tbuckley/cabot-search huggingface dataset:
Double blind, placebo controlled trial of metronidazole in Crohn's disease.
Authors: L Sutherland, J Singleton, J Sessions, S Hanauer, E Krawitt, G Rankin, R Summers, H Mekhjian, N Greenberger, M Kelly
Journal: Gut (1991)

A double blind study compared the efficacy of metronidazole in two doses (20 mg/kg, 10 mg/kg) with placebo in patients with Crohn9s disease. One hundred and five patients participated but only 56 completed the 16 week study -21 were withdrawn for deterioration of symptoms, 17 for adverse experiences, and 11 for protocol violation. Significant improvement in disease activity as measured by the Crohn9s disease activity index (metronidazole 20 mg/kg, 97 units; metronidazole 10 mg/kg, 67 units; placebo -1 unit, p = 0.002) and serum orosomucoid (metronidazole 20 mg/kg/day, 49; 10 mg/kg/day, 38; placebo, -9, p = 0.001)) were detected. Changes in C reactive protein concentrations did not achieve significance when all three groups were considered but were significant when all metronidazole treated patients were grouped and compared with the placebo treated patients (0.8 v -0.9, p less than 0.05). Although patients receiving metronidazole 20 mg/kg/day had a greater improvement in disease activity than those receiving 10 mg/kg/day (difference 30 units (95% confidence intervals -27-87), the small sample size may have precluded the detection of statistical significance. Preliminary analysis suggests that metronidazole was more effective in patients with disease confined to the large intestine or affecting both small and large bowel than in those with small bowel disease only. There were no differences in remission rates between metronidazole and placebo treated patients. We conclude that metronidazole warrants further assessment in the treatment of patients with active Crohn9s disease.
Stimulation of rat endothelial cell transforming growth factor-beta production by bleomycin.
Authors: S H Phan, M Gharaee-Kermani, F Wolber, U S Ryan
Journal: Journal of Clinical Investigation (1991)

This study examines the hypothesis that mediators from lung endothelial cells could promote lung collagen synthesis in pulmonary fibrosis. Since bleomycin induces pulmonary fibrosis in humans and animals, the effects of this drug on endothelial cells were examined. Endothelial cell conditioned media were prepared in the presence of various doses of bleomycin, and tested for their ability to stimulate lung fibroblast collagen synthesis. The results show a dose-dependent stimulation of endothelial cell secretion of collagen synthesis stimulatory activity by bleomycin, which peaked at a dose greater than or equal to 100 ng/ml. Stimulation was selective for collagenous protein synthesis. Gel filtration analysis showed most of the activity to reside in fractions with an estimated molecular mass range of 10-27 kD. The activity was inhibited by anti-transforming growth factor-beta (TGF-beta)antibody, but not by nonimmune control IgG. The presence of TGF-beta was confirmed using the mink lung epithelial cell assay. Northern blotting revealed significant increases in TGF-beta mRNA in bleomycin-stimulated endothelial cells. Thus in vitro stimulation of endothelial cells by bleomycin upregulates TGF-beta production, presumably by increased transcription. In view of the chemotactic and matrix synthesis stimulatory properties of this cytokine, such an increase in TGF-beta production may play an important role in bleomycin-induced pulmonary fibrosis.
Menopausal Status Should Be Taken Into Consideration for Patients With Luminal A Breast Cancer in Terms of the Effect of Differential Biology on Prognosis
Authors: Yutaka Yamamoto, Mutsuko Yamamoto-Ibusuki, Hirotaka Iwase
Journal: Journal of Clinical Oncology (2013)

