tbuckley/cabot-search huggingface dataset:
Arterial and Cardiac Aging: Major Shareholders in Cardiovascular Disease Enterprises
Authors: Edward G. Lakatta
Journal: Circulation (2003)

E vidence supporting the hypothesis that age-associated changes in cardiovascular structure/function are implicated in the markedly increased risk for cardiovascular disease in older persons has been presented in the preceding 2 articles in this series. 1,2It follows that therapies to prevent or delay cardiovascular changes that accompany aging may reduce the risk for age-associated cardiovascular diseases.Understanding the nature and effectiveness of such therapies, however, requires an understanding of heart and arterial aging at the cellular and molecular levels.Fortunately, many of the age-associated changes in cardiac and arterial structure or function that have been observed in humans also occur across a wide range of other species.Insights gained from cellular and molecular studies in these animal models may hold clues that will assist in directing future efforts toward developing novel therapies for age-associated arterial and cardiac structural and functional remodeling in humans. Vascular AgingAge-associated remodeling of the walls of large arteries of rodents (Table 1) and nonhuman primates is quite similar to that observed in humans and includes luminal dilation, intimal and medial thickening (Figure 1), vascular stiffening, and endothelial dysfunction.
Chronic infusion of dobutamine and nitroprusside in patients with end‐stage heart failure awaiting heart transplantation: safety and clinical outcome
Authors: Soccorso Capomolla, Oreste Febo, Cristina Opasich, Giampaolo Guazzotti, Angelo Caporotondi, Maria Teresa La Rovere, Marco Gnemmi, Andrea Mortara, Margherita Vona, Gian Domenico Pinna, Roberto Maestri, Franco Cobelli
Journal: European Journal of Heart Failure (2001)
Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c
Authors: Leonard C Edelstein, Lukas M Simon, Raúl Teruel Montoya, Michael Holinstat, Edward S Chen, Angela Bergeron, Xianguo Kong, Srikanth Nagalla, Narla Mohandas, David E Cohen, Jing-fei Dong, Chad Shaw, Paul F Bray
Journal: Nature Medicine (2013)
A Pilot Controlled Clinical Trial of ABT-418, a Cholinergic Agonist, in the Treatment of Adults With Attention Deficit Hyperactivity Disorder
Authors: T E Wilens, J Biederman, T J Spencer, J Bostic, J Prince, M C Monuteaux, J Soriano, C Fine, A Abrams, M Rater, D Polisner
Journal: American Journal of Psychiatry (1999)

Despite the increasing recognition of attention deficit hyperactivity disorder (ADHD) in adults, there is a paucity of controlled pharmacological trials. Recent reports have suggested the potential usefulness of cholinergic agents for ADHD. To this end, the authors completed a controlled study of ABT-418, a novel cholinergic activating agent, for the treatment of adults with ADHD.This was a double-blind, placebo-controlled, randomized, crossover trial that compared a transdermal patch of ABT-418 (75 mg/day) to placebo in adults who met DSM-IV criteria for ADHD. There were two 3-week treatment periods separated by 1 week of washout.Of the 32 subjects enrolled in the study (88% were men; mean age = 40 years, SD = 9), 29 completed the study. At the endpoint of each active arm (last observation carried forward), a significantly higher proportion of subjects was considered improved while receiving ABT-418 than while receiving placebo (40% versus 13%). Similarly, at endpoint there was a significantly greater reduction in ADHD symptom checklist scores (28% versus 15%). Symptoms reflective of attention, and subjects with less severe ADHD, responded more robustly to ABT-418. Treatment with ABT-418 was relatively well tolerated; dizziness and nausea were the most frequently reported adverse effects.The results of this investigation indicate that ABT-418, a nicotinic analog, may be a potentially useful agent for the treatment of ADHD.
Meniere's disease
Authors: J. Harcourt, K. Barraclough, A. M. Bronstein
Journal: BMJ (2014)

A young woman presented with podophyllin intoxication following topical application of podophyllin resin to genital condylomata acuminata. The disorder was marked by hallucinatory psychosis, bone marrow depression, and mild hepatic dysfunction. The psychosis and systemic disturbances resolved within 3 weeks, but were followed by autonomic and sensorimotor peripheral neuropathy. This case illustrates the transient central neurotoxicity and persistent peripheral neurotoxicity of podophyllin.
Activation of cultured rat hepatic lipocytes by Kupffer cell conditioned medium. Direct enhancement of matrix synthesis and stimulation of cell proliferation via induction of platelet-derived growth factor receptors.
Authors: S L Friedman, M J Arthur
Journal: Journal of Clinical Investigation (1989)

