tbuckley/cabot-search huggingface dataset:
Differential Role of Interleukin-6 in Lung Inflammation Induced by Lipoteichoic Acid and Peptidoglycan from<i>Staphylococcus aureus</i>
Authors: Jaklien C. Leemans, Margriet J. B. M. Vervoordeldonk, Sandrine Florquin, Kok P. van Kessel, Tom van der Poll
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Lipoteichoic acids (LTA) and peptidoglycans (PepG) are major components of the cell walls of gram-positive bacteria that trigger inflammatory responses in vitro. To study the in vivo effects of LTA and PepG from Staphylococcus aureus in lungs and to determine the role of interleukin (IL)-6 herein, these compounds were intranasally administered to IL-6 gene deficient (IL-6−/−) and wild type (IL-6+/+) mice. In IL-6+/+ mice, LTA and PepG induced acute pulmonary inflammation in a dose-dependent way, characterized by neutrophilic influx and IL-6 production in the bronchoalveolar lavage fluid. Endogenously produced IL-6 attenuated inflammation induced by 10 μg LTA, as reflected by enhanced neutrophil influx, and increased tumor necrosis factor-α, macrophage inflammatory protein-1-α, and cytokine-induced neutrophil chemoattractant (KC) release into bronchoalveolar lavage fluid of IL-6−/− mice, compared with IL-6+/+ mice. By contrast, pulmonary inflammation induced by 100 μg LTA was similar (neutrophil influx) or even tended to be attenuated (cytokine and chemokine release) in IL-6−/− mice. Endogenous IL-6 increased inflammation induced by PepG, as reflected by decreased neutrophil influx into lungs of IL-6−/− mice, compared with IL-6+/+ mice. These data suggest that IL-6 plays an anti-inflammatory role during LTA-induced pulmonary inflammation, which is dependent on the severity of the inflammatory challenge, and a proinflammatory role in peptidoglycan-induced acute lung inflammation. Thus, the contribution of IL-6 to lung inflammation may vary with the stimulus used.
Effects of ageing and smoking on SP-A and SP-D levels in bronchoalveolar lavage fluid
Authors: T. Betsuyaku, Y. Kuroki, K. Nagai, Y. Nasuhara, M. Nishimura
Journal: European Respiratory Journal (2004)

Surfactant protein (SP)-A and SP-D are collagen-like glycoproteins that are synthesised in the distal pulmonary epithelium. This study examined the effects of ageing and long-term smoking on SP-A and SP-D in the lungs. The possible links to the development of pulmonary emphysema were also investigated. Sequential lavage was performed in young and middle-aged or elderly nonsmokers and asymptomatic current smokers with various smoking histories. Middle-aged or elderly smokers were further categorised according to the presence of emphysema by high-resolution computed tomography. Levels of SP-A and SP-D in bronchial lavage (BL) fluid and in bronchoalveolar lavage (BAL) fluid were quantified by ELISA. Significant decreases in SP-A were seen with age in nonsmokers in BL fluid, but not in BAL fluid. Middle-aged or elderly smokers with emphysema had lower levels of SP-A in both BL and BAL fluids when compared with young subjects, and in BL fluid when compared with middle-aged or elderly smokers without emphysema. SP-D did not change with age alone, however, it was decreased in middle-aged or elderly smokers when compared with similarly aged nonsmokers. In conclusion, surfactant protein-A may decrease with age alone or due to the cumulative effects of long-term smoking and development of emphysema, while surfactant protein-D decreases due to long-term smoking.
Exaggerated coronary vasoreactivity to endothelin-1 in aged rats: Role of protein kinase C
Authors: D KORZICK, J MULLERDELP, P DOUGHERTY, C HEAPS, D BOWLES, K KRICK
Journal: Cardiovascular Research (2005)

