tbuckley/cabot-search huggingface dataset:
Intracellular myoglobin loading worsens H2O2-induced, but not hypoxia/reoxygenation-induced, in vitro proximal tubular injury.
Authors: R A Zager
Journal: Circulation Research (1993)

Intracellular iron reportedly mediates many forms of tissue injury, including ischemic and myohemoglobinuric acute renal failure. This action may be explained by the ability of iron to catalyze the formation of the highly toxic hydroxyl radical (.OH) from H2O2 via the Fenton/Haber-Weiss reactions. To assess whether renal tubular myoglobin/iron loading, induced by a physiological mechanism (endocytosis), alters its susceptibility to O2 deprivation/reoxygenation- and H2O2-mediated injury, rats were infused with myoglobin or its vehicle (5% dextrose, control rats), and after 2 hours, proximal tubular segments (PTSs) were isolated for study. This infusion caused substantial myoglobin endocytic uptake (approximately 25 micrograms/mg PTS protein), and it doubled PTS catalytic iron content (assessed by bleomycin assay). Nevertheless, PTS viability (percent lactate dehydrogenase release) was minimally affected (4% to 6% increase), and an increased .OH burden (assessed by the salicylate trap method) did not appear to result. Deferoxamine addition, reported to protect against in vivo acute renal failure, paradoxically increased .OH levels (approximately 25%) in myoglobin-loaded, but not control, PTSs. Conversely, dimethylthiourea (an .OH scavenger) depressed .OH (by approximately 80%) in all PTSs. Myoglobin/iron loading modestly increased PTS vulnerability to exogenous H2O2 addition (P &lt; .001). However, tubular susceptibility to hypoxia (15 and 30 minutes)/reoxygenation injury was not affected. .OH levels appeared to fall in response to both forms of injury, suggesting decreased .OH production and/or .OH scavenging. To assess whether myoglobin decreases .OH levels in the presence of Fenton reactants, myoglobin and six other test proteins were incubated with Fe2+/H2O2. Myoglobin decreased .OH levels by approximately 70%, a significantly greater decrement than was observed with the other proteins tested.(ABSTRACT TRUNCATED AT 250 WORDS)
Hemiplegia in Young Adults
Authors: G. J. Dixon
Journal: BMJ (1947)

OURNAL53death was not conclusive, so it is undesirable to base any conclusions on the figures; but experience of large numbers of these cases allows an examiner to group the probable causes of death with reasonable accuracy for registration purposes.Cases of sudden death .. .404cates Cardiovascular group 357 Respiratory diseases .21Nervous system diseases.8 Gastro-intestinal diseases.
Whole exome capture in solution with 3 Gbp of data
Authors: Matthew N Bainbridge, Min Wang, Daniel L Burgess, Christie Kovar, Matthew J Rodesch, Mark D'Ascenzo, Jacob Kitzman, Yuan-Qing Wu, Irene Newsham, Todd A Richmond, Jeffrey A Jeddeloh, Donna Muzny, Thomas J Albert, Richard A Gibbs
Journal: Genome biology (2010)

Abstract We have developed a solution-based method for targeted DNA capture-sequencing that is directed to the complete human exome. Using this approach allows the discovery of greater than 95% of all expected heterozygous singe base variants, requires as little as 3 Gbp of raw sequence data and constitutes an effective tool for identifying rare coding alleles in large scale genomic studies.
Efficacy and safety of the fully human anti-tumour necrosis factor monoclonal antibody adalimumab (D2E7) in DMARD refractory patients with rheumatoid arthritis: a 12 week, phase II study
Authors: L B A van de Putte
Journal: Annals of the Rheumatic Diseases (2003)

