tbuckley/cabot-search huggingface dataset:
Involvement of X-box binding protein 1 and reactive oxygen species pathways in the pathogenesis of tumour necrosis factor receptor-associated periodic syndrome
Authors: Laura J Dickie, Azad M Aziz, Sinisa Savic, Orso M Lucherini, Luca Cantarini, Janina Geiler, Chi H Wong, Robert Coughlan, Thirusha Lane, Helen J Lachmann, Philip N Hawkins, Philip A Robinson, Paul Emery, Dennis McGonagle, Michael F McDermott
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> To investigate convergence of endoplasmic reticulum stress pathways and enhanced reactive oxygen species (ROS) production, due to intracellular retention of mutant tumour necrosis factor receptor 1 (TNFR1), as a disease mechanism in TNFR-associated periodic syndrome (TRAPS). <h3>Methods</h3> Peripheral blood mononuclear cells from patients with TRAPS (n=16) and healthy controls (HC) (n=22) were studied alongside HEK293T cells expressing wild type-TNFR1 or TRAPS-associated mutations. Unfolded protein response (UPR)-associated proteins (protein kinase-like endoplasmic reticulum kinase, PERK), phosphorylated-PERK (p-PERK), phosphorylated inositol-requiring enzyme 1α (p-IRE1α) and spliced X-box binding protein 1 (<i>sXBP1</i>)) were measured by flow cytometry. <i>XBP1</i> splicing and UPR-associated transcript expression were assessed by reverse transcription PCR/quantitative real-time PCR. ROS levels were measured using CM-H<sub>2</sub>DCFDA and MitoSOX Red in patients9 monocytes or HEK293T cells by flow cytometry. <h3>Results</h3> Mutant TNFR1-expressing HEK293T cells had increased TNFR1 expression associated with intracellular aggregation. TRAPS patients had increased <i>sXBP1</i> transcripts (p&lt;0.01) compared with HC. Raised p-PERK protein was seen, indicative of an UPR, but other UPR-associated transcripts were normal. Increased ROS levels were observed in TRAPS monocytes compared with HCs (p&lt;0.02); these increased further upon IL-6 stimulation (p&lt;0.01). Lipopolysaccharide-stimulated peripheral blood mononuclear cells of patients with TRAPS, but not HCs, demonstrated increased <i>sXBP1</i> levels (p&lt;0.01), which were reduced by antioxidant treatment (p&lt;0.05). <h3>Conclusions</h3> Patients with TRAPS have evidence of increased <i>sXBP1</i> and PERK expression but without other signs of classical UPR, and also with high ROS generation that may contribute to the pro-inflammatory state associated with TRAPS. The authors propose a non-traditional <i>XBP1</i> pathway with enhanced <i>sXBP1</i> as a novel disease-contributing mechanism in TRAPS.
Increase in urinary leukotriene LTE4 levels in acute asthma: correlation with airflow limitation
Authors: S A Green
Journal: Thorax (2004)

<b>Background:</b> Leukotrienes play a key role in the pathophysiology of chronic asthma. Activation of leukotriene pathways is accompanied by rises in detectable urinary levels of leukotriene E<sub>4</sub> (LTE<sub>4</sub>). The relationship between urinary LTE<sub>4</sub> levels and factors associated with acute asthma has not been determined. <b>Methods:</b> Adults aged 15–54 years presenting with moderate to severe acute asthma were evaluated at emergency departments in 16 US sites. Forced expiratory volume in 1 second (FEV<sub>1</sub>) was measured during the first 60 minutes after arrival and at specified times until discharge or admission. Urine samples for measurement of LTE<sub>4</sub> levels were obtained either on arrival at the study site and/or before discharge. Patients were seen 2 weeks later for follow up, at which time repeat FEV<sub>1</sub> measurements and urine samples for LTE<sub>4</sub> were obtained. <b>Results:</b> One hundred and eighty four patients were evaluated; LTE<sub>4</sub> results from both the acute and follow up periods were available for analysis in 146. Urinary LTE<sub>4</sub> levels were increased during asthma exacerbations compared with levels obtained 2 weeks later (geometric means 111.7 and 75.6 pg/mg creatinine, respectively, mean percentage change −32.3; 95% confidence interval (CI) for the mean percentage change −39.6 to −24.3, p&lt;0.001). The correlation between improvement in FEV<sub>1</sub> and decline in LTE<sub>4</sub> over the 2 week interval was significant (p&lt;0.001, <i>r</i> = 0.43). <b>Conclusions:</b> Activation of leukotriene pathways in acute asthma is correlated with the degree of airflow obstruction, and resolution of the asthma exacerbation is associated with a reduction in leukotriene levels.
Interleukin-18 and interleukin-18 receptor- expression in allergic asthma
Authors: H. Imaoka, G. M. Gauvreau, R. M. Watson, S. G. Smith, B. Dua, A. J. Baatjes, K. Howie, T. Hoshino, K. J. Killian, H. Aizawa, P. M. O'Byrne
Journal: European Respiratory Journal (2011)

