tbuckley/cabot-search huggingface dataset:
Shutdown Underscored Vulnerability of US Public Health and Biomedical Research to Political Wrangling
Authors: Bridget M. Kuehn
Journal: JAMA (2013)

Thefederal shutdown in October left US public health and biomedical research systems reeling andexposed their vulnerability to national politics. The shutdown reduced staffing at the federal health agencies, crippling many programs and cutting off funding for health services, research laboratories, andotherefforts that depend on federal support. The interruption of public health efforts raised major concerns as the nation entered peakseasonsfor influenzaandothercommunicablediseases.Troublingstoriesemergedin the media about hundreds of patients who could not enroll in cancer clinical trials at the NationalInstitutesofHealth(NIH)ClinicalCenterbecausenewtrialshadbeenstopped(http: //wapo.st/1glMSxk) and about vulnerable families at risk of losing their federal food aid (http://onforb.es/18sraDB). In addition, amultistateoutbreakof antibiotic-resistant Salmonella Heidelberg emerged justas theCenters forDiseaseControl andPrevention (CDC) sidelined investigatorswhousuallywork toquickly spot and contain foodborne epidemics. Beyond the immediatepublichealthcrises, according to leaders fromseveralUSphysicianorganizations, the shutdown likely did lasting damage to the US public health and biomedical research enterprise, setting back research and public health programs by years.
Premalignant Lesions as Targets for Cancer Vaccines
Authors: Olivera J. Finn
Journal: The Journal of Experimental Medicine (2003)

The job of the immune system is to respond to signals released by tissues that are being destroyed by foreign invaders, such as viruses and bacteria, and to destroy the invaders. These signals have been termed “danger” signals ([1][1]). Destruction of tissues by uncontrolled cell growth
Pharmacologic Treatment of Heroin-Dependent Patients
Authors: Patrick G. O'Connor, David A. Fiellin
Journal: Annals of Internal Medicine (2000)

Patients with heroin dependence frequently present to internists and other physicians for heroin-related medical, psychiatric, and behavioral health problems and often seek help with reducing their heroin use. Thus, physicians should be familiar with the identification and diagnosis of heroin dependence in their patients and be able to initiate treatment of heroin dependence both directly and by referral. Recent research has provided much information concerning effective pharmacologically based treatment approaches for managing opioid withdrawal and helping patients to remain abstinent. Methadone maintenance and newer approaches using L-α acetylmethadol and buprenorphine seem to be particularly effective in promoting relapse prevention. Although these treatments are currently provided in special drug treatment settings, recent and ongoing research indicates that the physician's office may be an effective alternative site for these treatments.
Secondary in vitro responses of T lymphocytes to non-H-2 alloantigens self-H-2-restricted responses induced in heterologous serum are not dependent on primary-stimulating non-H-2 alloantigens.
Authors: A B Peck, L C Andersson, H Wigzell
Journal: The Journal of Experimental Medicine (1977)

The role of non-H-2 alloantigens, specifically Mls locus products, in secondary in vitro T-cell-mediated cytotoxicity has been studied. Splenic T lymphocytes, activated against Mls locus alloantigens in primary-mixed cultures and isolated by velocity sedimentation gradient separation techniques, were used as responding populations in secondary mixed leukocyte cultures (MLCs) and cell-mediated lympholysis (CML). Such T-cell clones could be shown to exhibit either "self"-H-2-restricted or anti-Mls locus-specific reactivity, with this dichotomy of reactivity depending only on the primary culture conditions. Mls locus-activated T lymphocytes generated in cultures supplemented with homologous serum exhibited specific memory responses in MLC, yet remained incapable of effecting target cell destruction against Mls locus antigens or against "self"-H-2-structures in CML. In contrast, activated T-cell clones generated in the presence of heterologous serum displayed H-2-restricted reactivity in both secondary MLC and CML. H-2-restricted MLC activation was controlled by products of the H-2 serologically defined regions. Although heterologous serum was a necessary (and sufficient) entity for development of H-2-restricted responses, evidence argues against the possibility that heterologous serum acts via modification of cell surface components.
Lipid alterations in isolated, working rat hearts during ischemia and reperfusion: its relation to myocardial damage.
Authors: M van Bilsen, G J van der Vusse, P H Willemsen, W A Coumans, T H Roemen, R S Reneman
Journal: Circulation Research (1989)

