tbuckley/cabot-search huggingface dataset:
Quality of life and clinical outcome in psoriasis patients using intermittent cyclosporin
Authors: C.R. Touw, L. Hakkaart-Van Roijen, P. Verboom, C. Paul, F.F.H. Rutten, A.Y. Finlay
Journal: British Journal of Dermatology (2001)

Psoriasis causes considerable patient morbidity and can seriously affect a patient's quality of life (QoL).To investigate the relationships between changes in QoL and measures of severity and extent of disease, and itch, in patients with chronic plaque psoriasis receiving intermittent short courses of cyclosporin (Neoral).This study was performed as part of an international trial investigating the safety, efficacy and total costs of intermittent short courses of cyclosporin (the PISCES study). All patients received cyclosporin until clearance and were then followed up until relapse. On relapsing, patients received another course. Patients were followed up for a minimum of 1 year during which they could receive as many courses of treatment as necessary. In a subgroup (n = 255) of patients in the trial, the Dermatology Life Quality Index (DLQI) was used to assess the impact of psoriasis and its treatment on the patients' health status at the beginning and end of each treatment period. At the beginning and end of each treatment period, as well as at 2-weekly visits, the extent and severity of disease, together calculated into a modified Psoriasis Area and Severity Index (PASI), and itch were recorded. Data were analysed using the Wilcoxon matched pairs test, multivariate Hotelling's T2 tests, and Spearman's rank correlation coefficients (rs).During treatment, a clear impact on the overall DLQI scores and in the scores in all six DLQI headings was found (i.e. an improvement in QoL; P < 0.001 in all scores). Also, significant decreases in PASI and itch scores were found (P < 0.001). Multivariate analyses confirmed that a decrease in PASI and itch scores was accompanied by an impact on the DLQI scores during and between the two treatment periods (P < 0.0001). Statistically significant but weak correlations were found between changes in QoL and changes in PASI (rs = 0.40 and 0.24 for the first and second treatment periods, respectively) and itch scores (rs = 0.31 and 0.42, respectively).Intermittent short courses of cyclosporin clearly improve the QoL of the patients and decrease the extent and severity of disease and itch. Changes in clinical outcome scores are accompanied by changes in QoL. The weak correlations between changes in QoL and clinical measures may suggest that no clear relationship between QoL and clinical outcomes exists. However, due to the inclusion and exclusion criteria of the study, both QoL and clinical outcome measures do not show much variation among this homogeneous group of patients. As long as the relationship between clinical outcome parameters and measures of QoL is not completely clear, both measures of health should be considered in adequate, patient-orientated clinical decision making.
Optimising corticosteroid treatment for autoimmune pancreatitis
Authors: A. Ghazale, S. T Chari
Journal: Gut (2007)

Unanswered questions

Autoimmune pancreatitis (AIP) is part of a systemic fibro-inflammatory disease that can involve multiple organs which characteristically have a lymphoplasmacytic infiltrate rich in IgG4-positive cells. IgG4-related systemic disease (ISD) has been proposed by Kamisawa et al as the umbrella term to describe this multi-organ disease.1 Although the fibrosis in ISD can often lead to damage and even destruction of the involved organ, the inflammatory process typically responds to steroid treatment. However, the resolution of the inflammatory process in ISD may occur spontaneously without steroid treatment, especially in AIP.2 3 The effect of steroid treatment on the natural history of AIP is not known as it is only recently that large series of AIP are being reported.

In this issue of Gut ( page 1719 ), Hirano et al 4 report the results of a retrospective review of 42 AIP patients of whom 19 were treated with steroids. The authors’ goal was to determine the effect of steroids on subsequent disease relapse by comparing “unfavourable events” in steroid treated patients with those in historical controls presenting before 2003 who did not receive steroids. “Unfavourable events” included the development of obstructive jaundice related to distal biliary stricture, sclerosing cholangitis with elevated liver enzymes, growing pancreatic pseudocyst or other extra pancreatic lesions that required treatment (retroperitoneal fibrosis, interstitial nephritis, sialoadenitis). “Unfavourable events” were less in the steroid treated group compared to controls (32% vs 70%, p _ 0.01). The authors conclude that steroid treatment could reduce subsequent disease relapse and thus recommend the early introduction of steroids.

