tbuckley/cabot-search huggingface dataset:
Microparticles-associated tissue factor activity is increased in bronchoalveolar lavage of patients with pulmonary fibrosis and correlates with functional impairment
Authors: Federica Novelli, Tommaso Neri, Concettina Noce, Laura Tavanti, Stella Cini, Federica Martino, Alessandro Celi, Pierluigi Paggiaro
Journal: European Respiratory Journal (2011)

Background:  The activation of the coagulation cascade plays a role in the pathogenesis of fibrotic lung diseases. Furthermore, anticoagulants are effective in experimental lung fibrosis and possibly in patients with idiopathic pulmonary fibrosis.  Microparticles (MP) are cell derived procoagulant and proinflammatory vesicles that can express tissue factor (TF); MP represent a storage pool of bioactive effectors and are emerging as a new family of physiologically relevant mediators.   Aim:  To evaluate the presence of TF-bearing MP in the bronchoalveolar lavage fluid (BALF) of patients with pulmonary fibrosis (PF) in comparison with control patients, and to correlate their concentration with the degree of functional impairment.   Methods:  Seven patients with PF and 10 control patients with suspected lung cancer or infectious diseases underwent bronchoscopy. The presence of MP was evaluated through a prothrombinase assay that measures phosphatidylserine (PS) concentration; TF activity was assessed by a one-stage clotting assay.   Results:  The BALF of patients with PF had a higher concentration of microparticles (87.23 [67.21-108.8] vs 49.19 [29.50-77.22] nM PS, p=.05) and a greater TF activity (27144 [17253-29998] vs 8596 [4019-21962] arbitrary U, p=.05) (data expressed as median [interquartile range]). We found a significant negative correlation between MP-associated TF activity and forced vital capacity% predicted (r 2 =.95, p 2 =.56, p=.05).   Conclusions:  Our preliminary data are consistent with an involvement of TF-bearing procoagulant MP in the pathogenesis of PF and in disease progression.
Mortality in Pharmacologically Treated Older Adults with Diabetes: The Cardiovascular Health Study, 1989–2001
Authors: Richard A Kronmal, Joshua I Barzilay, Nicholas L Smith, Bruce M Psaty, Lewis H Kuller, Gregory L Burke, Curt Furberg
Journal: PLoS Medicine (2006)

Background Diabetes mellitus (DM) confers an increased risk of mortality in young and middle-aged individuals and in women. It is uncertain, however, whether excess DM mortality continues beyond age 75 years, is related to type of hypoglycemic therapy, and whether women continue to be disproportionately affected by DM into older age. Methods and Findings From the Cardiovascular Health Study, a prospective study of 5,888 adults, we examined 5,372 participants aged 65 y or above without DM (91.2%), 322 with DM treated with oral hypoglycemic agents (OHGAs) (5.5%), and 194 with DM treated with insulin (3.3%). Participants were followed (1989–2001) for total, cardiovascular disease (CVD), coronary heart disease (CHD), and non-CVD/noncancer mortality. Compared with non-DM participants, those treated with OHGAs or insulin had adjusted hazard ratios (HRs) for total mortality of 1.33 (95% confidence interval [CI], 1.10 to 1.62) and 2.04 (95% CI, 1.62 to 2.57); CVD mortality, 1.99 (95% CI, 1.54 to 2.57) and 2.16 (95% CI, 1.54 to 3.03); CHD mortality, 2.47 (95% CI, 1.89 to 3.24) and 2.75 (95% CI, 1.95 to 3.87); and infectious and renal mortality, 1.35 (95% CI, 0.70 to 2.59) and 6.55 (95% CI, 4.18 to 10.26), respectively. The interaction of age (65–74 y versus ≥75 y) with DM was not significant. Women treated with OHGAs had a similar HR for total mortality to men, but a higher HR when treated with insulin. Conclusions DM mortality risk remains high among older adults in the current era of medical care. Mortality risk and type of mortality differ between OHGA and insulin treatment. Women treated with insulin therapy have an especially high mortality risk. Given the high absolute CVD mortality in older people, those with DM warrant aggressive CVD risk factor reduction.
The Phytochrome Gene Family in Tomato and the Rapid Differential Evolution of this Family in Angiosperms
Authors: R Alba, P M Kelmenson, M M Cordonnier-Pratt, L H Pratt
Journal: Molecular Biology and Evolution (2000)

