tbuckley/cabot-search huggingface dataset:
Boceprevir for Previously Treated Chronic HCV Genotype 1 Infection
Authors: Bruce R. Bacon, Stuart C. Gordon, Eric Lawitz, Patrick Marcellin, John M. Vierling, Stefan Zeuzem, Fred Poordad, Zachary D. Goodman, Heather L. Sings, Navdeep Boparai, Margaret Burroughs, Clifford A. Brass, Janice K. Albrecht, Rafael Esteban
Journal: New England Journal of Medicine (2011)

In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment.To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks.A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log(10) IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls.The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon-ribavirin alone. (Funded by Schering-Plough [now Merck]; HCV RESPOND-2 ClinicalTrials.gov number, NCT00708500.).
Dipeptide mimic oligomer transporter mediates intracellular delivery of Cathepsin D inhibitors: A potential target for cancer therapy
Authors: Marie Maynadier, Lubomir L. Vezenkov, Muriel Amblard, Vincent Martin, Céline Gandreuil, Ophélie Vaillant, Magali Gary-Bobo, Ilaria Basile, Jean-François Hernandez, Marcel Garcia, Jean Martinez
Journal: Journal of Controlled Release (2013)
Remission of psoriasis during haemodialysis.
Authors: T J Buselmeier, J S Cantieri
Journal: BMJ (1978)

pyrimidine monoadducts, by subsequent light irradiation.'The conversion of psoralen DNA-monoadducts to DNA-crosslinks is not without potential problems.For some as yet unknown period of time photosensitised skin may con- tinue to be further damaged by exposure to either direct or indirect sunlight as the conversion of monoadducts to crosslinks occur.Physicians would be well advised to realise that the cessation of black light irradiation is not the end of the treatment unless the lesions are kept in the dark, perhaps for several weeks.
Evaluation of food‐pollen cross‐reactivity by nose–mouth cross‐challenge in pollinosis with oral allergy syndrome
Authors: F. Marcucci, F. Frati, L. Sensi, G. D. Cara, E. Novembre, R. Bernardini, G. W. Canonica, G. Passalacqua
Journal: Allergy (2004)

Background: Oral allergy syndrome (OAS) is often associated with pollen‐induced rhinitis, and there are preferential associations between causative substances. If OAS and rhinitis are both immunoglobulin (Ig)E‐mediated and there are cross‐reacting proteins, it is expected that similar reactions can be elicited in the nose and mouth. In order to test this hypothesis we performed a series of ‘cross‐challenges’ with foods and pollens in both the nose and the mouth. Methods: Nine patients with ascertained OAS due to vegetables and rhinitis due to pollens were studied. On the first day a nasal challenge with pollen extracts and an oral challenge with fresh food was carried out. After a week, washout nasal challenge with food and an oral challenge with pollens were performed. Immediate symptoms, mucosal tryptase and soluble eosinophil cationic protein (ECP) were assessed after each challenge. Results: The administration of pollen into the nose and food into the mouth elicited symptoms as expected, but the cross‐challenge had no clinical effect. In parallel, tryptase and ECP increased after nasal challenge with pollens, whereas foods did not elicit a measurable response. Conclusion: The cross‐reactivity between foods and pollens, when evaluated at the shock organ, was not clinically evident. This data can be explained with a low concentration of cross‐reagent epitopes in pollen extracts and food homogenized because of degradation. The different behaviour upon challenge suggests that different immunological mechanisms may act in the nose and mouth.
Human Puberty SIMULTANEOUS AUGMENTED SECRETION OF LUTEINIZING HORMONE AND TESTOSTERONE DURING SLEEP
Authors: R. M. Boyar, R. S. Rosenfeld, S. Kapen, J. W. Finkelstein, H. P. Roffwarg, E. D. Weitzman, Leon Hellman
Journal: Journal of Clinical Investigation (1974)

