tbuckley/cabot-search huggingface dataset:
Global extent of chloroquine-resistant Plasmodium vivax: a systematic review and meta-analysis
Authors: Ric N Price, Lorenz von Seidlein, Neena Valecha, Francois Nosten, J Kevin Baird, Nicholas J White
Journal: The Lancet Infectious Diseases (2014)

Chloroquine is the first-line treatment for Plasmodium vivax malaria in most endemic countries, but resistance is increasing. Monitoring of antimalarial efficacy is essential, but in P. vivax infections the assessment of treatment efficacy is confounded by relapse from the dormant liver stages. We systematically reviewed P. vivax malaria treatment efficacy studies to establish the global extent of chloroquine resistance.We searched Medline, Web of Science, Embase, and the Cochrane Database of Systematic Reviews to identify studies published in English between Jan 1, 1960, and April 30, 2014, which investigated antimalarial treatment efficacy in P. vivax malaria. We excluded studies that did not include supervised schizonticidal treatment without primaquine. We determined rates of chloroquine resistance according to P. vivax malaria recurrence rates by day 28 whole-blood chloroquine concentrations at the time of recurrence and study enrolment criteria.We identified 129 eligible clinical trials involving 21,694 patients at 179 study sites and 26 case reports describing 54 patients. Chloroquine resistance was present in 58 (53%) of 113 assessable study sites, spread across most countries that are endemic for P. vivax. Clearance of parasitaemia assessed by microscopy in 95% of patients by day 2, or all patients by day 3, was 100% predictive of chloroquine sensitivity.Heterogeneity of study design and analysis has confounded global surveillance of chloroquine-resistant P. vivax, which is now present across most countries endemic for P. vivax. Improved methods for monitoring of drug resistance are needed to inform antimalarial policy in these regions.Wellcome Trust (UK).
Phase II Study of Cediranib, an Oral Pan–Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Recurrent Glioblastoma
Authors: Tracy T. Batchelor, Dan G. Duda, Emmanuelle di Tomaso, Marek Ancukiewicz, Scott R. Plotkin, Elizabeth Gerstner, April F. Eichler, Jan Drappatz, Fred H. Hochberg, Thomas Benner, David N. Louis, Kenneth S. Cohen, Houng Chea, Alexis Exarhopoulos, Jay S. Loeffler, Marsha A. Moses, Percy Ivy, A. Gregory Sorensen, Patrick Y. Wen, Rakesh K. Jain
Journal: Journal of Clinical Oncology (2010)

Purpose Glioblastoma is an incurable solid tumor characterized by increased expression of vascular endothelial growth factor (VEGF). We performed a phase II study of cediranib in patients with recurrent glioblastoma. Methods Cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor, was administered (45 mg/d) until progression or unacceptable toxicity to patients with recurrent glioblastoma. The primary end point was the proportion of patients alive and progression free at 6 months (APF6). We performed magnetic resonance imaging (MRI) and plasma and urinary biomarker evaluations at multiple time points. Results Thirty-one patients with recurrent glioblastoma were accrued. APF6 after cediranib was 25.8%. Radiographic partial responses were observed by MRI in 17 (56.7%) of 30 evaluable patients using three-dimensional measurements and in eight (27%) of 30 evaluable patients using two-dimensional measurements. For the 15 patients who entered the study taking corticosteroids, the dose was reduced (n = 10) or discontinued (n = 5). Toxicities were manageable. Grade 3/4 toxicities included hypertension (four of 31; 12.9%); diarrhea (two of 31; 6.4%); and fatigue (six of 31; 19.4%). Fifteen (48.4%) of 31 patients required at least one dose reduction and 15 patients required temporary drug interruptions due to toxicity. Drug interruptions were not associated with outcome. Changes in plasma placental growth factor, basic fibroblast growth factor, matrix metalloproteinase (MMP) -2, soluble VEGF receptor 1, stromal cell–derived factor-1α, and soluble Tek/Tie2 receptor and in urinary MMP-9/neutrophil gelatinase-associated lipocalin activity after cediranib were associated with radiographic response or survival. Conclusion Cediranib monotherapy for recurrent glioblastoma is associated with encouraging proportions of radiographic response, 6-month progression-free survival, and a steroid-sparing effect with manageable toxicity. We identified early changes in circulating molecules as potential biomarkers of response to cediranib. The efficacy of cediranib and the predictive value of these candidate biomarkers will be explored in prospective trials.
William Carlos Williams: Poet-Physician of Rutherford
Authors: Linda W. Wagner
Journal: JAMA (1968)