The interaction between advanced age and increased susceptibility to ischemic insult is well documented. Age-related increases in coronary vascular resistance, in part due to impaired dilator responses, have been reported. Our aim was to determine the role of endothelin-1 (ET-1) on enhanced constrictor responses in aged coronary arteries (CAs) and whether protein kinase C (PKC) signaling mechanisms impact ET-1 responses.Vasoreactivity was assessed in CAs isolated from aged (24 months; n=16) and adult (4 months; n=21) male F344 rats following ET-1 (10(-10)-10(-8)) with and without specific ETA/ETB receptor antagonists (BQ-123, 1 microM; BQ-788, 30 nM) or the PKC inhibitor bisindolylmaleimide (Bis; 10(-6) M). Constrictor responses to KCl (80 mM) were also measured and voltage-gated Ca2+ channel (VGCC) determined in isolated coronary smooth muscle cells. Dilator responses to acetylcholine (ACH) and sodium nitroprusside (SNP) were assessed.Passive diameter was greater (357+/-19 vs. 309+/-9; p<0.02) while spontaneous tone was similar in 24 months vs. 4 months. ET-1 resulted in greater constriction in 24 months vs. 4 months (79% vs. 67%; p<0.01). Group differences persisted following selective ETB inhibition with BQ-788 (p<0.02), while BQ-123 abolished contractile responses to ET-1. Importantly, inhibition of ET-1 constriction by Bis occurred in 24 months but not 4 months (p<0.01). Constrictor responses to KCl and peak VGCC current density were similar in 24 months vs. 4 months (48% vs. 50%). No age-related differences were observed in ACH- or SNP-mediated dilation. Western blotting revealed increases in Ca2+-sensitive PKCalpha, -betaI, and -betaII levels with age, while eNOS and ETA receptor protein levels were unchanged.Aberrant ETA constrictor responses and directional changes in PKC are likely to contribute to coronary vascular pathology with advanced age.
Health and climate change
Authors: M.J. Bouma, H.E. Sondorp, H.J. van der Kaay, RonaldE. LaPorte, Francois Sauer, Eric Marler, Carlos Gamboa, Shunichi Akazawa, Tony Gooch, M. Blumthaler, W. Ambach, Claus Kroegel, Andreas Zedtwitz, Peter Deibert, Dieter Häussinger, Wofgang Gerok, John Last
Journal: The Lancet (1994)
Domain Mapping Studies Reveal That the M Domain of hsp90 Serves as a Molecular Scaffold to Regulate Akt-Dependent Phosphorylation of Endothelial Nitric Oxide Synthase and NO Release
Authors: Jason Fontana, David Fulton, Yan Chen, Todd A. Fairchild, Timothy J. McCabe, Naoya Fujita, Takashi Tsuruo, William C. Sessa
Journal: Circulation Research (2002)

Protein-protein interactions with the molecular chaperone hsp90 and phosphorylation on serine 1179 by the protein kinase Akt leads to activation of endothelial nitric oxide synthase. However, the interplay between these protein-protein interactions remains to be established. In the present study, we show that vascular endothelial growth factor stimulates the coordinated association of hsp90, Akt, and resultant phosphorylation of eNOS. Characterization of the domains of hsp90 required to bind eNOS, using yeast 2-hybrid, cell-based coprecipitation experiments, and GST-fusion proteins, revealed that the M region of hsp90 interacts with the amino terminus of eNOS and Akt. The addition of purified hsp90 to in vitro kinase assays facilitates Akt-driven phosphorylation of recombinant eNOS protein, but not a short peptide encoding the Akt phosphorylation site, suggesting that hsp90 may function as a scaffold for eNOS and Akt. In vivo, coexpression of adenoviral or the cDNA for hsp90 with eNOS promotes nitric oxide release; an effect eliminated using a catalytically functional phosphorylation mutant of eNOS. These results demonstrate that stimulation of endothelial cells with vascular endothelial growth factor recruits eNOS and Akt to an adjacent region on the same domain of hsp90, thereby facilitating eNOS phosphorylation and enzyme activation.
Adolescent flexibility, endurance strength, and physical activity as predictors of adult tension neck, low back pain, and knee injury: a 25 year follow up study
Authors: L O Mikkelsson, H Nupponen, J Kaprio, H Kautiainen, M Mikkelsson, U M Kujala
Journal: British Journal of Sports Medicine (2006)

Objective: To examine whether adolescent flexibility, endurance strength, and physical activity can predict the later occurrence of recurrent low back pain, tension neck, or knee injury. Methods: In 1976, 520 men and 605 women participated in a sit and reach test (flexibility) and a 30 second sit up test (endurance strength). In 1976 and 2001 (aged 37 and 42 years) they completed a questionnaire. Lifetime occurrence and risk of self reported low back pain and self reported, physician diagnosed tension neck and knee injury were calculated for subjects divided into tertiles by baseline results of strength and flexibility tests. Results: Men from the highest baseline flexibility tertile were at lower risk of tension neck than those from the lowest tertile (odds ratio (OR) 0.51, 95% confidence interval (CI) 0.28 to 0.93). Women from the highest baseline endurance strength tertile were at lower risk of tension neck than those from the lowest tertile (OR 0.60, 95% CI 0.40 to 0.91). Men from the highest baseline endurance strength tertile were at higher risk of knee injury than those from the lowest tertile (OR 1.96, 95% CI 1.05 to 3.64). Men who at school age participated in physical activity were at lower risk of recurrent low back pain (OR 0.61; 95% CI 0.42 to 0.88) than those who did not. Conclusions: Overall good flexibility in boys and good endurance strength in girls may contribute to a decreased risk of tension neck. High endurance strength in boys may indicate an increased risk of knee injury.
Phase I/II Trial of Temsirolimus Combined With Interferon Alfa for Advanced Renal Cell Carcinoma
Authors: Robert J. Motzer, Gary R. Hudes, Brendan D. Curti, David F. McDermott, Bernard J. Escudier, Sylvie Negrier, Brigitte Duclos, Laurence Moore, Timothy O'Toole, Joseph P. Boni, Janice P. Dutcher
Journal: Journal of Clinical Oncology (2007)