Plasma luteinizing hormone (LH) and testosterone (T) were measured by radioimmunoassay in nine pubertal boys and three sexually mature young men at 20-min intervals for 24 h. Plasma LH and T were also measured in one boy during a delayed sleep onset study. Polygraphic monitoring was carried out to identify precisely sleep onset. Wakefulness, and specific sleep stages. In all nine pubertal boys the plasma T concentration fluctuated and was significantly higher during normal nocturnal sleep as compared to daytime waking. This increased T secretion during sleep was temporally linked to the characteristic pubertal sleep augmentation of LH secretion. To define further the relationship of this increased T secretion to sleep, plasma LH and T were also measured in three of the pubertal boys after acute (1-day) reversal of the sleep-wake cycle. One of these boys was also studied after 3 days of sleep-wake cycle reversal. The results of these studies showed that plasma T was now augmented during the reversed daytime sleep period; the mean T concentrations during this period were significantly higher (P < 0.001) than during nocturnal waking in all four studies. Measurement of plasma LH and T in the three sexually mature young men showed episodic secretion of LH and T during both waking and sleep periods; there was no consistent significant augmentation of LH or T secretion during sleep. This study demonstrates that (a) in normal pubertal boys and sexually mature young men plasma T fluctuates episodically; (b) there is marked augmentation of T secretion during sleep in pubertal boys, which is dependent on increased LH secretion; (c) this pubertal LH-T secretory "program" is dependent on sleep, since it shifts with delayed sleep onset and reversal of the sleep-wake cycle; and (d) this demonstrable tropic effect of LH on T is evident only during puberty, since sexually mature young men fail to show any consistent relationship between LH and T secretion either awake or asleep.
Circadian variation in ischemic threshold. A mechanism underlying the circadian variation in ischemic events.
Authors: A A Quyyumi, J A Panza, J G Diodati, E Lakatos, S E Epstein
Journal: Circulation (1992)

There is a circadian pattern in the occurrence of cardiac events in patients with coronary artery disease. Whether changes in coronary vascular tone contribute to these phenomena is unknown. We measured the ischemic threshold, defined as either the heart rate or rate-pressure product at 1-mm ST segment depression during treadmill exercise and used it as an index of the lowest coronary vascular resistance; the premise was that when ischemic threshold became lower, coronary vascular resistance was higher, and vice versa.Fifteen patients (group A) with stable coronary artery disease underwent four identical treadmill exercise tests in 24 hours, and ischemic threshold was measured as the heart rate at the onset of 1-mm ST depression. Before each treadmill test, postischemic forearm vascular resistance was measured after 5 minutes of forearm occlusion, using strain-gauge plethysmography. Sixteen additional patients (group B) underwent two treadmill tests at 8 AM and 1 PM, and ischemic threshold was measured as the heart rate-blood pressure product at 1-mm ST depression. A circadian variation was noted: In group A, the heart rate-derived ischemic threshold was lower at 8 AM and 9 PM compared with noon and 5 PM (p less than 0.03). Also, in group B, the rate-pressure product-derived ischemic threshold was 8 +/- 2% lower at 8 AM compared with 1 PM (p = 0.008). A circadian variation parallel to the observed variation in ischemic threshold was also noted in the postischemic forearm blood flow, which was lower in the morning and at night (p less than 0.004). There was a strong correlation between postischemic forearm blood flow and ischemic threshold (p less than 0.0001), such that ischemic threshold was lower at the time of day when postischemic forearm blood flow was lower, and vice versa.A lower ischemic threshold in the morning suggests that the ischemia-induced coronary vascular resistance is increased at this time, a finding supported by a similar variation in postischemic forearm vascular resistance. Parallel changes in forearm and coronary resistance suggest that generalized (neural or humoral factors) rather than local factors are responsible for the observed circadian changes. Increased coronary tone in the mornings may not only contribute to the higher incidence of transient ischemia but may help trigger acute cardiac events at this time.
Review of treatment options for psoriasis in pregnant or lactating women: From the Medical Board of the National Psoriasis Foundation
Authors: Yoon-Soo Cindy Bae, Abby S. Van Voorhees, Sylvia Hsu, Neil J. Korman, Mark G. Lebwohl, Melody Young, Bruce Bebo, Alexa Boer Kimball
Journal: Journal of the American Academy of Dermatology (2011)
Urinary Retention in Patients with BPH Treated with Finasteride or Placebo over 4 Years
Authors: Claus G. Roehrborn, Reginald Bruskewitz, G. Curtis Nickel, Stanley Glickman, Clair Cox II, Ronald Anderson, Stanley Kandzari, Richard Herlihy, George Kornitzer, B. Thomas Brown, H. Logan Holtgrewe, Alice Taylor, Daniel Wang, Joanne Waldstreicher
Journal: European Urology (2000)
Immigrants' Experience with Publicly Funded Private Health Insurance
Authors: Ruth Hertzman-Miller, Malgorzata Dawiskiba, Cassie Frank
Journal: New England Journal of Medicine (2010)