Disturbances in lipid metabolism may play an important role in the onset of irreversible myocardial damage. To investigate the effect of ischemia and reperfusion on lipid homeostasis and to delineate its possible consequences for myocardial damage, Krebs-Henseleit-perfused, working rat hearts were subjected to various periods of no-flow ischemia (10 to 90 minutes) with or without 30 minutes of reperfusion. During ischemia, the rise in nonesterified fatty acids (NEFAs) was preceded by the accumulation of substantial amounts of glycerol, indicating the presence of an active triacylglycerol-NEFA cycle. The subsequent rise in NEFAs (from 0.25 to 1.64 mumol/g dry residue wt after 90 minutes [means]) coincided with the reduction of ATP to values lower than 10 mumol/g dry wt and the rise of AMP, a potent inhibitor of acyl-coenzyme A synthetase, to values exceeding 2 mumol/g dry wt, making the latter compound a good candidate to hamper the turnover of endogenous lipids during prolonged ischemia. Reperfusion resulted in an additional rise in NEFAs (up to 4.1 mumol/g dry residue wt after 60 minutes of ischemia). Neither ischemia nor reperfusion resulted in significant decreases in the tissue content of triacylglycerols and the various phospholipids. During reperfusion recovery of stroke volume was still adequate at tissue NEFA levels thought to be incompatible with normal mitochondrial function. A positive correlation (r = 0.81) was found between NEFA content of reperfused hearts and cumulative release of lactate dehydrogenase during reperfusion. Accordingly it is concluded that 1) reperfusion results in additional changes in myocardial lipid homeostasis, 2) the accumulating NEFAs are compartmentalized, possibly at the cellular level, and 3) the accumulation of NEFAs is a sensitive marker for myocardial cell damage.
Different Effects of Point Mutations within the <b> <i>B-Raf</i> </b> Glycine-Rich Loop in Colorectal Tumors on Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase/Extracellular Signal-Regulated Kinase and Nuclear Factor κB Pathway and Cellular Transformation
Authors: Tsuneo Ikenoue, Yohko Hikiba, Fumihiko Kanai, Jun Aragaki, Yasuo Tanaka, Jun Imamura, Takaaki Imamura, Miki Ohta, Hideaki Ijichi, Keisuke Tateishi, Takayuki Kawakami, Masayuki Matsumura, Takao Kawabe, Masao Omata
Journal: Cancer Research (2004)

Recently, mutations in the B-Raf gene have been identified in a variety of human cancers, such as melanoma and colorectal carcinoma, and more than 80% of the B-Raf mutations have been V599E. Although other mutations have been reported, their functional consequences are poorly understood. In our earlier study, we demonstrated that colon tumor-associated B-Raf mutations within the kinase activation segment are not necessarily associated with an increase in mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase (MEK/Erk) or nuclear factor kappaB (NFkappaB) signaling activity or in NIH3T3-transforming ability. In this study, we examined the effect of colon tumor-associated mutations within the B-Raf glycine-rich loop (G loop) on MEK/Erk and NFkappaB signaling and on the transformation of NIH3T3 fibroblasts or IEC-6 intestinal epithelial cells. Of the six G loop mutations examined, only the B-Raf G468A significantly increased MEK/Erk and NFkappaB signaling and NIH3T3 transformation. Only this mutation induced transformed phenotypes of IEC-6 cells. In contrast, the B-Raf G468E mutation significantly decreased MEK/Erk signaling and NIH3T3 transformation and had no effect on NFkappaB signaling. The B-Raf F467C mutation moderately elevated MEK/Erk signaling and NIH3T3 transformation. The other three B-Raf mutations, R461I, I462S, and G463E, did not increase MEK/Erk or NFkappaB signaling or NIH3T3 transformation. Except for F467C, none of the tumors with B-Raf mutations examined in this study had K-Ras mutations. These results suggest that some of the B-Raf G loop mutations reported in colorectal tumors do not increase kinase or transforming activities but might contribute to carcinogenesis via other mechanisms or be irrelevant to carcinogenesis.
Persistent or Recurrent Anemia Is Associated With Severe and Disabling Inflammatory Bowel Disease
Authors: Ioannis E. Koutroubakis, Claudia Ramos–Rivers, Miguel Regueiro, Efstratios Koutroumpakis, Benjamin Click, Robert E. Schoen, Jana G. Hashash, Marc Schwartz, Jason Swoger, Leonard Baidoo, Arthur Barrie, Michael A. Dunn, David G. Binion
Journal: Clinical Gastroenterology and Hepatology (2015)
Restriction of LABA use to combination ICS/LABA inhaler therapy in asthma
Authors: Richard Beasley, James Fingleton, Mark Weatherall
Journal: Thorax (2012)