"How do you find the time, Doc?" people were always asking the genial New Jersey physician, as he published book after book in the midst of his busy medical career. "It's not finding time, it's<i>using</i>it," Williams would reply gruffly. "Two parts of a whole," he called medicine and poetry. And he wrote in his<i>Autobiography</i>, As a writer I have never felt that medicine interfered with me but rather that it was my very food and drink, the very thing that made it possible for me to write. Was I not interested in men? There the thing was, right in front of me. Modest as Williams was about his two occupations, his energy gives most of us pause. In this era of hypertension, a person like William Carlos Williams is a rarity. He survived the pressures of not one job, but two. Strong in his ambition to create,
<scp>l</scp>-Arginine-Induced Vasodilation of the Renal Vasculature Is Not Altered in Hypertensive Patients With Type 2 Diabetes
Authors: Christian Delles, Markus P. Schneider, Sebastian Oehmer, Erwin H. Fleischmann, Roland E. Schmieder
Journal: Diabetes Care (2003)

OBJECTIVE—Diabetes, arterial hypertension, hypercholesterolemia, and aging are associated with endothelial dysfunction in various vasculatures. Endothelium-dependent vasodilation of the renal vasculature cannot be easily assessed, but infusion of l-arginine, the substrate of endothelial nitric oxide synthase, leads to an increase in renal plasma flow (RPF) in humans. We have examined the effect of l-arginine infusion on renal hemodynamics in hypertensive patients with type 2 diabetes. RESEARCH DESIGN AND METHODS—Twenty-three elderly patients with type 2 diabetes (age, 65 ± 6 years; HbA1c, 7.8 ± 1.6%) with coexisting arterial hypertension (158 ± 19/83 ± 11 mmHg) and elevated cholesterol levels (total cholesterol, 215 ± 33 mg/dl) were examined. These patients were compared with a young and healthy reference group (n = 20; age, 26 ± 2 years). The effect of l-arginine infusion (100 mg/kg over 30 min) on RPF and glomerular filtration rate were measured using the constant input clearance technique with p-aminohippurate and inulin, respectively. RESULTS—l-Arginine infusion similarly influenced renal hemodynamics in patients and reference subjects: RPF increased by 7 ± 11 and 7 ± 11% in diabetic and reference subjects, respectively (P = NS). Other parameters of renal hemodynamics such as glomerular filtration rate (5 ± 5 vs. 4 ± 4%) and filtration fraction (−1 ± 8 vs. −1 ± 9%) were not significantly different between diabetic and reference subjects, too. CONCLUSIONS—l-Arginine-induced vasodilation of the renal vasculature is not different between a group of hypertensive diabetic patients and a young, healthy reference group. These data were obtained using low-dose l-arginine infusion.
Reversibility of Adverse, Calcineurin-Dependent Cardiac Remodeling
Authors: Jeff M. Berry, Vien Le, David Rotter, Pavan K. Battiprolu, Bennett Grinsfelder, Paul Tannous, Jana S. Burchfield, Michael Czubryt, Johannes Backs, Eric N. Olson, Beverly A. Rothermel, Joseph A. Hill
Journal: Circulation Research (2011)

