tbuckley/cabot-search huggingface dataset:
Abstract 4976: Crif1, a new negative regulator of Nrf2
Authors: Insoo Bae, Hyo Jin Kang, Hee Jeong Kim, Yong Bin Hong, Young Soo Chang
Journal: Cancer Research (2010)

Abstract Abstract Free radicals generated by oxidative stress cause damage that can contribute to numerous chronic diseases. Mammalian cells respond to this damage by increased transcription of cytoprotective phase II genes, which are regulated by Nrf2. Previously, it has been shown that Nrf2 protein levels increase after oxidative stress because its negative regulator, Keap1, loses its ability to bind Nrf2 and cause its proteasomal-mediated degradation during oxidative stress. Here, we show that Crif1 is also able to negatively regulate Nrf2 protein stability. However, and in contrast to Keap1, which regulates Nrf2 stability only under normal reducing conditions, Crif1 regulates Nrf2 stability, accumulation and target gene expression under both reducing and oxidative stress conditions. Thus, Crif1-Nrf2 interactions and their consequences are redox-independent. In addition, Crif1, but not Keap1 (which only interacts with N-terminal region of Nrf2), physically interacts with both N- and C-terminal regions of Nrf2 and promote Nrf2 ubiquitination and proteasomal-mediated degradation. Finally, Crif1 can modulate cells’ sensitivity to oxidative stress-induced cytotoxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4976.
DIRECT COMPARISON BETWEEN TWO HYPOGLYCEMIC AGENTS: EFFECTS ON MYOCARDIAL ISCHEMIC PRECONDITIONING IN DIABETIC PATIENTS WITH SYMPTOMATIC CORONARY DISEASE
Authors: Rosa Maria Rahmi Garcia, Whady Hueb, Augusto Uchida, Paulo Cury Rezende, Paulo Jorge Moffa, Cibele Larrosa Garzillo, Eduardo Lima, Paulo Soares, Jose Ramires, Roberto Kalil-Filho
Journal: Journal of the American College of Cardiology (2012)
Cat antigen in homes with and without cats may induce allergic symptoms
Authors: Mary Elizabeth Bollinger, Peyton A. Eggleston, Elizabeth Flanagan, Robert A. Wood
Journal: Journal of Allergy and Clinical Immunology (1996)

Although Fel d 1, the major cat allergen, has been found in settled dust samples from homes both with and without cats, the clinical relevance of this allergen has never been studied.In this study we measured airborne concentrations of Fel d I in homes both with and without cats and then attempted to relate these levels to those obtained in our experimental cat challenge model to assess their clinical significance.In baseline samples we found measurable levels of airborne Fel d 1 in all 37 homes with cats (range, 1.8 to 578 ng/m3, 9 median, 45.9 ng/m 3) and in 10 of the 40 homes without cats (for detectable samples: range, 2.8 to 88.5 ng/m3, 9 median, 17 ng/m3).Fel d I was present in the settled dust of 38 of 40 homes without cats (range, 39 to 3750 ng/gm; median, 258 ng/gm), although these levels were only weakly predictive of airborne levels.Repeat samples obtained weekly from 12 homes without cats yielded measurable airborne Fel d I in at least one of the four samples from all homes.When compared with challenges performed in our cat room facility at low levels of airborne Fel d 1 (<500 ng/m3), these home levels are within the range capable of causing upper and lower respiratory symptoms in subjects allergic to cats.We therefore conclude that the low level cat exposure that occurs in many homes without cats is capable of inducing symptoms in some patients who are sensitive to cats.The assessment of cat exposure should not be based solely on the presence or absence of a cat in the home.(J ALLERGY CLIN IMMUNOL 1996;97:907-14.)
The thyroid and the heart.
Authors: R Polikar, A G Burger, U Scherrer, P Nicod
Journal: Circulation (1993)