In 2011 the British asthma guidelines recommended for the first time that long-acting beta agonists (LABAs) should be prescribed in fixed dose combination inhaled corticosteroid (ICS)/LABA inhalers in the treatment of asthma.1 This represented a revision to the 2009 BTS guidelines in which LABAs were recommended if used with ICS, either as separate inhalers or as a combination ICS/LABA inhaler.2 The revision was based on the evidence that LABAs have the potential to increase the risk of asthma mortality when used by patients with unstable asthma without concomitant ICS therapy or scheduled medical review,3 that there is no evidence of an increased risk of asthma mortality with combination ICS/LABA inhaler therapy in asthma,4 and that it is only with combination ICS/LABA products that it could be guaranteed that LABA monotherapy can be avoided.5 It recognised that the use of separate inhalers inevitably results in periods of LABA monotherapy in a proportion of patients, because patients who are poorly adherent to prescribed ICS therapy may continue using their LABA inhaler for symptomatic relief.5–7

The extent to which this may occur is now described in an audit of prescribing from a Scottish GP database, reported in this edition of the journal by Morales et al .8 Of the 29% of patients with asthma who were prescribed a LABA during the 2006 calendar year, about one in four were prescribed a LABA in the form of a separate inhaler …
Effect of Obesity on Prognosis After Early-Stage Breast Cancer
Authors: Marianne Ewertz, Maj-Britt Jensen, Katrín Á. Gunnarsdóttir, Inger Højris, Erik H. Jakobsen, Dorte Nielsen, Lars E. Stenbygaard, Ulla B. Tange, Søren Cold
Journal: Journal of Clinical Oncology (2010)

Purpose This study was performed to characterize the impact of obesity on the risk of breast cancer recurrence and death as a result of breast cancer or other causes in relation to adjuvant treatment. Patients and Methods Information on body mass index (BMI) at diagnosis was available for 18,967 (35%) of 53,816 women treated for early-stage breast cancer in Denmark between 1977 and 2006 with complete follow-up for first events (locoregional recurrences and distant metastases) up to 10 years and for death up to 30 years. Information was available on prognostic factors and adjuvant treatment for all patients. Univariate analyses were used to compare the associations of known prognostic factors and risks of recurrence or death according to BMI categories. Cox proportional hazards regression models were used to assess the influence of BMI after adjusting for other factors. Results Patients with a BMI of 30 kg/m 2 or more were older and had more advanced disease at diagnosis compared with patients with a BMI below 25 kg/m 2 (P &lt; .001). When data were adjusted for disease characteristics, the risk of developing distant metastases after 10 years was significantly increased by 46%, and the risk of dying as a result of breast cancer after 30 years was significantly increased by 38% for patients with a BMI of 30 kg/m 2 or more. BMI had no influence on the risk of locoregional recurrences. Both chemotherapy and endocrine therapy seemed to be less effective after 10 or more years for patients with BMIs greater than 30 kg/m 2 . Conclusion Obesity is an independent prognostic factor for developing distant metastases and for death as a result of breast cancer; the effects of adjuvant therapy seem to be lost more rapidly in patients with breast cancer and obesity.
A Phase I Dose-Finding Study of 5-Azacytidine in Combination with Sodium Phenylbutyrate in Patients with Refractory Solid Tumors
Authors: Jianqing Lin, Jill Gilbert, Michelle A. Rudek, James A. Zwiebel, Steve Gore, Anchalee Jiemjit, Ming Zhao, Sharyn D. Baker, Richard F. Ambinder, James G. Herman, Ross C. Donehower, Michael A. Carducci
Journal: Clinical Cancer Research (2009)