A reexamination of the genome of the tomato (renamed Solanum lycopersicum L.) indicates that it contains five, or at most perhaps six, phytochrome genes (PHY), each encoding a different apoprotein (PHY). Five previously identified tomato PHY genes have been designated PHYA, PHYB1, PHYB2, PHYE, and PHYF. A molecular phylogenetic analysis is consistent with the hypothesis that the angiosperm PHY family is composed of four subfamilies (A, B, C/F, and E). Southern analyses indicate that the tomato genome does not contain both a PHYC and a PHYF. Molecular phylogenetic analyses presented here, which utilize for the first time full-length PHY sequences from two completely characterized angiosperm gene families, indicate that tomato PHYF is probably an ortholog of Arabidopsis PHYC. They also confirm that the angiosperm PHY family is undergoing relatively rapid differential evolution. Assuming PHYF is an ortholog of PHYC, PHY genes in eudicots are evolving (Ka/site) at 1.52–2.79 times the rate calculated as average for other plant nuclear genes. Again assuming PHYF is an ortholog of PHYC, the rate of evolution of the C and E subfamilies is at least 1.33 times the rate of the A and B subfamilies. PHYA and PHYB in eudicots are evolving at least 1.45 times as fast as their counterparts in the Poaceae. PHY functional domains also exhibit different evolutionary rates. The C-terminal region of angiosperm PHY (codons 800–1105) is evolving at least 2.11 times as fast as the photosensory domain (codons 200–500). The central region of a domain essential for phytochrome signal transduction (codons 652–712) is also evolving rapidly. Nonsynonymous substitutions occur in this region at 2.03–3.75 times the average rate for plant nuclear genes. It is not known if this rapid evolution results from selective pressure or from the absence of evolutionary constraint.
Studies on autoantibodies to poly (adenosine diphosphate-ribose) in SLE and other autoimmune diseases.
Authors: W J Morrow, D A Isenberg, H F Parry, L Shen, E E Okolie, F Farzaneh, S Shall, M L Snaith
Journal: Annals of the Rheumatic Diseases (1982)

Sera from 41 patients with systemic lupus erythematosus (SLE), 87 controls with various diseases, and 30 normal subjects were examined for poly (adenosine diphosphate-ribose) and ds DNA binding. Elevated levels of poly (ADP-ribose) binding were found in 73% of the SLE patients compared with 58% who had raised ds DNA binding. In a further study of 160 sera from 27 patients with SLE, levels of antipoly (ADP-ribose) antibodies were shown to correlate with clinical activity better than either anti-ds DNA or ss DNA antibodies.
A Common RET Variant Is Associated with Reduced Newborn Kidney Size and Function
Authors: Zhao Zhang, Jackie Quinlan, Wendy Hoy, Michael D Hughson, Mathieu Lemire, Thomas Hudson, Pierre-Alain Hueber, Alice Benjamin, Anne Roy, Elena Pascuet, Meigan Goodyer, Chandhana Raju, Fiona Houghton, John Bertram, Paul Goodyer
Journal: Journal of the American Society of Nephrology (2008)

Congenital nephron number varies five-fold among normal humans, and individuals at the lower end of this range may have an increased lifetime risk for essential hypertension or renal insufficiency; however, the mechanisms that determine nephron number are unknown. This study tested the hypothesis that common hypomorphic variants of the RET gene, which encodes a tyrosine kinase receptor critical for renal branching morphogenesis, might account for subtle renal hypoplasia in some normal newborns. A common single-nucleotide polymorphism (rs1800860 G/A) was identified within an exonic splicing enhancer in exon 7. The adenosine variant at mRNA position 1476 reduced affinity for spliceosome proteins, enhanced the likelihood of aberrant mRNA splicing, and diminished the level of functional transcript in human cells. In vivo, normal white newborns with an rs1800860(1476A) allele had kidney volumes 10% smaller and cord blood cystatin C levels 9% higher than those with the rs1800860(1476G) allele. These findings suggest that the RET(1476A) allele, in combination with other common polymorphic developmental genes, may account for subtle renal hypoplasia in a significant proportion of the white population. Whether this gene variant affects clinical outcomes requires further study.
The light at the end of the tunnel: is COPD prevalence changing?
Authors: B.R. Celli
Journal: European Respiratory Journal (2010)