how can an ER-positive cancer stem cell produced under high levels of estrogen be considered the same as an ER-positive cancer stem cell produced under low levels of estrogen? Moreover, we hypothesize that ER-positive tumors consist of three types—tumors that were both generated and detected by screening before menopause; tumors gen- erated before menopause but detected after menopause; and tumors that were both generated and detected after menopause—and that it may be difficult to distinguish correctly between these three ER- positive subtypes. Logically, these tumors would be expected to have different biologic features according to the different circumstances during development. Furthermore, Haynes et al 5 recently reported that expression levels of PR significantly differed across the menstrual cycle in ER-positive breast cancer. In conclusion, premenopausal and postmenopausal patients among the ER-positive breast cancer population should be distin- guished and their respective prognoses evaluated. We speculate that the prognostic impact of PR expression levels among patients with ER-positive tumors treated with endocrine therapy may differ be- tween premenopausal and postmenopausal patients. We would be grateful if the authors would provide us with information on the prognostic value of their newly proposed immunohistochemistry- based luminal A classification according to menopausal status.
An Evidence-based Staging System for Cutaneous Melanoma
Authors: C. M. Balch, S.-J. Soong, M. B. Atkins, A. C. Buzaid, N. Cascinelli, D. G. Coit, I. D. Fleming, J. E. Gershenwald, A. Houghton, J. M. Kirkwood, K. M. McMasters, M. F. Mihm, D. L. Morton, D. S. Reintgen, M. I. Ross, A. Sober, J. A. Thompson, J. F. Thompson
Journal: CA A Cancer Journal for Clinicians (2004)

A completely revised staging system for cutaneous melanoma was implemented in 2003. The changes were validated with a prognostic factors analysis involving 17,600 melanoma patients from prospective databases. This major collaborative study of predicting melanoma outcome was conducted specifically for this project, and the results were used to finalize the criteria for this evidence-based staging system. In fact, this was the largest prognostic factors analysis of prospectively followed melanoma patients ever conducted. Important results that shaped the staging criteria involved both the tumor-node-metastasis (TNM) criteria and stage grouping for all four stages of melanoma. Major changes in the staging include: (1) melanoma thickness and ulceration are the dominant predictors of survival in patients with localized melanoma (Stages I and II); deeper level of invasion (ie, IV and V) was independently associated with reduced survival only in patients with thin or T1 melanomas. (2) The number of metastatic lymph nodes and the tumor burden were the most dominant predictors of survival in patients with Stage III melanoma; patients with metastatic nodes detected by palpation had a shorter survival compared with patients whose nodal metastases were first detected by sentinel node excision of clinically occult or "microscopic" metastases. (3) The site of distant metastases (nonvisceral versus lung versus all other visceral metastatic sites) and the presence of elevated serum lactate dehydrogenase (LDH) were the dominant predictors of outcome in patients with Stage IV or distant metastases. (4) An upstaging was implemented for all patients with Stage I, II, and III disease when a primary melanoma is ulcerated by histopathological criteria. (5) Satellite metastases around a primary melanoma and in-transit metastases were merged into a single staging entity that is grouped into Stage III disease. (6) A new convention was implemented for defining clinical and pathological staging so as to take into account the new staging information gained from lymphatic mapping and sentinel node biopsy.
Identification of a costimulatory molecule rapidly induced by CD40L as CD44H.
Authors: Y Guo, Y Wu, S Shinde, M S Sy, A Aruffo, Y Liu
Journal: The Journal of Experimental Medicine (1996)

The interaction between CD40 ligand and CD40 is critical for activation of T and B cells in vivo. We have recently demonstrated that this interaction rapidly induces a novel costimulatory activity distinct from B7 and independent of CD28. To study the molecular basis of the costimulatory activity, we have produced a novel monoclonal antibody, TM-1, that binds an 85-kilodalton costimulatory molecule rapidly induced by CD40L. Expression cloning reveals that TM-1 binds CD44H. CD44H expressed on Chinese hamster ovary cells has potent costimulatory activity for clonal expansion of T cells isolated from both wild-type mice and these with a targeted mutation of CD28. Thus, CD44H costimulates T cell proliferation by a CD28-independent mechanism. These results revealed that CD44H is a costimulatory molecule rapidly induced by CD40L.
Self-reported adherence to pulmonary hypertension medications: Preliminary results from a longitudinal cohort study
Authors: Janelle Yorke, Iain Armstrong, Malcolm Campbell, Christi Deaton, Linda McGowen, Paul Sephton
Journal: European Respiratory Journal (2014)

