tbuckley/cabot-search huggingface dataset:
Sarcoidosis: clinical update
Authors: U. Costabel
Journal: European Respiratory Journal (2001)

Many advances have been made regarding sarcoidosis in the past 2 decades. As a result, sarcoidosis is now defined as a multisystem disorder with a heightened cellular immune response at sites of disease activity in patients with a predisposition for sarcoidosis and a presumed exposure to as yet unknown transmissible environmental agents. Recent International Consensus Statement recommendations regarding diagnosis and therapy have been published. The diagnosis of sarcoidosis is based on a compatible clinical and/or radiological picture, histological evidence of noncaseating granulomas and exclusion of other diseases capable of producing a similar histological or clinical picture. Therapy is based on corticosteroids, although there are indications of valuable alternatives. Except for life- and sight-threatening organ involvement, it should be carefully considered whether the patient might benefit from treatment. For asymptomatic pulmonary sarcoidosis, a watch and wait approach is appropriate; treatment should mainly be considered if symptoms develop or lung function deteriorates.
Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2 year results from the MOBILE study
Authors: J-Y Reginster, Silvano Adami, Peter Lakatos, Maria Greenwald, Jan J Stepan, Stuart L Silverman, Claus Christiansen, Lucy Rowell, Nicole Mairon, Bernard Bonvoisin, Marc K Drezner, Ronald Emkey, Dieter Felsenberg, Cyrus Cooper, Pierre D Delmas, Paul D Miller
Journal: Annals of the Rheumatic Diseases (2005)

Reducing bisphosphonate dosing frequency may improve suboptimal adherence to treatment and therefore therapeutic outcomes in postmenopausal osteoporosis. Once-monthly oral ibandronate has been developed to overcome this problem.To confirm the 1 year results and provide more extensive safety and tolerability information for once-monthly dosing by a 2 year analysis.MOBILE, a randomised, phase III, non-inferiority study, compared the efficacy and safety of once-monthly ibandronate with daily ibandronate, which has previously been shown to reduce vertebral fracture risk in comparison with placebo.1609 postmenopausal women were randomised. Substantial increases in lumbar spine bone mineral density (BMD) were seen in all treatment arms: 5.0%, 5.3%, 5.6%, and 6.6% in the daily and once-monthly groups (50 + 50 mg, 100 mg, and 150 mg), respectively. It was confirmed that all once-monthly regimens were at least as effective as daily treatment, and in addition, 150 mg was found to be better (p<0.001). Substantial increases in proximal femur (total hip, femoral neck, trochanter) BMD were seen; 150 mg produced the most pronounced effect (p<0.05 versus daily treatment). Independent of the regimen, most participants (70.5-93.5%) achieved increases above baseline in lumbar spine or total hip BMD, or both. Pronounced decreases in the biochemical marker of bone resorption, sCTX, observed in all arms after 3 months, were maintained throughout. The 150 mg regimen consistently produced greater increases in BMD and sCTX suppression than the 100 mg and daily regimens. Ibandronate was well tolerated, with a similar incidence of adverse events across groups.Once-monthly oral ibandronate is at least as effective and well tolerated as daily treatment. Once-monthly administration may be more convenient for patients and improve therapeutic adherence, thereby optimising outcomes.
Prognostic Factors Related to Clinical Response in Patients with Metastatic Melanoma Treated by CTL-Associated Antigen-4 Blockade
Authors: Stephanie G. Downey, Jacob A. Klapper, Franz O. Smith, James C. Yang, Richard M. Sherry, Richard E. Royal, Udai S. Kammula, Marybeth S. Hughes, Tamika E. Allen, Catherine L. Levy, Michael Yellin, Geoffrey Nichol, Donald E. White, Seth M. Steinberg, Steven A. Rosenberg
Journal: Clinical Cancer Research (2007)