Chronic obstructive pulmonary disease (COPD) is, and will remain, a global health problem as far as we can prognosticate. In the developed world (in contrast to the other big killers: coronary artery disease, cancer and cerebrovascular accident) COPD has the dubious honour of maintaining unabated and continued growth 1, 2. Because the transfer of wealth from more developed to lesser developed countries is associated with a shift in the health pattern of those societies to resemble that of the richer ones, it is only reasonable to expect similar changes in the causes of death over time in the most populated parts of our globe. The completion of spirometrically defined surveys in different parts of the world, through the PLATINO project in Latin America 3 and the Burden of Obstructive Lung Disease (BOLD) initiative 4, have provided a cross-sectional picture of the state of the world with regard to COPD, which can be summarised as follows: COPD is highly prevalent, its prevalence varies by regions, and whether it is due to cigarette smoking or environmental exposure COPD is consistently under-diagnosed, under-treated and its research under-funded. There is no epidemiologically sound longitudinal follow-up of populations that can provide an accurate picture of the success, or failure, of the efforts that over the past decades have been made to prevent and treat COPD.

While estimates based on data modelling present a very bleak picture of the effect of COPD on society 2, this issue of the European Respiratory Journal provides, for the first time, some data from two different cross-sectional studies at two …
Fontolizumab, a humanised anti-interferon antibody, demonstrates safety and clinical activity in patients with moderate to severe Crohn's disease
Authors: D W Hommes
Journal: Gut (2005)

<b>Introduction:</b> Interferon γ is a potent proinflammatory cytokine implicated in the inflammation of Crohn's disease (CD). We evaluated the safety and efficacy of fontolizumab, a humanised anti-interferon γ antibody, in patients with moderate to severe CD. <b>Methods:</b> A total of 133 patients with Crohn's disease activity index (CDAI) scores between 250 and 450, inclusive, were randomised to receive placebo or fontolizumab 4 or 10 mg/kg. Forty two patients received one dose and 91 patients received two doses on days 0 and 28. Investigators and patients were unaware of assignment. Study end points were safety, clinical response (decrease in CDAI of 100 points or more), and remission (CDAI ⩽150). <b>Results:</b> There was no statistically significant difference in the primary end point of the study (clinical response) between the fontolizumab and placebo groups after a single dose at day 28. However, patients receiving two doses of fontolizumab demonstrated doubling in response rate at day 56 compared with placebo: 32% (9/28) versus 69% (22/32, p = 0.02) and 67% (21/31, p = 0.03) for the placebo, and 4 and 10 mg/kg fontolizumab groups, respectively. Stratification according to elevated baseline C reactive protein levels resulted in a decreased placebo response and pronounced differences in clinical benefit. Two grade 3 adverse events were reported and were considered to be related to CD. One death (during sleep) and one serious adverse event (an elective hospitalisation) occurred, both considered unrelated. <b>Conclusion:</b> Treating active CD with fontolizumab was well tolerated and resulted in increased rates of clinical response and remission compared with placebo.
Angiotensin II, via AT1 and AT2 Receptors and NF-κB Pathway, Regulates the Inflammatory Response in Unilateral Ureteral Obstruction
Authors: Vanesa Esteban, Oscar Lorenzo, Mónica Rupérez, Yusuke Suzuki, Sergio Mezzano, Julia Blanco, Mathias Kretzler, Takeshi Sugaya, Jesús Egido, Marta Ruiz-Ortega
Journal: Journal of the American Society of Nephrology (2004)