Abstract Purpose: This was a phase I trial to determine the minimal effective dose and optimal dose schedule for 5-azacytidine (5-AC) in combination with sodium phenylbutyrate in patients with refractory solid tumors. The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied. Experimental Design: Three dosing regimens were studied in 27 patients with advanced solid tumors, and toxicity was recorded. The pharmacokinetics of the combination of drugs was evaluated. Repeat tumor biopsies and peripheral blood mononuclear cells (PBMC) were analyzed to evaluate epigenetic changes in response to therapy. EBV titers were evaluated as a surrogate measure for gene re-expression of epigenetic modulation in PBMC. Results: The three dose regimens of 5-AC and phenylbutyrate were generally well tolerated and safe. A total of 48 cycles was administrated to 27 patients. The most common toxicities were bone marrow suppression–related neutropenia and anemia, which were minor. The clinical response rate was disappointing for the combination of agents. One patient showed stable disease for 5 months whereas 26 patients showed progressive disease as the best tumor response. The administration of phenylbutyrate and 5-AC did not seem to alter the pharmacokinetics of either drug. Although there were individual cases of targeted DNA methyltransferase activity and histone H3/4 acetylation changes from paired biopsy or PBMC, no conclusive statement can be made based on these limited correlative studies. Conclusion: The combination of 5-AC and phenylbutyrate across three dose schedules was generally well tolerated and safe, yet lacked any real evidence for clinical benefit. (Clin Cancer Res 2009;15(19):6241–9)
Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter
Authors: Jun-ichi Nezu, Ikumi Tamai, Asuka Oku, Rikiya Ohashi, Hikaru Yabuuchi, Noriyoshi Hashimoto, Hiroko Nikaido, Yoshimichi Sai, Akio Koizumi, Yutaka Shoji, Goro Takada, Toyojiro Matsuishi, Makoto Yoshino, Hirohisa Kato, Toshihiro Ohura, Gozoh Tsujimoto, Jun-ichiro Hayakawa, Miyuki Shimane, Akira Tsuji
Journal: Nature Genetics (1999)
Mitogenic effect of serotonin on vascular endothelial cells.
Authors: R Pakala, J T Willerson, C R Benedict
Journal: Circulation (1994)

BACKGROUND Recent studies indicate that serotonin (5-HT) has a growth-promoting effect on several different cell types, including smooth muscle cells. After percutaneous transluminal coronary angioplasty, there is damage and denudation of vascular endothelial cells, which promotes platelet aggregation at the site of injury. Aggregating platelets release 5-HT; thus, a high concentration of the amine may be present at sites of endothelial damage, which may act as a mitogen to endothelial cells. METHODS AND RESULTS The mitogenic effect of 5-HT was examined on canine and bovine aortic endothelial cells by (1) assessing the increase in [3H]thymidine incorporation into DNA and (2) assessing the increase in the absolute number of cells after stimulation with 5-HT. 5-HT at an added concentration of 200 to 1000 mumol/L in the media induced a significant increase in [3H]thymidine incorporation into endothelial cells and an increase in cell number. This effect was not observed with fibroblasts. As the concentrations of added 5-HT were decreased, the endothelial cells had to be stimulated with 5-HT for longer periods to induce the same degree of cellular proliferation. The precursors and metabolic breakdown products of 5-HT were inactive. The 5-HT-induced endothelial proliferation was reversed by 5-HT2 receptor antagonists and pertussis toxin. These data suggest that the mitogenic effect of 5-HT on endothelial cells is mediated by the 5-HT2 receptor, which is coupled to a G protein. CONCLUSIONS 5-HT is a mitogen for endothelial cells at concentrations likely to be present at sites of vascular injury. This effect is probably mediated via the 5-HT2 receptor. The growth-promoting effects of 5-HT on endothelial cells may facilitate the healing of intima after vascular damage.
FOCAL INFECTION AND MENTAL DISEASE
Authors: Nicholas Kopeloff, George H. Kirby
Journal: American Journal of Psychiatry (1923)

1. In a series of 120 cases showing manic-depressive, dementia præcox, psychoneurotic, and psychopathic personality reactions, the removal of focal infection in 58 cases did not result in a higher percentage of improvement or recoveries than in a comparable group of 62 cases in which foci of infection were not removed. 2. Reviewing the entire group of operated cases showing recovery or improvement, and comparing the original prognoses with the subsequent course, our observations demonstrate that in every case that recovered, a recovery had been forecast before treatment was started; and that no case recovered in which a poor prognosis had been given. Furthermore, in only one case did an unexpected improvement occur. 3. A critical study of the methods used by Cotton for establishing focal infection has proven them to be unsatisfactory for teeth, stomach, lower intestine, and cervix. 4. It is desirable to eliminate focal infection when adequately demonstrated in psychotic patients in the same way as one should attempt to alleviate any physical disorder in mentally diseased patients. Nevertheless, it has not been shown that focal infection is the etiological factor in the functional psychoses.
Thrombocytopenia in lupus: baseline C3 as an independent risk factor for relapse
Authors: P D Ziakas, L S Poulou, S Giannouli, A G Tzioufas, M Voulgarelis
Journal: Annals of the Rheumatic Diseases (2006)