CTL-associated antigen 4 (CTLA-4) can inhibit T-cell activation and helps maintain peripheral self-tolerance. Previously, we showed immune-related adverse events (IRAE) and objective, durable clinical responses in patients with metastatic melanoma treated with CTLA-4 blockade. We have now treated 139 patients in two trials and have sufficient follow-up to examine factors associated with clinical response.A total of 139 patients with metastatic melanoma were treated: 54 patients received ipilimumab in conjunction with peptide vaccinations and 85 patients were treated with intra-patient dose escalation of ipilimumab and randomized to receive peptides in accordance with HLA-A*0201 status.Three patients achieved complete responses (CR; ongoing at 29+, 52+, and 53+ months); an additional 20 patients achieved partial responses (PR) for an overall objective response rate of 17%. The majority of patients (62%, 86 of 139) developed some form of IRAE, which was associated with a greater probability of objective antitumor response (P = 0.0004); all patients with CR had more severe IRAEs. Prior therapy with IFNalpha-2b was a negative prognostic factor, whereas prior high-dose interleukin-2 did not significantly affect the probability of response. There were no significant differences in the rate of clinical response or development of IRAEs between the two trials. The duration of tumor response was not affected by the use of high-dose steroids for abrogation of treatment-related toxicities (P = 0.23). There were no treatment-related deaths.In patients with metastatic melanoma, ipilimumab can induce durable objective clinical responses, which are related to the induction of IRAEs.
Elevated lipogenesis and diminished cholesterol synthesis in patients with hepatitis C viral infection compared to healthy humans
Authors: Jennifer E. Lambert, Vincent G. Bain, Edmond A. Ryan, Alan B.R. Thomson, Michael T. Clandinin
Journal: Hepatology (2012)

Hepatitis C virus (HCV) exerts a profound influence on host lipid metabolism. It has been suggested that the synthesis of both fatty acids (FA) and cholesterol is dysregulated in HCV but this has not been directly quantified in humans. The purpose of this study was to measure lipogenesis and cholesterol synthesis using stable isotopes in patients with HCV (n = 5) and healthy control (n = 9) subjects recruited from the University of Alberta hospital. Blood samples were taken at fasting (0 and 24 hours) and after meals over the day to mimic typical food consumption and postprandial metabolism. Isolation of free cholesterol (FC), cholesteryl ester (CE), and triglyceride (TG) from plasma and very low-density lipoproteins (VLDL) was used to measure FA and cholesterol synthesis using deuterium uptake and isotope ratio mass spectrometry. FA composition was analyzed by gas chromatography. VLDL-TG levels of polyunsaturated fatty acids (PUFA), including linoleic and linolenic acid, were lower in HCV compared to control (P < 0.05 for both). Fasting hepatic lipogenesis was significantly higher in HCV (2.80 ± 0.55%) compared to control (1.19 ± 0.27%; P = 0.03). Conversely, fasting whole-body synthesis of FC (HCV 1.64 ± 0.28% versus control 8.78 ± 1.59%) and CE (HCV 0.26 ± 0.08% versus control 1.92 ± 0.25%), as well as hepatic FC synthesis (HCV 1.68 ± 0.26% versus control 8.12 ± 0.77%) was lower in HCV (P < 0.001 for all). Conclusion: These data provide evidence that lipogenesis is elevated while cholesterol synthesis is impaired in HCV, supporting previous findings from cellular and animal models. Low PUFA levels combined with elevated lipogenesis suggests a role for dietary PUFA supplementation in HCV patients. (HEPATOLOGY 2013)
CORRELATION OF THE LEVEL OF HEPATIC RIBOFLAVIN WITH THE APPEARANCE OF LIVER TUMORS IN RATS FED AMINOAZO DYES
Authors: E. C. Miller, J. A. Miller, B. E. Kline, H. P. Rusch
Journal: The Journal of Experimental Medicine (1948)