Cardiovascular manifestations are a frequent finding in hyperthyroid and hypothyroid states. In this review, potential mechanisms by which thyroid hormones may exert their cardiovascular effects and pathophysiological consequences of such effects are briefly discussed. Two major concepts have emerged about how thyroid hormones exert their cardiovascular effects. First, there is increasing evidence that thyroid hormones exert direct effects on the myocardium, which are mediated by stimulation of specific nuclear receptors, which in turn leads to specific mRNAs production. Furthermore, there is some evidence that thyroid hormones may also activate extranuclear sites and may directly alter plasma membrane function. Second, thyroid hormones interact with the sympathetic nervous system by altering responsiveness to sympathetic stimulation presumably by modulating adrenergic receptor function and/or density. Pathophysiological consequences of such direct and indirect thyroid hormone effects include increased myocardial contractility and relaxation that may be related to stimulation by T3 of specific myocardial enzymes. However, when left ventricular hypertrophy occurs in association with hyperthyroidism, it may be related to either direct thyroid hormone-induced stimulation of myocardial protein synthesis or to thyrotoxicosis-induced increases in cardiac work load. Although hyperthyroidism generally has little or no effect on mean arterial blood pressure, hypothyroidism is often associated with increases in diastolic blood pressure that are reversible after hormone substitution and may be mediated in part by sympathetic activation. Moreover, there is increasing evidence that thyroid hormones have direct chronotropic effect on the heart that are independent of the sympathetic nervous system.(ABSTRACT TRUNCATED AT 250 WORDS)
Theory and in Vivo Application of Electroporative Gene Delivery
Authors: Stella Somiari, Jill Glasspool-Malone, Joseph J. Drabick, Richard A. Gilbert, Richard Heller, Mark J. Jaroszeski, Robert W. Malone
Journal: Molecular Therapy (2000)

Efficient and safe methods for delivering exogenous genetic material into tissues must be developed before the clinical potential of gene therapy will be realized. Recently, in vivo electroporation has emerged as a leading technology for developing nonviral gene therapies and nucleic acid vaccines (NAV). Electroporation (EP) involves the application of pulsed electric fields to cells to enhance cell permeability, resulting in exogenous polynucleotide transit across the cytoplasmic membrane. Similar pulsed electrical field treatments are employed in a wide range of biotechnological processes including in vitro EP, hybridoma production, development of transgenic animals, and clinical electrochemotherapy. Electroporative gene delivery studies benefit from well-developed literature that may be used to guide experimental design and interpretation. Both theory and experimental analysis predict that the critical parameters governing EP efficacy include cell size and field strength, duration, frequency, and total number of applied pulses. These parameters must be optimized for each tissue in order to maximize gene delivery while minimizing irreversible cell damage. By providing an overview of the theory and practice of electroporative gene transfer, this review intends to aid researchers that wish to employ the method for preclinical and translational gene therapy, NAV, and functional genomic research.
Chemical Control Stability in Patients with Obstructive Sleep Apnea
Authors: MAGDY YOUNES, MICHELE OSTROWSKI, WAYNE THOMPSON, COLLEEN LESLIE, WARREN SHEWCHUK
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

The role of chemical control instability in the pathogenesis of obstructive sleep apnea (OSA) is not clear. We studied 32 patients with OSA during sleep while their upper airway was stabilized with continuous positive airway pressure. Twelve patients had repetitive OSA whenever they were asleep, regardless of body position or sleep stage, and were classified as having severe OSA (apnea–hypopnea index [AHI] = 88 ± 19). The remaining 20 patients had sporadic OSA or repetitive OSA for only part of the time (mild/moderate OSA; AHI = 27 ± 16). Susceptibility to periodic breathing (PB) was assessed by gradually increasing controller gain, using proportional assist ventilation. The increase in loop gain (LG) at each assist level was quantified from the ratio of assisted tidal volume (Vt) to the Vt obtained during single-breath reloading tests (Vt amplification factor [VtAF]). Nine of 12 patients with severe OSA developed PB, with recurrent central apneas, whereas only six of 20 patients in the mild/moderate group developed PB (p < 0.02). This difference was observed despite the subjection of the mild/moderate group to greater amplification of LG; the highest values of VtAF in the mild/moderate and severe groups were 2.7 ± 1.0 and 1.9 ± 0.7, respectively (p < 0.01). We conclude that the chemical control system is more unstable in patients with severe OSA than in patients with milder OSA. We speculate that this may contribute to the severity of OSA, at least in some patients.
Effects of High Thoracic Epidural Analgesia on Myocardial Blood Flow in Patients With Ischemic Heart Disease
Authors: Eigil Nygård, Klaus F. Kofoed, Jacob Freiberg, Søren Holm, Jan Aldershvile, Kirsten Eliasen, Henning Kelbæk
Journal: Circulation (2005)