<b>Objectives:</b> To evaluate efficacy, dose response, safety, and tolerability of adalimumab (D2E7) in disease modifying antirheumatic drug (DMARD) refractory patients with longstanding, active rheumatoid arthritis (RA). <b>Methods:</b> During a 12 week, double blind, placebo controlled study, 284 patients were randomly allocated to receive weekly subcutaneous injections of adalimumab 20 mg (n = 72), 40 mg (n = 70), or 80 mg (n = 72) or placebo (n = 70) without concomitant DMARDs. <b>Results:</b> Adalimumab significantly improved the signs and symptoms of RA for all efficacy measures. ACR20 responses with adalimumab were significant at each assessment versus placebo (p⩽0.01). Additionally, ACR responses with adalimumab were achieved more rapidly than with placebo, with 82/115 (71%) of the ultimate ACR20 response rate to adalimumab treatment achieved at week 2. At week 12, for adalimumab 20, 40, and 80 mg, ACR20 response rates were 50.7%, 57.1%, and 54.2%, respectively, versus 10.0% for placebo (p⩽0.001 for all comparisons); ACR50 rates were 23.9%, 27.1%, and 19.4%, respectively, versus 1.4% for placebo (p⩽0.001 for all comparisons); and ACR70 rates were 11.3%, 10.0%, and 8.3%, respectively, versus 0.0% for placebo (p⩽0.05 for all comparisons). All adalimumab doses significantly improved all ACR core criteria at all assessments. The 40 mg and 80 mg doses provided similar benefit. Adalimumab at all doses was generally well tolerated, with only mild or moderate adverse events. Completion rates were 87% for adalimumab and 67% for placebo. <b>Conclusions:</b> Adalimumab given as monotreatment to patients with longstanding, severe RA refractory to traditional DMARDs produced a rapid, sustained response and was safe and well tolerated, with no dose limiting side effects.
Enhanced detection of Legionnaires' disease by PCR testing of induced sputum and throat swabs
Authors: Michael J. Maze, Sandy Slow, Anne-Marie Cumins, Kenjin Boon, Patricia Goulter, Roslyn G. Podmore, Trevor P. Anderson, Kevin Barratt, Sheryl A. Young, Alan D. Pithie, Michael J. Epton, Anja M. Werno, Stephen T. Chambers, David R. Murdoch
Journal: European Respiratory Journal (2013)

To the Editor: 

Legionnaires’ disease, particularly that caused by non-pneumophila species, is notoriously underdiagnosed [1, 2]. We recently found a four-fold increase in case detection of Legionnaires’ disease through a laboratory-initiated strategy of systematic PCR testing for Legionella species of all lower respiratory specimens from patients with pneumonia or immune compromised status [3]. This strategy relies on the availability of lower respiratory specimens and the recording of relevant clinical information on laboratory requisition forms by clinicians. We recognised that this strategy will miss testing patients who could not expectorate sputum and when inadequate clinical information is written on laboratory requisition forms. To address this diagnostic gap we enhanced case detection by actively identifying patients with community-acquired pneumonia (CAP) and by collecting induced sputum from those unable to expectorate voluntarily. In addition, we evaluated throat swabs as an alternative specimen for PCR testing.

From October 2012 to March 2013 patients admitted to Christchurch Hospital and The Princess Margaret Hospital (both in Christchurch, New Zealand) with CAP and aged ≥18 years were recruited. For logistical reasons, recruitment occurred on weekdays only. The study period was chosen to coincide with peak Legionnaires’ disease activity in Christchurch [3]. Patients were excluded if the pneumonia was hospital acquired or associated with bronchial obstruction, bronchiectasis or tuberculosis. Patients were not eligible for sputum induction if they required high-flow oxygen or assisted ventilation at enrolment.

Ethical approval was obtained from the New Zealand Northern A Ethics Committee. Informed consent was obtained from the patient or their next of kin with …
Interleukin 12 administration induces T helper type 1 cells and accelerates autoimmune diabetes in NOD mice.
Authors: S Trembleau, G Penna, E Bosi, A Mortara, M K Gately, L Adorini
Journal: The Journal of Experimental Medicine (1995)

T cells play a major role in the development of insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. Administration of interleukin 12 (IL-12), a key cytokine which guides the development of T helper type 1 (Th1) CD4+ T cells, induces rapid onset of IDDM in NOD, but not in BALB/c mice. Histologically, IL-12 administration induces massive infiltration of lymphoid cells, mostly T cells, in the pancreatic islets of NOD mice. CD4+ pancreas-infiltrating T cells, after activation by insolubilized anti T cell receptor antibody, secrete high levels of interferon gamma and low levels of IL-4. Therefore, IL-12 administration accelerates IDDM development in genetically susceptible NOD mice, and this correlates with increased Th1 cytokine production by islet-infiltrating cells. These results hold implications for the pathogenesis, and possibly for the therapy of IDDM and of other Th1 cell-mediated autoimmune diseases.
Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species
Authors: Kyra A. Gelderman, Malin Hultqvist, Angela Pizzolla, Ming Zhao, Kutty Selva Nandakumar, Ragnar Mattsson, Rikard Holmdahl
Journal: Journal of Clinical Investigation (2007)

