tbuckley/cabot-search huggingface dataset:
Aspirin Dose and Cardiovascular Disease Prevention
Authors: George Kwok Chu Wong
Journal: JAMA (2007)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Fibrin(ogen) mediates acute inflammatory responses to biomaterials.
Authors: L Tang, J W Eaton
Journal: The Journal of Experimental Medicine (1993)

Although "biocompatible" polymeric elastomers are generally nontoxic, nonimmunogenic, and chemically inert, implants made of these materials may trigger acute and chronic inflammatory responses. Early interactions between implants and inflammatory cells are probably mediated by a layer of host proteins on the material surface. To evaluate the importance of this protein layer, we studied acute inflammatory responses of mice to samples of polyester terephthalate film (PET) that were implanted intraperitoneally for short periods. Material preincubated with albumin is "passivated," accumulating very few adherent neutrophils or macrophages, whereas uncoated or plasma-coated PET attracts large numbers of phagocytes. Neither IgG adsorption nor surface complement activation is necessary for this acute inflammation; phagocyte accumulation on uncoated implants is normal in hypogammaglobulinemic mice and in severely hypocomplementemic mice. Rather, spontaneous adsorption of fibrinogen appears to be critical: (a) PET coated with serum or hypofibrinogenemic plasma attracts as few phagocytes as does albumin-coated material; (b) in contrast, PET preincubated with serum or hypofibrinogenemic plasma containing physiologic amounts of fibrinogen elicits "normal" phagocyte recruitment; (c) most importantly, hypofibrinogenemic mice do not mount an inflammatory response to implanted PET unless the material is coated with fibrinogen or the animals are injected with fibrinogen before implantation. Thus, spontaneous adsorption of fibrinogen appears to initiate the acute inflammatory response to an implanted polymer, suggesting an interesting nexus between two major iatrogenic effects of biomaterials: clotting and inflammation.
Early enhancement of fluid transport in rabbit proximal straight tubules after loss of contralateral renal excretory function.
Authors: K Tabei, D J Levenson, B M Brenner
Journal: Journal of Clinical Investigation (1983)