When discussing treatment in AIP, it is important to use specific terms that help identify treatment goals and responses. Remission refers to the resolution of disease-related symptoms and radiological abnormalities, whether spontaneously (spontaneous remission) or with steroids (steroid-induced remission), keeping in mind that in …
Bystander-Initiated CPR by Design, Not by Chance
Authors: Comilla Sasson, David J. Magid
Journal: New England Journal of Medicine (2015)

Every hour in the United States, 38 people have an out-of-hospital cardiac arrest, and fewer than 1 of 10 survive.1 Increasing data show that timely provision of cardiopulmonary resuscitation (CPR) saves lives, and tens of millions of people have been trained to perform it. Yet, less than half of persons with cardiac arrest in the United States receive bystander-initiated CPR,1 and there are significant disparities in its provision.2 Factors that affect these disparities include a person's neighborhood and his or her race or ethnic group. In two well-designed studies in this issue of the Journal, Hasselqvist-Ax and colleagues examine . . .
Paneth cell extrusion and release of antimicrobial products is directly controlled by immune cell–derived IFN-γ
Authors: Henner F. Farin, Wouter R. Karthaus, Pekka Kujala, Maryam Rakhshandehroo, Gerald Schwank, Robert G.J. Vries, Eric Kalkhoven, Edward E.S. Nieuwenhuis, Hans Clevers
Journal: The Journal of Experimental Medicine (2014)

Paneth cells (PCs) are terminally differentiated, highly specialized secretory cells located at the base of the crypts of Lieberkühn in the small intestine. Besides their antimicrobial function, PCs serve as a component of the intestinal stem cell niche. By secreting granules containing bactericidal proteins like defensins/cryptdins and lysozyme, PCs regulate the microbiome of the gut. Here we study the control of PC degranulation in primary epithelial organoids in culture. We show that PC degranulation does not directly occur upon stimulation with microbial antigens or bacteria. In contrast, the pro-inflammatory cytokine Interferon gamma (IFN-γ) induces rapid and complete loss of granules. Using live cell imaging, we show that degranulation is coupled to luminal extrusion and death of PCs. Transfer of supernatants from in vitro stimulated iNKT cells recapitulates degranulation in an IFN-γ-dependent manner. Furthermore, endogenous IFN-γ secretion induced by anti-CD3 antibody injection causes Paneth loss and release of goblet cell mucus. The identification of IFN-γ as a trigger for degranulation and extrusion of PCs establishes a novel effector mechanism by which immune responses may regulate epithelial status and the gut microbiome.
Joint Effect of Diet and Environmental Tobacco Smoke on Risk of Lung Cancer Among Nonsmokers
Authors: P. Brennan
Journal: JNCI Journal of the National Cancer Institute (2000)

A recent meta-analysis based on 4626 cases concluded that the relative risk of lung cancer in lifelong nonsmokers who lived with a smoker was 1.24 (95% confidence interval [CI] 4 1.13‐ 1.36) (1). Subsequently, we reported in the Journal (2) the results from a large case‐control study of environmental tobacco smoke (ETS) and lung cancer based in 12 European centers. This study provided an odds ratio (OR) for lung cancer of 1.14 (95% CI 4 0.88‐ 1.47) for spousal and workplace exposure to ETS; the increase was most apparent among those in the top quartile of exposure (OR 4 1.31; 95% CI 4 0.88‐ 1.94) and the top decile of exposure (OR 4 1.46; 95% CI 4 0.96‐2.22) (P value for trend 4 .01). It could be argued that such increased risks associated with ETS might not represent a causal effect but may be due to confounding by dietary factors. To further elucidate this critical issue, we have analyzed the data of the European study by examining the joint relationship between dietary consumption, exposure to ETS, and lung cancer. Eight of the 12 centers have collected detailed food-frequency information on both case patients and control subjects, including information on intake of various fruits and vegetables, allowing weighted estimates of intake of several carotenoids combined (a-carotene, b-carotene, lutein, zeaxanthin, and lycopene), b-carotene alone, and retinol to be calculated (3). Dietary variables that showed a protective effect for lung cancer in the overall analysis and that were available for a majority of the centers included fruit, lettuce, tomato, carrot, and cheese consumption as well as intake of carotenoids, b-carotene, and retinol (3). To enable direct comparisons, the ORs for combined spousal and workplace exposures to high levels of ETS (upper quartile versus lower three quartiles) were calculated for the subset of centers with dietary information. The ORs for high ETS exposure were 1.40 in all eight centers (95% CI 4 1.05‐1.88), 1.36 in seven centers with information on fruit consumption (95% CI 4 1.01‐ 1.83), 1.32 in seven centers with information on lettuce consumption (95% CI 4 0.97‐1.81), 1.58 in seven centers with information on carotene consumption (95% CI 4 1.20‐2.08), and 1.16 in the five centers with information on tomato consumption (95% CI 4 0.77‐ 1.75). Table 1 reports the results of the analysis. Increased ORs for ETS were consistently observed both among subjects with high dietary consumption (OR in the fifth column versus those in the third column) and among subjects with low dietary consumption (OR in the sixth column versus OR in the fourth column), indicating no confounding by dietary items in the association between ETS and lung cancer. In addition, the highest ORs were observed when com
Tamoxifen in liver disease: Potential exacerbation of hepatic dysfunction
Authors: L.C. Floren, M.F. Hebert, A.P. Venook, V.C. Jordan, A. Cisneros, K.A. Somberg
Journal: Annals of Oncology (1998)

