tbuckley/cabot-search huggingface dataset:
Nitrite levels in breath condensate of patients with cystic fibrosis is elevated in contrast to exhaled nitric oxide
Authors: L P Ho, J A Innes, A P Greening
Journal: Thorax (1998)

<h3>BACKGROUND</h3> Nitric oxide (NO) is released by activated macrophages, neutrophils, and stimulated bronchial epithelial cells. Exhaled NO has been shown to be increased in patients with asthma and has been put forward as a marker of airways inflammation. However, we have found that exhaled NO is not raised in patients with cystic fibrosis, even during infective pulmonary exacerbation. One reason for this may be that excess airway secretions may prevent diffusion of gaseous NO into the airway lumen. We hypothesised that exhaled NO may not reflect total NO production in chronically suppurative airways and investigated nitrite as another marker of NO production. <h3>METHODS</h3> Breath condensate nitrite concentration and exhaled NO levels were measured in 21 clinically stable patients with cystic fibrosis of mean age 26 years and mean FEV<sub>1</sub> 57% and 12 healthy normal volunteers of mean age 31 years. Breath condensate was collected with a validated method which excluded saliva and nasal air contamination and nitrite levels were measured using the Griess reaction. Exhaled NO was measured using a sensitive chemiluminescence analyser (LR2000) at an exhalation rate of 250 ml/s. Fourteen patients with cystic fibrosis had circulating plasma leucocyte levels and differential analysis performed on the day of breath collection. <h3>RESULTS</h3> Nitrite levels were significantly higher in patients with cystic fibrosis than in normal subjects (median 1.93 μM compared with 0.33 μM). This correlated positively with circulating plasma leucocytes and neutrophils (<i>r</i> = 0.6). In contrast, exhaled NO values were not significantly different from the normal range (median 3.8 ppb vs 4.4 ppb). There was no correlation between breath condensate nitrite and lung function and between breath condensate nitrite and exhaled NO. <h3>CONCLUSIONS</h3> Nitrite levels in breath condensate were raised in stable patients with cystic fibrosis in contrast to exhaled NO. This suggests that nitrite levels may be a more useful measure of NO production and possibly airways inflammation in suppurative airways and that exhaled NO may not reflect total NO production.
Loss of Cdk2 and Cyclin A2 Impairs Cell Proliferation and Tumorigenesis
Authors: Lakshmi Gopinathan, Shawn Lu Wen Tan, V. C. Padmakumar, Vincenzo Coppola, Lino Tessarollo, Philipp Kaldis
Journal: Cancer Research (2014)

Abstract Cell-cycle inhibition has yet to offer a generally effective approach to cancer treatment, but a full evaluation of different combinations of cell-cycle inhibitors has not been evaluated. Cyclin A2, a core component of the cell cycle, is often aberrantly expressed in cancer where it may impact cell proliferation. In this study, we investigated the role of cyclin A2 in tumorigenesis using a conditional genetic knockout mouse model. Cyclin A2 deletion in oncogene-transformed mouse embryonic fibroblasts (MEF) suppressed tumor formation in immunocompromised mice. These findings were confirmed in mice with cyclin A2–deficient hepatocytes, where a delay in liver tumor formation was observed. Because cyclin A2 acts in complex with Cdk2 in the cell cycle, we explored a hypothesized role for Cdk2 dysregulation in this effect through conditional deletions of both genes. In oncogene-transformed MEFs lacking both genes, tumor formation was strongly suppressed in a manner associated with decreased proliferation, premature senescence, and error-prone recovery from serum deprivation after immortalization. Whereas loss of cyclin A2 led to a compensatory increase in Cdk1 activity, this did not occur with loss of both Cdk2 and cyclin A2. Our work offers a rationale to explore combinations of Cdk1 and Cdk2 inhibitors as a general approach in cancer therapy. Cancer Res; 74(14); 3870–9. ©2014 AACR.
DNA methylation signatures for breast cancer classification and prognosis
Authors: Moshe Szyf
Journal: Genome Medicine (2012)