The livers of rats fed 10 diets previously found to inhibit or accelerate the induction of tumors by 4-dimethylaminoazobenzene were analyzed for riboflavin, biotin, and vitamin B(6) after 6 and 19 weeks on the diets. Those fed diets accelerating tumor induction had average hepatic riboflavin levels of 9 to 11 microg. per gm. The livers of the control and protected rats averaged 14 and 15 to 19 microg. per gm., respectively. The hepatic levels of vitamin B(6) and biotin averaged 7.0 and 0.54 microg. per gm., respectively, and were independent of the protective nature of the diet. The livers of rats fed the same diets in the absence of 4-dimethylaminoazobenzene contained about 50 per cent more of each of these vitamins than those from dye-fed rats. In a second series the tumor incidence and the hepatic riboflavin and vitamin B(6) were determined simultaneously. In this experiment urethane decreased the level of hepatic riboflavin and increased the rate of induction of tumors slightly. Methionine inhibited tumor induction to a small extent while cystine had a more pronounced retarding effect; the level of hepatic riboflavin for both groups was higher than in the controls. The livers of rats fed the basal diet, 0.054 per cent of 4-dimethylaminoazobenzene, or equimolar amounts of its 2-, 2'-, 3'-, or 4'-methyl derivatives were analyzed for riboflavin at various times over a 16 week period. In each case the level of hepatic riboflavin decreased throughout the experimental period, but the rate and extent of the riboflavin loss were greatest with the more carcinogenic compounds.
Bax is downregulated in inflamed colonic mucosa of ulcerative colitis
Authors: M Iimura
Journal: Gut (2000)

<h3>BACKGROUND AND AIMS</h3> One form of epithelial cell injury in inflamed colonic mucosa in ulcerative colitis (UC) is reported to involve apoptosis of these cells. Bcl-2 family proteins Bax and Bcl-2 are the major regulators of apoptosis. The aim of this study was to elucidate the involvement of the Bax/Bcl-2 system in induction of apoptosis of the inflamed colonic epithelium in UC. <h3>METHODS</h3> Colonic epithelium was isolated from colonic biopsy specimens. Expression of CD95, Bax, Bcl-xL, and Bcl-2 proteins was determined by western blotting. Bax gene expression was assessed by both reverse transcription-polymerase chain reaction (RT-PCR) followed by Southern hybridisation and a real time PCR assay. <h3>RESULTS</h3> Equal levels of expression of CD95, Bcl-xL, and Bcl-2 proteins were noted in normal and UC colonic epithelia. Equal levels of expression of Bax protein and mRNA were noted in epithelia of normal colon and inactive UC. Levels of expression of Bax protein and mRNA were markedly reduced in inflamed UC colonic epithelium. <h3>CONCLUSIONS</h3> Our study showed for the first time downregulation of Bax in inflamed colonic epithelium of UC. The Bax/Bcl-2 system did not seem to be involved in induction of apoptosis of epithelial cells in the inflamed colonic mucosa of UC.
Late-breaking abstract: Lethal impact of antenatal nicotine and inflammation in newborn mice
Authors: Thilini Samarasinghe, Marcel Nold, Ina Rudloff, Elizabeth. M Skuza, Nikeh Shariatian, Mandar. S Joshi, Philip. J Berger, Claudia. A Nold-Petry
Journal: European Respiratory Journal (2014)

INTRODUCTION: Combined perinatal infection and nicotine exposure is linked with elevated risk of fetal death, growth restriction and abnormal lung development. Alarmingly, 25% of pregnant Australian women continue to smoke and 30% have infection. To date we have no explanation for the danger posed by smoking and infection during pregnancy. We recently noted that nicotine and lipopolysaccharide (LPS) treatment caused high mortality in newborn pups. We hypothesized that the two insults affect survival by producing lung inflammation and impairing perinatal lung liquid reabsorption.  METHODS: At E14, C57BL/6 dams were implanted with osmotic mini-pumps to deliver nicotine (NIC, 6mg/kg/day) or water (VEH) for 14 days. At E16, implanted mice were injected with LPS (150µg/kg; ip) or left untreated. At E18, lungs underwent cytokine analysis, histology, abundance of pulmonary IL1-β. Expression of α-ENaC, a component of epithelial channels vital for lung liquid clearance, was detected by immunoblot. In separate pups we compared wet/dry lung ratios at birth in NIC+LPS vs VEH groups.  RESULTS: On day 1, mortality was zero in VEH pups, 50% in NIC (p=0.055) and 95% in NIC+LPS (p  CONCLUSION: We suggest the lethality of antenatal nicotine and inflammation results from impaired gas exchange across a wet and inflamed pulmonary epithelium.
Identification and validation of PROM1 and CRTC2 mutations in lung cancer patients
Authors: Yanqi He, Yalun Li, Zhixin Qiu, Bin Zhou, Shaoqin Shi, Kui Zhang, Yangkun Luo, Qian Huang, Weimin Li
Journal: Molecular Cancer (2014)

