Ex vivo innate immune cytokine signature of enhanced risk of relapsing brucellosis.

BackgroundBrucellosis, a zoonotic infection caused by one of the Gram-negative intracellular bacteria of the Brucella genus, is an ongoing public health problem in Perú. While most patients who receive standard antibiotic treatment recover, 5-40% suffer a brucellosis relapse. In this study, we examined the ex vivo immune cytokine profiles of recovered patients with a history of acute and relapsing brucellosis.Methodology/principal findingsBlood was taken from healthy control donors, patients with a history of acute brucellosis, or patients with a history of relapsing brucellosis. Peripheral blood mononuclear cells were isolated and remained in culture without stimulation or were stimulated with a panel of toll-like receptor agonists or heat-killed Brucella melitensis (HKBM) isolates. Innate immune cytokine gene expression and protein secretion were measured by quantitative real-time polymerase chain reaction and a multiplex bead-based immunoassay, respectively. Acute and relapse patients demonstrated consistently elevated cytokine gene expression and secretion levels compared to controls. Notably, these include: basal and stimulus-induced expression of GM-CSF, TNF-α, and IFN-γ in response to LPS and HKBM; basal secretion of IL-6, IL-8, and TNF-α; and HKBM or Rev1-induced secretion of IL-1β, IL-2, GM-CSF, IFN-Υ, and TNF-α. Although acute and relapse patients were largely indistinguishable by their cytokine gene expression profiles, we identified a robust cytokine secretion signature that accurately discriminates acute from relapse patients. This signature consists of basal IL-6 secretion, IL-1β, IL-2, and TNF-α secretion in response to LPS and HKBM, and IFN-γ secretion in response to HKBM.Conclusions/significanceThis work demonstrates that informative cytokine variations in brucellosis patients can be detected using an ex vivo assay system and used to identify patients with differing infection histories. Targeted diagnosis of this signature may allow for better follow-up care of brucellosis patients through improved identification of patients at risk for relapse

Global clinical response in C ushing's syndrome patients treated with mifepristone

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106755/1/cen12332.pd

The hepatoadrenal syndrome: A common yet unrecognized clinical condition

Objective: Adrenal failure is common in critically ill patients, particularly those with sepsis. As liver failure and sepsis are both associated with increased circulating levels of endotoxin and proinflammatory mediators and reduced levels of apoprotein-1/ high-density lipoprotein, we postulated that adrenal failure may be common in patients with liver disease. Design: Clinical study. Setting: Liver transplant intensive care unit. Patients: The study cohort included 340 patients with liver disease. Interventions: Based on preliminary observational data, all patients admitted to our 28-bed liver transplant intensive care unit (LTICU) undergo adrenal function testing. An honest broker system was used to extract clinical, hemodynamic, medication, and laboratory data on patients admitted to the LTICU from March 2002 to March 2004. A random (stress) cortisol level <20 μg/dL in a highly stressed patient (respiratory failure, hypotension) was used to diagnose adrenal insufficiency. In all other patients, a random cortisol level <15 μg/dL or a 30-min level <20 μg/dL post-low-dose (1 μg) cosyntropin was considered diagnostic of adrenal insufficiency. Patients were grouped as follows: a) chronic liver failure; b) fulminant hepatic failure; c) patients immediately status post-orthotopic liver transplantation receiving a steroid-free protocol of immunosuppression; and d) patients status post-remote liver transplant (≥6 months). The decision to treat patients with stress doses of hydrocortisone was at the discretion of the treating intensivist and transplant surgeon. Measurements and Main Results: Two-hundred and forty-five (72%) patients met our criteria for adrenal insufficiency (the hepatoadrenal syndrome). Eight (33%) patients with fulminant hepatic failure, 97 (66%) patients with chronic liver disease, 31(61%) patients with a remote history of liver transplantation, and 109 (92%) patients who had undergone liver transplantation under steroid-free immunosuppression were diagnosed with adrenal insufficiency. The high-density lipoprotein level at the time of adrenal testing was the only variable predictive of adrenal insufficiency (p < .0001). In vasopressor-dependent patients with adrenal insufficiency, treatment with hydrocortisone was associated with a significant reduction (p = .02) in the dose of norepinephrine at 24 hrs, whereas the dose of norepinephrine was significantly higher (p = .04) in those patients with adrenal failure not treated with hydrocortisone. In vasopressor-dependent patients without adrenal insufficiency, treatment with hydrocortisone did not affect vasopressor dose at 24 hrs. One hundred and forty-one patients (26.4%) died during their hospitalization. The baseline serum cortisol was 18.8 ± 16.2 μg/dL in the nonsurvivors compared with 13.0 ± 11.8 μg/dL in the survivors (p < .001). Of those patients with adrenal failure who were treated with glucocorticoids, the mortality rate was 26% compared with 46% (p = .002) in those who were not treated. In those patients receiving vasopressor agents at the time of adrenal testing, the baseline cortisol was 10.0 ± 4.8 μg/dL in those with adrenal insufficiency compared with 35.6 ± 21.2 μg/dL in those with normal adrenal function. Vasopressor-dependent patients who did not have adrenal failure had a mortality rate of 75%. Conclusions: Patients with liver failure and patients post-liver transplantation have an exceedingly high incidence of adrenal failure, which may be pathophysiologically related to low levels of high-density lipoprotein. Treatment of patients with adrenal failure may improve outcome. High baseline serum cortisol levels may be a maker of disease severity and portend a poor prognosis. Copyright © 2005 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins

Effect of spironolactone and potassium canrenoate on cytosolic and nuclear androgen and estrogen receptors of rat liver