Reduced capacity to produce ROS increases the severity of T cell-dependent arthritis in both mice and rats with polymorphisms in neutrophil cytosolic factor 1 (Ncf1) (p47phox). Since T cells cannot exert oxidative burst, we hypothesized that T cell responsiveness is downregulated by ROS produced by APCs. Macrophages have the highest burst capacity among APCs, so to study the effect of macrophage ROS on T cell activation, we developed transgenic mice expressing functional Ncf1 restricted to macrophages. Macrophage-restricted expression of functional Ncf1 restored arthritis resistance to the level of that of wild-type mice in a collagen-induced arthritis model but not in a T cell-independent anti-collagen antibody-induced arthritis model. T cell activation was downregulated and skewed toward Th2 in transgenic mice. In vitro, IL-2 production and T cell proliferation were suppressed by macrophage ROS, irrespective of T cell origin. IFN-gamma production, however, was independent of macrophage ROS but dependent on T cell origin. These effects were antigen dependent but not restricted to collagen type II. In conclusion, macrophage-derived ROS play a role in T cell selection, maturation, and differentiation, and also a suppressive role in T cell activation, and thereby mediate protection against autoimmune diseases like arthritis.
Maternal Immunization With Haemophilus influenzae Type b Polysaccharide—Tetanus Protein Conjugate Vaccine in The Gambia
Authors: Kim Mulholland
Journal: JAMA (1996)

<h3>Objective.</h3> —To evaluate maternal responses to<i>Haemophilus influenzae</i>type b (Hib) polysaccharide—tetanus protein conjugate vaccine (polyribosylribitol phosphate—tetanus or PRP-T) given to pregnant Gambian women, the transplacental transfer of antibody, and the effect of maternal immunization on infant responses to the vaccine. <h3>Design.</h3> —An open, randomized immunogenicity study. <h3>Setting.</h3> —A busy urban health center in The Gambia. <h3>Study participants.</h3> —A total of 451 pregnant women enrolled during the third trimester of pregnancy. <h3>Intervention.</h3> —Study participants were randomized to three groups. In one group, mothers were given PRP-T during the third trimester and their infants were given PRP-T at 2, 3, and 4 months of age. In the second group, mothers received PRP-T and infants were given inactivated poliovirus vaccine. In the third group, mothers received meningococcal A and C vaccine, and their infants received PRP-T. <h3>Main Outcome Measures.</h3> —Anti-PRP antibody measurements of maternal, cord, and infant blood. <h3>Results.</h3> —Vaccinated women had a marked increase in total anti-PRP antibody (geometric mean titer, 9.0 μg/mL), which was greatest in women in their first or second pregnancy. Previous tetanus vaccination during the same pregnancy and high concentrations of antitetanus antibody were associated with lower anti-PRP responses. In infants of PRP-T recipients, cord blood anti-PRP IgG concentrations were 61% of simultaneous maternal concentrations. In vaccinated infants of vaccinated mothers, geometric mean anti-PRP antibody concentrations at birth, 2 months of age, and 5 months of age were 1.92, 0.35, and 2.84 μg/mL, respectively, while in vaccinated infants of unvaccinated mothers, the corresponding concentrations were 0.29, 0.12, and 3.91 μg/mL. At 2 months of age, 60% of infants of vaccinated mothers and 26% of infants of unvaccinated mothers had anti-PRP antibody concentrations considered to be protective (&gt;0.15 μg/mL). <h3>Conclusions.</h3> —In areas where much invasive Hib disease occurs in infants younger than 6 months, maternal immunization may help to reduce the risk of Hib disease in infants too young for immunization. (<i>JAMA</i>. 1996;275:1182-1188)
Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl. III. Interaction of effector suppressor T cells is restricted by H-2 and Igh-V genes.
Authors: J Z Weinberger, B Benacerraf, M E Dorf
Journal: The Journal of Experimental Medicine (1980)

4-Hydroxy-3-nitrophenyl acetyl (NP)-derivatized syngeneic spleen cells administered intravenously induced a population of suppressor T cells that could suppress mice previously primed to NP. The effect was demonstrable when the suppressor cells were transferred to NP-primed mice on the day of challenge for delayed-type hypersensitivity (DTH) responses. In contrast to the suppressor T cell population, which abrogates 5-iodo derivative of NP (NIP)-specific DTH responses when administered before antigen priming, the effector-phase suppressors did not efficiently suppress NIP-specific DTH responses, and were not lysed by treatment with antiidiotype plus complement. Adoptive transfer experiments between major histocompatibility complex and allotype congenic strains of mice allowed demonstration of both Igh-V and I-A restrictions in the transfer of this cell population. The implications of these data in terms of network theories and proposed cellular models for negative immunoregulation were discussed.
FURTHER STUDIES ON THE ROLE OF PROTEASES IN THE ALLERGIC REACTION
Authors: Georges Ungar, Takuso Yamura, Jacqueline B. Isola, Sidney Kobrin
Journal: The Journal of Experimental Medicine (1961)