To assess the renal functional adaptation to reduced excretory capacity, we studied whole kidney and single nephron function in anesthetized volume-replete rabbits after unilateral (left kidney) nephrectomy (UNX), ureteral obstruction (UO), or ureteroperitoneostomy (UP). At 24 h, despite the absence of measurable hypertrophy of the contralateral (right) kidney, these procedures significantly increased p-aminohippurate clearance (45-54%) and inulin clearance (CIN) (64-110%) compared with sham-operated control animals. In each group, whole kidney sodium reabsorption increased in proportion to the rise in CIN. To determine whether the intrinsic transport capacity of proximal tubule segments is altered by these maneuvers, we measured fluid volume reabsorption rate (Jv) in isolated superficial proximal straight tubule (PST) segments perfused in vitro, comparing each control tubule (obtained by biopsy of the left kidney immediately before an experimental maneuver) with a corresponding tubule segment obtained 24 h or 7 d later from the contralateral kidney. Control tubule Jv in sham-24 h animals averaged 0.48 +/- 0.04 nl/(min X mm). Jv did not change significantly at 24 h or 7 d after sham maneuvers but increased significantly at 24 h after UNX [delta Jv = 0.13 +/- 0.03 nl/(min X mm)], UO [delta Jv = 0.10 +/- 0.04 nl/(min X mm)], and UP [delta Jv = 0.13 +/- 0.04 nl/(min X mm)]. Jv remained increased by similar amounts at 7 d after UNX and UO. To evaluate whether an increase in glomerular filtration rate (GFR) might be the stimulus to this augmentation in Jv values, methylprednisolone (MP) (15 mg/kg per d) was administered daily to sham-operated animals, a maneuver which induced a 73% rise in CIN by day 5. This procedure also produced a significant increase in Jv in PST at 5 d [delta Jv = 0.16 +/- 0.05 nl/(min X mm)]. The increase in Jv evident in each group at 5 or 7 d was paralleled by an equivalent change in tubule cell volume and apparent tubule luminal surface area in UNX-7d and MP-5d; no such increments in these indices, or in apparent tubule serosal surface area were evident at 24 h in any group. Thus, a 50% reduction in renal excretory function in the rabbit provokes adjustments in renal plasma flow rate and GFR in the contralateral kidney, which are evident by 24 h. The concurrent change in Jv in PST is closely related to CIN or some associated hemodynamic process, but does not appear to require an increase in tubule cell volume or apparent surface area. The ability to detect these small in vivo changes in Jv may derive from the enhanced sensitivity of paired-kidney experiments using tubule segments obtained by renal biopsy.
Pulsatile Administration of the Epidermal Growth Factor Receptor Inhibitor Gefitinib Is Significantly More Effective than Continuous Dosing for Sensitizing Tumors to Paclitaxel
Authors: David B. Solit, Yuhong She, Jose Lobo, Mark G. Kris, Howard I. Scher, Neal Rosen, Frank M. Sirotnak
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Gefitinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. Continuous inhibition of EGFR signaling is thought necessary for optimal inhibition of tumor cell proliferation. We hypothesized that continuous gefitinib may antagonize the effects of cytotoxics that inhibit tumor cells in other phases of the cell cycle. Furthermore, we hypothesized that intermittent dosing would allow for dose escalation and greater inhibition of EGFR-dependent antiapoptotic pathways. Experimental Design: To test these assertions, we compared combinations of paclitaxel and gefitinib using either intermittent or continuous dosing schedules in mice. Results: We found that when used in combination with paclitaxel, pulsatile gefitinib was significantly superior to continuous dosing. When gefitinib was administered for one or two consecutive days before paclitaxel, much higher doses could be given safely. Two days of gefitinib treatment before paclitaxel was most effective, causing significantly greater mean tumor regression and a higher percentage of complete responses than other schedules. Conclusions: The results suggest that the dose and schedule of an EGFR inhibitor required to effectively inhibit proliferation may differ from that required to stimulate apoptosis or to induce other effects. The former may require continuous EGFR inhibition to maintain cell cycle arrest, whereas sensitization to apoptosis may be optimally induced by profound but temporary inhibition of survival pathways. Our data suggest that the effects of receptor inhibition vary as a function of dose and schedule and that continuous administration of tyrosine kinase inhibitors may not be the best schedule with which to combine such agents with taxanes.
I <sup>131</sup> -Diodrast Studies in Unilateral Renal Disease
Authors: JEROME B. BLOCK, GERALD J. HINE, BELTON A. BURROWS, Valentine Bikerman
Journal: Circulation (1960)

A procedure utilizing I 131 -Diodrast with carrier Diodrast and a ratiometer has been evaluated for the early diagnosis of unilateral renal disease. Relative differences in function between kidneys demonstrated by this procedure correlated well with findings at surgical exploration or autopsy. In 3 patients with unilateral renal arterial stenosis who had normal intravenous pyelograms, I 131 -Diodrast results were abnormal. Although normal I 131 -Diodrast results may rule out unilateral renal disease, an abnormal result with I 131 -Diodrast may be seen with any lesion resulting in urine flow differences between kidneys.
CD8+ T lymphocytes provide helper activity for IgE synthesis in human immunodeficiency virus-infected patients with hyper-IgE.
Authors: R Paganelli, E Scala, I J Ansotegui, C M Ausiello, E Halapi, E Fanales-Belasio, G D'Offizi, I Mezzaroma, F Pandolfi, M Fiorilli, A Cassone, F Aiuti
Journal: The Journal of Experimental Medicine (1995)