Purpose Temsirolimus, an inhibitor of the mammalian target of rapamycin, has single-agent activity against advanced renal cell carcinoma (RCC). A recommended dose and safety profile for the combination of temsirolimus and interferon alfa (IFN) were determined in patients with advanced RCC. Patients and Methods Patients were enrolled onto a multicenter, ascending-dose study of temsirolimus (5, 10, 15, 20, or 25 mg) administered intravenously once a week combined with IFN (6 or 9 million units [MU]) administered subcutaneously three times per week. An expanded cohort was treated at the recommended dose to obtain additional safety and efficacy information. Results Seventy-one patients were entered to receive one of six dose levels. The recommended dose was temsirolimus 15 mg/IFN 6 MU based on dose-limiting toxicities of stomatitis, fatigue, and nausea/vomiting, which were observed at higher doses of temsirolimus and IFN. The most frequent grade 3 or 4 toxicities occurring in any cycle included leukopenia, hypophosphatemia, asthenia, anemia, and hypertriglyceridemia for all patients and those who received the recommended dose. Among patients who received the recommended dose (n = 39), 8% achieved partial response and 36% had stable disease for at least 24 weeks. Median progression-free survival for all patients in the study was 9.1 months. Conclusion The combination of temsirolimus and IFN has an acceptable safety profile and displays antitumor activity in patients with advanced RCC. Temsirolimus 15 mg plus IFN 6 MU is the recommended dose for evaluation in a randomized phase III study.
Conflicts of interest and pandemic flu
Authors: F. Godlee
Journal: BMJ (2010)

Allogeneic hematopoietic cell transplantation (HCT) is the most potent curative therapy for cancers of the bone marrow; however, graft-versus-host disease (GVHD) continues to be the major limitation to successful HCT, with mortality rates around 50%. Current strategies to suppress GVHD also compromise the beneficial graft-versus-tumor (GVT) activity. We have shown that elevated IL-33-sequestering soluble ST2 in the plasma is a risk factor for severe GVHD. In addition, the IL-9-secreting Th9 and Tc9 cell subsets have higher antitumor activity than Th1 and Tc1. We hypothesized that induction of the ST2/IL-33 pathway will both alleviate GVHD and increase GVT activity. Differentiation of Th9 with IL-33 increased expression of membrane ST2 (ST2L) and PU.1, a transcription factor that promotes IL-9 production. Adoptive transfer of IL-33-treated Th9 cells with bone marrow cells in HCT murine models showed less severe GVHD compared to Th9 without IL-33, or Th2 cells that are protective of GVHD. Polarization of total T cells with IL-33 to IL-9 secreting cells showed that IL-9 was also increased in Tc9 cells via Th9 help. Transcriptome analysis of IL-33-T9 cells showed increased expression of genes with anti-tumor activity. Higher GVT activity with IL-33-T9 cells was demonstrated in models of GFP+MLL-AF9 acute myeloid leukemia. Human IL-33-T9 cells also showed a strong anti-leukemia cytolytic activity. Thus, IL-33-T9 cells represent a promising curative cellular therapy following HCT.
The treatment of retained stones in the common bile duct with sodium cholate infusion
Authors: C. Lansford, S. Mehta, F. Kern
Journal: Gut (1974)

In order to investigate the relationship between oesophageal motor abnormalities and oesophagitis, we carried out four hour studies of oesophageal motility and 24 hour pH measurements in fasting and fed conditions in eight patients before, during (pH only), and after medical healing of erosive oesophagitis. Gastrooesophageal acid reflux decreased (ns) during the treatment, but tended to return to basal values at the end. Oesophageal body motility was unchanged after healing, while the lower oesophageal sphincter basal tone was significantly increased at the end of the study in the postcibal period. The results suggest that the impairment of the sphincter tone in reflux oesophagitis is secondary to the presence of the oesophageal lesions. Macroscopic healing is not paralleled by improved major pathogenic factors of the disease, however--that is, acid reflux and oesophageal body motility.
Microalbuminuria and Risk of Venous Thromboembolism
Authors: Bakhtawar K. Mahmoodi
Journal: JAMA (2009)