Hepatic lipocytes appear to be central to the pathogenesis of hepatic fibrosis, undergoing activation during inflammation to a matrix-producing, proliferative cell type. We have studied the activation process in culture by examining the response of lipocytes to conditioned medium from hepatic macrophages (Kupffer cells). Lipocytes exposed to Kupffer cell medium (KCM) exhibited cellular and nuclear enlargement associated with up to a threefold increase in collagen and total protein synthesis per cell. Cell proliferation was also stimulated as measured by [3H]thymidine incorporation and direct cell counting. The latter effect was serum dependent and inhibited by antibodies to platelet-derived growth factor (PDGF). Proliferation could be stimulated by recombinant PDGF, but only after preincubation of cells with KCM. These findings suggested that KCM was eliciting expression of the PDGF receptor in lipocytes, and this was confirmed by immunoblot analysis with antibodies to the PDGF receptor. DNA synthesis in lipocytes exposed to KCM occurred at 48 h, which reflected the time required for PDGF receptor expression (24 h) plus initiation of [3H]thymidine incorporation (24 h). These results indicate that KCM has multiple stimulatory effects on cultured lipocytes similar to activation of these cells observed in vivo.
Validation of OMERACT preliminary rheumatoid arthritis flare domains in the NOR-DMARD study
Authors: Elisabeth Lie, Thasia G Woodworth, Robin Christensen, Tore K Kvien, Vivien Bykerk, Daniel E Furst, Clifton O Bingham, Ernest H Choy
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Abstract</h3> <h3>Objective</h3> Understanding neurophysiological changes that accompany transitions between anaesthetized and conscious states is a key objective of anesthesiology and consciousness science. This study aimed to characterize the dynamics of auditory-evoked potential morphology in mice along a continuum of consciousness. <h3>Approach</h3> Epidural field potentials were recorded from above the primary auditory cortices of two groups of laboratory mice: urethane-anaesthetized (A, n = 14) and conscious (C, n = 17). Both groups received auditory stimulation in the form of a repeated pure-tone stimulus, before and after receiving 10 mg/kg i.p. ketamine (AK and CK). Evoked responses were then ordered by ascending sample entropy into AK, A, CK, and C, considered to reflect physiological correlates of awareness. These data were used to train a recurrent neural network (RNN) with an input parameter encoding state. Model outputs were compared with grand-average event-related potential (ERP) waveforms. Subsequently, the state parameter was varied to simulate changes in the ERP that occur during transitions between states, and relationships with dominant peak amplitudes were quantified. <h3>Main results</h3> The RNN synthesized output waveforms that were in close agreement with grand-average ERPs for each group (r<sup>2</sup> &gt; 0.9, p &lt; 0.0001). Varying the input state parameter generated model outputs reflecting changes in ERP morphology predicted to occur between states. Positive peak amplitudes within 25 to 50 ms, and negative peak amplitudes within 50 to 75 ms post-stimulus-onset, were found to display a sigmoidal characteristic during the transition from anaesthetized to conscious states. In contrast, negative peak amplitudes within 0 to 25 ms displayed greater linearity. <h3>Significance</h3> This study demonstrates a method for modelling changes in ERP morphology that accompany transitions between states of consciousness using a RNN. In future studies, this approach may be applied to human data to support the clinical use of ERPs to predict transition to consciousness.
Observation and Experiment
Authors: A. Bradford Hill
Journal: New England Journal of Medicine (1953)

TWO years ago, in his Cutter Lecture, one of my predecessors pointed out that the object of any science is "the accumulation of systematized verifiable knowledge," and that this is to be achieved through "observation, experiment and thought" — the last including both criticism and imagination. He then added, "the use of the experimental method has brilliant discoveries to its credit, whereas the method of observation has achieved little."1 This dictum must surely prove, at least at first sight, more than a little disconcerting to the exponent of preventive medicine. In dealing with the characteristics of human populations, in sorting . . .
Targeting Human Medulloblastoma: Oncolytic Virotherapy with Myxoma Virus Is Enhanced by Rapamycin
Authors: Xue Qing Lun, Hongyuan Zhou, Tommy Alain, Beichen Sun, Limei Wang, John W. Barrett, Marianne M. Stanford, Grant McFadden, John Bell, Donna L. Senger, Peter A. Forsyth
Journal: Cancer Research (2007)