Introduction: The level of adherence to pulmonary hypertension (PH) medications, and its potential determinates, is not currently known. We explored beliefs about medications held by people with PH and what factors influence adherence. Methods: Data included demographics, functional class (FC), and self-report questionnaires: Medication Adherence Scale (MAS), Beliefs about Medicines Questionnaire (BMQ); EmPHasis-10, Dyspnoea-12 and the Hospital Anxiety and Depression Scale (HADS). Results: 167 patients with PH (idiopathic 39%, congenital 19% or connective disease 18% aetiology; mean age 56 years, SD 13; Female 67%; FC II 35%, FC III 38%, FC IV 5%) were recruited from 9 centres in the UK. Less than half the sample reported a high level of adherence (41%). Most respondents agreed that their current health (90%) and future health (89%) depends on PH medications; although 54% were concerned about long term effects. The overall BMQ necessity score was higher than the BMQ concerns score (mean difference 9, SD 5; P
Reference values of total respiratory resistance, determined with the "opening" interruption technique
Authors: PH Vooren, BC van Zomeren
Journal: European Respiratory Journal (1989)

In a large epidemiological survey of lung function the subjects performed maximum expiratory flow volume (MEFV) manoeuvres. They were also interviewed by trained interviewers using a standardized questionnaire. In a random subset of the subjects the resistance of the respiratory system was measured with the "opening" interruption technique, in which the mouth pressure before the end of the interruption period is divided by the flow shortly after the end of it. The subset contained men and women, and smokers as well as nonsmokers, 229 of whom were considered to be healthy because they had no history of complaints and a "normal" flow-volume curve. In this group mean inspiratory and expiratory resistances did not differ significantly (0.27 and 0.29 for men and 0.39 and 0.38 kPa.l-1.s for women). The averages of in- and expiratory resistance were 0.28 +/- 0.10 kPa.l-1.s for men and 0.39 +/- 0.11 kPa.l-1.s for women. The resistance values were slightly but significantly correlated with body height, FEV1 and MEF50, but not with smoking habits. Due to the considerable variability the method does not permit sharp discrimination between normal and abnormal subjects. However, it appears to be useful in histamine challenge testing, to detect and monitor bronchial asthma, being not subjected to the disturbing effect of forced ins- and expirations.
EFFECTS OF PROTEINURIA ON THE KIDNEY
Authors: James H. Baxter, George C. Cotzias
Journal: The Journal of Experimental Medicine (1949)

Repeated intraperitoneal injections twice daily of various proteins into young rats were regularly accompanied by an increase in the protein content of the urine, significant renal enlargement, and often some degree of renal pallor. The most marked changes were induced by gelatin, followed in order by human albumin and bovine globulin. Rat serum produced similar but less conclusive changes. Similar changes were not produced by equivalent amounts of urea or casein hydrolysate. In sections from the kidneys of animals receiving gelatin, the cells of the convoluted tubules appeared enlarged, and they contained clear "spaces" throughout the cytoplasm. The tubular cells of the animals receiving the other solutions were not obviously altered in size or shape, and the cytoplasmic changes were slight or absent. There was little evidence of increased multiplication of cells or of tubular dilatation in the kidneys of any of the groups. Changes in concentrations of plasma proteins and hemoglobin, and the results of preliminary studies of the injected proteins in urine and renal tissue following the injections, are described and their possible significance discussed. It appears that the renal enlargement, as well as the increase in proteinuria and the tubular alterations which followed the protein injections, might have been caused in part by effects on the kidney of protein molecules per se, perhaps most likely by the effects on the tubular cells of an increased amount of protein filtered through the glomerular membranes, rather than entirely by effects of products of protein digestion and metabolism reaching the kidney through the blood stream. In the majority of animals there was no evidence from the morphological or functional studies, that the prolonged and continuous proteinuria induced by the protein injections resulted in renal damage, unless the renal enlargement, and the cytoplasmic changes which occurred regularly with gelatin, are considered evidence of damage. Renal enlargement and proteinuria promptly regressed after injections were discontinued. Lesions characterized by severe degrees of tubular damage, possibly as a result of tubular plugging, were observed in some of the animals of one group receiving gelatin solution of the usual concentration, and dilatation of renal tubules and glomerular capsules was present in some other gelatin-treated animals autopsied after relatively brief injection periods. A description is also presented of lesions of remarkable character which developed in the kidneys of all the animals of one small group receiving homologous serum obtained from severely anoxic donors. The possible relationship between the renal changes in the protein-injected animals and certain alterations of the kidneys observed in diseases characterized by large amounts of protein in the urine, is considered.
STUDIES ON DELAYED CUTANEOUS INFLAMMATORY REACTIONS ELICITED BY INOCULATION OF HOMOLOGOUS CELLS INTO HAMSTERS' SKINS
Authors: Hansruedy Ramseier, R. E. Billingham
Journal: The Journal of Experimental Medicine (1966)