To the Editors:

The inflammatory process in allergic asthma is initiated by T-helper (Th) type-2 cells, which produce a repertoire of cytokines, including interleukin (IL)-4, IL-5, IL-9 and IL-13, which are necessary for immunoglobulin (Ig)E production, airway eosinophilia and goblet cell hyperplasia [1]. IL-18 is another pro-inflammatory cytokine, initially described as interferon (IFN)-γ-inducing factor [2]. IL-18 can act as a cofactor for Th2 cell development and IgE production [3]. Recently, an IL-18 gene polymorphism was reported to be associated with asthma severity and higher serum IL-18 levels: the rs5744247 variant, which has higher transcriptional activity than the wildtype allele [4]. In addition, the IL-18 receptor (IL-18R) gene (on 2q21) has been identified as a candidate gene associated with increased susceptibility to asthma in children [5], and polymorphisms of the gene have been associated with allergic asthma and airway hyperresponsiveness (AHR) [6]. We have evaluated serum levels of IL-18 and the expression of IL-18Rα, as well as other Th2-associated cytokines, in stable allergic asthmatic subjects, compared with allergic nonasthmatic subjects and healthy controls.

We studied 36 subjects, which included 15 allergic asthmatic subjects, 11 nonasthmatic allergic subjects and 10 healthy controls (table 1). All subjects underwent a methacholine inhalation challenge [7] and had skin-prick tests to a panel of 16 environmental allergens. Total IgE, and serum IL-18, IL-4, IL-10, IL-12, IL-13 and IFN-γ were measured using commercially available ELISA kits (Medical and Biological Laboratories Co., Nagoya, Japan; RD DRG International Inc., Mountainside, NJ, USA). The allergic subjects were studied outside …
Phase II Study of Erlotinib in Patients With Advanced Biliary Cancer
Authors: Philip A. Philip, Michelle R. Mahoney, Cristine Allmer, James Thomas, Henry C. Pitot, George Kim, Ross C. Donehower, Tom Fitch, Joel Picus, Charles Erlichman
Journal: Journal of Clinical Oncology (2006)

Epidermal growth factor receptor/human epidermal growth factor receptor 1 and ligand expression is common in biliary cancers (BILI) and may be associated with worse outcome. The primary objective of this study was to determine the proportion of patients with advanced BILI who were progression-free at 6 months.Patients with either unresectable or metastatic disease were studied. Only one prior systemic or locoregional therapy was allowed. Erlotinib was administered continuously at a dose of 150 mg per day orally.Forty-two patients with BILI were enrolled. The median age was 67 years (range, 33 to 82 years). Fifty-two percent of patients had Eastern Cooperative Oncology Group performance status of 1. Fifty-seven percent of patients had received prior chemotherapy for advanced BILI. HER1/EGFR expression by immunohistochemistry in tumor cells was detected in 29 (81%) of the 36 assessable patients. Seven of the patients (17%; 95% CI, 7% to 31%) were progression free at 6 months. Three patients had partial response by Response Evaluation Criteria in Solid Tumors Group classification of duration 4, 4, and 14 months, respectively. All responding patients had mild (grade 1/2) skin rash and two patients had positive tumoral HER1/EGFR expression. Three patients (7%) had toxicity-related dose reductions of erlotinib due to grade 2/3 skin rash.Results suggest a therapeutic benefit for EGFR blockade with erlotinib in patients with biliary cancer. Additional studies with erlotinib as a single agent and in combination with other targeted agents are warranted in this disease.
Efficacy and Safety of Abiraterone Acetate in an Elderly Patient Subgroup (Aged 75 and Older) with Metastatic Castration-resistant Prostate Cancer After Docetaxel-based Chemotherapy
Authors: Peter F.A. Mulders, Arturo Molina, Michael Marberger, Fred Saad, Celestia S. Higano, Kim N. Chi, Jinhui Li, Thian Kheoh, Christopher M. Haqq, Karim Fizazi
Journal: European Urology (2013)
Vital Capacity as a Predictor of Incident Type 2 Diabetes
Authors: Hsin-Chieh Yeh, Naresh M. Punjabi, Nae-Yuh Wang, James S. Pankow, Bruce B. Duncan, Frederick L. Brancati
Journal: Diabetes Care (2005)

