tbuckley/cabot-search huggingface dataset:
Leishmaniasis in the era of tumor necrosis factor alpha antagonist therapy – a research agenda for Europe
Authors: P Zanger, S Gabrysch
Journal: Eurosurveillance (2013)

A number of published case reports suggest an association of tumor necrosis factor (TNF) alpha antagonist use and manifest leishmaniasis. Despite increasing popularity of antagonising TNF alpha for the treatment of autoimmune disorders, systematic research on the risk of opportunistic leishmaniasis in patients receiving these drugs is lacking. This perspective identifies areas of uncertainty regarding the safety profile of TNF alpha antagonist drugs and their clinical use in patients at risk of leishmaniasis. Then, we reflect on how current pharmacovigilance activities in Europe could be enhanced to help reduce these uncertainties. Our aim is to stimulate a debate about this important drug safety issue with potential consequences for patients receiving TNF alpha antagonists living in or travelling to areas endemic for leishmaniasis.
Bronchoalveolar lavage for diagnosing bacterial pneumonia in mechanically ventilated patients.
Authors: S Aubas, P Aubas, X Capdevila, H Darbas, J P Roustan, J Du Cailar
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

To assess the usefulness of BAL in diagnosing bacterial pneumonia in mechanically ventilated patients, 80 BAL fluid samples obtained from 72 patients with lung infiltrates were studied using the following parameters: infected cell count (polymorphonuclear leukocytes or macrophages with intracellular organisms), microscopic examination of stained smears, and quantitative culture with the determination of the simplified bacterial index (SBI) and the predominant species index (PSI). Of the 80 BAL samples studied, 56 were performed under antibiotic therapy. Bacterial pneumonia was the final diagnosis in 28 cases. The SBI is the sum of the whole numbers of each bacterial concentration expressed as a common logarithm. The PSI is the whole number of the predominant microorganism's concentration expressed as a common logarithm. The discriminative value of each test was assessed using a receiver operating characteristic (ROC) curve, whereby the possibility of establishing a cutoff value used to discriminate between the presence or absence of pneumonia is evaluated. The percentage of infected cells was higher in the pneumonia group (8.8 +/- 18.1 versus 0.4 +/- 1.1%, p < 10(-3), but no cutoff value could be proposed. Under microscopic examination, the presence of bacteria was noted with a significantly greater frequency in the pneumonia group (sensitivity 67.8% and specificity 82.7%). A total of 58 BAL samples were positive when cultured. The SBI was significantly higher in the pneumonia group (6.5 +/- 2.9 versus 1.6 +/- 1.7, p < 10(-4).(ABSTRACT TRUNCATED AT 250 WORDS)
A Mechanism of Hypoxia-Mediated Escape from Adaptive Immunity in Cancer Cells
Authors: Ivraym B. Barsoum, Chelsea A. Smallwood, D. Robert Siemens, Charles H. Graham
Journal: Cancer Research (2013)

Immune escape is a fundamental trait of cancer in which mechanistic knowledge is incomplete. Here, we describe a novel mechanism by which hypoxia contributes to tumoral immune escape from cytotoxic T lymphocytes (CTL). Exposure of human or murine cancer cells to hypoxia for 24 hours led to upregulation of the immune inhibitory molecule programmed cell death ligand-1 (PD-L1; also known as B7-H1), in a manner dependent on the transcription factor hypoxia-inducible factor-1α (HIF-1α). In vivo studies also demonstrated cellular colocalization of HIF-1α and PD-L1 in tumors. Hypoxia-induced expression of PD-L1 in cancer cells increased their resistance to CTL-mediated lysis. Using glyceryl trinitrate (GTN), an agonist of nitric oxide (NO) signaling known to block HIF-1α accumulation in hypoxic cells, we prevented hypoxia-induced PD-L1 expression and diminished resistance to CTL-mediated lysis. Moreover, transdermal administration of GTN attenuated tumor growth in mice. We found that higher expression of PD-L1 induced in tumor cells by exposure to hypoxia led to increased apoptosis of cocultured CTLs and Jurkat leukemia T cells. This increase in apoptosis was prevented by blocking the interaction of PD-L1 with PD-1, the PD-L1 receptor on T cells, or by addition of GTN. Our findings point to a role for hypoxia/HIF-1 in driving immune escape from CTL, and they suggest a novel cancer immunotherapy to block PD-L1 expression in hypoxic-tumor cells by administering NO mimetics.
The Pathophysiological Consequences of Somatostatin Receptor Internalization and Resistance
Authors: Leo J. Hofland, Steven W. J. Lamberts
Journal: Endocrine Reviews (2003)

