Julia Guerrero

Thyroid hormone-induced oxidative stress triggers nuclear factor-κB activation and cytokine gene expression in rat liver

Nuclear factor-kappaB (NF-kappaB) is a redox-sensitive factor responsible for the transcriptional activation of cytokine-encoding genes. In this study, we show that 3,3,5-triiodothyronine (T(3)) administration to rats activates hepatic NF-kappaB, as assessed by electrophoretic mobility shift assay. This response coincides with the onset of calorigenesis and enhancement in hepatic respiration, and is suppressed by the antioxidants alpha-tocopherol and N-acetylcysteine or by the Kupffer cell inactivator gadolinium chloride. Livers from hyperthyroid rats with enhanced NF-kappaB DNA-binding activity show induced mRNA expression of the NF-kappaB-responsive genes for tumor necrosis factor-alpha (TNF-alpha) and interleukin- (IL-) 10, as evidenced by reverse transcription-polymerase chain reaction assay, which is correlated with increases in the serum levels of the cytokines. T(3) also increased the hepatic levels of mRNA for IL-1alpha and those of IL-1alpha in serum, with a time profile closely related to that of TNF-alpha. It is concluded that T(3)-induced oxidative stress enhances the DNA-binding activity of NF-kappaB and the NF-kappaB-dependent expression of TNF-alpha and IL-10 genes.

Effects of Acute γ-Hexachlorocyclohexane Intoxication in Relation to the Redox Regulation of Nuclear Factor-κB, Cytokine Gene Expression, and Liver Injury in the Rat

γ-Hexachlorocyclohexane-induced hepatotoxicity is associated with oxidative stress. We tested the hypothesis that γ-hexachlorocyclohexane triggers the redox activation of nuclear factor-κB (NF-κB), leading to proinflammatory cytokine expression. Liver NF-κB activation (electrophoretic mobility shift assay), tumor necrosis factor-α (TNF-α) and interleukin-1α (IL-1α) mRNA expression (reverse transcription-polymerase chain reaction), and their serum levels (enzyme-linked immunosorbent assay) were measured at different times after γ-hexachlorocyclohexane treatment (50 mg/kg). The relationship between these and hepatic O2 uptake, glutathione and protein carbonyl levels, and sinusoidal lactate dehydrogenase (LDH) efflux in liver perfusion studies was determined. γ-Hexachlorocyclohexane increased liver NF-κB DNA binding at 14-22 h after treatment, concomitantly with significant glutathione depletion and an increase in the rate of O2 consumption, the content of protein carbonyls, and the sinusoidal LDH efflux. In...

Earlier immunomodulatory treatment is associated with better visual outcomes in a subset of patients with Vogt-Koyanagi-Harada disease

To evaluate clinical outcomes of first‐line immunomodulatory therapy (IMT) and prednisone alone or late IMT in Vogt‐Koyanagi‐Harada disease.

Increased Expression of the Glucocorticoid Receptor β in Infants With RSV Bronchiolitis

OBJECTIVES: The majority of studies on glucocorticoid treatment in respiratory syncytial virus (RSV) bronchiolitis concluded that there are no beneficial effects. We hypothesized that RSV-infected patients may have an increased glucocorticoid receptor (GR) β expression, the isoform that is unable to bind cortisol and exert an antiinflammatory action. METHODS: By using real-time polymerase chain reaction, we studied the expression of α and β GR in the peripheral blood mononuclear cells obtained from 49 RSV-infected infants (<1 year of age) with severe (n = 29) and mild to moderate (n = 20) illness. In plasma, we analyzed the level of cortisol by radioimmunoassay and inflammatory cytokines interleukin (IL)-10, IL-6, tumor necrosis factor-α, IL-1β, IL-8, IL-12p70, IL-2, IL-4, IL-5, interferon-γ, and IL-17 by cytometric beads assay. Statistical analysis was performed by nonparametric analysis of variance. RESULTS: We found a significant increase of β GR expression in patients with severe illness compared with those with mild disease (P < .001) and with a group of healthy controls (P < .01). The α:β GR ratio decreased significantly in infants with severe disease compared with those with mild illness (P < .01) and with normal controls (P < .001). The expression of β GR was positively correlated with the clinical score of severity (r = .54; P < .0001). CONCLUSIONS: The decrease of the α:β GR ratio by an increase of β receptors expression is related to illness severity and may partly explain the insensitivity to corticoid treatment in RSV-infected infants. The increased expression of β GR could be a marker of disease severity.

High prevalence of Pneumocystis jirovecii dihydropteroate synthase gene mutations in patients with first episode of Pneumocystis pneumonia in Santiago, Chile, and their clinical response to trimethoprim-sulfamethoxazole therapy.