Rationale: Studies to dissect the role of calcineurin in pathological cardiac remodeling have relied heavily on murine models, in which genetic gain- and loss-of-function manipulations are initiated at or before birth. However, the great majority of clinical cardiac pathology occurs in adults. Yet nothing is known about the effects of calcineurin when its activation commences in adulthood. Furthermore, despite the fact that ventricular hypertrophy is a well-established risk factor for heart failure, the relative pace and progression of these 2 major phenotypic features of heart disease are unknown. Finally, even though therapeutic interventions in adults are designed to slow, arrest, or reverse disease pathogenesis, little is known about the capacity for spontaneous reversibility of calcineurin-dependent pathological remodeling. Objective: We set out to address these 3 questions by studying mice engineered to harbor in cardiomyocytes a constitutively active calcineurin transgene driven by a tetracycline-responsive promoter element. Methods and Results: Expression of the mutant calcineurin transgene was initiated for variable lengths of time to determine the natural history of disease pathogenesis, and to determine when, if ever, these events are reversible. Activation of the calcineurin transgene in adult mice triggered rapid and robust cardiac growth with features characteristic of pathological hypertrophy. Concentric hypertrophy preceded the development of systolic dysfunction, fetal gene activation, fibrosis, and clinical heart failure. Furthermore, cardiac hypertrophy reversed spontaneously when calcineurin activity was turned off, and expression of fetal genes reverted to baseline. Fibrosis, a prominent feature of pathological cardiac remodeling, manifested partial reversibility. Conclusions: Together, these data establish and define the deleterious effects of calcineurin signaling in the adult heart and reveal that calcineurin-dependent hypertrophy with concentric geometry precedes systolic dysfunction and heart failure. Furthermore, these findings demonstrate that during much of the disease process, calcineurin-dependent remodeling remains reversible.
A Dangerous Liaison between Two Major Killers
Authors: Stefan H.E. Kaufmann, Ulrich E. Schaible
Journal: The Journal of Experimental Medicine (2002)

With 2.9 million and 1.7 million deaths in 2000, the HIV and Mycobacterium tuberculosis , respectively, again top the infamous WHO list of excess deaths caused by infectious agents (1; Fig. 1).To further worsen the situation, these two pathogens do not operate independently.More than half a million of those who died last year were already coinfected with both pathogens and more than 50 million individuals coinfected with HIV and M. tuberculosis envisage a similar fate in the upcoming years.One third of the total world population (2 billion people) is infected with M. tuberculosis and coinfection with HIV exacerbates the risk of developing active tuberculosis from 1 in 10 during lifetime to 1 in 10 during the year after HIV infection (2).As long as the immune system remains competent, M. tuberculosis is normally held at bay, though the immune response fails to achieve sterile eradication.Once, however, the strength of the immune response declines, active disease can develop normally through reactivation of quiescent organisms and in some cases through reinfection (2, 3).This is where HIV comes into play.With its notorious capacity to target CD4 T cells, HIV impairs the major host cell responsible for preventing conversion of mere infection to active tuberculosis (4).Now an additional link in the dangerous liaison between HIV and M. tuberculosis has been uncovered.Two papers in this issue reveal that the dendritic cell (DC)-specific surface receptor DC-SIGN (DC-specific ICAM-3-grabbing nonintegrin) is not only exploited by HIV as shown previously (5-7) but also by M. tuberculosis.The tubercle bacillus and its cell wall glycolipid lipoarabinomannan seem to bind to and to induce, via DC-SIGN, an intracellular signal leading to IL-10 production, which in turn could impair activation of protective T cell responses directed against M. tuberculosis and HIV (8, 9).The detrimental consequences of HIV on M. tuberculosis infection have been known for some time.Now it appears that, through DC-SIGN-mediated immunosuppression, M. tuberculosis also plays its part in this fatal liaison.
Type 1 von Willebrand disease mutation Cys1149Arg causes intracellular retention and degradation of heterodimers: a possible general mechanism for dominant mutations of oligomeric proteins
Authors: Imre Bodó, Akira Katsumi, Elodee A. Tuley, Jeroen C. J. Eikenboom, Zhengyu Dong, J. Evan Sadler
Journal: Blood (2001)
Police commissioners call for rethink on minimum pricing of alcohol
Authors: A. O'Dowd
Journal: BMJ (2014)