Inflammatory cell infiltration plays a key role in the onset and progression of renal injury. The NF-κB participates in the inflammatory response, regulating many proinflammatory genes. Angiotensin II (Ang II), via AT1 and AT2 receptors, activates NF-κB. Although the contribution of Ang II to kidney damage progression is already established, the receptor subtype involved in the inflammatory cell recruitment is not clear. For investigating this issue, the unilateral ureteral obstruction (UUO) model was used in mice, blocking Ang II production/receptors and NF-κB pathway. Two days after UUO, obstructed kidneys of wild-type mice presented a marked interstitial inflammatory cell infiltration and increased NF-κB activity. Treatment with AT1 or AT2 antagonists partially decreased NF-κB activation, whereas only the AT2 blockade diminished monocyte infiltration. Obstructed kidneys of AT1-knockout mice showed interstitial monocyte infiltration and NF-κB activation; both processes were abolished by an AT2 antagonist, suggesting AT2/NF-κB involvement in monocyte recruitment. In wild-type mice, only angiotensin-converting enzyme inhibition or combined therapy with AT1 plus AT2 antagonists blocked monocyte infiltration, NF-κB activation, and upregulation of NF-κB–related proinflammatory genes. Therefore, AT1 and AT2 blockade is necessary to arrest completely the inflammatory process. Treatment with two different NF-κB inhibitors, pirrolidin-dithiocarbamate and parthenolide, diminished monocyte infiltration and gene overexpression. These data show that Ang II, via AT1 and AT2 receptors and NF-κB pathway, participates in the regulation of renal monocyte recruitment and may provide a rationale to investigate further the role of AT2 in human kidney diseases.
Off to the Organelles - Killing Cancer Cells with Targeted Gold Nanoparticles
Authors: Mohamed Kodiha, Yi Meng Wang, Eliza Hutter, Dusica Maysinger, Ursula Stochaj
Journal: Theranostics (2015)

Gold nanoparticles (AuNPs) are excellent tools for cancer cell imaging and basic research.However, they have yet to reach their full potential in the clinic.At present, we are only beginning to understand the molecular mechanisms that underlie the biological effects of AuNPs, including the structural and functional changes of cancer cells.This knowledge is critical for two aspects of nanomedicine.First, it will define the AuNP-induced events at the subcellular and molecular level, thereby possibly identifying new targets for cancer treatment.Second, it could provide new strategies to improve AuNP-dependent cancer diagnosis and treatment.Our review summarizes the impact of AuNPs on selected subcellular organelles that are relevant to cancer therapy.We focus on the nucleus, its subcompartments, and mitochondria, because they are intimately linked to cancer cell survival, growth, proliferation and death.While non-targeted AuNPs can damage tumor cells, concentrating AuNPs in particular subcellular locations will likely improve tumor cell killing.Thus, it will increase cancer cell damage by photothermal ablation, mechanical injury or localized drug delivery.This concept is promising, but AuNPs have to overcome multiple hurdles to perform these tasks.AuNP size, morphology and surface modification are critical parameters for their delivery to organelles.Recent strategies explored all of these variables, and surface functionalization has become crucial to concentrate AuNPs in subcellular compartments.Here, we highlight the use of AuNPs to damage cancer cells and their organelles.We discuss current limitations of AuNP-based cancer research and conclude with future directions for AuNP-dependent cancer treatment. Key words: Gold nanoparticles
Adolescent Overweight and Future Adult Coronary Heart Disease
Authors: Kirsten Bibbins-Domingo, Pamela Coxson, Mark J. Pletcher, James Lightwood, Lee Goldman
Journal: New England Journal of Medicine (2007)

We estimated the prevalence of obese 35-year-olds in 2020 on the basis of adolescent overweight in 2000 and historical trends regarding overweight adolescents who become obese adults. We then used the CHD Policy Model, a state-transition computer simulation of U.S. residents who are 35 years of age or older, to project the annual excess incidence and prevalence of CHD, the total number of excess CHD events, and excess deaths from both CHD and other causes attributable to obesity from 2020 to 2035. We also modeled the effect of treating obesity-related increases in blood pressure and dyslipidemia.
IL-4 and IL-13 Induction of SOCS-3 Negatively Regulates TNF-α and IFN-γ Induced Human β Defensin (HBD)-3 Expression in Keratinocytes
Authors: H.R. Fairchild, D.Y.M. Leung, M.D. Howell
Journal: Journal of Allergy and Clinical Immunology (2007)
Hyperglycemia After Myocardial Infarction
Authors: Ketan Dhatariya
Journal: Diabetes Care (2003)

In their article on hyperglycemia in subjects admitted with myocardial infarction, Dandona, Aljada, and Bandyopadhyay (1) summarize much of the current knowledge about the anti-inflammatory effects of insulin. They propose mechanisms to explain the decreased morbidity and mortality seen in subjects on insulin infusions with tight blood glucose control. This may explain the results seen in another …
Short-term effects of light and heavy load interventions on service velocity and precision in elite young tennis players
Authors: Alexander Ferrauti, Kenneth Bastiaens
Journal: British Journal of Sports Medicine (2007)