Context Microalbuminuria (albuminuria 30-300 mg per 24-hour urine collection) is a well-known risk marker for arterial thromboembolism.It is assumed that microalbuminuria reflects generalized endothelial dysfunction.Hence, microalbuminuria may also predispose for venous thromboembolism (VTE).Objective To assess whether microalbuminuria is associated with VTE.Design, Setting, and Participants Prevention of Renal and Vascular End-stage Disease (PREVEND) study, an ongoing community-based prospective cohort study initiated in 1997.All inhabitants of Groningen, the Netherlands, aged 28 through 75 years (n=85 421) were sent a postal questionnaire and a vial to collect a first morning urine sample for measurement of urinary albumin concentration.Of those who responded (40 856), a cohort (8592 participants) including more participants with higher levels of urinary albumin concentration completed screening at an outpatient clinic.Screening data were collected on urinary albumin excretion (UAE) and risk factors for cardiovascular and renal disease.Main Outcome Measure Symptomatic and objectively verified VTE (ie, deep vein thrombosis, pulmonary embolism, or both) between study initiation and June 1, 2007. ResultsOf 8574 evaluable participants (mean [SD] age, 49 [13] years; 50% men), 129 experienced VTE during a mean (SD) follow-up period of 8.6 (1.8) years, corresponding to overall annual incidence of 0.14% (95% confidence interval [CI], 0.11%-0.19%).Annual incidences were 0.12%, 0.20%, 0.40%, and 0.56% in participants with UAE of less than 15 (n=6013), 15-29 (n=1283), 30-300 (n=1144), and greater than 300 (n=134) mg per 24-hour urine collection, respectively (P for trend Ͻ.001).When adjusted for age, cancer, use of oral contraceptives, and atherosclerosis risk factors, hazard ratios associated with UAE levels of 15-29, 30-300, and greater than 300 mg/24 h were 1.40 (95% CI, 0.86-2.35),2.20 (95% CI, 1.44-3.36),and 2.82 (95% CI, 1.21-6.61),respectively, compared with participants with UAE of less than 15 mg/24 h (global P=.001).Adjusted hazard ratio for microalbuminuria vs normoalbuminuria (UAE Ͻ30 mg/24 h) was 2.00 (95% CI, 1.34-2.98;PϽ.001).Microalbuminuria-related number needed to harm was 388 per year. ConclusionMicroalbuminuria is independently associated with an increased risk for VTE.
Knee and hip articular cartilage have distinct epigenomic landscapes: implications for future cartilage regeneration approaches
Authors: W den Hollander, Y F M Ramos, S D Bos, N Bomer, R van der Breggen, N Lakenberg, W J de Dijcker, Bouke J Duijnisveld, P E Slagboom, Rob G H H Nelissen, I Meulenbelt
Journal: Annals of the Rheumatic Diseases (2014)

Objectives To elucidate the functional epigenomic landscape of articular cartilage in osteoarthritis (OA) affected knee and hip joints in relation to gene expression. Methods Using Illumina Infinium HumanMethylation450 BeadChip arrays, genome-wide DNA methylation was measured in 31 preserved and lesioned cartilage sample pairs (14 knees and 17 hips) from patients who underwent a total joint replacement due to primary OA. Using previously published genome-wide expression data of 33 pairs of cartilage samples, of which 13 pairs were overlapping with the current methylation dataset, we assessed gene expression differences in differentially methylated regions (DMRs). Results Principal component analysis of the methylation data revealed distinct clustering of knee and hip samples, irrespective of OA pathophysiology. A total of 6272 CpG dinucleotides were differentially methylated between the two joints, comprising a total of 357 DMRs containing 1817 CpGs and 245 unique genes. Enrichment analysis of genes proximal of the DMRs revealed significant enrichment for developmental pathways and homeobox (HOX) genes. Subsequent transcriptomic analysis of DMR genes exposed distinct knee and hip expression patterns. Conclusions Our findings reveal consistent DMRs between knee and hip articular cartilage that marked transcriptomic differences among HOX genes, which were not reflecting the temporal sequential HOX expression pattern during development. This implies distinct mechanisms for maintaining cartilage integrity in adulthood, thereby contributing to our understanding of cartilage homeostasis and future tissue regeneration approaches.
Tortuous Varicosities in Chronic Schistosomiasis
Authors: André Rodrigues Durães, Lilian Souza Araujo
Journal: New England Journal of Medicine (2009)