To the Editor: On October 31, 2009, Massachusetts involuntarily transferred about 30,000 legal immigrants (mostly “green card” holders) from Commonwealth Care, the state-subsidized insurance program, to a new private insurance plan. CeltiCare, a subsidiary of the out-of-state, for-profit insurer Centene, agreed to take over their care for only $1,300 per person, one third of the state's previous cost1 and well below the average cost of adequate care nationally.2 CeltiCare excluded several hospitals (and their affiliated community health centers) that have traditionally provided safety-net care for immigrants, including Boston Medical Center and Cambridge Health Alliance (CHA), where we work.3 We used . . .
Activation of Histamine H <sub>3</sub> -Receptors Inhibits Carrier-Mediated Norepinephrine Release During Protracted Myocardial Ischemia
Authors: Michiaki Imamura, Harry M. Lander, Roberto Levi
Journal: Circulation Research (1996)

Abstract We previously showed that prejunctional histamine H 3 -receptors downregulate norepinephrine exocytosis, which is markedly enhanced in early myocardial ischemia. In the present study, we investigated whether H 3 -receptors modulate nonexocytotic norepinephrine release during protracted myocardial ischemia. In this setting, decreased pH i in sympathetic nerve endings sequentially leads to a compensatory activation of the Na + -H + antiporter (NHE), accumulation of intracellular Na + , reversal of the neuronal uptake of norepinephrine, and thus carrier-mediated release of norepinephrine. Accordingly, norepinephrine overflow from isolated guinea pig hearts undergoing 20-minute global ischemia and 45-minute reperfusion was attenuated ≈80% by desipramine (10 nmol/L) and 70% by 5-( N -ethyl- N -isopropyl)-amiloride (EIPA, 10 μmol/L), inhibitors of norepinephrine uptake and NHE, respectively. The H 3 -receptor agonist imetit (0.1 μmol/L) decreased carrier-mediated norepinephrine release by ≈50%. This effect was blocked by the H 3 -receptor antagonist thioperamide (0.3 μmol/L), indicating that H 3 -receptor activation inhibits carrier-mediated norepinephrine release. At lower concentrations, imetit (10 nmol/L) or EIPA (3 μmol/L) did not inhibit carrier-mediated norepinephrine release. However, a 25% inhibition occurred with imetit (10 nmol/L) and EIPA (3 μmol/L) combined. This synergism suggests an association between H 3 -receptors and NHE. Conceivably, activation of H 3 -receptors may lead to inhibition of NHE. In fact, α 2 -adrenoceptor activation, which is known to stimulate NHE, enhanced norepinephrine release, whereas α 2 -adrenoceptor blockade attenuated it. Furthermore, activation of adenosine A 1 -receptors markedly attenuated norepinephrine release, whereas their inhibition potentiated it. Because norepinephrine release directly correlated with the severity of reperfusion arrhythmia and imetit reduced the incidence of ventricular fibrillation by 50%, our findings with H 3 -receptor agonists may further the development of novel pharmacological means to reduce reperfusion arrhythmias in the clinical setting.
Shigella
Authors: Benoit Marteyn, Anastasia Gazi, Philippe Sansonetti
Journal: Gut Microbes (2012)

Much is known about the molecular effectors of pathogenicity of gram-negative enteric pathogens, among which Shigella can be considered a model. This is due to its capacity to recapitulate the multiple steps required for a pathogenic microbe to survive close to its mucosal target, colonize and then invade its epithelial surface, cause its inflammatory destruction and simultaneously regulate the extent of the elicited innate response to likely survive the encounter and achieve successful subsequent transmission. These various steps of the infectious process represent an array of successive environmental conditions to which the bacteria need to successfully adapt. These conditions represent the selective pressure that triggered the "arms race" in which Shigella acquired the genetic and molecular effectors of its pathogenic armory, including the regulatory hierarchies that regulate the expression and function of these effectors. They also represent cues through which Shigella achieves the temporo-spatial expression and regulation of its virulence effectors. The role of such environmental cues has recently become obvious in the case of the major virulence effector of Shigella, the type three secretion system (T3SS) and its dedicated secreted virulence effectors. It needs to be better defined for other major virulence components such as the LPS and peptidoglycan which are used as examples here, in addition to the T3SS as models of regulation as it relates to the assembly and functional regulation of complex macromolecular systems of the bacterial surface. This review also stresses the need to better define what the true and relevant environmental conditions can be at the various steps of the progression of infection. The "identity" of the pathogen differs depending whether it is cultivated under in vitro or in vivo conditions. Moreover, this "identity" may quickly change during its progression into the infected tissue. Novel concepts and relevant tools are needed to address this challenge in microbial pathogenesis.
Too soon to discard advice against saturated fats, professors say
Authors: N. Hawkes
Journal: BMJ (2014)

Dietary guidelines that stigmatise saturated fats should not be hastily abandoned despite a meta-analysis published earlier this year that found no evidence to support the guidelines, a panel of four UK professors of nutrition has advised. The team was assembled by the Science Media Centre for a press briefing in London on 7 October.