We have shown previously the oncolytic potential of myxoma virus in a murine xenograft model of human glioma. Here, we show that myxoma virus used alone or in combination with rapamycin is effective and safe when used in experimental models of medulloblastoma in vitro and in vivo. Nine of 10 medulloblastoma cell lines tested were susceptible to lethal myxoma virus infection, and pretreatment of cells with rapamycin increased the extent of in vitro oncolysis. Intratumoral injection of live myxoma virus when compared with control inactivated virus prolonged survival in D341 and Daoy orthotopic human medulloblastoma xenograft mouse models [D341 median survival: 21 versus 12.5 days; P = 0.0008; Daoy median survival: not reached (three of five mice apparently "cured" after 223 days) versus 75 days; P = 0.0021]. Rapamycin increased the extent of viral oncolysis, "curing" most Daoy tumor-bearing mice and reducing or eliminating spinal cord and ventricle metastases. Rapamycin enhanced tumor-specific myxoma virus replication in vivo and prolonged survival of D341 tumor-bearing mice (median survival of mice treated with live virus (LV) and rapamycin, versus LV alone, versus rapamycin alone, versus inactivated virus: 25 days versus 19, 13, and 11 days, respectively; P < 0.0001). Rapamycin increased the levels of constitutively activated Akt in Daoy and D341 cells, which may explain its ability to enhance myxoma virus oncolysis. These observations suggest that myxoma virus may be an effective oncolytic agent against medulloblastoma and that combination therapy with signaling inhibitors that modulate activity of the phosphatidylinositol 3-kinase/Akt pathway will further enhance the oncolytic potential of myxoma virus.
Efficacy, Tolerability, and Safety of a Novel Once-Daily Extended-Release Metformin in Patients With Type 2 Diabetes
Authors: Sherwyn Schwartz, Vivian Fonseca, Bret Berner, Marilou Cramer, Yu-Kun Chiang, Andrew Lewin
Journal: Diabetes Care (2006)

OBJECTIVE—The purpose of this study was to determine the efficacy and safety of a novel extended-release metformin in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS—Adults with type 2 diabetes (newly diagnosed, treated with diet and exercise only, or previously treated with oral diabetic medications) were randomly assigned to receive one of three extended-release metformin treatment regimens (1,500 mg/day q.d., 1,500 mg/day twice daily, or 2,000 mg/day q.d.) or immediate-release metformin (1,500 mg/day twice daily) in a double-blind 24-week trial. RESULTS—Significant decreases (P &amp;lt; 0.001) in mean HbA1c (A1C) levels were observed by week 12 in all treatment groups. The mean changes from baseline to end point in the two groups given 1,500 mg extended-release metformin (−0.73 and −0.74%) were not significantly different from the change in the immediate-release metformin group (−0.70%), whereas the 2,000-mg extended-release metformin group showed a greater decrease in A1C levels (−1.06%; mean difference [2,000 mg extended-release metformin − immediate-release metformin]: −0.36 [98.4% CI −0.65 to −0.06]). Rapid decreases in fasting plasma glucose levels were observed by week 1, which continued until week 8, and were maintained for the duration of the study. The overall incidence of adverse events was similar for all treatment groups, but fewer patients in the extended-release metformin groups discontinued treatment due to nausea during the initial dosing period than in the immediate-release metformin group. CONCLUSIONS—Once- or twice-daily extended-release metformin was as safe and effective as twice-daily immediate-release metformin and provided continued glycemic control for up to 24 weeks of treatment.
Drug‐Target Residence Time—A Case for G Protein‐Coupled Receptors
Authors: Dong Guo, Julia M. Hillger, Adriaan P. IJzerman, Laura H. Heitman
Journal: Medicinal Research Reviews (2014)