Protease activity was measured through the hydrolysis of synthetic amino acid esters in body fluids and tissues of guinea pigs, rats, mice, and humans. Significant in vitro activation was observed in serum and lung slices of sensitized guinea pigs on addition of the specific antigen. Increased proteolytic activity was also seen in reverse anaphylaxis. More marked activation occurred when guinea pig serum was treated with peptone and guinea pig or rat serum was treated with agar. Protease activation was demonstrated in specimens of human skin under the influence of a poison ivy extract or croton oil added in vitro. Urinary protease activity of guinea pigs increased significantly during the first hours of anaphylactic shock and very markedly in peptone shock. Peptone shock, elicited in mice pretreated with H. pertussis, was accompanied by a considerable increase in protease activity in the peritoneal fluid as compared with non-pretreated mice which were insensitive to peptone. Proteolytic activity resulting from the activation procedures was due to a number of proteases. The dominant substrate affinity and inhibition patterns suggest that serum and urine proteases are similar to but not identical with plasmin. Anaphylactic activation exhibited patterns different from those resulting from the action of anaphylactoid agents. Tissue enzymes are either of cathepsin- or chymotrypsin-type or mixtures of both. Some of the activated enzymes, although remarkably effective in hydrolyzing amino acid esters, show no activity on protein substrates. This does not justify, however, their designation as "esterases." They probably belong to the class of specific proteases acting only on a single or a small number of functionally significant protein substrates. There is at present sufficient evidence to prove not only that protease activation does occur in anaphylaxis and anaphylactoid conditions but also that it is an important component of the chain of reactions leading to the allergic response.
Quality of hallucinatory experiences: differences between a clinical and a non‐clinical sample
Authors: GIOVANNI STANGHELLINI, ÁLVARO I. LANGER, ALESSANDRA AMBROSINI, ADOLFO J. CANGAS
Journal: World Psychiatry (2012)

In this study, we asked people from two samples (a clinical one, consisting of patients with schizophrenia, and a non-clinical one, including university students) to complete the Revised Hallucination Scale (RHS) as a self-questionnaire. When the participants responded positively to an item, they were encouraged to provide further detailed descriptions (i.e., examples of their own experiences) concerning that item. We found that the kinds of descriptions provided by the two groups were very different. We suggest that it is not advisable to explore the presence of hallucinations in non-clinical samples using research protocols based exclusively on yes-or-no answers to questionnaires like the RHS. Hallucinatory or hallucinatory-like experiences cannot be reliably and validly assessed without a precise characterization of the phenomenal quality of the experience.
Inhaled corticosteroids can modulate the immunopathogenesis of pulmonary sarcoidosis
Authors: MA Spiteri, SP Newman, SW Clarke, LW Poulter
Journal: European Respiratory Journal (1989)

We investigated the effect of inhaled corticosteroids on the phenotypes and functional capacity of macrophages obtained by bronchoalveolar lavage from patients with pulmonary sarcoidosis. The results were correlated with clinical status and therapeutic efficacy. Ten symptomatic sarcoid patients (previously untreated) with radiological parenchymal shadowing and abnormal pulmonary function received inhaled budesonide, 800 micrograms m twice daily via a Nebuhaler for 16 weeks. A placebo group included ten healthy volunteers and five sarcoid patients with similar features to the treated group. Drug distribution studies showed that 10% of the inhaled drug was deposited in the alveolar region. All ten treated sarcoid patients had symptomatic relief with no adverse effects. Three of these ten patients had significant resolution of their radiological shadowing. No significant difference in pulmonary function was observed. At the cellular level, a significant decrease in lavage lymphocytosis was seen after 16 weeks, during which time there was a concomitant change in the phenotype and functional characteristics of the alveolar macrophage population. No similar changes were observed in the placebo group. Our results suggest that inhaled budesonide can modulate the aberrant immunological reactions existent in the lung in pulmonary sarcoidosis, and produce concomitant symptomatic relief with no side effects. It is postulated that this effect may occur through action on the local alveolar macrophage population.
Defective major histocompatibility complex class II assembly, transport, peptide acquisition, and CD4+ T cell selection in mice lacking invariant chain expression.
Authors: E K Bikoff, L Y Huang, V Episkopou, J van Meerwijk, R N Germain, E J Robertson
Journal: The Journal of Experimental Medicine (1993)