Genetic alterations could be responsible lung cancer, the leading cause of worldwide cancer death. This study investigated gene mutations in a Han Chinese family of lung cancer using the whole genome exome sequencing and subsequent Sanger sequencing validation and then confirmed alteration of prominin 1(PROM1) and cyclic AMP-response element binding protein-regulated transcription co-activator2 (CRTC2) in blood samples of 343 sporadic lung cancer patients vs. 280 healthy controls as well as in 200 pairs of lung cancer and the corresponding normal tissues using PCR-restriction fragment length polymorphism and directed DNA sequencing of PCR products. The data showed PROM1 (p. S281R) and CRTC2 (p. R379C) mutations, in 5 and 2 cases of these 343 sporadic lung cancer patients, respectively. Notably, these mutations were absent in the healthy controls. Furthermore, in the 200 lung cancer and the matched normal tissues, PROM1 mutation occurred in 3 patients (i.e., one squamous cell carcinoma and two adenocarcinomas) with a mutation frequency of 1.5%, while CRTC2 mutation occurred in 5 patients (two squamous cell carcinomas and three adenocarcinomas) with a mutation frequency of 2.5%. The data from the current study demonstrated novel PROM1 and CRTC2 mutations, which could promote lung cancer development.
Association Between Pancreatic Intraductal Papillary Mucinous Neoplasms and Extrapancreatic Malignancies
Authors: Giovanni Marchegiani, Giuseppe Malleo, Jan G. D’Haese, Patrick Wenzel, Muharrem Keskin, Luigi Pugliese, Alex Borin, Valentina Benning, Linda Nilsson, Nevin Oruc, Ralf Segersvard, Helmut Friess, Roland Schmid, Matthias Löhr, Patrick Maisonneuve, Claudio Bassi, Güralp O. Ceyhan, Roberto Salvia, Marco Del Chiaro
Journal: Clinical Gastroenterology and Hepatology (2014)
Increase in Creatinine and Cardiovascular Risk in Patients with Systolic Dysfunction after Myocardial Infarction
Authors: Powell Jose, Hicham Skali, Nagesh Anavekar, Charles Tomson, Harlan M. Krumholz, Jean L. Rouleau, Lemuel Moye, Marc A. Pfeffer, Scott D. Solomon
Journal: Journal of the American Society of Nephrology (2006)

Baseline renal function is a potent independent risk factor for adverse events after acute myocardial infarction (MI). Worsening renal function (WRF) has been shown to influence outcomes in the heart failure population, but its impact on cardiovascular risk in the post-MI period has not been well defined. For assessment of the prognostic importance of WRF, 2231 patients who had left ventricular dysfunction and were enrolled in the Survival and Ventricular Enlargement (SAVE) trial were studied. Patients were randomly assigned between 3 and 16 d (average 11 d) after acute MI to receive captopril or placebo; those with a serum creatinine of >2.5 mg/dl were excluded from SAVE. WRF was defined as an increase in creatinine of >0.3 mg/dl measured from baseline to 2 wk after randomization. The predictive value of WRF on cardiovascular morbidity and mortality was examined during 42 mo of follow-up. Paired serum creatinine measurements at baseline and 2 wk were available in 1854 patients. WRF occurred in 223 (12.0%) patients and was a stronger predictor of death (hazard ratio [HR] 1.46; 95% confidence interval [CI] 1.05 to 2.02) than baseline creatinine (HR 1.31; 95% CI 1.01 to 1.70). WRF also showed an increased risk for cardiovascular death (HR 1.62; 95% CI 1.14 to 2.30) and the composite end point (HR 1.32; 95% CI 1.03 to 1.70). When stratified by treatment, 104 (5.7%) and 116 (6.4%) patients with WRF in the placebo and captopril groups had no significant association between treatment group and WRF (P = 0.38). The risk for death associated with WRF was HR 1.63 (95% CI 1.05 to 2.52) in the placebo group compared with HR 1.33 (95% CI 0.81 to 2.21) in the captopril group (P = 0.49 for interaction). WRF as early as 2 wk after MI was not uncommon (12.0%) and was associated with increased mortality in patients without renal dysfunction at baseline. Patients who received captopril did not demonstrate more WRF than patients who received placebo. Monitoring serum creatinine in patients during the first few weeks after MI may help to identify those who are at highest risk and guide effective long-term therapeutic choices.
Diagnostic value of epithelioid cell granulomas in bronchoscopic biopsies
Authors: Edvardas Danila, Edvardas Zurauskas, Rolandas Zablockis, Vygantas Gruslys
Journal: European Respiratory Journal (2011)