ABSTRACT Mutations in the dihydropteroate synthase (DHPS) gene of Pneumocystis jirovecii are associated with the failure of sulfa prophylaxis. They can develop by selection in patients receiving sulfa drugs or be acquired via person-to-person transmission. DHPS mutations raise concern about the decreasing efficacy of sulfa drugs, the main available therapeutic tool for Pneumocystis pneumonia (PCP). The prevalence of Pneumocystis DHPS mutations was examined in Pneumocystis isolates from 56 sulfa-prophylaxis-naive adults with a first episode of PCP from 2002 to 2010 in Santiago, Chile. Their clinical history was reviewed to analyze the effect of these mutations on response to trimethoprim-sulfamethoxazole (TMP-SMX) therapy and outcome. Mutant genotypes occurred in 22 (48%) of 46 HIV-infected patients and in 5 (50%) of 10 HIV-uninfected patients. Compared to patients with a wild-type genotype, those with mutant genotypes were more likely to experience sulfa treatment-limiting adverse reactions and to have a twice-longer duration of mechanical ventilation if mechanically ventilated. Specific genotypes did not associate with death, which occurred in none of the HIV-infected patients and in 50% of the non-HIV-infected patients. Chile has a high prevalence of DHPS mutations, which were presumably acquired through interhuman transmission because patients were not on sulfa prophylaxis. These results contrast with the low prevalence observed in other Latin American countries with similar usage of sulfa drugs, suggesting that additional sources of resistant genotypes may be possible. The twice-longer duration of mechanical ventilation in patients with mutant DHPS genotypes suggests a decreased efficacy of TMP-SMX and warrants collaborative studies to assess the relevance of DHPS mutations and further research to increase therapeutic options for PCP.

Diálisis con albúmina MARS (Molecular Adsorbent Recirculating System) como puente para el trasplante hepático en insuficiencia hepática fulminante: presentación de 3 casos

The most successful therapy for acute liver failure is liver transplantation. However, due to the low number of donors, organ support therapies need to be used as a bridge to liver transplantation. Molecular Adsorbents Recirculating System (MARS) is a dialysis treatment that uses a recirculating dialysate containing albumin. This allows the removal of both hydrosoluble and albumin-related substances. This system improves hepatic encephalopathy, renal dysfunction and some clinical parameters in acute liver failure, but there is no clear decrease in mortality. We report three women aged 23, 21 and 61 years, that were subjected to liver transplantation, in whom this therapy was successfully used.The most successful therapy for acute liver failure is livertransplantation. However, due to the low number of donors, organ support therapies need to be usedas a bridge to liver transplantation. Molecular Adsorbents Recirculating System (MARS) is a dialysistreatment that uses a recirculating dialysate containing albumin. This allows the removal of bothhydrosoluble and albumin-related substances. This system improves hepatic encephalopathy, renaldysfunction and some clinical parameters in acute liver failure, but there is no clear decrease inmortality. We report three women aged 23, 21 and 61 years, that were subjected to livertransplantation, in whom this therapy was successfully used (Rev Med Chile 2004; 132: 601-7).(

Evaluation of the Glucocorticoid Receptor as a Biomarker of Treatment Response in Vogt-Koyanagi-Harada Disease

Purpose This study is aimed to investigate the role of glucocorticoid receptor (GR) isoforms in peripheral blood mononuclear cells (PBMC) as biomarkers of glucocorticoid (GC) resistance and to validate a set of clinical predictive factors in patients with Vogt-Koyanagi-Harada (VKH) disease. Methods This was a prospective cohort study that included a total of 21 patients with VKH. A complete ophthalmologic evaluation was carried out at baseline that recorded the presence of any clinical predictive factors (visual acuity ≤ 20/200, tinnitus, chronic disease, and fundus depigmentation). Real-time quantitative PCR was performed to measure the mRNA levels of GR alpha (GRα) and beta (GRβ) isoforms at baseline and at 2 weeks after prednisone therapy initiation. Results There were no differences between GRα and GRβ levels in GC-sensitive and GC-resistant patients at baseline before treatment initiation. After 2 weeks of prednisone treatment, GC-sensitive patients had a median 5.5-fold increase in levels of GRα, whereas GC-resistant patients had a median 0.7-fold decrease in levels of this isoform (P = 0.003). Similarly, GRβ increased in GC-sensitive patients, in comparison with GR-resistant patients (6.49-fold versus 1.01 fold, respectively, I = 0.04). The mRNA levels of GR isoforms were independent of disease activity. Fundus depigmentation and chronic disease at diagnosis were associated with GC resistance (P = 0.03, odds ratio = 21.0; and P = 0.008, odds ratio = 37.8, respectively). However, associations with visual acuity or tinnitus were not confirmed in this study. Conclusions The evaluation of clinical predictive factors and determination of the change in expression of GR isoforms as potential biomarkers can contribute to the early identification of GC-resistant patients with VKH.

Para entender la acción de cortisol en inflamación aguda: una mirada desde la glándula suprarrenal hasta la célula blanco

Glucocorticoids (cortisol in humans) are essential for numerous biological functions. Among critically ill patients, therapy with cortisol has gained strength in recent years, but clinical results have been mixed. A series of events, that may explain the diversity of clinical responses, occur from the synthesis of cortisol in the adrenal gland to the activation of the cortisol receptor by the hormone when it enters the nucleus of the target cell. Some of these events are revised; a proposition for identifying critically ill patients who may benefit with this therapy.