Increased levels of serum IgE and eosinophilia have been described in human immunodeficiency virus (HIV) infection, almost exclusively in patients with CD4+ cell count &amp;lt; 200 cells/microliters. IgE production is regulated by CD4+ T helper type 2 (Th-2) lymphocytes, producing interleukin 4 (IL-4) and expressing a ligand for the B cell-specific CD40 molecule (CD40 ligand [L]). A shift to a Th-2-like pattern of cytokine secretion has been postulated to be associated with progression toward acquired immunodeficiency syndrome (AIDS). We studied three AIDS patients with very high levels of IgE and almost complete depletion of CD4+ lymphocytes, suggesting that IgE synthesis could not be driven by CD4+ cells. IgE in vitro synthesis by cells from such patients was, however, inhibited by anti-IL-4. We show that both CD8+ T cell lines and the majority of CD8+ T cells clones derived from these patients produce IL-4, IL-5, and IL-6 in half of the cases together with interferon gamma (IFN-gamma). 44% of CD8+ T cell clones expressed a CD40L, and the supernatants of the clones were capable of inducing IgE synthesis by normal B cells costimulated with anti-CD40. CD8+ T cells in these patients therefore functionally mimic Th-2 type cells and may account for hyper-IgE and eosinophilia in the absence of CD4+ cells. The presence of such CD8+ cells may also provide a source of IL-4 directing the development of predominant Th-2 responses in HIV infection.
Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis
Authors: Brian G. Feagan, Paul Rutgeerts, Bruce E. Sands, Stephen Hanauer, Jean-Frédéric Colombel, William J. Sandborn, Gert Van Assche, Jeffrey Axler, Hyo-Jong Kim, Silvio Danese, Irving Fox, Catherine Milch, Serap Sankoh, Tim Wyant, Jing Xu, Asit Parikh
Journal: New England Journal of Medicine (2013)

Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis.We conducted two integrated randomized, double-blind, placebo-controlled trials of vedolizumab in patients with active disease. In the trial of induction therapy, 374 patients (cohort 1) received vedolizumab (at a dose of 300 mg) or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label vedolizumab at weeks 0 and 2, with disease evaluation at week 6. In the trial of maintenance therapy, patients in either cohort who had a response to vedolizumab at week 6 were randomly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks. A response was defined as a reduction in the Mayo Clinic score (range, 0 to 12, with higher scores indicating more active disease) of at least 3 points and a decrease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1.Response rates at week 6 were 47.1% and 25.5% among patients in the vedolizumab group and placebo group, respectively (difference with adjustment for stratification factors, 21.7 percentage points; 95% confidence interval [CI], 11.6 to 31.7; P<0.001). At week 52, 41.8% of patients who continued to receive vedolizumab every 8 weeks and 44.8% of patients who continued to receive vedolizumab every 4 weeks were in clinical remission (Mayo Clinic score ≤2 and no subscore >1), as compared with 15.9% of patients who switched to placebo (adjusted difference, 26.1 percentage points for vedolizumab every 8 weeks vs. placebo [95% CI, 14.9 to 37.2; P<0.001] and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo [95% CI, 17.9 to 40.4; P<0.001]). The frequency of adverse events was similar in the vedolizumab and placebo groups.Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis. (Funded by Millennium Pharmaceuticals; GEMINI 1 ClinicalTrials.gov number, NCT00783718.).
Generation of diversity in T cell receptor repertoire specific for pigeon cytochrome c.
Authors: S B Sorger, S M Hedrick, P J Fink, M A Bookman, L A Matis
Journal: The Journal of Experimental Medicine (1987)