Christine Williams, of the University of Reading, cast doubt on the validity of the study, which was led by Rajiv Chowdhury of the Cardiovascular Epidemiology Unit at the University of Cambridge, and which concluded, “Current evidence does not clearly support cardiovascular guidelines that encourage high consumption of polyunsaturated fatty acids and low consumption of total saturated fats.”1 2 …
<i>MAX</i> Mutations Cause Hereditary and Sporadic Pheochromocytoma and Paraganglioma
Authors: Nelly Burnichon, Alberto Cascón, Francesca Schiavi, Nicole Paes Morales, Iñaki Comino-Méndez, Nasséra Abermil, Lucía Inglada-Pérez, Aguirre A. de Cubas, Laurence Amar, Marta Barontini, Sandra Bernaldo de Quirós, Jérôme Bertherat, Yves-Jean Bignon, Marinus J. Blok, Sara Bobisse, Salud Borrego, Maurizio Castellano, Philippe Chanson, María-Dolores Chiara, Eleonora P.M. Corssmit, Mara Giacchè, Ronald R. de Krijger, Tonino Ercolino, Xavier Girerd, Encarna B. Gómez-García, Álvaro Gómez-Graña, Isabelle Guilhem, Frederik J. Hes, Emiliano Honrado, Esther Korpershoek, Jacques W.M. Lenders, Rocío Letón, Arjen R. Mensenkamp, Anna Merlo, Luigi Mori, Arnaud Murat, Peggy Pierre, Pierre-François Plouin, Tamara Prodanov, Miguel Quesada-Charneco, Nan Qin, Elena Rapizzi, Victoria Raymond, Nicole Reisch, Giovanna Roncador, Macarena Ruiz-Ferrer, Frank Schillo, Alexander P.A. Stegmann, Carlos Suarez, Elisa Taschin, Henri J.L.M. Timmers, Carli M.J. Tops, Miguel Urioste, Felix Beuschlein, Karel Pacak, Massimo Mannelli, Patricia L. M. Dahia, Giuseppe Opocher, Graeme Eisenhofer, Anne-Paule Gimenez-Roqueplo, Mercedes Robledo
Journal: Clinical Cancer Research (2012)

Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest-derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL.We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics.Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine.Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients.
Airway remodeling in asthma
Authors: Jack A. Elias, Zhou Zhu, Geoffrey Chupp, Robert J. Homer
Journal: Journal of Clinical Investigation (1999)

Asthma is estimated to affect 15 million people in the United States. After declining in the 1970s, its prevalence, morbidity, and mortality have increased since the 1980s. It now affects 1 in 7 children in the United Kingdom, and is the most frequent reason for preventable childhood hospitalizations in the United States. In 1990, total asthma-related health care costs were estimated at 6.2 billion dollars in the United States. This figure exceeded 10 billion dollars by 1995.
Phenolsulfonphthalein (PSP) in Assessment of Renal Function
Authors: Mathew H. Gault
Journal: JAMA (1967)

Since the first report<sup>1</sup>of the rapid excretion of phenolsulfonphthalein (PSP) or phenol red by the kidney, PSP has been used widely to assess renal function, without serious mishap.<sup>2</sup>Use of the intravenous route and earlier measurement of excretion (starting at 15 minutes) have enhanced the value of the test. The mechanism of tubular excretion of PSP has been reviewed.<sup>3</sup>Its maximal excretory rate in man is about 36 mg/min/1.73 sq m; 50% to 60% is extracted by the kidney in one circulation, and clearance averages 400 ml/min.<sup>4</sup>Glomerular filtration is small compared with the amount secreted by active tubular transport. Ordinarily about 2% to 3% is excreted into the bile and limited intestinal absorption occurs.<sup>5</sup>Binding to albumin in vivo appears much less than the 80% suggested by studies in vitro, and some PSP appears to enter cells other than kidney, liver, and intestine.
Building and maintaining the epithelium of the lung
Authors: Craig R. Rackley, Barry R. Stripp
Journal: Journal of Clinical Investigation (2012)

Airspaces of the lung are lined by an epithelium whose cellular composition changes along the proximal-to-distal axis to meet local functional needs for mucociliary clearance, hydration, host defense, and gas exchange. Advances in cell isolation, in vitro culture techniques, and genetic manipulation of animal models have increased our understanding of the development and maintenance of the pulmonary epithelium. This review discusses basic cellular mechanisms that regulate establishment of the conducting airway and gas exchange systems as well as the functional maintenance of the epithelium during postnatal life.