Spironolactone and potassium canrenoate are diuretics that are used widely for management of cirrhotic ascites. The administration of spironolactone frequently leads to feminization, which has been noted less frequently with the use of potassium canrenoate, a salt of the active metabolite of spironolactone. The use of these two drugs has been associated with decreases in serum testosterone levels and spironolactone with a reduction in androgen receptor (AR) activity. This decrease in AR has been cited as the cause of the antiandrogen effect of these drugs. We therefore assessed the effect of both drugs on levels of androgen and estrogen receptors (ER) in the liver, a tissue that is responsive to sex steroids. Three groups of male rats (n = 12 rats each) were studied. Group 1 (control) received vehicle only; group 2 received spironolactone (5 mg/day); group 3 received potassium canrenoate (5 mg/day). After 21 days of treatment, the animals of all groups were killed and liver tissue was assayed for nuclear and cytosolic AR and ER, and for male specific estrogen binder (MEB), an androgen-responsive protein. Both drugs drastically decreased the nuclear AR content, as compared with the control group, but only spironolactone decreased cytosolic AR. When the total hepatic content of AR is considered, a highly significant decrease is observed only in rats treated with spironolactone. This reduction in hepatic AR content suggested loss of androgen responsiveness of liver. We confirmed this by assessing levels of MEB, and found that livers from group 2 animals had no detectable MEB activity, whereas livers from both group 1 and 3 had normal MEB activity. No changes were observed in nuclear ER and cytosolic ER of group 3 as compared with group 1. Nuclear estrogen receptor decreased and cytosolic ER increased in group 2, but with no change in total ER content. These results indicate that (a) only spironolactone appears to act as an antiandrogen in liver, resulting in a decrease in both AR and male specific estrogen binder content, and (b) neither drug results in elevated hepatic ER content, although spironolactone-treated animals show an altered subcellular localization. © 1987

Some Strategies of Concealment in Hardy’s Language

The focus of this analysis on three major novels of Thomas Hardy: Tess of the D’Urbervilles, The Return of the Native and Far From the Madding Crowd will study aspects of language, phonetics and stylistics in these three books. Manipulating language effectively entails a certain level of education. In general, formal English, or at least “Standard” English, is used in narrative text, dialogues or poems. However, in Hardy’s novels, the words are not only written, but they can be read orally and we find a gap, even a paradox between what is written and what is said. All through the novels, this ambiguity is strengthened by various language registers. Words are means of both written and oral communication. Fitted together, they create sounds and give to Hardy’s sentences a second meaning. Indeed, Hardy’s heroes and heroines fit into their rural landscape and try to cross the line which symbolically divides them from worldly, urban society, by correcting their pronunciation or code of language. A reel of words weaves its way through those outward cultures or language groups. Through both silent and audible forms of communication, words may reveal hidden links within this microsociety. Consequently, Hardy’s words might be seen as a series of letters or literary missives, whose purpose is to convey a message to the reader. Some methods and techniques of assembling letters and sounds to represent specific dialectal forms of expression will provide the core of this article.Cette étude, centrée sur trois œuvres majeures de Thomas Hardy : Far from the Madding Crowd, The Return of the Native et Tess of the d’Urbervilles, s’oriente vers les aspects linguistiques – phonétique et stylistique – de la langue anglaise à la fin du XIXe siècle. Les « lettres » peuvent être tout d’abord comprises comme un ensemble des connaissances et des études littéraires et relèvent d’une certaine éducation. Elles reflètent donc un anglais soutenu, ou tout du moins « standard », que l’on retrouve dans les passages lettrés et narratifs, voire même dans les poèmes. Néanmoins, les lettres ne sont pas seulement écrites, mais peuvent être lues oralement, soulevant ainsi une ambiguïté entre l’écrit et l’oral et plus généralement sur le langage. Dans la société hardyenne, cette équivoque est renforcée par différents registres de langue. En effet, les héros et héroïnes de Hardy appartiennent au paysage pastoral et tentent de franchir la frontière qui les sépare de la société mondaine de la ville en modifiant leur code de langage. Une ronde des mots se profile au travers de ces deux cultures langagières que pourtant tout oppose. Autour d’une communication audible ou silencieuse, la lettre ou les lettres sont révélatrices de liens sociaux qui se tissent dans cette microsociété. Subséquemment, chez Hardy, ces lettres peuvent être perçues comme un ensemble de missives littéraires destinées à véhiculer un message au lecteur. Par ailleurs, cet article vise à saisir quelques méthodes et techniques dont l’écrivain usa pour harmoniser lettres et sons et créer son propre graphisme dialectique

Spatio-Temporal Distribution of Supra-Glacial Ponds and Ice Cliffs on Verde Glacier, Chile

Known for their important role in locally enhancing surface melt, supraglacial ponds and ice cliffs are common features on debris-covered glaciers. We use high resolution satellite imagery to describe pond-cliff systems and surface velocity on Verde debris-covered glacier, Monte Tronador, and Southern Chile. Ponds and ice cliffs represent up to 0.4 and 2.7% of the glacier debris-covered area, respectively. Through the analyzed period and the available data, we found a seasonality in the number of detected ponds, with larger number of ponds at the beginning of the ablation season and less at the end of it. Using feature tracking, we determined glacier surface velocity, finding values up to 55 m/yr on the upper part of the debris-covered area, and decreasing almost to stagnation in the terminus. We found that larger ponds develop in glacier zones of low velocity, while zones of high velocity only contain smaller features. Meanwhile, ice cliffs appeared to be less controlled by surface velocity and gradient. Persistent ice cliffs were detected between 2009 and 2019 and backwasting up to 24 m/yr was measured, highlighting significant local glacier wastage.Fil: Loriaux, Thomas. Centro de Estudios Cientificos; ChileFil: Ruiz, Lucas Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; Argentin