17 T cell clones and 3 T cell lines, specific for pigeon cytochrome c, were analyzed for fine specificity and rearranged T cell receptor (TCR) gene elements. Clones of similar fine specificities were grouped into one of four phenotypes, and correlations between phenotype differences and gene usage could be made. All the lines and clones rearranged a member of the V alpha 2B4 gene family to a limited number of J alpha regions. The beta chain was made up of one of three non-cross-hybridizing V beta regions, each rearranging to only one or two J beta s. The use of alternate V beta regions could be correlated with phenotype differences, which were manifested either as MHC- or MHC and antigen-specificity changes. In addition, the presence of alloreactivity, which defined a phenotype difference, could be correlated solely with the use of an alternate J alpha region. These observations were substantiated by prospective analyses of pigeon cytochrome c-specific T cell lines that were selected for alternate MHC specificity or alloreactivity and were found to express the correlated alpha and beta chain rearrangements. Previously, the TCR DNA sequences from two clones, each representing a variant of one phenotype, showed sequence differences only in the N regions of their TCR genes. Since only these two variants, using identical V alpha-J alpha and V beta-J beta gene elements, were repeatedly observed in this study, we would predict that the junctional diversity differences are selectable. In this T cell response, all the gene elements involved in the generation of diversity appear to be selected, and may therefore be important in the determination of TCR specificity. This high degree of receptor gene selection represents a fundamental difference from the diversity seen in several extensively analyzed antibody responses.
Frequent p16-Independent Inactivation of p14ARF in Human Melanoma
Authors: Daniel E. Freedberg, Sushila H. Rigas, Julie Russak, Weiming Gai, Margarita Kaplow, Iman Osman, Faye Turner, Juliette A. Randerson-Moor, Alan Houghton, Klaus Busam, D. Timothy Bishop, Boris C. Bastian, Julia A. Newton-Bishop, David Polsky
Journal: JNCI Journal of the National Cancer Institute (2008)

The tumor suppressors p14(ARF) (ARF) and p16(INK4A) (p16) are encoded by overlapping reading frames at the CDKN2A/INK4A locus on chromosome 9p21. In human melanoma, the accumulated evidence has suggested that the predominant tumor suppressor at 9p21 is p16, not ARF. However, recent observations from melanoma-prone families and murine melanoma models suggest a p16-independent tumor suppressor role for ARF. We analyzed a group of melanoma metastases and cell lines to investigate directly whether somatic alterations to the ARF gene support its role as a p16-independent tumor suppressor in human melanoma, assuming that two alterations (genetic and/or epigenetic) would be required to inactivate a gene.We examined the p16/ARF locus in 60 melanoma metastases from 58 patients and in 9 human melanoma cell lines using multiplex ligation-dependent probe amplification and multiplex polymerase chain reaction (PCR) to detect deletions, methylation-specific PCR to detect promoter methylation, direct sequencing to detect mutations affecting ARF and p16, and, in a subset of 20 tumors, immunohistochemistry to determine the effect of these alterations on p16 protein expression. All statistical tests were two-sided.We observed two or more alterations to the ARF gene in 26/60 (43%) metastases. The p16 gene sustained two or more alterations in 13/60 (22%) metastases (P = .03). Inactivation of ARF in the presence of wild-type p16 was seen in 18/60 (30%) metastases.Genetic and epigenetic analyses of the human 9p21 locus indicate that modifications of ARF occur independently of p16 inactivation in human melanoma and suggest that ARF is more frequently inactivated than p16.
The Activated Type 1–Polarized Cd8+ T Cell Population Isolated from an Effector Site Contains Cells with Flexible Cytokine Profiles
Authors: Anthony G. Doyle, Kathy Buttigieg, Penny Groves, Barbara J. Johnson, Anne Kelso
Journal: The Journal of Experimental Medicine (1999)

The capacity of activated T cells to alter their cytokine expression profiles after migration into an effector site has not previously been defined. We addressed this issue by paired daughter analysis of a type 1–polarized CD8+ effector T cell population freshly isolated from lung parenchyma of influenza virus–infected mice. Single T cells were activated to divide in vitro; individual daughter cells were then micromanipulated into secondary cultures with and without added IL-4 to assess their potential to express type 2 cytokine genes. The resultant subclones were analyzed for type 1 and 2 cytokine mRNAs at day 6–7. When the most activated (CD44highCD11ahigh) CD8+ subpopulation from infected lung was compared with naive or resting (CD44lowCD11alow) CD8+ cells from infected lung and from normal lymph nodes (LNs), both clonogenicity and plasticity of the cytokine response were highest in the LN population and lowest in the activated lung population, correlating inversely with effector function. Multipotential cells were nevertheless detected among clonogenic CD44highCD11ahigh lung cells at 30–50% of the frequency in normal LNs. The data indicate that activated CD8+ T cells can retain the ability to proliferate and express new cytokine genes in response to local stimuli after recruitment to an effector site.
Independent Effects of Alternative Splicing and Structural Constraint on the Evolution of Mammalian Coding Exons
Authors: F.-C. Chen, C.-L. Pan, H.-Y. Lin
Journal: Molecular Biology and Evolution (2011)