Changes in gene expression that reset a cell program from a normal to a diseased state involve multiple genetic circuitries, creating a characteristic signature of gene expression that defines the cell's unique identity. Such signatures have been demonstrated to classify subtypes of breast cancers. Because DNA methylation is critical in programming gene expression, a change in methylation from a normal to diseased state should be similarly reflected in a signature of DNA methylation that involves multiple gene pathways. Whole-genome approaches have recently been used with different levels of success to delineate breast-cancer-specific DNA methylation signatures, and to test whether they can classify breast cancer and whether they could be associated with specific clinical outcomes. Recent work suggests that DNA methylation signatures will extend our ability to classify breast cancer and predict outcome beyond what is currently possible. DNA methylation is a robust biomarker, vastly more stable than RNA or proteins, and is therefore a promising target for the development of new approaches for diagnosis and prognosis of breast cancer and other diseases. Here, I review the scientific basis for using DNA methylation signatures in breast cancer classification and prognosis. I discuss the role of DNA methylation in normal gene regulation, the aberrations in DNA methylation in cancer, and candidate-gene and whole-genome approaches to classify breast cancer subtypes using DNA methylation markers.
Use of p16-INK4A overexpression to increase the specificity of human papillomavirus testing: a nested substudy of the NTCC randomised controlled trial
Authors: Francesca Carozzi, Massimo Confortini, Paolo Dalla Palma, Annarosa Del Mistro, Anna Gillio-Tos, Laura De Marco, Paolo Giorgi-Rossi, Giovanni Pontenani, Stefano Rosso, Cristina Sani, Catia Sintoni, Nereo Segnan, Manuel Zorzi, Jack Cuzick, Raffaella Rizzolo, Guglielmo Ronco
Journal: The Lancet Oncology (2008)
Lung elastic recoil and reduced airflow in clinically stable asthma.
Authors: D S McCarthy, M Sigurdson
Journal: Thorax (1980)

Lung volumes, maximum expiratory flow rates, and static volume-ressure curves were measured in 16 patients with clinically stable asthma. It was found that flow rates were reduced in such patients because of the combined effects of reduced elastic recoil (transpulmonary pressure) and intrinsic diseases of the airways. In nine patients treated with an aerosol of isoprenaline, flow rates improved as a result of reduction in airways resistance as the static recoil pressure of the lungs fell further in those patients. The possibility is suggested that muscle tone in peripheral airways or alveolar ducts contributed to the elastic recoil measurements.
Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol
Authors: Thomas Reiberger, Gregor Ulbrich, Arnulf Ferlitsch, Berit Anna Payer, Philipp Schwabl, Matthias Pinter, Birgit B Heinisch, Michael Trauner, Ludwig Kramer, Markus Peck-Radosavljevic
Journal: Gut (2012)

<h3>Objective</h3> Non-selective β-blockers or endoscopic band ligation (EBL) are recommended for primary prophylaxis of variceal bleeding in patients with oesophageal varices. Additional α-adrenergic blockade (as by carvedilol) may increase the number of patients with haemodynamic response (reduction in hepatic venous pressure gradient (HVPG) of ≥20% or to values &lt;12 mm Hg). <h3>Design</h3> Patients with oesophageal varices undergoing measurement of HVPG before and under propranolol treatment (80–160 mg/day) were included. HVPG responders were kept on propranolol (PROP group), while non-responders were placed on carvedilol (6.25–50 mg/day). Carvedilol responders continued treatment (CARV group), while non-responders to carvedilol underwent EBL. The primary aim was to assess haemodynamic response rates to carvedilol in propranolol non-responders. <h3>Results</h3> 36% (37/104) of patients showed a HVPG response to propranolol. Among the propranolol non-responders 56% (38/67) eventually achieved a haemodynamic response with carvedilol, while 44% (29/67) patients were finally treated with EBL. The decrease in HVPG was significantly greater with carvedilol (median 12.5 mg/day) than with propranolol (median 100 mg/day): −19±10% versus −12±11% (p&lt;0.001). During a 2 year follow-up bleeding rates for PROP were 11% versus CARV 5% versus EBL 25% (p=0.0429). Fewer episodes of hepatic decompensation (PROP 38%/CARV 26% vs EBL 55%; p=0.0789) and significantly lower mortality (PROP 14%/CARV 11% vs EBL 31%; p=0.0455) were observed in haemodynamic responders compared to the EBL group. <h3>Conclusions</h3> Carvedilol leads to a significantly greater decrease in HVPG than propranolol. Using carvedilol for primary prophylaxis a substantial proportion of non-responders to propranolol can achieve a haemodynamic response, which is associated with improved outcome with regard to prevention of variceal bleeding, hepatic decompensation and death.
Recent advances: diagnosis and treatment of early breast cancer
Authors: M. J Silverstein
Journal: BMJ (1997)