<h3>Abstract</h3> Advances in library-based methods for peptide detection from data independent acquisition (DIA) mass spectrometry have made it possible to detect and quantify tens of thousands of peptides in a single mass spectrometry run. However, many of these methods rely on a comprehensive, high quality spectral library containing information about the expected retention time and fragmentation patterns of peptides in the sample. Empirical spectral libraries are often generated through data-dependent acquisition and may suffer from biases as a result. Spectral libraries can be generated <i>in silico</i> but these models are not trained to handle all possible post-translational modifications. Here, we propose a false discovery rate controlled spectrum-centric search workflow to generate spectral libraries directly from gas-phase fractionated DIA tandem mass spectrometry data. We demonstrate that this strategy is able to detect phosphorylated peptides and can be used to generate a spectral library for accurate peptide detection and quantitation in wide window DIA data. We compare the results of this search workflow to other library-free approaches and demonstrate that our search is competitive in terms of accuracy and sensitivity. These results demonstrate that the proposed workflow has the capacity to generate spectral libraries while avoiding the limitations of other methods.
Selecting Patients for Treatment with Epidermal Growth Factor Tyrosine Kinase Inhibitors
Authors: Philip D. Bonomi, Lela Buckingham, John Coon
Journal: Clinical Cancer Research (2007)

Abstract Identification of objective tumor regressions with epidermal growth factor receptor tyrosine kinases (EGFR TKI) in non–small cell lung cancer (NSCLC) patients has resulted in intense, worldwide clinical and basic research directed toward finding the optimal use of EGFR TKIs in NSCLC. EGFR TKI clinical trials have shown that higher response rates and longer survival are associated with specific patient characteristics and that using conventional chemotherapy simultaneously with EGFR TKIs in unselected patients does not increase survival. Molecular studies have revealed that EGFR-activating mutations and high EGFR gene copy number are frequently found in patients who have the best outcomes with EGFR TKIs. More recent studies suggest that KRAS mutations may identify the subset of patients who have the worst outcome with the EGFR TKI treatment. Currently, investigators are trying to determine the optimal approach to selecting patients for treatment with EGFR TKIs. Studies that have evaluated the potential predictive value of clinical features and/or molecular profiles in EGFR TKI-treated NSCLC patients are discussed in this review.
Asthma increases pulmonary thromboembolism risk: a nationwide population cohort study
Authors: W.-S. Chung, C.-L. Lin, F.-M. Ho, R.-Y. Li, F.-C. Sung, C.-H. Kao, J.-J. Yeh
Journal: European Respiratory Journal (2013)

Studies on the association between asthma and pulmonary thromboembolism are considerably limited. We investigated whether pulmonary embolism is associated with asthma using a nationwide cohort study. We identified 31 356 patients with newly diagnosed asthma in 2002–2008 and 125 157 individuals without asthma randomly selected from the general population, frequency matched by age, sex and index year using the National Health Insurance Research Database. Both cohorts were followed-up until the end of 2010 to measure the incidence of pulmonary embolism. Cox proportional hazards regression analysis was used to measure the hazard ratio of pulmonary embolism for the asthmatic cohort, compared with the nonasthmatic cohort. We followed 186 182 person-years for asthmatic patients and 743 374 person-years for nonasthmatic subjects. The hazard ratio of pulmonary embolism was 3.24 for the asthmatic cohort, compared with the nonasthmatic cohort after adjusting for sex, age, comorbidities and oestrogen supplementation. The risk of developing pulmonary embolism significantly increased with the increased frequency of asthma exacerbation and hospitalisation. This nationwide cohort study suggests that the risk of developing pulmonary embolism is significantly increased in asthmatic patients compared to the general population. Frequent asthma exacerbation and hospitalisation are significantly associated with pulmonary embolism risk.
Testing Psychodynamic Psychotherapy Skills Among Psychiatric Residents: The Psychodynamic Psychotherapy Competency Test
Authors: Linda S. Mullen, Ronald O. Rieder, Robert A. Glick, Bruce Luber, Paul J. Rosen
Journal: American Journal of Psychiatry (2004)