Background— In patients with ischemic heart disease, high thoracic epidural analgesia (TEA) has been proposed to improve abnormalities of coronary function by inhibiting cardiac sympathetic tone. We evaluated the effect of TEA on myocardial blood flow in patients with ischemic heart disease. Methods and Results— Twenty male patients with multivessel ischemic heart disease were studied. An epidural catheter was inserted between the second and third thoracic vertebral interspace (Th2 to Th3). Analgesia was induced by epidural injection of bupivacaine 0.5%, and a sensory block from the sixth cervical (C6 to C7) to Th10 (Th8 to Th11) vertebral interspace was achieved. Myocardial blood flow was measured with dynamic 13 N-ammonia PET with and without TEA at rest, during pharmacological vasodilation with dipyridamole, and during sympathetic stimulation with the cold pressor test. Myocardial blood flow during dipyridamole increased similarly, regardless of TEA, in all regions except in myocardium subtended by collateral arteries in which blood flow increased more with than without TEA ( P &lt;0.05). Without TEA, myocardial blood flow during the cold pressor test remained unchanged compared with myocardial blood flow at rest. In contrast, with TEA, myocardial blood flow increased in all vascular territories. Coronary vascular resistance increased during the cold pressor test without TEA, whereas with TEA, coronary resistance decreased in myocardium subtended by nonstenotic and stenotic coronary vessels and remained unchanged in myocardium subtended by occluded vessels. Conclusions— In patients with multivessel ischemic heart disease, TEA partly normalizes the myocardial blood flow response to sympathetic stimulation.
Inhibition of glycogen synthase kinase 3 beta ameliorates liver ischemia reperfusion injury by way of an interleukin-10-mediated immune regulatory mechanism
Authors: Feng Ren, Zhongping Duan, Qiao Cheng, Xiuda Shen, Feng Gao, Li Bai, Jun Liu, Ronald W. Busuttil, Jerzy W. Kupiec-Weglinski, Yuan Zhai
Journal: Hepatology (2011)

The ubiquitous serine/threonine kinase glycogen synthase kinase 3 beta (Gsk3β) differentially regulates macrophage Toll-like receptor (TLR)-triggered pro- and anti-inflammatory cytokine programs. This study was designed to determine the in vivo role and therapeutic potential of Gsk3β modulation in tissue inflammation and injury in a murine model of liver partial warm ischemia/reperfusion injury (IRI). As a constitutively activated liver kinase, Gsk3β became quickly inactivated (phosphorylated) following IR. The active Gsk3β, however, was essential for the development of IRI pathology, as administration of its specific inhibitor, SB216763, ameliorated the hepatocellular damage, evidenced by reduced serum alanine aminotransferase (sALT) levels and well-preserved liver architecture compared with controls. The liver protective effect of Gsk3β inhibition was dependent on an immune regulatory mechanism, rather than direct cytoprotection via mitochondria permeability transition pores (MPTP). Indeed: (1) coadministration of SB216763 and atractyloside (MPTP opener) failed to abrogate a local cytoprotective Gsk3β inhibition effect; (2) SB216763 selectively inhibited IR-triggered liver pro-inflammatory, but spared interleukin (IL)-10, gene induction programs; and (3) IL-10 neutralization restored liver inflammation and IRI in SB216763-treated mice. Gsk3β inactivation by IR was a self-regulatory mechanism in liver homeostasis, critically dependent on phosphoinositide 3 (PI3)-kinase activation, as administration of a PI3 kinase inhibitor, wortmannin, reduced Gsk3 phosphorylation and augmented liver damage. In vitro, IL-10 was critical for the suppression of pro-inflammatory gene programs by Gsk3 inhibition in bone marrow-derived macrophages in response to TLR4 stimulation.Our novel findings document the key immune regulatory function of Gsk3β signaling in the pathophysiology of liver IRI, and provide a rationale to target Gsk3β as a refined therapeutic strategy to ameliorate liver IRI.
THE TOTAL AND THE NITROGENOUS METABOLISM IN EXOPHTHALMIC GOITER
Authors: WALTER M. BOOTHBY
Journal: JAMA (1923)

Friedrich Müller,<sup>1</sup>in 1893, demonstrated a general increase in metabolism in exophthalmic goiter by showing that a patient with this disease lost weight and nitrogenous substances on a diet more than sufficient to prevent such losses in a normal individual. Since that time the conception has been prevalent that the increase in the basal metabolism is generally accompanied by, and even dependent on, an increase in the rate of destruction of the patient's own protein tissue. However, as shown by the studies of Magnus-Levy,<sup>2</sup>of Falta<sup>3</sup>and of Du Bios,<sup>4</sup>who likewise have presented summaries of the subject, an increased protein destruction does not always occur, and these authors are rather guarded in their conclusions. Magnus-Levy says: Sometimes, at least, a deleterious influence is exerted by the disease upon the protein metabolism. To establish a state of nitrogenous equilibrium it is necessary not only to increase
The drug victim is too often the same: the fetus
Authors: Carla Carlson
Journal: JAMA (1982)