When this review was commissioned, the topic seemed straightforward: early breast cancer.But I struggled, writing pages of unfocused and confusing material, darting back and forth between invasive and noninvasive disease.The problem stemmed from the fact that there is no universally accepted definition of what constitutes early breast cancer.Should an early lesion be defined by size, by the amount of invasion, by lymph node negativity, by clinical or histologic findings, by how long it has been growing?What was meant by early breast cancer 30 years ago, what is meant by early cancer today, and what will be meant by early cancer five to 10 years from now are all different.In addition, today's biologists, geneticists, and clinicians all define early breast cancer differently.
Using a Drug Facts Box to Communicate Drug Benefits and Harms
Authors: Lisa M. Schwartz
Journal: Annals of Internal Medicine (2009)

Background: Direct-to-consumer prescription drug ads typically fail to provide fundamental information that consumers need to make informed decisions: data on how well the drug works. Objective: To see whether providing consumers with a drug facts box—a table quantifying outcomes with and without the drug—improves knowledge and affects judgments about prescription medications. Design: Two randomized, controlled trials conducted between October 2006 and April 2007: a symptom drug box trial using direct-to-consumer ads for a histamine-2 blocker and a proton-pump inhibitor to treat heartburn, and a prevention drug box trial using direct-to-consumer ads for a statin and clopidogrel to prevent cardiovascular events. Setting: National sample of U.S. adults identified by random-digit dialing. Participants: Adults age 35 to 70 years who completed a mailed survey; the final samples comprised 231 participants with completed surveys in the symptom drug box trial (49% response rate) and 219 in the prevention drug box trial (46% response rate). Intervention: In both trials, the control group received 2 actual drug ads (including both the front page and brief summary). The drug box group received the same ads, except that the brief summary was replaced by a drug facts box. Measurements: Choice between drugs (primary outcome of the symptom drug box trial) and accurate perceptions of drug benefits and side effects (primary outcome of the prevention drug box trial). Results: In the symptom drug box trial, 70% of the drug box group and 8% of the control group correctly identified the PPI as being "a lot more effective" than the histamine-2 blocker (P < 0.001), and 80% and 38% correctly recognized that the side effects of the 2 drugs were similar (P < 0.001). When asked what they would do if they had bothersome heartburn and could have either drug for free, 68% of the drug box group and 31% of the control group chose the proton-pump inhibitor, the superior drug (P < 0.001). In the prevention drug box trial, the drug box improved consumers' knowledge of the benefits and side effects of a statin and clopidogrel. For example, 72% of the drug box group and 9% of the control group correctly quantified the benefit (absolute risk reduction) of the statin (P < 0.001). Most of the control participants overestimated this benefit, and 65% did so by a factor of 10 or more. Limitations: The trials tested drug boxes in only 4 direct-to-consumer ads. If other direct-to-consumer ads were to communicate outcome data better, the effect of the drug box would be reduced. Conclusion: A drug facts box improved U.S. consumers' knowledge of prescription drug benefits and side effects. It resulted in better choices between drugs for current symptoms and corrected the overestimation of benefit in the setting of prevention. Primary Funding Source: National Cancer Institute and Attorney General Consumer and Prescriber Education Program.
The Effect of ACTH on Experimental Myocardial Infarcts
Authors: WILLIAM B. WARTMAN, LINN A. CAMPBELL, ROBERT L. CRAIG, Robert B. Jennings
Journal: Circulation Research (1955)

Measurable myocardial infarcts of predictable size and location were produced in dogs by low ligation of the left descending coronary artery just proximal to the origin of the apical branch. Two groups of dogs with such infarcts were studied, one group being treated intramuscularly with two daily closes of 20 units of Acthar Gel for 9 to 11 days and the other group being untreated. At the end of the experimental period there was no demonstrable difference between the two groups with respect to the size, site or histologic appearance of the infarcts.
Hazards of Dietary Supplements
Authors: R. M. GULLEY
Journal: JAMA (1979)