We used gene targeting techniques to produce mice lacking the invariant chain associated with major histocompatibility complex (MHC) class II molecules. Cells from these mice show a dramatic reduction in surface class II, resulting from both defective association of class II alpha and beta chains and markedly decreased post-Golgi transport. The few class II alpha/beta heterodimers reaching the cell surface behave as if empty or occupied by an easily displaced peptide, and display a distinct structure. Mutant spleen cells are defective in their ability to present intact protein antigens, but stimulate enhanced responses in the presence of peptides. These mutant mice have greatly reduced numbers of thymic and peripheral CD4+ T cells. Overall, this striking phenotype establishes that the invariant chain plays a critical role in regulating MHC class II expression and function in the intact animal.
Decreased clinical response to infliximab in ankylosing spondylitis is correlated with anti-infliximab formation
Authors: M. K de Vries, G. J. Wolbink, S. O Stapel, H. de Vrieze, J C. van Denderen, B. A C Dijkmans, L. A Aarden, I. E van der Horst-Bruinsma
Journal: Annals of the Rheumatic Diseases (2007)

Correlation of serum trough infliximab levels and antibodies to infliximab (anti-infliximab) with clinical response in ankylosing spondylitis.In accordance with the international ASsessment in Ankylosing Spondylitis (ASAS) consensus statement, patients were treated with infliximab (5 mg/kg) every 6 weeks after a starting regimen. Preinfusion sera were collected at baseline, 24 and 54 weeks. At every visit, the 20% improvement response (ASAS-20) was assessed and laboratory tests performed.24 of the 38 (63%) patients fulfilled ASAS-20 response criteria after 24 weeks of treatment and 21 (53%) after 54 weeks. After 54 weeks, 11 (29%) patients showed undetectable serum trough infliximab levels and detectable anti-infliximab; six of these patients developed an infusion reaction. Anti-infliximab was found significantly more often (p = 0.04) in ASAS-20 non-responders compared with responders at week 54. Serum trough infliximab levels were significantly (p<0.0001) lower in patients with (mean 0.02 mg/l) than in those without (12.7 mg/l) anti-infliximab.In ankylosing spondylitis, high levels of serum trough infliximab correlated with a good clinical response. Detection of anti-infliximab within 54 weeks is associated with undetectable serum trough infliximab levels, reduced response to treatment and increased risk of developing an infusion reaction.
Cytosolic calcium in the ischemic rabbit heart: assessment by pH- and temperature-adjusted rhod-2 spectrofluorometry
Authors: C Stamm
Journal: Cardiovascular Research (2003)

Cytosolic calcium ([Ca(2+)](i)) mediates ischemia-reperfusion (I/R) injury, but magnitude and time course of I/R-induced [Ca(2+)](i) overload remain unclear. Fluorescent indicators are commonly used to measure [Ca(2+)](i), and have a dissociation constant (K(d)) that depends on pH and temperature. We hypothesized that changes of K(d) during I/R lead to misleading interpretations of [Ca(2+)](i) recordings.(1) In isolated rabbit hearts (n=4 each), intracellular pH was measured during I/R at 37 degrees C, 20 degrees C, and 4 degrees C with and without cardioplegic arrest by (31)P-NMR-spectroscopy. (2) K(d) for rhod-2 and calcium was determined at varying pH and temperature in in vitro experiments. (3) Isolated rabbit hearts were subjected to I/R, and [Ca(2+)](i) was recorded by surface rhod-2 spectrofluorometry. Finally, [Ca(2+)](i) was computed using either the conventional K(d), or the pH- and temperature-adjusted K(d).K(d)(Ca(2+)Rhod-2) remained stable between pH 7.1 and 6.8, but increased exponentially with lower pH and/or temperature. Calculations using a static K(d) indicated that [Ca(2+)](i) rose only mildly during warm ischemia and did not rise during cardioplegic arrest, while a large Ca(2+) influx appeared to occur during early reperfusion. When the pH and temperature-adjusted K(d) was used for calculation, [Ca(2+)](i) rose significantly during ischemia (431+/-37% during 20 min 37 degrees C ischemia, and 78+/-19% during 20 min cardioplegic arrest at 20 degrees C). During early reperfusion, [Ca(2+)](i) decreased rapidly, without significant further [Ca(2+)](i) elevation.In contrast to previous reports, [Ca(2+)](i) accumulation occurs during unprotected ischemia as well as hypothermic ischemia with cardioplegic arrest, without further net Ca(2+) influx on reperfusion. This finding has important implications for timing of protective strategies during myocardial ischemia.