Tamoxifen, a non-steroidal anti-estrogen, has been used successfully for a decade as post-operative adjuvant therapy for breast cancer.Tamoxifen is generally well tolerated with few side effects, especially at the typical dose of 10 mg twice daily.However, hepatic effects have been reported after tamoxifen administration and are usually found to be cholestatic in nature.Although previous reports concentrate on tamoxifen as a probable cause of drug-induced hepatotoxicity, very little attention has been focused on the use of tamoxifen in patients with pre-existing liver dysfunction and the possible need for dose adjustment.We present the case of a 48-year-old woman with an acute exacerbation of her pre-existing liver dysfunction and subsequent elevations of tamoxifen blood levels after approximately one year of tamoxifen therapy for adjuvant treatment of breast cancer.Tamoxifen dosing was adjusted based on serum levels.
Gender-dependent reduction of spontaneous motor activity and growth in rats subjected to portacaval shunt
Authors: Hari S. Conjeevaram, Kevin D. Mullen, Elizabeth J. May, Arthur J. McCullough
Journal: Hepatology (1994)

Alterations in behavior are frequently described in rats subjected to portacaval shunt. Previous work has reported reduced spontaneous motor activity in various settings (nighttime, red light, decreased illumination) in this animal model. We investigated this phenomenon in rats of both genders subjected to portacaval shunt to determine whether our previously observed divergent growth patterns (males reduced, females unchanged) had any impact on the alterations in spontaneous motor activity in this model. Dietary intake, growth, motor activity and serum ammonia and amino acid concentrations were measured, in addition to final liver and spleen weights, in each animal after 3 to 4 wk of observation. Our results reconfirm the differential impact of portacaval shunt on growth in male (35% reduction p < 0.01) but not female rats (5% reduction, NS) compared with their respective-gender sham-operated controls. In addition, spontaneous motor activity was significantly reduced in male (congruent to 50%, p = 0.01) but not female rats subjected to portacaval shunt. The reduction of activity in male rats subjected to portacaval shunt did not correlate with any of the measured biochemical data or calculated nutritional/growth parameters. Thus we observed gender-dependent reduction in spontaneous motor activity after portacaval shunt in the rat. The mechanism for this phenomenon is unknown, but it is easily investigated with this reproducible model.
Endothelial transcytosis of myeloperoxidase confers specificity to vascular ECM proteins as targets of tyrosine nitration
Authors: Stephan Baldus, Jason P. Eiserich, Alireza Mani, Laura Castro, Mario Figueroa, Phillip Chumley, Wenxin Ma, Albert Tousson, C. Roger White, Daniel C. Bullard, Marie-Luise Brennan, Aldons J. Lusis, Kevin P. Moore, Bruce A. Freeman
Journal: Journal of Clinical Investigation (2001)