OBJECTIVE—To test the hypothesis that lower vital capacity is cross-sectionally associated with features of insulin resistance and is an independent predictor of incident type 2 diabetes. RESEARCH DESIGN AND METHODS—We conducted a prospective cohort study of vital capacity as a predictor of incident type 2 diabetes using 9-year follow-up data on 11,479 middle-aged adults without diabetes at baseline from the Atherosclerosis Risk in Communities (ARIC) Study. RESULTS—Forced vital capacity (FVC) and forced expiratory volume in 1 s were measured at baseline using standard spirometry. Incident type 2 diabetes cases were ascertained during follow-up. At baseline, low FVC (% predicted) was independently associated with indicators of the insulin resistance syndrome, including higher fasting levels of glucose, insulin, and triglycerides; lower fasting HDL cholesterol; and higher systolic blood pressure. In prospective analyses, there were graded associations between low FVC (% predicted) and incidence of type 2 diabetes in men and women. These associations persisted in multivariable analyses that adjusted for age, race, adiposity, smoking, physical activity, and ARIC center. Compared with individuals in the highest quartile of FVC (% predicted), the fully adjusted hazard ratio (95% CI) of diabetes in individuals in the lowest quartile was 1.6 (1.3–2.0) in men and 1.7 (1.3–2.1) in women. These relationships were stronger in those who have never smoked. CONCLUSIONS—Lower vital capacity is an independent predictor of incident type 2 diabetes. Pulmonary factors related to vital capacity deserve attention as possible risk factors for insulin resistance and diabetes.
Neuronal Network Plasticity and Recovery From Depression
Authors: Eero Castrén
Journal: JAMA Psychiatry (2013)

The brain processes sensory information in neuronal networks that are shaped by experience, particularly during early life, to optimally represent the internal and external milieu. Recent surprising findings have revealed that antidepressant drugs reactivate a window of juvenile-like plasticity in the adult cortex. When antidepressant-induced plasticity was combined with appropriate rehabilitation, it brought about a functional recovery of abnormally wired neuronal networks. These observations suggest that antidepressants act permissively to facilitate environmental influence on neuronal network reorganization and so provide a plausible neurobiological explanation for the enhanced effect of combining antidepressant treatment with psychotherapy. The results emphasize that pharmacological and psychological treatments of mood disorders are closely entwined: the effect of antidepressant-induced plasticity is facilitated by rehabilitation, such as psychotherapy, that guides the plastic networks, and psychotherapy benefits from the enhanced plasticity provided by the drug treatment. Optimized combinations of pharmacological and psychological treatments might help make best use of existing antidepressant drugs and reduce the number of treatment-resistant patients. The network hypothesis of antidepressant action presented here proposes that recovery from depression and related mood disorders is a gradual process that develops slowly and is facilitated by structured guidance and rehabilitation.
Early Duplication and Functional Diversification of the Opsin Gene Family in Insects
Authors: J. Spaethe
Journal: Molecular Biology and Evolution (2004)

Recent analysis of the complete mosquito Anopheles gambiae genome has revealed a far higher number of opsin genes than for either the Drosophila melanogaster genome or any other known insect. In particular, the analysis revealed an extraordinary opsin gene content expansion, whereby half are long wavelength–sensitive (LW) opsin gene duplicates. We analyzed this genomic data in relationship to other known insect opsins to estimate the relative timing of the LW opsin gene duplications and to identify "missing" paralogs in extant species. The inferred branching patterns of the LW opsin gene family phylogeny indicate at least one early gene duplication within insects before the emergence of the orders Orthoptera, Mantodea, Hymenoptera, Lepidoptera, and Diptera. These data predict the existence of one more LW opsin gene than is currently known from most insects. We tested this prediction by using a degenerate PCR strategy to screen the hymenopteran genome for novel LW opsin genes. We isolated two LW opsin gene sequences from each of five bee species, Bombus impatiens, B. terrestris, Diadasia afflicta, D. rinconis, and Osmia rufa, including 1.1 to 1.2 kb from a known (LW Rh1) and 1 kb from a new opsin gene (LW Rh2). Phylogenetic analysis suggests that the novel hymenopteran gene is orthologous to A. gambiaeGPRop7, a gene that is apparently missing from D. melanogaster. Relative rate tests show that LW Rh2 is evolving at a slower rate than LW Rh1 and, therefore, may be a useful marker for higher-level hymenopteran systematics. Site-specific rate tests indicate the presence of several amino acid sites between LW Rh1 and LW Rh2 that have undergone shifts in selective constraints after duplication. These sites and others are discussed in relationship to putative structural and functional differences between the two genes.
The New Zealand Rugby Injury and Performance Project: V. Epidemiology of a season of rugby injury.
Authors: Y N Bird, A E Waller, S W Marshall, J C Alsop, D J Chalmers, D F Gerrard
Journal: British Journal of Sports Medicine (1998)