Alternative splicing (AS) is known to significantly affect exon-level protein evolutionary rates in mammals. Particularly, alternatively spliced exons (ASEs) have a higher nonsynonymous-to-synonymous substitution rate (dN/dS) ratio than constitutively spliced exons (CSEs), possibly because the former are required only occasionally for normal biological functions. Meanwhile, intrinsically disordered regions (IDRs), the protein regions lacking fixed 3D structures, are also reported to have an increased evolutionary rate due to lack of structural constraint. Interestingly, IDRs tend to be located in alternative protein regions. Yet which of these two factors is the major determinant of the increased dN/dS in mammalian ASEs remains unclear. By comparing human–macaque and human–mouse one-to-one orthologous genes, we demonstrate that AS and protein structural disorder have independent effects on mammalian exon evolution. We performed analyses of covariance to demonstrate that the slopes of the (dN/dS-percentage of IDR) regression lines differ significantly between CSEs and ASEs. In other words, the dN/dS ratios of both ASEs and CSEs increase with the proportion of IDR (PIDR), whereas ASEs have higher dN/dS ratios than CSEs when they have similar PIDRs. Since ASEs and IDRs may less frequently overlap with protein domains (which also affect dN/dS), we also examined the correlations between dN/dS ratio and exon type/PIDR by controlling for the density of protein domain. We found that the effects of exon type and PIDR on dN/dS are both independent of domain density. Our results imply that nature can select for different biological features with regard to ASEs and IDRs, even though the two biological features tend to be localized in the same protein regions.
Effects of Rosuvastatin and Atorvastatin on LDL and HDL Particle Concentrations in Patients With Metabolic Syndrome
Authors: Robert S. Rosenson, James D. Otvos, Judith Hsia
Journal: Diabetes Care (2009)

OBJECTIVE The purpose of this study was to examine the effects of statin therapy on lipoprotein particle concentrations in patients with the metabolic syndrome. Changes in lipoprotein particle concentration may predict the risk of coronary heart disease more accurately than lipoprotein cholesterol levels. RESEARCH DESIGN AND METHODS Patients with dyslipidemia and the metabolic syndrome (n = 318) were randomly assigned in a double-blind study comparing 10 mg rosuvastatin (RSV), 10 mg atorvastatin, or placebo daily for 6 weeks. From weeks 6 to 12, patients in the RSV and placebo groups received 20 mg RSV, whereas the ATV group increased their dose to 20 mg daily. Lipoprotein particle concentrations were measured by nuclear magnetic resonance spectroscopy, LDL cholesterol was measured by β-quantification, and other lipoproteins were measured by standard methods at baseline, 6 weeks, and 12 weeks. Lipoprotein levels were compared by analysis of covariance. RESULTS Statins reduced LDL particle concentration less than LDL cholesterol (−30 to −38 vs. −38 to −51%). Reductions were greater with RSV than with ATV (P &amp;lt; 0.05 for LDL particle concentration and P &amp;lt; 0.001 for LDL cholesterol). Most patients attained LDL cholesterol &amp;lt;2.59 mmol/l (100 mg/dl) at 12 weeks (80% with RSV and 59% with ATV; P = 0.003), but only 27% of patients receiving RSV and 19% receiving ATV attained the goal of LDL particle concentration &amp;lt;1,000 nmol/l (P = 0.07). CONCLUSIONS In patients with the metabolic syndrome, statin-induced changes in LDL cholesterol do not accurately reflect changes in LDL particle concentration. Consequently, despite attainment of LDL cholesterol goals, these patients may retain considerable residual coronary heart disease risk.