The intracutaneous inoculation of lymph node cell suspensions from normal hamsters into normal, homologous hosts causes the development of delayed inflammatory reactions, normal lymphocyte transfer (NLT) reactions, the intensities of which reflect the antigenic disparity between donor and recipient. The immunogenetic situations in which they occur indicate that these reactions are due to sensitization in situ on the part of inoculated immunologically competent cells against alien antigens of the host. They are graft versus host reactions. If hamsters are sensitized by cellular or solid tissue homografts and then challenged intracutaneously with lymphoid or epidermal cells from the donor strain, direct reactions are provoked. A positive correlation exists between the development of transplantation immunity and the capacity to give direct reactions. The sensitivity responsible for direct reactions can be suppressed by irradiation or administration of cortisone, and it is transferable by means of viable lymphoid tissues or cells but not by means of serum. Intracutaneous inoculation of viable node or splenic cells from specifically sensitized hamsters into hosts of the donor strain incites transfer reactions, the intensities of which depend upon the number of cells transferred and the level of sensitivity in the animal that provided them. These reactions are not incitable by thymocytes, by killed lymphoid cells, or by serum. Transfer reactions differ from NLT reactions only on a quantitative and chronologic basis. However, a sharp experimental distinction can be drawn between them. For example, if normal MHA node cells and node cells from MHA hamsters sensitized against CB antigens are injected into the skins of MHA's tolerant of CB tissue, only the sensitized cells incite reactions. Both direct and transfer reactions are highly specific immunologically. The inability of node cells to incite NLT or transfer reactions in heavily irradiated hosts and other findings sustain the thesis that it is host cells of hematologic origin, rather than indigenous skin cells, that contribute the antigenic stimulus required for these reactions. All the findings presented are consistent with the hypothesis that the various delayed inflammatory reactions described are manifestations of immunological responses on the part of immunologically competent cells against alien transplantation antigens.
Inhibitory Effect of Sodium Ascorbate on Ethylurea and Sodium Nitrite Carcinogenesis and Negative Findings in Progeny After Intestinal Inoculation of Precursors Into Pregnant Hamsters2
Authors: Mario Rustia
Journal: JNCI Journal of the National Cancer Institute (1975)

To assess their carcinogenic effects, the ethylnitrosourea (ENU) precursors, ethylurea and sodium nitrite, [were administered to pregnant hamsters as a single intragastic] dose on day 15 of gestation, or introduced into the cecum on day 14. Since sodium ascorbate (NaASC) inhibits the biosynthesis of nitrosamides, identical doses of the precursors were given concomitantly with NaASC. Progeny of mothers treater intragastrically developed significant incidences of neurogenic tumors of the peripheral nervous system, with a predominance in females. The concurrent administration of NaASC with ENU precursors prevented carcinogenic effects in the progency, whereas the simultaneous inoculation of the precursors into the cecum produced no carcinogenic effects in the offspring.
Inhibiting glycosphingolipid synthesis ameliorates hepatic steatosis in obese mice
Authors: Hongmei Zhao, Malgorzata Przybylska, I-Huan Wu, Jinhua Zhang, Panagiotis Maniatis, Joshua Pacheco, Peter Piepenhagen, Diane Copeland, Cynthia Arbeeny, James A. Shayman, Johannes M. Aerts, Canwen Jiang, Seng H. Cheng, Nelson S. Yew
Journal: Hepatology (2009)