OBJECTIVE: To describe the incidence, nature, and circumstances of injury experienced by a cohort of rugby union players during a full competitive club season. METHODS: A prospective cohort study followed up 356 male and female rugby players throughout the 1993 competitive club season. Players were interviewed by telephone each week to obtain information on the amount of rugby played and the injury experienced. RESULTS: Detailed information was collected for 4403 player-games and 8653 player-practices. A total of 671 injury events were reported, of which 569 were rugby related. The injury rate for games was higher than that for practices (rate ratio 8.3). At 10.9 injuries per 100 player-games, males had a higher rate of injury than females at 6.1 injuries per 100 player-games (p&lt;0.001). Injury rates varied by position, with male locks (13.0 injuries per 100 player-games) and female inside backs (12.3 injuries per 100 player-games) having the highest rate in their respective sexes. The lower limb was the body region most often injured in games (42.5%) and practices (58.4%). Sprains/strains were the most common type of injury in games (46.7%) and practices (76.1%). In games the tackle was the phase of play in which the most injuries occurred (40%), followed by rucks (17%) and mauls (12%). Thirteen per cent of game injury events were the result of foul play. CONCLUSIONS: Rugby injury was common among the study subjects and varied according to grade and gender. Identifying the causes of injuries in the tackle, lower limb injuries, and dealing with the issue of foul play are priority areas for the prevention of rugby injury.
Estimating the Cost of Cancer: Results on the Basis of Claims Data Analyses for Cancer Patients Diagnosed With Seven Types of Cancer During 1999 to 2000
Authors: Stella Chang, Stacey R. Long, Lucie Kutikova, Lee Bowman, Denise Finley, William H. Crown, Charles L. Bennett
Journal: Journal of Clinical Oncology (2004)

Cancer accounts for 60.9 billion dollars in direct medical costs and 15.5 billion dollars for indirect morbidity costs. These estimates are derived primarily from national surveys or Federal databases. We derive estimates of the costs of cancer using administrative databases, which include claims and employment-related information on individuals insured by private or Medicare supplemental health plans.A retrospective matched-cohort control analysis was performed using 1998 to 2000 databases with information on insurance claims, benefits, and health productivity for 3 million privately insured employees, their dependents, and early retirees. Study patients had new diagnoses of one of seven types of cancer (n = 12,709). Controls without cancer were matched at a 3:1 ratio by demographics. A variable follow-up length was used (maximum of 2 years). Direct costs included health care costs for patients and deductibles and copayments for caregivers. Indirect costs of work absence and short-term disability (STD) were calculated for a subgroup of cancer patients and caregivers.Mean monthly health care costs ranged from 2,187 dollars for prostate cancer to 7,616 dollars for pancreatic cancer, most often driven by hospitalization. Costs for controls were 329 dollars per month. Indirect morbidity costs to employees with cancer averaged 945 dollars, a result of a mean monthly loss of 2.0 workdays and 5.0 STD days.The economic burden of cancer is substantial. It is feasible to derive tumor-specific estimates of direct and indirect costs for large numbers of cancer patients using administrative databases. Policy makers charged with providing annual cost-of-cancer estimates should incorporate data obtained from a broad range of sources.
Novel arterial pathology in mice and humans hemizygous for elastin.
Authors: D Y Li, G Faury, D G Taylor, E C Davis, W A Boyle, R P Mecham, P Stenzel, B Boak, M T Keating
Journal: Journal of Clinical Investigation (1998)