This study was conducted to investigate the acute effects of a complex throwing intervention set-up, with light or heavy loads, on the service velocity of elite junior tennis players.On 3 separate test days, 13 elite juniors (mean (SD) 12.3 (0.8) years, 149 (9) cm, 37.5 (5.5) kg) performed four sets of six serves with different between-set conditions. In a cross-over design, the players performed respectively 6, 4 and 2 maximum effort throws with a 200 g ball (LI, light intervention), 6, 4 and 2 maximum effort throws with a 600 g ball (HI, heavy intervention) and no throws (NI, no intervention) during the 2 min in between-set period. Participants were instructed to serve, with maximum speed, to a target near the midline of the deuce court service box. A two-factor analysis of variance was used to determine the effects of intervention type and set number on "service velocity", "service precision" (eg, percentage of serves in) and "service touch" (11 point rating scale).Mean (SD) service velocity decreased significantly in HI (124.3 (7.8) km/h) as compared to NI (126.6 (9.3) km/h, p<0.05, effect size d = 0.26), yet no such differences were found between LI (125.2 (7.9) km/h) and NI. Service velocity also remained constant between sets (p = 0.406). Service precision and service touch were unaffected by the interventions.Under the conditions of our study, a heavy throwing intervention during service training has no beneficial effect on service velocity in young elite tennis players (under 14).
Stem cell transplantation in neurodegenerative disorders of the gastrointestinal tract: future or fiction?
Authors: Subhash Kulkarni, Laren Becker, Pankaj Jay Pasricha
Journal: Gut (2011)

Current advances in our understanding of stem and precursor cell biology and in the protocols of stem cell isolation and transplantation have opened up the possibility of transplanting neural stem cells for the treatment of gastrointestinal motility disorders. This review summarises the current status of research in this field, identifies the major gaps in our knowledge and discusses the potential opportunities and hurdles for clinical application.
Worsening of Bullous Pemphigoid Following Bacillus Calmette-Guérin Treatment for Bladder Cancer
Authors: Jamie L. Johnson, Daniel A. West, Jeffrey B. Travers
Journal: JAMA Dermatology (2013)

Bullous pemphigoid is an autoimmune disease characterized by subepidermal bullae that can involve nearly any skin surface and primarily affects the elderly. Only in a minority of cases are there known precipitating factors, some of which include vaccinations.1
The two membrane proximal domains of CD4 interact with the T cell receptor.
Authors: D A Vignali, R T Carson, B Chang, R S Mittler, J L Strominger
Journal: The Journal of Experimental Medicine (1996)

During T cell activation, CD4 is intimately involved in colocalizing the T cell receptor (TCR) with its specific peptide ligand bound to class II molecules of the major histocompatibility complex (MHC). Previously, the COOH-terminal residues, Trp62/63, which flank the immunodominant epitope of hen egg lysozyme (HEL 52-61), were shown to have a profound effect on TCR recognition. CD4 maintains the fidelity of this interaction when short peptides are used. To determine which portion of CD4 was responsible for this effect, a series of CD4 mutants were made and transfected into CD4 loss variants of two HEL 52-61-specific T cell hybridomas. Surprisingly, some CD4 mutants that failed to interact with MHC class II molecules (D2 domain mutant) or with p56kk (cytoplasmic-tailless mutant) restored responsiveness. Nevertheless, a significant reduction in association between cytoplasmic-tailless CD4 and the TCR, as determined by fluorescence resonance energy transfer, was observed. Thus, neither colocalization of CD4 and the TCR nor signal transduction via CD4 was solely responsible for the functional restoration of these T cell hybridomas by wild-type CD4. However, substitution of the two membrane proximal domains of murine CD4 (D3 and D4) with domains from human CD4 or intercellular adhesion molecule 1 not only abrogated its ability to restore function, but also substantially reduced its ability to associate with the TCR. Furthermore, the mouse/human CD4 chimera had a potent dominant negative effect on T cell function in the presence of equimolar concentrations of wild-type CD4. These data suggest that the D3/D4 domains of CD4 may interact directly or indirectly with the TCR-CD3 complex and influence the signal transduction processes. Given the striking structural differences between CD4 and CD8 in this region, these data define a novel and unique function for CD4.