Somatostatin receptors expressed on tumor cells form the rationale for somatostatin analog treatment of patients with somatostatin receptor-positive neuroendocrine tumors. Nevertheless, although somatostatin analogs effectively control hormonal hypersecretion by GH-secreting pituitary adenomas, islet cell tumors, and carcinoid tumors, significant differences are observed among patients with respect to the efficacy of treatment. This may be related to a differential expression of somatostatin receptor subtypes among tumors. In addition, the property of somatostatin receptor subtypes to undergo agonist-induced internalization has important consequences for visualizing, as well as for therapy, of receptor-postive tumors using radioisotope- or chemotherapeutic-compound-coupled somatostatin analogs. This review covers the pathophysiological role of somatostatin receptor subtypes in determining the efficacy of treatment of patients with somatostatin receptor-positive tumors using somatostatin analogs, as well as the preclinical and clinical consequences of agonist-induced receptor internalization for somatostatin receptor-targeted radio- and chemotherapy. Herein, the development and potential role of novel somatostatin analogs is discussed.
Expressed wishes and incidence of euthanasia in advanced lung cancer patients
Authors: Koen Pardon, Reginald Deschepper, Robert Vander Stichele, Jan L. Bernheim, Freddy Mortier, Denis Schallier, Paul Germonpré, Daniella Galdermans, Willem Van Kerckhoven, Luc Deliens
Journal: European Respiratory Journal (2012)

This study explores expressed wishes and requests for euthanasia ( i.e. administration of lethal drugs at the explicit request of the patient), and incidence of end-of-life decisions with possible life-shortening effects (ELDs) in advanced lung cancer patients in Flanders, Belgium. We performed a prospective, longitudinal, observational study of a consecutive sample of advanced lung cancer patients and selected those who died within 18 months of diagnosis. Immediately after death, the pulmonologist/oncologist and general practitioner (GP) of the patient filled in a questionnaire. Information was available for 105 out of 115 deaths. According to the specialist or GP, one in five patients had expressed a wish for euthanasia; and three in four of these had made an explicit and repeated request. One in two of these received euthanasia. Of the patients who had expressed a wish for euthanasia but had not made an explicit and repeated request, none received euthanasia. Patients with a palliative treatment goal at inclusion were more likely to receive euthanasia. Death was preceded by an ELD in 62.9% of patients. To conclude, advanced lung cancer patients who expressed a euthanasia wish were often determined. Euthanasia was performed significantly more among patients whose treatment goal after diagnosis was exclusively palliative.
S77 Benchmarking standards in paediatric pleural infection management
Authors: AM Long, J Smith-Williams, S Mayell, J Couriel, MO Jones, PD Losty
Journal: Thorax (2013)