Training in psychodynamic psychotherapy remains a core requirement of psychiatric residency training programs, yet no standard measures of competency exist to document residents' knowledge and skills in this area. To address this issue, the authors developed a written test of applied knowledge of psychodynamic psychotherapy technique and theory, the Psychodynamic Psychotherapy Competency Test. Their goal in this article was to evaluate the validity of this test.The test was given to a group of 36 psychoanalytic experts and 206 residents in their second, third, and fourth psychiatric postgraduate years from 10 programs located in different parts of the United States. Program directors provided information on the number of hours of psychodynamic didactic teaching, supervision, and resident-conducted psychodynamic psychotherapy and rated the psychodynamic psychotherapy skills of residents in their fourth postgraduate year on the basis of cumulative supervisor reports.There were significant differences in test performance between residents and faculty experts and between residents in their second and fourth postgraduate years: more advanced residents and experts had progressively better scores. The mean scores of fourth-year residents in different programs differed significantly, but the scores of second-year residents did not. Higher test scores were positively associated with both number of hours of resident-conducted psychotherapy and number of hours of supervision. Among fourth-year residents, test scores correlated significantly with program director evaluations.This initial study supports the validity of the Psychodynamic Psychotherapy Competency Test as well as the feasibility of testing psychotherapy skills in a standardized fashion.
A Study of the Mechanisms Involved in the Pulmonary Arterial Pressor Response to Hypoxia
Authors: EDWARD H. BERGOFSKY, SEYMOUR HOLTZMAN
Journal: Circulation Research (1967)

The mechanisms underlying the pulmonary arterial pressor response to hypoxia have been investigated by studying specimens of pulmonary and systemic vascular smooth muscle and the isolated pulmonary and systemic circulations. Hypoxia caused a unique and reversible loss of potassium and gain in sodium by pulmonary arterial smooth muscle that did not occur in pulmonary veins or systemic arteries. These changes in electrolyte concentrations were calculated by the Nernst equation to be associated with depolarization of the smooth muscle cell of the pulmonary artery. Moreover, artificial hyperpolarization and depolarization in the isolated perfused pulmonary circulation were attended by blunting and accentuation, respectively, of the pulmonary arterial pressor response to hypoxia. Such data suggest that one of the actions of hypoxia on the pulmonary circulation involves a depolarization of the muscle cell so that it is closer to its excitatory threshold and thereby more readily able to diminish the cross-sectional area of the pulmonary vascular bed.
Association Between Urinary Albumin Excretion and Plasma 5-Hydroxyindole-3-Acetic Acid Concentration in Men With Type 2 Diabetes
Authors: Michiaki Fukui, Hiroyuki Ose, Goji Hasegawa, Toshikazu Yoshikawa, Naoto Nakamura
Journal: Diabetes Care (2007)

Serotonin (5-hydroxytryptamine [5-HT]) mediates vasoconstriction and induces the activation of platelets, which may promote atherosclerosis. Plasma 5-HT concentrations have been reported to be high in diabetic patients (1,2); this may be one of the underlying mechanisms of diabetes complications. The 5-HT2A receptor has been identified in glomerular mesangial cells (3), suggesting involvement of 5-HT in the development of diabetic nephropathy through proliferation and matrix sysnthesis in mesangial lesions. Male sex is an independent risk factor for cardiovascular disease (4). Moreover, elevated urinary albumin excretion (UAE) has been reported to be associated with increased risk of cardiovascular mortality (5). Few studies have examined the association between plasma 5-HT concentration and atherosclerosis (6). To our knowledge, a relationship between plasma 5-HT concentration and degree of UAE has never been explored in men with type 2 diabetes. In this study, we evaluated the relationships between plasma 5-hydroxyindole-3-acetic acid (5-HIAA), a derivative end product of 5-HT, concentration and degree of UAE, and markers of subclinical atherosclerosis, such as pulse wave velocity (PWV), ankle-brachial index (ABI), carotid intima-media thickness (IMT), or plaque score in men with type 2 diabetes.

The relationships of plasma 5-HIAA concentrations with degree of UAE and major cardiovascular risk factors were investigated in 205 consecutive men with type 2 diabetes recruited from the outpatient clinic at the Kyoto Prefectural University of Medicine (Kyoto, Japan). Additionally, the relationships between plasma …