Nitrotyrosine formation is a hallmark of vascular inflammation, with polymorphonuclear neutrophil-derived (PMN-derived) and monocyte-derived myeloperoxidase (MPO) being shown to catalyze this posttranslational protein modification via oxidation of nitrite (NO(2)(-)) to nitrogen dioxide (NO(2)(*)). Herein, we show that MPO concentrates in the subendothelial matrix of vascular tissues by a transcytotic mechanism and serves as a catalyst of ECM protein tyrosine nitration. Purified MPO and MPO released by intraluminal degranulation of activated human PMNs avidly bound to aortic endothelial cell glycosaminoglycans in both cell monolayer and isolated vessel models. Cell-bound MPO rapidly transcytosed intact endothelium and colocalized abluminally with the ECM protein fibronectin. In the presence of the substrates hydrogen peroxide (H(2)O(2)) and NO(2)(-), cell and vessel wall-associated MPO catalyzed nitration of ECM protein tyrosine residues, with fibronectin identified as a major target protein. Both heparin and the low-molecular weight heparin enoxaparin significantly inhibited MPO binding and protein nitrotyrosine (NO(2)Tyr) formation in both cultured endothelial cells and rat aortic tissues. MPO(-/-) mice treated with intraperitoneal zymosan had lower hepatic NO(2)Tyr/tyrosine ratios than did zymosan-treated wild-type mice. These data indicate that MPO significantly contributes to NO(2)Tyr formation in vivo. Moreover, transcytosis of MPO, occurring independently of leukocyte emigration, confers specificity to nitration of vascular matrix proteins.
Anergy and exhaustion are independent mechanisms of peripheral T cell tolerance.
Authors: B Rocha, A Grandien, A A Freitas
Journal: The Journal of Experimental Medicine (1995)

We studied the interactions of male-specific T cell receptor (TCR)-alpha/beta-transgenic (TG) cells with different concentrations of male antigen in vivo. We constructed mouse chimeras expressing different amounts of male antigen by injecting thymectomized, lethally irradiated mice with various ratios of male (immunoglobulin [Ig] Ha) and female (IgHb) bone marrow. These chimeras were injected with male-specific TCR-alpha/beta-trangenic cells. These experiments allowed us to monitor antigen persistence and characterize antigen-specific T cells in terms of their frequency, reactivity, and effector functions (as tested by elimination of male B cells in vivo). In the absence of antigen, virgin TG cells persisted but did not expand. Transient exposure to antigen resulted in cell expansion, followed by the persistence of increased numbers of antigen-reactive T cells. In contrast, antigen persistence was followed by two independent mechanisms of tolerance induction: anergy (at high antigen concentrations), where T cells did not differentiate into effector functions but persisted in vivo as unresponsive T cells, and exhaustion (at lower antigen concentrations), where differentiation into effector functions (B cell elimination) occurred but was followed by the disappearance of antigen-specific T cells.
Effect of motor vehicle emissions on respiratory health in an urban area.
Authors: David L Buckeridge, Richard Glazier, Bart J Harvey, Michael Escobar, Carl Amrhein, John Frank
Journal: Environmental Health Perspectives (2002)

Motor vehicles emit particulate matter < 2.5 microm in diameter (PM(2.5)), and as a result, PM(2.5) concentrations tend to be elevated near busy streets. Studies of the relationship between motor vehicle emissions and respiratory health are generally limited by difficulties in exposure assessment. We developed a refined exposure model and implemented it using a geographic information system to estimate the average daily census enumeration area (EA) exposure to PM(2.5). Southeast Toronto, the study area, includes 334 EAs and covers 16 km(2) of urban area. We used hospital admission diagnostic codes from 1990 to 1992 to measure respiratory and genitourinary conditions. We assessed the effect of EA exposure on hospital admissions using a Poisson mixed-effects model and examined the spatial distributions of variables. Exposure to PM(2.5) has a significant effect on admission rates for a subset of respiratory diagnoses (asthma, bronchitis, chronic obstructive pulmonary disease, pneumonia, upper respiratory tract infection), with a relative risk of 1.24 (95% confidence interval, 1.05-1.45) for a log(10) increase in exposure. We noted a weaker effect of exposure on hospitalization for all respiratory conditions, and no effect on hospitalization for nonrespiratory conditions.
Plant thymidine kinase 1: a novel efficient suicide gene for malignant glioma therapy
Authors: Z. Khan, W. Knecht, M. Willer, E. Rozpedowska, P. Kristoffersen, A. R. Clausen, B. Munch-Petersen, P. M. Almqvist, Z. Gojkovic, J. Piskur, T. J. Ekstrom
Journal: Neuro-Oncology (2010)