<h3><b>Introduction and Objectives</b></h3> In our centre patients are managed using a protocol-driven integrated-care pathway. Intra-pleural urokinase is administered via a fine bore chest-drain as primary therapy for significant pleural disease. We analysed patient outcomes with this approach to benchmark standards of care whilst examining patterns of disease severity with introduction of the pneumococcal conjugate vaccine. In addition we aimed to identify factors associated with failure of fibrinolytic therapy, defined as the need for a second intervention, (second chest-drain, VATS or thoracotomy). <h3>Methods</h3> Medical case-records were reviewed on all children managed at a tertiary centre from Jan 2006-Dec 2012. We examined outcomes on all patients including those with significant medical comorbidities. Data were analysed using binary logistic regression in order to try to identify factors associated with therapy failure, (SPSS Version 20). The effect of; age, comorbidities, number of days of intravenous antibiotics prior to drainage, number of doses of urokinase given and whether initial imaging, (plain radiograph, ultrasound or CT), showed evidence of necrotising disease. <h3>Results</h3> A total of 242 children were treated; age range 4 months-19 yrs; median 4 yrs. We observed a decreasing number of children presenting year-on-year with complicated pleural infection, (Figure 1). The vast majority of children were managed without surgery using either antibiotics alone (28%), or a fine-bore chest-drain and urokinase (70%), with good outcome. Only 2% children required a primary thoracotomy whilst 14.6% failed fibrinolytic therapy and required a second intervention. The only factor that appeared to predict failure was the suspicion of necrotising disease on initial imaging (p = 0.01, OR 0.11). Median length-of-stay for all children, including those with medical co-morbidity, was 10 days (range 1–118 days). <h3>Conclusions</h3> We have observed a decreasing incidence of complicated pleural infection at this centre since 2006. Good patient outcome supports timely management of children using an integrated care-pathway led by a multidisciplinary team. The vast majority of children may be safely managed without surgery.
Differential Promoter Methylation of Macrophage Genes Is Associated With Impaired Vascular Growth in Ischemic Muscles of Hyperlipidemic and Type 2 Diabetic Mice
Authors: Mohan Babu, Thota Durga Devi, Petri Mäkinen, Minna Kaikkonen, Hanna P. Lesch, Sini Junttila, Asta Laiho, Bishwa Ghimire, Attila Gyenesei, Seppo Ylä-Herttuala
Journal: Circulation Research (2015)

Hyperlipidemia and type 2 diabetes mellitus (T2DM) severely impair adaptive vascular growth responses in ischemic muscles. This is largely attributed to dysregulated gene expression, although details of the changes are unknown.To define the role of promoter methylation in adaptive vascular growth in hyperlipidemia (LDLR(-/-)ApoB(100/100)) and T2DM (IGF-II/LDLR(-/-)ApoB(100/100)) mouse models of hindlimb ischemia.Unilateral hindlimb ischemia was induced by ligating femoral artery. Perfusion was assessed using ultrasound, and capillary and arteriole parameters were assessed using immunohistochemistry. Genome-wide methylated DNA sequencing was performed with DNA isolated from ischemic muscle, tissue macrophages (Mϕs), and endothelial cells. Compared with the controls, hyperlipidemia and T2DM mice showed impaired perfusion recovery, which was associated with impaired angiogenesis and arteriogenesis. Genome-wide proximal promoter DNA methylation analysis suggested differential patterns of methylation in Mϕ genes in ischemic muscles. Classically activated M1-Mϕ gene promoters, including Cfb, Serping1, and Tnfsf15, were significantly hypomethylated, whereas alternatively activated M2-Mϕ gene promoters, including Nrp1, Cxcr4, Plxnd1, Arg1, Cdk18, and Fes, were significantly hypermethylated in Mϕs isolated from hyperlipidemia and T2DM ischemic muscles compared with controls. These results combined with mRNA expression and immunohistochemistry showed the predominance of proinflammatory M1-Mϕs, compared with anti-inflammatory and proangiogenic M2-Mϕs in hyperlipidemia and T2DM ischemic muscles.We found significant promoter hypomethylation of genes typical for proinflammatory M1-Mϕs and hypermethylation of anti-inflammatory, proangiogenic M2-Mϕ genes in hyperlipidemia and T2DM ischemic muscles. Epigenetic alterations modify Mϕ phenotype toward proinflammatory M1 as opposed to anti-inflammatory, proangiogenic, and tissue repair M2 phenotype, which may contribute to the impaired adaptive vascular growth under these pathological conditions.
Effect of intra-articular infliximab on synovial membrane pathology in a patient with a seronegative spondyloarthropathy
Authors: M J Ahern, D G Campbell, H Weedon, V Papangelis, M D Smith
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objective:</h3> To demonstrate the efficacy of intra-articular infliximab in a patient with a persistent monarthritis who had previously had two arthroscopic synovectomies with limited success, and to determine the effect of intra-articular infliximab on synovial membrane pathology <h3>Method:</h3> Arthroscopic synovial biopsy specimens were collected before and after treatment with intra-articular infliximab. The synovial tissue was stained for a range of inflammatory cell subsets, cell adhesion molecules and cytokines using immunohistochemical techniques and quantified using digital image analysis and a semiquantitative scoring method. <h3>Results:</h3> Clinical improvement in the knee synovitis was seen after the first two intra-articular infliximab treatments, with a sustained clinical remission lasting for more than 12 months after the third treatment. Significant changes in cellular infiltration and expression of cytokines and cell adhesion molecules occurred as a result of treatment with intra-articular infliximab, with a reduction in some but not all cells in the inflammatory infiltrate, as well as a reduction in the expression of cell adhesion molecules (intercellular adhesion molecule-1 and vascular adhesion molecule-1) and production of cytokines (interleukin 1β and tumour necrosis factor α). <h3>Conclusion:</h3> Intra-articular infliximab administration is a viable treatment for a persistent monarthritis resistant to other treatment options and can successfully modulate the inflammatory milieu within the synovial membrane.
Parallels between attention deficit hyperactivity disorder and behavioral deficits produced by neurotoxic exposure in monkeys.
Authors: D C Rice
Journal: Environmental Health Perspectives (2000)