Abstract A vast number of marketed drugs act on G protein‐coupled receptors (GPCRs), the most successful category of drug targets to date. These drugs usually possess high target affinity and selectivity, and such combined features have been the driving force in the early phases of drug discovery. However, attrition has also been high. Many investigational new drugs eventually fail in clinical trials due to a demonstrated lack of efficacy. A retrospective assessment of successfully launched drugs revealed that their beneficial effects in patients may be attributed to their long drug‐target residence times (RTs). Likewise, for some other GPCR drugs short RT could be beneficial to reduce the potential for on‐target side effects. Hence, the compounds’ kinetics behavior might in fact be the guiding principle to obtain a desired and durable effect in vivo . We therefore propose that drug‐target RT should be taken into account as an additional parameter in the lead selection and optimization process. This should ultimately lead to an increased number of candidate drugs moving to the preclinical development phase and on to the market. This review contains examples of the kinetics behavior of GPCR ligands with improved in vivo efficacy and summarizes methods for assessing drug‐target RT.
Mechanics of Distension of Dog Veins and Other Very Thin-Walled Tubular Structures
Authors: AUGUSTO H. MORENO, ADOLPH I. KATZ, LOUIS D. GOLD, R. V. REDDY
Journal: Circulation Research (1970)

We present first phenomenological characterizations of the pressure-volume relationships (a) in veins excised from dogs under anesthesia and (b) in thinwalled latex tubes. We measured their cross-sectional areas and perimeters from cinefluorographic enlargements during distension. From flattened to circular cross sections, the perimeter of latex tubes remained constant while the area increased exclusively by bending of the walls. Compliance was large in this regime. After circular cross sections were reached, further increases in area were associated with increments in perimeter and there was stretching of the wall. Compliance declined sharply. Veins did not show a distinct two-regime behavior but a combination of bending and stretching which extended the region of large compliance to values of transmural pressure of physiological interest. Using classical theory of elasticity, we propose mathematical relationships describing the proportionality between the pressure and the curvature of the wall during the regime where bending is the primary controlling mechanism. We mechanized these relationships on an analog computer and correlated the solutions with the physical experiments. We conclude that no modulus of elasticity, alone, can relate the pressure and the volume when bending is predominant. In this regime the significant quantity is the modulus of flexural rigidity.
Hodgkin's Disease — Time for a Change
Authors: Robert S. Schwartz
Journal: New England Journal of Medicine (1997)

Reed–Sternberg cells and their variants have long held fascination for students of Hodgkin's disease. What are these cells, and how do they relate to the clinical manifestations of the lymphoma? Recent work indicates that they are clones of neoplastic B cells that, by secreting potent cytokines, not only cause the symptoms of Hodgkin's disease but also promote their own growth and evade immune surveillance.1 The morphologically distinctive and multinucleated Reed–Sternberg cells — classic Reed–Sternberg cells — may derive from T cells in some cases, but the weight of the evidence suggests that they usually originate from B lymphocytes in germinal . . .
Heterologous immunity provides a potent barrier to transplantation tolerance
Authors: Andrew B. Adams, Matthew A. Williams, Thomas R. Jones, Nozomu Shirasugi, Megan M. Durham, Susan M. Kaech, E. John Wherry, Thandi Onami, J. Gibson Lanier, Kenneth E. Kokko, Thomas C. Pearson, Rafi Ahmed, Christian P. Larsen
Journal: Journal of Clinical Investigation (2003)

Many strategies have been proposed to induce tolerance to transplanted tissue in rodents; however, few if any have shown equal efficacy when tested in nonhuman primate transplant models. We hypothesized that a critical distinction between specific pathogen-free mice and nonhuman primates or human patients is their acquired immune history. Here, we show that a heterologous immune response — specifically, virally induced alloreactive memory — is a potent barrier to tolerance induction. A critical threshold of memory T cells is needed to promote rejection, and CD8+ "central" memory T cells are primarily responsible. Finally, treatment with deoxyspergualin, an inhibitor of NF-κB translocation, together with costimulation blockade, synergistically impairs memory T cell activation and promotes antigen-specific tolerance of memory. These data offer a potential explanation for the difficulty encountered when inducing tolerance in nonhuman primates and human patients and provide insight into the signaling pathways essential for memory T cell activation and function.
Heterogeneous Sympathetic Innervation Influences Local Myocardial Repolarization in Normally Perfused Rabbit Hearts
Authors: Koichiro Yoshioka, Dong-Wei Gao, Michael Chin, Carol Stillson, Elizabeth Penades, Michael Lesh, William O’Connell, Michael Dae
Journal: Circulation (2000)