Steatosis in the liver is a common feature of obesity and type 2 diabetes and the precursor to the development of nonalcoholic steatohepatitis (NASH), cirrhosis, and liver failure. It has been shown previously that inhibiting glycosphingolipid (GSL) synthesis increases insulin sensitivity and lowers glucose levels in diabetic rodent models. Here we demonstrate that inhibiting GSL synthesis in ob/ob mice not only improved glucose homeostasis but also markedly reduced the development of hepatic steatosis. The ob/ob mice were treated for 7 weeks with a specific inhibitor of glucosylceramide synthase, the initial enzyme involved in the synthesis of GSLs. Besides lowering glucose and hemoglobin A1c (HbA1c) levels, drug treatment also significantly reduced the liver/body weight ratio, decreased the accumulation of triglycerides, and improved several markers of liver pathology. Drug treatment reduced liver glucosylceramide (GL1) levels in the ob/ob mouse. Treatment also reduced the expression of several genes associated with hepatic steatosis, including those involved in lipogenesis, gluconeogenesis, and inflammation. In addition, inhibiting GSL synthesis in diet-induced obese mice both prevented the development of steatosis and partially reversed preexisting steatosis.These data indicate that inhibiting GSL synthesis ameliorates the liver pathology associated with obesity and diabetes, and may represent a novel strategy for treating fatty liver disease and NASH.
Tumor Necrosis Factor-α Antagonism Improves Vasodilation During Hyperinsulinemia in Metabolic Syndrome
Authors: Manfredi Tesauro, Francesca Schinzari, Valentina Rovella, Domenico Melina, Nadia Mores, Angela Barini, Marco Mettimano, Davide Lauro, Micaela Iantorno, Michael J. Quon, Carmine Cardillo
Journal: Diabetes Care (2008)

Obesity is associated with chronic inflammation due to overproduction of proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha. We assessed the effects of TNF-alpha neutralization by infliximab on vascular reactivity during hyperinsulinemia in obesity-related metabolic syndrome.Vascular responses to intra-arterial infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed in patients with metabolic syndrome, before and after administration of infliximab.Patients had blunted vasodilator responses to ACh and SNP during hyperinsulinemia compared with control subjects; a potentiation of the responsiveness to both ACh and SNP, however, was observed in patients following infliximab. The antioxidant vitamin C improved the vasodilator response to ACh in patients with metabolic syndrome, but its effect was not further enhanced by concurrent administration of infliximab.TNF-alpha neutralization ameliorates vascular reactivity in metabolic syndrome during hyperinsulinemia, likely in relation to decreased oxidative stress, thereby suggesting an involvement of inflammatory cytokines in vascular dysfunction of these patients.
Clean air in Europe: beyond the horizon?
Authors: Bert Brunekreef, Nino Künzli, Juha Pekkanen, Isabella Annesi-Maesano, Bertil Forsberg, Torben Sigsgaard, Menno Keuken, Francesco Forastiere, Maeve Barry, Xavier Querol, Roy M. Harrison
Journal: European Respiratory Journal (2014)

When the European Union (EU) set its first Air Quality Limit Values for particulate matter in outdoor air (particulate matter <10 μm in diameter (PM10)) back in 1999, it promised to set a much stricter limit by 2010 [1]. The goal at the time was for an annual limit value of 20 µg·m−3, equivalent to the World Health Organization (WHO) Air Quality Guideline set in 2005 [2]. When it was time to do so, however, the new directive adopted in 2008 had no trace of it, and essentially preserved the limit values set in 1999, to which a rather unambitious limit value for fine particles (PM2.5) was added [3]. The limit value for PM2.5 is an annual average of 25 µg·m−3, to be reached by the year 2015: 2.5 times higher than the WHO guideline value (10 µg·m−3), based on the science available already in 2005 [2], and twice the current standard of 12 µg·m−3 in the USA. The 2008 directive, however, did introduce a voluntary exposure reduction scheme aiming for much lower levels of urban PM2.5 up to 2020, with the intention of being made mandatory by 2013. In December 2013, at the end of the EU Year of Air, the Commission finally presented its new policy plan. This does not revise the limit values in the Air Quality Directive and does not make mandatory the voluntary exposure reduction targets, but now proposes introducing a medium-size combustion plant emissions directive and further reductions of the so-called National Emission Ceilings [4–6]. These reductions (as we will show here) are rather unambitious until 2020, but call for much stronger reductions in 2030, i.e. well over the horizon. The current EU limit values for PM2.5 and PM10 are far too high <http://ow.ly/E6HUR>