Attention deficit hyperactivity disorder (ADHD) is a disability that affects between 3 and 7% of children, with a significant number of individuals continuing to be affected into adolescence and adulthood. ADHD is characterized in part by an inability to organize complex sequences of behavior, to persist in the face of distracting stimuli, and to respond appropriately to the consequences of past behavior. There are some parallels between the features of ADHD and the behavior of monkeys exposed developmentally to lead or polychlorinated biphenyls (PCBs), as evidenced by research from our laboratory. Both lead and PCB exposure produce deficits on discrimination reversal and spatial delayed alternation performance; treated monkeys exhibit deficits in their ability to change an already established response strategy and inhibit inappropriate responses. Monkeys exposed developmentally to lead or PCBs also perform differently from control monkeys on a fixed interval schedule of reinforcement, which requires the temporal organization of behavior using only internal cues. Whereas the etiology of ADHD is multifactorial, the possibility that neurotoxic agents in the environment contribute to the incidence of ADHD warrants attention.
Nasal polyposis, eosinophil dominated inflammation, and allergy
Authors: N. Mygind
Journal: Thorax (2000)

A polyp is an oedematous mucous membrane which forms a pedunculating process with a slim or broad stalk or base.Nasal polyps originate in the upper part of the nose around the openings to the ethmoidal sinuses.The polyps extend into the nasal cavity from the middle meatus, resulting in nasal blockage and restricted airflow to the olfactory region.The polyp stroma is highly oedematous with a varying density of inflammatory cells.Nasal polyposis, consisting of recurrent, multiple polyps, is part of an inflammatory reaction involving the mucous membrane of the nose, paranasal sinuses, and often the lower airways.The polyps are easily accessible for immunological and histological studies and an increasing number of publications have appeared in recent years, including two monographs. 1 2 Nasal polyps have long been associated with rhinitis and asthma.However, the role of allergy in the aetiology and pathogenesis of nasal polyps is a controversial issue.It has been postulated that allergy is an aetiological factor for nasal polyposis.If this is so, then it can be expected that allergic patients will have polyps more often than a control population and that patients with polyps have an increased occurrence of positive allergy testing.In this paper we will describe the possible connection between nasal polyposis and allergy, based on an analysis of (1) the occurrence of polyps and of allergy, (2) the anatomy and histology of nasal polyps, (3) the inflammation in nasal polyps, (4) the occurrence of positive allergy tests in patients with polyps, (5) the eVect of allergen exposure on nasal symptoms in patients with polyps, and (6) the response to treatment.
Sex Differences in Acute Coronary Syndrome Symptom Presentation in Young Patients
Authors: Nadia A. Khan
Journal: JAMA Internal Medicine (2013)