The prognosis for malignant gliomas remains poor, and new treatments are urgently needed. Targeted suicide gene therapy exploits the enzymatic conversion of a prodrug, such as a nucleoside analog, into a cytotoxic compound. Although this therapeutic strategy has been considered a promising regimen for central nervous system (CNS) tumors, several obstacles have been encountered such as inefficient gene transfer to the tumor cells, limited prodrug penetration into the CNS, and inefficient enzymatic activity of the suicide gene. We report here the cloning and successful application of a novel thymidine kinase 1 (TK1) from the tomato plant, with favorable characteristics in vitro and in vivo. This enzyme (toTK1) is highly specific for the nucleoside analog prodrug zidovudine (azidothymidine, AZT), which is known to penetrate the blood-brain barrier. An important feature of toTK1 is that it efficiently phosphorylates its substrate AZT not only to AZT monophosphate, but also to AZT diphosphate, with excellent kinetics. The efficiency of the toTK1/AZT system was confirmed when toTK1-transduced human glioblastoma (GBM) cells displayed a 500-fold increased sensitivity to AZT compared with wild-type cells. In addition, when neural progenitor cells were used as delivery vectors for toTK1 in intracranial GBM xenografts in nude rats, substantial attenuation of tumor growth was achieved in animals exposed to AZT, and survival of the animals was significantly improved compared with controls. The novel toTK1/AZT suicide gene therapy system in combination with stem cell-mediated gene delivery promises new treatment of malignant gliomas.
Macrophages: Development and Tissue Specialization
Authors: Chen Varol, Alexander Mildner, Steffen Jung
Journal: Annual Review of Immunology (2015)

Macrophages are myeloid immune cells that are strategically positioned throughout the body tissues, where they ingest and degrade dead cells, debris, and foreign material and orchestrate inflammatory processes. Here we review two major recent paradigm shifts in our understanding of tissue macrophage biology. The first is the realization that most tissue-resident macrophages are established prenatally and maintained through adulthood by longevity and self-renewal. Their generation and maintenance are thus independent from ongoing hematopoiesis, although the cells can be complemented by adult monocyte-derived macrophages. Second, aside from being immune sentinels, tissue macrophages form integral components of their host tissue. This entails their specialization in response to local environmental cues to contribute to the development and specific function of their tissue of residence. Factors that govern tissue macrophage specialization are emerging. Moreover, tissue specialization is reflected in discrete gene expression profiles of macrophages, as well as epigenetic signatures reporting actual and potential enhancer usage.
Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation
Authors: L Moberg, H Johansson, A Lukinius, C Berne, A Foss, R Källen, Ø Østraat, K Salmela, A Tibell, G Tufveson, G Elgue, K Nilsson Ekdahl, O Korsgren, B Nilsson
Journal: The Lancet (2002)
Hyperbaric Oxygen Therapy for Diabetic Foot Wounds
Authors: Benjamin A. Lipsky, Anthony R. Berendt
Journal: Diabetes Care (2010)

“ One must always hope when one is desperate, and doubt when one hopes .” Gustave Flaubert.

Hyperbaric oxygen therapy (HBOT) has been promoted as an effective treatment for diabetic foot wounds, and the first controlled trial for this indication was reported (in Diabetes Care ) over 20 years ago (1). Advocates have suggested that the experimentally demonstrated effects of HBOT on improving wound tissue hypoxia, enhancing perfusion, reducing edema, downregulating inflammatory cytokines, promoting fibroblast proliferation, collagen production, and angiogenesis make it a useful adjunct in clinical practice for “problem wounds,” such as diabetic foot ulcers (2,3). HBOT is also touted for eradicating difficult to treat soft tissue and bone infections by mechanisms that include killing microorganisms, improving leukocyte and macrophage function, and enhancing the effect of antimicrobials (4). If realized clinically, these beneficial effects, although requiring expensive technology, might powerfully reduce the risk of lower-extremity amputation in diabetic patients with foot wounds. Thus, rigorously assessing the clinical effectiveness of HBOT in diabetic foot ulceration is an important enterprise. But, because both patients and clinicians are strongly motivated to avoid the devastating outcome of amputation, there is a high potential for bias in poorly designed trials. Proof of benefit requires properly conducted clinical trials that minimize the possibility that preexisting prejudices will influence the allocation of patients, diligence of foot care, or other key management decisions.

Most of the published reports on the effect of HBOT for treating diabetic foot wounds have been case series or nonrandomized trials with major methodological limitations. Although these are a poor source of evidence, the consistency of positive results is noteworthy. More recently, several randomized controlled trials have been conducted. A Cochrane database systematic review published in 2004 concluded, based on results from four such trials, that “HBOT significantly reduced the risk of …