Background:  The granulomatous inflammatory response is a manifestation of many lung diseases.   Objective:  To evaluate the diagnostic value of epithelioid cell granulomas in bronchoscopic biopsies in daily clinical practice.   Methods:  The data of 157 consecutive patients with epithelioid cell granulomas in biopsy tissue who had undergone the bronchoscopic lung biopsy or bronchial biopsy were examined. All cases were divided into non-necrotizing epithelioid cell granulomas and epithelioid cell granulomas with necrosis.   Results:  Of all the cases 108 had non-necrotizing epithelioid cell granulomas and 49 had epithelioid cell granulomas with necrosis. Without respect to the presence of necrosis in granulomas, the majority of the patients had sarcoidosis (50%) or tuberculosis (34%). 95% of the patients with sarcoidosis had non-necrotizing epithelioid cell granulomas and the remaining 5% had granulomas with necrosis. The sensitivity of non-necrotizing epithelioid cell granuloma for the diagnosis of sarcoidosis was 95% and specificity 57%. The positive and negative predictive values were 69% and 92%, respectively.  Of the patients with culture positive tuberculosis 72% had epithelioid cell granulomas with necrosis and 28% had non-necrotizing epithelioid cell granulomas. The sensitivity of epithelioid cell granuloma with necrosis for the diagnosis of tuberculosis was 72% and specificity 90%. The positive and negative predictive values were 80%, and 86%, respectively.   Conclusion:  A significant overlap in types of granulomatous inflammation between tuberculosis and sarcoidosis was found. The type of epithelioid cell granuloma alone was not sufficient for the final clinical diagnosis.
Assessing interactions between mdm-2, p53, and bcl-2 as prognostic variables in muscle-invasive bladder cancer treated with neo-adjuvant chemotherapy followed by locoregional surgical treatment
Authors: F.C. Maluf, C. Cordon-Cardo, D.A. Verbel, J.M. Satagopan, M.G. Boyle, H. Herr, D.F. Bajorin
Journal: Annals of Oncology (2006)
Egr-1 deficiency in bone marrow-derived cells reduces atherosclerotic lesion formation in a hyperlipidaemic mouse model
Authors: Claudia Albrecht, Michael R. Preusch, Götz Hofmann, Samuel Morris-Rosenfeld, Erwin Blessing, Michael E. Rosenfeld, Hugo A. Katus, Florian Bea
Journal: Cardiovascular Research (2010)