IMPORTANCELittle is known about whether sex differences in acute coronary syndrome (ACS) presentation exist in young patients and what factors determine absence of chest pain in ACS presentation.OBJECTIVES To evaluate sex differences in ACS presentation and to estimate associations between sex, sociodemographic, gender identity, psychosocial and clinical factors, markers of coronary disease severity, and absence of chest pain in young patients with ACS.
POTASSIUM AND SODIUM RESTRICTION IN THE NORMAL HUMAN 1
Authors: Richard A. Womersley, James H. Darragh
Journal: Journal of Clinical Investigation (1955)

dium was restored to the diet but potassium restriction was continued.Blood samples were drawn, without stasis, under oil at the beginning and end of each period and at intermediate points.After clotting, they were centrifuged for 15 minutes and the serum drawn off.Urine was collected in 24-hour periods under mineral oil and toluol and kept refrigerated until analyzed.Stools for each period were collected, carmine red markers being used, and pre- served by the addition of sulfuric acid.The subjects were weighed daily at 9 a.m. in the postabsorptive state.Serum was analyzed for sodium, potassium, inorganic phosphorus, carbon dioxide, chloride, total proteins, and creatinine.Urine was analyzed for sodium, potassium, ammonia, titratable acid, chloride, phosphorus, carbon dioxide, pH, creatinine, and nitrogen.Feces were ana- lyzed for sodium, potassium, chloride, and nitrogen.The basic diet for study RW1 was Mead Johnson's Laboratory Product No. 4124.This product contains the solids from milk, rendered low in sodium and potas- sium, with added Dextri-maltose®.Four hundred and fifty-four grams of this product, which contained 15 mEq. of potassium, were made up in distilled water for each day's basic diet.In order to lower this figure for po- tassium, the solution was treated with an ion-exchange resin in the ammonium cycle (except on the last three study days) and an aliquot was analyzed for sodium, po- tassium, and nitrogen.By this means the basic dietary potassium intake was reduced to between 2 and 3 mEq.per day.The basic diet for studies RW2 and JD was Mead Johnson's Laboratory Product No. 412A.4This is similar to Product No. 412 except that 454 gm.provided approximately 1 mEq. of potassium and 1 mEq. of sodium.Both diets were adequate in calories and nitrogen and provided 8 mEq. of chloride per day.In all studies sup- plements of sodium and potassium, as the chloride salts, were added to the basic diets in the Initial periods and in the other periods, as indicated previously, to give the daily intakes indicated in Table I.Additional calcium chloride was given in study RW1 only.Two hundred extra grams of glucose were taken daily in all studies, except on day 14 of study RW2 when only 78 gm. were taken.Distilled water was allowed ad lib.External balances of water were calculated from the weight of the diet, the measured fluid intake, the weight lost isq excreta, the urine volume, the changes in body 4These products were supplied by: Mead Johnson and Co., Evansville, Indiana.
Rheumatoid arthritis and pregnancy; not only for rheumatologists interested in female health issues
Authors: Radboud J E M Dolhain
Journal: Annals of the Rheumatic Diseases (2010)

In this issue of the Annals of the Rheumatic Diseases Wallenius et al 1 report an increase in the onset of rheumatoid arthritis (RA) and other arthritides just after delivery ( see article on page 332 ). They have shown this by linking two national registers—namely, the Norwegian Disease-Modifying Antirheumatic Drug (NOR-DMARD) Register and the Medical Birth Register of Norway. This report confirms previous studies2 3 4 on RA and additionally extends our knowledge to other forms of arthritis. Owing to the low incidence of RA occurring simultaneously or just after pregnancy, the previous studies on this subject were mainly of a matched case–control design.2 4 Since every study design carries the risk of introducing its own type of bias, conformation of this finding in a different setting is important.

In these previous studies it has been shown that the increased incidence of RA after delivery is accompanied by a lower incidence during pregnancy.2 4 This suggests that the increased incidence of RA after delivery is not a true increased incidence, but rather that the occurrence of RA is postponed until after delivery.

How can these data be interpreted? It is clear that they can be seen in the scope of the well-known ameliorating effect of pregnancy on the course of existing RA and the flare-up of disease activity in the postpartum period. Since the first description of this phenomenon by Hench in 1938,5 this finding has been reconfirmed in several studies,6 7 most recently in a large prospective study from before conception and onwards.8 In this first large prospective study using validated instruments to determine disease activity,9 it was shown that almost half of …