measures (3). They are able to provide the detailed glucose profile required in CF patients before and after an established diagnosis of cystic fibrosis-related diabetes (CFRD). Many of these new methods rely on sampling glucose levels in interstitial fluid and its …
Hepatobronchial fistula caused by hydatid disease. The Dunedin experience 1952-79.
Authors: J Borrie, J H Shaw
Journal: Thorax (1981)

Despite intensive hydatid control measures in New Zealand, hepatopulmonary fistula resulting from infection by the echinococcus granulosus still occurs. Although the patients may quickly become debilitated from coughing bile and pus and associated septic complications, appropriate surgical therapy is usually effective. The exact diagnosis may be obscure, but it is helped by a high index of suspicion. A retrospective study of eight patients seen over a 27-year period is presented, and principles of management are outlined. Where biliary hypertension is not present adequate evacuation of the intrahepatic cysts, obliteration of the cyst space, freeing of the adherent lung, and closure of the pulmonary fistula(e) usually give satisfactory long-term results. Pulmonary lobectomy or segmental resection is seldom required.
Mitochondrial Basis for Immune Deficiency
Authors: Enrico Arpaia, Patricia Benveniste, Antonio Di Cristofano, Yiping Gu, Ilan Dalal, Susan Kelly, Michael Hershfield, Pier Paolo Pandolfi, Chaim M. Roifman, Amos Cohen
Journal: The Journal of Experimental Medicine (2000)

We generated purine nucleoside phosphorylase (PNP)-deficient mice to gain insight into the mechanism of immune deficiency disease associated with PNP deficiency in humans. Similar to the human disease, PNP deficiency in mice causes an immunodeficiency that affects T lymphocytes more severely than B lymphocytes. PNP knockout mice exhibit impaired thymocyte differentiation, reduced mitogenic and allogeneic responses, and decreased numbers of maturing thymocytes and peripheral T cells. T lymphocytes of PNP-deficient mice exhibit increased apoptosis in vivo and higher sensitivity to gamma irradiation in vitro. We propose that the immune deficiency in PNP deficiency is a result of inhibition of mitochondrial DNA repair due to the accumulation of dGTP in the mitochondria. The end result is increased sensitivity of T cells to spontaneous mitochondrial DNA damage, leading to T cell depletion by apoptosis.
"Polypill" to fight cardiovascular disease: Authors' reply
Authors: N. Wald
Journal: BMJ (2003)

EDITOR—Your correspondents overlook the extent of the health gain achievable with the “Polypill” and of the large amount of evidence underpinning our estimates of efficacy and adverse effects.1

About one person in three would benefit, and the Polypill would offer many people important extra years of active and useful life, with benefits evident over decades. The adverse effects, on the other hand, would mostly be apparent after a few weeks, in which case a variant of the pill could be substituted—for example, one without aspirin.

Of course, the Polypill is not an alternative to adopting a healthy lifestyle such as not smoking or not becoming overweight: it is a complementary means of prevention. We agree that work on the Polypill needs to continue so that after the necessary clinical trials it can be made available.

Ramos's view, that medicine should remain a patient based practice, is too limited; it would forgo important …
Examination of the Nasal Cavities from the Front
Authors: E. C. Baber
Journal: BMJ (1886)

may be treated successfully without a great deal of attention, there are others-and their number is larse-in which no trouble must be spared to effect the desired cure.Zhe adaptation of the apparatu § mayrequirb frequent alteration; the position of the patient during recwmbency, and even the management of every detail of his life, may have to be supervised, or at least directed, by the strgeon.We must not rest content with saying that some cases will recover and others will die.I would rather urge my belief that every case, if dealt with with sufficient energy, and if taken in hand before the constitution is undermined, may be cured provided no intercurrent disease be present to complicate the case.Mr: JnssorP remarked upon one or two signs of carious spine, on which, in cases of difflculty and obscurity, he relied with some confidence.First came the power of the patient to twist his spine, as in looking behind him, whilst his feet were kept in apposition and motionless.Then there was the effect of pressure upon the head by the hands of the surgeon, a means of diagnosis which, if attended with some.danger in advanced cases, was safely applicable in those which were obscure ; again, there was the pain elicited by jumping from a chair or table.He mentioned these chiefly because Mr. Smith, in his remarks, seemed to condemn them, and he desired it to be understood that he applied them only in cases of obscurity, and therefore pre- sumably of early disease.
An FGF21-Adiponectin-Ceramide Axis Controls Energy Expenditure and Insulin Action in Mice
Authors: William L. Holland, Andrew C. Adams, Joseph T. Brozinick, Hai H. Bui, Yukiko Miyauchi, Christine M. Kusminski, Steven M. Bauer, Mark Wade, Esha Singhal, Christine C. Cheng, Katherine Volk, Ming-Shang Kuo, Ruth Gordillo, Alexei Kharitonenkov, Philipp E. Scherer
Journal: Cell Metabolism (2013)
Patients with non-Jo-1 anti-tRNA-synthetase autoantibodies have worse survival than Jo-1 positive patients
Authors: Rohit Aggarwal, Elaine Cassidy, Noreen Fertig, Diane Carol Koontz, Mary Lucas, Dana P Ascherman, Chester V Oddis
Journal: Annals of the Rheumatic Diseases (2013)

To compare the cumulative survival and event free survival in patients with Jo-1 versus non-Jo-1 anti-tRNA synthetase autoantibodies (anti-synAb).Anti-synAb positive patients initially evaluated from 1985 to 2009 were included regardless of the connective tissue disease (CTD) diagnosis. Clinical data were extracted from a prospectively collected database and chart review. Survival between Jo-1 and non-Jo-1 was compared by log rank and Cox proportional hazards methods.202 patients possessed anti-synAb: 122 Jo-1 and 80 non-Jo-1 (35 PL-12; 25 PL-7; 9 EJ; 6 KS; 5 OJ). The diagnoses at first visit for Jo-1 and non-Jo-1 patients were myositis in 83% and 40.0%, overlap or undifferentiated CTD in 17% and 47.5%, and systemic sclerosis in 0% and 12.5%, respectively (p<0.001). The median delay in diagnosis was 0.4 years in Jo-1 patients versus 1.0 year in non-Jo-1 patients (p<0.001). The most common causes of death in the overall cohort were pulmonary fibrosis in 49% and pulmonary hypertension in 11%. The 5- and 10-year unadjusted cumulative survival was 90% and 70% for Jo-1 patients, and 75% and 47% for non-Jo-1 patients (p<0.005). The hazard ratio (HR) of non-Jo-1 patients compared with Jo-1 patients was 1.9 (p=0.01) for cumulative and 1.9 (p=0.008) for event free survival from diagnosis. Age at first diagnosis and diagnosis delay but not gender, ethnicity and CTD diagnosis influenced survival.Non-Jo-1 anti-synAb positive patients have decreased survival compared with Jo-1 patients. The difference in survival may be partly attributable to a delay in diagnosis in the non-Jo-1 patients.