<h3>To the Editor.—</h3> Recently one of us had occasion to embark on a protein-supplemented fast. While on the way to a noon meeting that promised to be particularly dull, and while suffering moderate hunger, this person purchased a package of 12 mints advertised as being sugar-free. Paying no attention to the label, he proceeded to consume all of the 12 mints during the two-hour meeting. Thirty minutes after the last mint was consumed, he began to experience marked abdominal distention, passed extremely large amounts of flatus, and experienced abdominal cramping. This was followed shortly by the development of profuse, watery diarrhea that persisted for the next 30 minutes and amounted to an estimated 1 to 1.5 L of fluid. Five hours after consuming the mints, the subject ate his evening meal, which consisted of 180 g (6 oz) of steak, and noted persistent vague abdominal distress with considerable flatus. Thirty
Effect of Dietary Protein Quality on Development of Aflatoxin B1 -Induced Hepatic Preneoplastic Lesions
Authors: D. A. Schulsinger, M. M. Root, T. C. Campbell
Journal: JNCI Journal of the National Cancer Institute (1989)

The effect of the quality of dietary protein on the post-initiation development of aflatoxin B1-initiated putatively preneoplastic foci in Fischer 344 rat liver was compared with the effect of the quantity of dietary protein. Feeding wheat gluten, a low-quality protein, during the post-initiation period (between the end of aflatoxin B1 dosing and the death of the rats) inhibited the development of γ-glutamyltransferase-positive foci when compared with that in animals fed high-quality protein (casein) diets during the same period. Lysine supplementation of wheat gluten during the postinitiation period enhanced the γ-glutamyltransferase-positive response to a level comparable with that of the high-quality protein. These results suggest that one can inhibit the development of foci either by decreasing the quantity of protein intake and holding the quality of the protein constant or by decreasing the quality and holding the quantity constant. [J Natl Cancer Inst 81:1241–1245, 1989]
Analysis of arousability of upper airway stimulation in obstructive sleep apnea
Authors: Johan Verbraecken, Joachim T Maurer, Lennart Knaack, Winfried Hohenhorst, Olivier Vanderveken, Paul Van de Heyning, Wilfried De Backer
Journal: European Respiratory Journal (2012)

Background: Previous studies showed that electrical stimulation of the hypoglossal nerve (N XII) can improve obstructive sleep apnea (OSA). In this study we looked to the effect on the different arousals indices in both responders and non-responders. Methods: Upper Airway Stimulation (Inspire Medical Systems, Inc) systems were implanted in moderate-to-severe OSA patients who failed, or were intolerant of CPAP. The system is intended to reduce sleep apnea by stimulating the N XII to advance the tongue-base. AHI (events/hr), Micro Arousal Index (MAI, events/hr), total number of arousals and respiratory arousals were collected using lab-based PSG in 7 patients including comparison of responders (n=4) vs. non-responders (n=3) at baseline (pre-implant) and 6-M post-implant.  All arousal indices decreased statistically significantly in responders and there was no stimulation disturbance seen in the non-responder group.  Conclusion: Upper Airway Stimulation to treat OSA has a clear therapy efficacy at 6-M post-implant in a selected group of moderate-to-severe OSA subjects and that there is no arousal effect of the stimulation itself. It confirms the non-arousal effect of N XII stimulation as shown in our earlier pilot study (Arch Otolaryngol Head Neck Surg 2001;127:1216-23).
Angiotensin II Induces Vascular Cell Adhesion Molecule-1 Expression In Rat Vasculature
Authors: Pradyumna E. Tummala, Xi-Lin Chen, Cynthia L. Sundell, Jørn Bech Laursen, C. Patricia Hammes, R. Wayne Alexander, David G. Harrison, Russell M. Medford
Journal: Circulation (1999)

Background —Cardiovascular ischemic events may occur more frequently in hypertensive patients with activated renin-angiotensin systems. We tested the hypothesis that angiotensin II (Ang II) may contribute to atherosclerosis by increasing expression of vascular inflammatory genes such as vascular cell adhesion molecule-1 (VCAM-1). Methods and Results —Rats infused with norepinephrine or Ang II for 6 days developed similar hypertensive responses, but only Ang II-treated rats exhibited significant increases in aortic VCAM-1 protein and mRNA expression. Oral losartan treatment (50 mg · kg −1 · d −1 ) inhibited Ang II-induced hypertension and aortic VCAM-1 mRNA expression. Ang II treatment significantly increased VCAM-1 mRNA expression in cultured rat aortic smooth muscle cells (RASMCs). Ang II also induced nuclear NF-κB-like binding activity and transactivated an NF-κB–driven VCAM-1 promoter. Losartan and proteasome inhibitors blocked Ang II-induced NF-κB activation and VCAM-1 mRNA accumulation. IκB-α overexpression in RASMCs inhibited Ang II-induced VCAM-1 promoter transactivation. Conclusions —Ang II may contribute to atherogenesis by activation of VCAM-1 through proteasome dependent, NF-κB-like transcriptional mechanisms.
Assessment of the efficacy and safety of three dose levels of cetirizine given once daily in children with perennial allergic rhinitis
Authors: S. Jobst, W. van den Wijngaart, A. Schubert, H. van de Venne
Journal: Allergy (1994)