Once again, drug abuse affects more than the user. At the recent meeting of the American Pediatric Society and the Society for Pediatric Research in Washington, DC, Ira J. Chasnoff, MD, reported how "Ts and blues," a drug combination used as a substitute for heroin, affects the infants of drug-using mothers. During the Iranian crisis, the amount of heroin coming into this country dropped severely and, consequently, the cost of available heroin skyrocketed. As an alternative to the poor-quality heroin originating from Mexico, street people in the Chicago area began to inject a combination solution consisting of crushed tablets of Talwin (pentazocine) and the antihistamine pyribenzamine (tripelennamine), available in the familiar blue tablet form. Chasnoff, of Northwestern University Medical School, Chicago, and the Department of Pediatrics at Northwestern Memorial Hospital, said that the Ts and blues combination "gives a quick rush and prolongs the high." He added that it is
Newer insulins in type 2 diabetes
Authors: E. A. M. Gale
Journal: BMJ (2012)

A 68 year old woman with a body mass index (weight (kg)/(height (m))2) of 31 has a five year history of type 2 diabetes. She is reasonably active but takes treatment for hypertension, hyperlipidaemia, and angina. She has signs of early diabetic background retinopathy. Her current treatment for diabetes is with metformin 850 mg twice daily and gliclazide 160 mg daily. Her haemoglobin A1c (HbA1c) concentration has risen from 0.076 to 0.085 over the past year, and she is keen to improve her glucose control.

After review of her diabetes management, she opts for insulin as the next step in treatment. She mentions that a friend has just started a special new insulin and wonders if that is what she will be taking too. After discussion of the evidence for insulin analogues, she agrees to start taking isophane insulin rather than an analogue.

In health, glucose control is achieved by feedback regulation, such that food intake is matched by sharp spikes of insulin, and the glucose concentration remains stable between meals because of regulated basal insulin secretion. By contrast, injected insulin has no feedback regulation, enters the systemic rather than the portal circulation, is delivered into subcutaneous tissue rather than the bloodstream, and diffuses variably into the circulation. Standard, short acting insulins reach the circulation more slowly than food, so blood glucose tends to swing too high after each meal and to drop too low before the next. Longer acting human insulins reach peak absorption 4-16 hours after injection, which means that insulin injected before the evening meal tends to produce a glucose dip in the middle of the night, followed by a rebound as insulin fades before breakfast. Injection therapy thus tends to produce unwanted oscillations in glucose control, with an increased risk of hypoglycaemia before …
Insulin Resistance and Chronic Cardiovascular Inflammatory Syndrome
Authors: José Manuel Fernández-Real, Wifredo Ricart
Journal: Endocrine Reviews (2003)