A 34-year-old Brazilian man presented with a 24-year history of prominent, progressively dilating superficial veins. Gynecomastia, splenomegaly, and bilateral varicoceles also developed. There was no evidence of liver failure. Ultrasonography of the abdomen showed periportal fibrosis, splenomegaly, and high portal flow.
Postconditioning: if you snooze, you lose: AUTHOR'S RETROSPECTIVE
Authors: J. Vinten-Johansen
Journal: Cardiovascular Research (2012)

This editorial refers to an article by H. Kin et al .[19][1] published in Cardiovascular Research in 2004 (see [Box 1][2]). It is accompanied by an editorial by M. Ovize, pp. 181–182, this issue, as part of this Spotlight on Landmark Papers in Cardiovascular Research . 

Early work from Dr Braunwald's group demonstrated that the infarct size was not a predetermined entity, but could be modified by interventions applied during ischaemia.1 This gave birth to the field of cardioprotection for non-surgical infarction, which has seen active investigation for cardioprotective therapies for over four decades. The finding by Reimer et al .2 that the infarct size was related to ischaemic time led to the corollary that the infarct size could be limited by initiating reperfusion as early as possible. This conclusion ushered in thrombolysis and percutaneous coronary intervention (angioplasty and stenting), which are currently the standard of care treatments for acute myocardial infarction. There was now a scientific rationale to develop therapies to reduce the infarct size that were aimed at attenuating the recognized contributors to ischaemic injury. Later, preconditioning was introduced3 and has become the ‘gold standard’ treatment by which other therapies are judged. Studies became focused on pharmacologically inducing a preconditioning-like adaptive state. Many of these approaches succeeded in experimental laboratories, only to fail in clinical trials. The recognition that reperfusion injury may also contribute to the ultimate infarct size suggested that the lack of clinical success in these clinical trials may also be due to failure to attenuate reperfusion injury. At that time the concept of reperfusion injury was highly controversial,4 and it remained to be demonstrated convincingly that reperfusion injury was not merely a laboratory oddity but a clinical entity.

The failure of clinical trials to show efficacy of experimentally successful drugs (remember oxygen …

 [1]: #ref-19
 [2]: #F1
Retroperitoneal gas after colonoscopy
Authors: I R Daniels, T Sullivan, J Hale
Journal: Journal of the Royal Society of Medicine (1999)

A woman aged 50 had severe chronic constipation, and physiological and radiological studies at a tertiary referral centre revealed slow transit and enlarged colon. A course of biofeedback (to relax the external anal sphincter) gave marginal improvement. Thereafter she underwent left hemicolectomy, which gave only short-lived benefit despite her continuation of a high-fibre diet and regular laxatives. Several years later symptoms were still severe and a loop ileostomy was performed. The patient felt much improved and declined reversal of the ileostomy. The latest referral was for investigation of rectal discomfort and tenesmus. As she had a family history of carcinoma of the colon, colonoscopy was recommended. The procedure was uneventful, the colonoscope being passed to the caecum, and three biopsies were taken. The appearances were of an extensive colitis, consistent with bypassing of the colon. The histology of the mucosal biopsies revealed mild colitis only. Afterwards the patient was allowed home. Next day she was seen in the emergency department complaining of a swollen neck, difficulty in swallowing and pain from her upper chest to neck. On examination there was pronounced surgical emphysema in the neck; there was epigastric tenderness but signs of peritonitis were absent; temperature was 37.7°C. She was admitted and given intravenous fluids, antibiotics and analgesics. Figure 1 shows a plain X-ray of the abdomen. After forty-eight hours the surgical emphysema, neck pain and pyrexia had subsided and she went home well.
Active Surveillance of Small Renal Masses: Progression Patterns of Early Stage Kidney Cancer
Authors: Michael A.S. Jewett, Kamal Mattar, Joan Basiuk, Christopher G. Morash, Stephen E. Pautler, D. Robert Siemens, Simon Tanguay, Ricardo A. Rendon, Martin E. Gleave, Darrel E. Drachenberg, Raymond Chow, Hannah Chung, Joseph L. Chin, Neil E. Fleshner, Andrew J. Evans, Brenda L. Gallie, Masoom A. Haider, John R. Kachura, Ghada Kurban, Kimberly Fernandes, Antonio Finelli
Journal: European Urology (2011)