The present study compared the efficacy and safety of three dose levels of cetirizine (2.5. 5, and 10 mg) once a day with placebo over 14 days in 6–12‐year‐old children with perennial allergic rhinitis. The design was a double‐blind, randomized, multicenter, parallel‐group study. Five symptoms (sneezing, nasal discharge, nasal obstruction, nasal pruritus, and ocular pruritus) were rated according to severity by investigators at the visits and daily by patients. Eighty‐three patients were randomized to placebo, 84 to 2.5 mg cetirizine, 85 to 5 mg cetirizine, and 76 to 10 mg cetirizine. Groups were comparable at inclusion. The primary efficacy variable was the percentage of days with no or only mild symptoms: at all doses, cetirizine appeared to be more effective than placebo, but a significant difference was reached only in the 10‐mg group (difference in medians of 22%; P = 0.016). The test of linearity was significant ( P = 0.026) for the percentage of asymptomatic days. The investigators’ assessments at each visit scored the symptoms in the placebo group higher, i.e., more severe, than in the active groups, the 10‐mg dose causing the greatest reduction in symptoms. Adverse events were infrequent and generally mild or moderate in severity. It was concluded that cetirizine at a 10‐mg, once daily dose could be used to treat effectively 6–12‐year‐old children with perennial allergic rhinitis.
Selective transmission of variant genomes from mother to infant in neonatal fulminant hepatitis B
Authors: Fritz Von Weizsäcker, Irmgard Pult, Katja Geiss, Stefan Wirth, Hubert E. Blum
Journal: Hepatology (1995)

Hepatitis B virus (HBV) nucleotide sequences isolated from mother/child pairs were analyzed in three cases of neonatal fulminant hepatitis B (FHB). Heterogeneous HBV sequences consistent with both adw2 and ayw subtype were found in all three mothers. In one case, in which the child survived, both subtypes were transmitted. By contrast, only the ayw subtype was present in the two other children with a fatal course of FHB. In one fatal case, studied in greater detail, multiple HBV variants (viral quasi-species) were identified in both mother and child. A direct sequence comparison showed that only a subfraction of the virus pool from the mother was transmitted and that multiple new mutations emerged in the child. These data suggest that a minor HBV subpopulation from the mother may prevail as the dominant species in the child and that neonatal FHB is associated with the selection of mutant strains.
Analysis of mutations from SCID and Omenn syndrome patients reveals the central role of the Rag2 PHD domain in regulating V(D)J recombination
Authors: Chrystelle Couëdel, Christopher Roman, Alison Jones, Paolo Vezzoni, Anna Villa, Patricia Cortes
Journal: Journal of Clinical Investigation (2010)

Rag2 plays an essential role in the generation of antigen receptors. Mutations that impair Rag2 function can lead to severe combined immunodeficiency (SCID), a condition characterized by complete absence of T and B cells, or Omenn syndrome (OS), a form of SCID characterized by the virtual absence of B cells and the presence of oligoclonal autoreactive T cells. Here, we present a comparative study of a panel of mutations that were identified in the noncanonical plant homeodomain (PHD) of Rag2 in patients with SCID or OS. We show that PHD mutant mouse Rag2 proteins that correspond to those found in these patients greatly impaired endogenous recombination of Ig gene segments in a Rag2-deficient pro-B cell line and that this correlated with decreased protein stability, impaired nuclear localization, and/or loss of the interaction between Rag2 and core histones. Our results demonstrate that point mutations in the PHD of Rag2 compromise the functionality of the entire protein, thus explaining why the phenotype of cells expressing PHD point mutants differs from those expressing core Rag2 protein that lacks the entire C-terminal region and is therefore devoid of the regulation imposed by the PHD. Together, our findings reveal the various deleterious effects of PHD Rag2 mutations and demonstrate the crucial role of this domain in regulating antigen receptor gene assembly. We believe these results reveal new mechanisms of immunodeficiency in SCID and OS.