Background —Heterogeneity of sympathetic innervation is thought to contribute to the potential for fatal arrhythmia. However, little is known about the effects of heterogeneous innervation on repolarization. Methods and Results —To assess this relationship, we measured activation recovery intervals (ARIs) from 64 epicardial sites in 11 rabbits studied 2 weeks after regional denervation produced by phenol and 4 sham-operated rabbits. ARI results were compared with the distribution of sympathetic innervation measured from 3D reconstructions of serial autoradiographs of [ 125 I]metaiodobenzylguanidine and 99m Tc-sestamibi. ARIs were recorded during baseline sinus rhythm, norepinephrine (NE) infusion (0.1 μg · kg −1 · min −1 ), and left stellate ganglion stimulation (SS). NE shortened ARI in 98% of electrodes in the denervated region. The degree of ARI shortening and dispersion increased ( P &lt;0.001 and P &lt;0.01, respectively) as denervation became more severe. SS shortened ARI in 30% of electrodes in the denervated area, with increased shortening and dispersion related to increased severity of denervation ( P &lt;0.01). SS prolonged ARI in 70% of electrodes in the denervated area, with no correlation with severity of denervation. Conclusions —The magnitude and dispersion of local repolarization responses are related to the severity of denervation, as well as the type of stimulation: neural (SS) versus humoral (NE). The differences may relate to the concentration of NE released.
Protease Activity of Urokinase and Tumor Progression in a Syngeneic Mammary Cancer Model
Authors: Jaime R. Merchan, Jian Tang, Guang Hu, Yanfeng Lin, Walter Mutter, Caili Tong, S. Ananth Karumanchi, Stephen J. Russell, Vikas P. Sukhatme
Journal: JNCI Journal of the National Cancer Institute (2006)

We and others have previously shown that plasminogen activators generate endogenous angiogenesis inhibitors and induce antiangiogenic activity. Here we assessed the effects of plasminogen activator overexpression on tumor progression in a syngeneic mammary cancer model.Genes encoding murine tissue plasminogen activator (tPA), urokinase (uPA), and vector controls were stably transfected into 4T1 murine mammary cancer cells, and cell proliferation in vitro was analyzed. Cells were also implanted into female BALB/c mice (n = 12 per group), and tumor growth, lung metastases, and survival were compared. Tumor cell proliferation and microvessel formation were analyzed by immunohistochemistry using antibodies to proliferating cell nuclear antigen and CD31, respectively. 4T1 cells transfected with proteolytically inactive uPA mutants (A and B) were assayed for proliferation in vitro and tumor growth in vivo by using the same syngeneic model (eight to 10 mice per group). All statistical tests were two-sided.In vitro growth of uPA- and tPA-overexpressing and control 4T1 cells was similar. In vivo, however, inhibition of tumor growth and lung metastasis were inhibited in the mice carrying tPA- and uPA-overexpressing tumors, compared with controls (tumor weight at day 34: control, mean = 1760 mg, 95% confidence interval [CI] = 1434 to 2087 mg; tPA, mean = 921, 95% CI = 624 to 1217 mg; P < .001; uPA, mean = 395 mg, 95% CI = 161 to 629 mg; P < .001; number of lung metastases at day 34: control, mean = 117, 95% CI = 74 to 159; tPA, mean = 33, 95% CI = 13 to 52; uPA, mean = 15, 95% CI = 4 to 25; P < .001). Median survival was 42 (95% CI = 36 to 44), 55 (95% CI = 48 to 61), and 73 (95% CI = 51 to 86) days in the control, tPA, and uPA groups, respectively (P < .001). uPA- and tPA-expressing tumors had reduced angiogenesis and cell proliferation compared with controls. Tumors overexpressing uPA mutants grew faster than tumors expressing wild-type uPA (tumor volume at day 30: wild-type uPA, mean = 203, 95% CI = 121 to 285 mm3; control, mean = 534, 95% CI = 460 to 608 mm3; P < .001; mutant A, mean = 600, 95% CI = 520 to 679 mm3; P < .001; and mutant B, mean = 435, 95% CI = 358.9 to 511 mm3; P = .005).In this mouse model, uPA expression delayed tumor progression and had antiangiogenic and antiproliferative effects that may be mediated by uPA's protease activity. These results challenge the current dogma of proteases being exclusively tumor promoting and provide further rationale for exploring plasminogen activators as antitumor agents.