Early growth response gene-1 (Egr-1) regulates the expression of genes important to cardiovascular disease. Within atherosclerotic lesions, Egr-1 is expressed in smooth muscle cells, endothelial cells, and macrophages. Since macrophages play a pivotal role in atherosclerotic lesion initiation and progression, this study investigated the effects of Egr-1 deficiency within bone marrow-derived cells on the development of atherosclerosis in a hyperlipidaemic mouse model. Bone marrow from Egr-1-deficient mice and wild-type controls was transplanted into lethally irradiated LDL receptor null mice. After 26 weeks on a high fat diet, atherosclerotic lesion size within the aortic sinus of recipients was evaluated. Mice receiving Egr-1-deficient bone marrow had significantly decreased lesion size compared with controls. Lesions of these mice contained fewer macrophages and had reduced expression of vascular cell adhesion molecule-1 (VCAM-1), tissue factor, as well as transforming growth factor receptor type II, which are target genes of Egr-1. These results were validated by in vitro analysis of Egr-1-deficient peritoneal macrophages which, after lipopolysaccharide stimulation, had decreased VCAM-1 and tissue factor mRNA expression compared with wild-type controls. This study demonstrates that bone marrow-derived Egr-1 promotes macrophage accumulation, atherosclerotic lesion development, and lesion complexity.
Relationship between the Metabolic and Vasodilator Effects of Epinephrine in Human Forearm Muscle
Authors: HERMES A. KONTOS, DAVID W. RICHARDSON, JOHN L. PATTERSON
Journal: Circulation Research (1967)

The effect of intra-arterial and intravenous epinephrine on skeletal muscle blood flow and metabolism were studied in the human forearm following complete suppression of the circulation to forearm skin by epinephrine inotophoresis. Epinephrine by either route of administration increased blood flow, O 2 consumption and CO 2 production, and decreased arteriovenous differences of O 2 and CO 2 across the forearm. The increments in blood flow did not correlate with the increments in O 2 consumption or CO 2 production. In the intact forearm intravenous epinephrine increased deep forearm venous Po 2 but not venous PCo 2 . Hypocapnia, induced by voluntary hyperventilation, did not alter the response of forearm blood flow to intravenous epinephrine. These results show that the vasodilator response of skeletal muscle vessels to epinephrine is not dependent on decrease in Po 2 or increase in PCO 2 in the environment of the high resistance vessels. They also suggest that the calorigenic effect of the hormone is not a dominant factor in its vasodilator effect in skeletal muscle.
Tripling Survival From Sudden Cardiac Arrest Via Early Defibrillation Without Traditional Education in Cardiopulmonary Resuscitation
Authors: Alessandro Capucci, Daniela Aschieri, Massimo F. Piepoli, Gust H. Bardy, Efrosini Iconomu, Maurizio Arvedi
Journal: Circulation (2002)

Early defibrillation is the most important intervention affecting survival from sudden cardiac arrest (SCA). To improve public access to early defibrillation, we established Piacenza Progetto Vita (PPV), the first system of out-of-hospital early defibrillation by first-responder volunteers.The system serves a population of 173 114 residents in the Piacenza region of Italy. Equipment for the system comprises 39 semiautomatic external biphasic defibrillators (AEDs): 12 placed in high-risk locations, 12 in lay-staffed ambulances, and 15 in police cars; 1285 lay volunteers trained in use of the AED, without traditional education in cardiac pulmonary resuscitation, responded to all cases of suspected SCA, in coordination with the Emergency Medical System (EMS). During the first 22 months, 354 SCA occurred (72+/-12 years, 73% witnessed). The PPV volunteers treated 143 SCA cases (40.4%), with an EMS call-to-arrival time of 4.8+/-1.2 minutes (versus 6.2+/-2.3 minutes for EMS, P=0.05). Overall survival rate to hospital discharge was tripled from 3.3% (7 of 211) for EMS intervention to 10.5% (15 of 143) for PPV intervention (P=0.006). The survival rate for witnessed SCA was tripled by PPV: 15.5% versus 4.3% in the EMS-treated group (P=0.002). A "shockable" rhythm was present in 23.8% (34 of 143) of the PPV patients versus 15.6% (33 of 211) of the EMS patients (P=0.055). The survival rate from shockable dysrhythmias was higher for PPV versus EMS: 44.1% (15 of 34) versus 21.2% (7 of 33), P=0.046. The neurologically intact survival rate was higher in PPV-treated versus EMS-treated patients: 8.4% (12 of 143) versus 2.4% (5 of 211), P=0.009.Broad dissemination of AEDs for use by nonmedical volunteers enabled early defibrillation and tripled the survival rate for out-of-hospital SCA.