Insulin resistance is increasingly recognized as a chronic, low-level, inflammatory state. Hyperinsulinemia and insulin action were initially proposed as the common preceding factors of hypertension, low high-density lipoprotein cholesterol, hypertriglyceridemia, abdominal obesity, and altered glucose tolerance, linking all these abnormalities to the development of coronary heart disease. The similarities of insulin resistance with another inflammatory state, atherosclerosis, have been described only in the last few decades. Atherosclerosis and insulin resistance share similar pathophysiological mechanisms, mainly due to the actions of the two major proinflammatory cytokines, TNF-α and IL-6. Genetic predisposition to increased transcription rates of these cytokines is associated with metabolic derangement and simultaneously with coronary heart disease. Dysregulation of the inflammatory axis predicts the development of insulin resistance and type 2 diabetes mellitus. The knowledge of how interactions between metabolic and inflammatory pathways occur will be useful in future therapeutic strategies. The effective administration of antiinflammatory agents in the treatment of insulin resistance and atherosclerosis is only the beginning of a promising approach in the management of these syndromes.
FRI0490-HPR Hand flexor and extensor muscle activity in daily activities and hand exercises in women with rheumatoid arthritis or hand osteoarthritis
Authors: S. Brorsson, A. Nilsdotter, C. Thorstensson, A. Bremander
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Impaired hand grip function is common and occurs early in the course of disease in patients with rheumatoid arthritis (RA) and hand osteoarthritis (HOA), affecting daily life activities and quality of life. <h3>Objectives</h3> To evaluate muscle activity in forearm flexors and extensors during daily activities and clinically well-known hand exercises in women with RA and HOA compared with healthy controls. <h3>Methods</h3> The RA patients were consecutively included from a specialist clinic and had a disease duration of at least one year. Women with HOA were allocated from out-patients primary health care clinics in the same area and clinically diagnosed with symptomatic HOA. The age matched control group had no history of hand/arm injuries, inflammatory or muscle diseases. Full active finger extension ability was required for all subjects. Hand force (Newton) was measured with EX-it (extension) and Grippit (flexion), both validated instruments. Muscle activity was measured in m. extensor digitorum communis (EDC) and m. flexor carpi radialis (FCR) with surface EMG (S-EMG) on the dominant hand while performing four daily activities (ADL) and four hand exercises and described as percent of maximal voluntary isometric contraction (% MVIC) based on data from EX-it and Grippit. Pain was measured with Visual Analogue Scale (VAS) 0-10 (best to worst). Differences between groups were analyzed and controlled for age. <h3>Results</h3> Fifty-six women were included; 20 with RA (age mean (SD) 59.2 (10.7) years, VAS pain 2.2 (1.6)), 16 with HOA (age 67.5 (9.3) years, VAS pain 4.1 (1.9)) and 20 healthy controls (age 56.0 (9.7) years). Women with RA and HOA showed decreased extension and flexion force compared with healthy women (p&lt;0.03).There was a tendency towards higher % MVIC in all tests for women with RA and HOA compared with healthy women, with a statistically significant difference between HOA and healthy women for EDC (p&lt;0.05). ADL activities “writing with a pen”, and “cutting with scissors” showed the highest % MVIC in both EDC and FCR in all groups. The exercises “isolated opposition”, and “rolling the dough with flat hands”, had high % MVIC in EDC, while “squeezing the dough” and “isolated opposition” had high % MVIC in FCR. <h3>Conclusions</h3> Women with RA and HOA tend to use a higher % MVIC than healthy women in many daily activities and in hand exercises. Strengthening exercises should include both extensor and flexor specific training. <h3>Disclosure of Interest</h3> None Declared
Replacing adenoviral vector HVR1 with a malaria B cell epitope improves immunogenicity and circumvents preexisting immunity to adenovirus in mice
Authors: Takayuki Shiratsuchi, Urvashi Rai, Anja Krause, Stefan Worgall, Moriya Tsuji
Journal: Journal of Clinical Investigation (2010)

Although adenovirus (Ad) has been regarded as an excellent vaccine vector, there are 2 major drawbacks to using this platform: (a) Ad-based vaccines induce a relatively weak humoral response against encoded transgenes, and (b) preexisting immunity to Ad is highly prevalent among the general population. To overcome these obstacles, we constructed an Ad-based malaria vaccine by inserting a B cell epitope derived from a Plasmodium yoelii circumsporozoite (CS) protein (referred to as the PyCS-B epitope) into the capsid proteins of WT/CS-GFP, a recombinant Ad expressing P. yoelii CS protein and GFP as its transgene. Multiple vaccinations with the capsid-modified Ad induced a substantially increased level of protection against subsequent malaria challenge in mice when compared with that of unmodified WT/CS-GFP. Increased protection correlated with augmented antibody responses against the PyCS-B epitope expressed in the capsid. Furthermore, replacement of hypervariable region 1 (HVR1) of the Ad capsid proteins with the PyCS-B epitope circumvented neutralization of the modified Ad by preexisting Ad-specific antibody, both in vivo and in vitro. Importantly, the immunogenicity of the Ad-containing PyCS-B epitope in the HVR1 and a P. yoelii CS transgene was maintained. Overall, this study demonstrates that the HVR1-modifed Ad vastly improves upon Ad as a promising malaria vaccine platform candidate.
US Republicans take aim at health reform after electoral gains
Authors: J. H. Tanne
Journal: BMJ (2010)

Republican victories in the US mid-term elections on 2 November are likely to result in attempts to repeal or gut the health reform act passed by the US Congress in March.

In the elections Barack Obama’s Democratic party lost control of the House of Representatives but kept control of the Senate. The victors—including members of the Tea Party group, who are nominally Republican but more right wing than the party mainstream—will take office in January, a few weeks after more reforms required by the act take effect.

Repeal of health reform is unlikely, as President Obama can veto such a bill. However, the Senate minority leader Mitch McConnell (Republican, Kentucky) was widely …