Obstructive vascular disease is an important health problem in the industrialized world. Through a series of molecular genetic studies, we demonstrated that loss-of-function mutations in one elastin allele cause an inherited obstructive arterial disease, supravalvular aortic stenosis (SVAS). To define the mechanism of elastin's effect, we generated mice hemizygous for the elastin gene (ELN +/-). Although ELN mRNA and protein were reduced by 50% in ELN +/- mice, arterial compliance at physiologic pressures was nearly normal. This discrepancy was explained by a paradoxical increase of 35% in the number of elastic lamellae and smooth muscle in ELN +/- arteries. Examination of humans with ELN hemizygosity revealed a 2. 5-fold increase in elastic lamellae and smooth muscle. Thus, ELN hemizygosity in mice and humans induces a compensatory increase in the number of rings of elastic lamellae and smooth muscle during arterial development. Humans are exquisitely sensitive to reduced ELN expression, developing profound arterial thickening and markedly increased risk of obstructive vascular disease.
The Predictive Value of Short-Term Changes in Hemoglobin Concentration in Patients Presenting With Acute Decompensated Heart Failure
Authors: Peter van der Meer, Douwe Postmus, Piotr Ponikowski, John G. Cleland, Christopher M. O'Connor, Gad Cotter, Marco Metra, Beth A. Davison, Michael M. Givertz, George A. Mansoor, John R. Teerlink, Barry M. Massie, Hans L. Hillege, Adriaan A. Voors
Journal: Journal of the American College of Cardiology (2013)
Ultrasonography shows no abnormality of pelvic structures in women with severe idiopathic constipation.
Authors: M A Kamm, A McLean, M J Farthing, J E Lennard-Jones
Journal: Gut (1989)

Patients with severe idiopathic constipation are almost exclusively women. Common presenting features include lower abdominal pain, irregular and painful menstruation, and a past history of gynaecological surgery. Pelvic ultrasonography was undertaken in 26 patients with severe idiopathic constipation and 21 age matched control women to detect any gynaecological abnormality. No difference was found in ovarian, uterine or pelvic vein morphology or size. The abdominal pain in these patients is related to the bowel disorder, and minor abnormalities of pelvic morphology on ultrasound are probably incidental findings.
Bone Marrow Stromal Cells Attenuate Lung Injury in a Murine Model of Neonatal Chronic Lung Disease
Authors: Muhammad Aslam, Rajiv Baveja, Olin D. Liang, Angeles Fernandez-Gonzalez, Changjin Lee, S. Alex Mitsialis, Stella Kourembanas
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Rationale: Neonatal chronic lung disease, known as bronchopulmonary dysplasia (BPD), remains a serious complication of prematurity despite advances in the treatment of extremely low birth weight infants.Objectives: Given the reported protective actions of bone marrow stromal cells (BMSCs; mesenchymal stem cells) in models of lung and cardiovascular injury, we tested their therapeutic potential in a murine model of BPD.Methods: Neonatal mice exposed to hyperoxia (75% O2) were injected intravenously on Day 4 with either BMSCs or BMSC-conditioned media (CM) and assessed on Day 14 for lung morphometry, vascular changes associated with pulmonary hypertension, and lung cytokine profile.Measurements and Main Results: Injection of BMSCs but not pulmonary artery smooth muscle cells (PASMCs) reduced alveolar loss and lung inflammation, and prevented pulmonary hypertension. Although more donor BMSCs engrafted in hyperoxic lungs compared with normoxic controls, the overall low numbers suggest protective mechanisms other than direct tissue repair. Injection of BMSC-CM had a more pronounced effect than BMSCs, preventing both vessel remodeling and alveolar injury. Treated animals had normal alveolar numbers at Day 14 of hyperoxia and a drastically reduced lung neutrophil and macrophage accumulation compared with PASMC–CM-treated controls. Macrophage stimulating factor 1 and osteopontin, both present at high levels in BMSC-CM, may be involved in this immunomodulation.Conclusions: BMSCs act in a paracrine manner via the release of immunomodulatory factors to ameliorate the parenchymal and vascular injury of BPD in vivo. Our study suggests that BMSCs and factor(s) they secrete offer new therapeutic approaches for lung diseases currently lacking effective treatment.
Matrix metalloproteinase-9 contributes to brain extravasation and edema in fulminant hepatic failure mice
Authors: Justin H. Nguyen, Satoshi Yamamoto, Jeffery Steers, Daniel Sevlever, Wenlang Lin, Naoki Shimojima, Monica Castanedes-Casey, Petrina Genco, Todd Golde, Elliott Richelson, Dennis Dickson, Michael McKinney, Christopher B. Eckman
Journal: Journal of Hepatology (2005)