Thrombocytopenia in patients with systemic lupus erythematosus (SLE) requires immunosuppressive treatment to restore normal platelet counts and treat concomitant organ involvement in other systems.1–6 However, relapses are quite common during the course of the disease.7

From 1995 to 2004, 38 consecutive patients with SLE with a first episode of thrombocytopenia (platelet count  150 000). Severe thrombocytopenia (<20 000/μl) was recorded in 34.2% of patients with rare haemorrhagic manifestations. Organ involvement included, in descending order, arthritis (31.6%), renal disease (29%), rash (18.5%), manifestations of the central nervous system (13.2%) and serositis (9%). Low C3 levels …
Coronary vasodilator reserve after human orthotopic cardiac transplantation.
Authors: A L McGinn, R F Wilson, M T Olivari, D C Homans, C W White
Journal: Circulation (1988)

Cardiac transplantation is frequently associated with accelerated coronary atherosclerosis and immune-mediated microvascular injury. To determine if orthotopic cardiac transplantation impairs the capacity of the coronary vasculature to vasodilate and conduct hyperemic blood flow, maximal coronary vasodilator reserve was measured in 25 cardiac allograft recipients with no evidence of rejection 6-57 months after transplantation and in 20 normal subjects. Left ventricular wall thickness was assessed echocardiographically, and epicardial coronary anatomy was evaluated by quantitative coronary angiography. Coronary vasodilator reserve (CVDR) was measured in all patients with a coronary Doppler catheter and a maximally vasodilating dose of intracoronary papaverine. CVDR measured in the transplant recipients with normal coronary arteries, left ventricular function, and wall thickness (5.0 +/- 0.3 [mean +/- SEM] peak/resting velocity; range, 3.8-7.3; n = 16) was not different from that of normal subjects (4.8 +/- 0.2; range, 3.7-8.3). CVDR in the five cardiac allograft recipients with diffuse coronary atherosclerosis producing 30 +/- 5% narrowing (range, 25-38%) of epicardial vessel diameter also was normal (5.1 +/- 0.3; range, 4.3-6.2; n = 5). The CVDR was reduced, however, in two of the four cardiac allograft recipients with left ventricular hypertrophy. In the only transplant recipient in whom a regional wall motion abnormality was present, CVDR was abnormal in the vascular distribution of the hypokinetic wall segment (1.8) but was normal in the artery that supplied normally functioning myocardium (4.0). These findings demonstrate that in the absence of allograft rejection, acquired left ventricular hypertrophy, and regional wall motion abnormalities, coronary vasodilator reserve is normal after orthotopic human cardiac transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)
Cerebral Blood Flow Changes Associated With Attribution of Emotional Valence to Pleasant, Unpleasant, and Neutral Visual Stimuli in a PET Study of Normal Subjects
Authors: Sergio Paradiso, Debra L. Johnson, Nancy C. Andreasen, Daniel S. O’Leary, G. Leonard Watkins, Laura L. Boles Ponto, Richard D. Hichwa
Journal: American Journal of Psychiatry (1999)

OBJECTIVE: To assist in the development of a model for the psychopathology of emotions, the present study sought to identify the neural circuits associated with the evaluation of visual stimuli for emotional valence. METHOD: Seventeen healthy individuals were shown three sets of emotionally laden pictures carrying pleasant, unpleasant, and neutral content. While subjects evaluated the picture set for emotional valence, regional cerebral blood flow was measured with the use of [15O] water positron emission tomography. Subjective ratings of the emotional valence of the picture sets were recorded. Data were analyzed by comparing the images acquired during the neutral condition with the unpleasant and pleasant image sets and the unpleasant and pleasant conditions with each other. RESULTS: Processing of pleasant stimuli was associated with increased blood flow in the dorsal-lateral, orbital, and medial frontal cortex relative to the unpleasant condition and in the cingulate, precuneus, and visual cortex relative to the neutral condition. Evaluation of unpleasant stimuli activated the amygdala, visual cortex, and cerebellum relative to the pleasant condition and the nucleus ­accumbens, precuneus, and visual cortex relative to the neutral condition. CONCLUSIONS: Observing and assigning emotional value to unpleasant stimuli produced activations in subcortical limbic regions, whereas evaluation of pleasant stimuli produced activations in cortical limbic areas. These findings are consistent with the notion of a subcortical and archaic danger recognition system and a system detecting pleasantness in events and situations that is phylogenetically younger, involving primarily the prefrontal cortex.