Factores pronósticos de remisión a largo plazo tras cirugía transesfenoidal en la enfermedad de Cushing

There is no consensus on the remission criteria for Cushing's disease or on the definition of disease recurrence after transsphenoidal surgery, and comparison of the different published series is therefore difficult. A long-term recurrence rate of Cushing's disease ranging from 2%-25% has been reported. Predictors of long-term remission reported include: 1) adenoma–related factors (aggressiveness, size, preoperative identification in MRI), 2) surgery-related factors, mainly neurosurgeon experience, 3) clinical factors, of which dependence on and duration of glucocorticoid treatment are most important, and 4) biochemical factors. Among the latter, low postoperative cortisol levels, less than 2 mcg/dL predict for disease remission. However, even when undetectable plasma cortisol levels are present, long-term recurrence may still occur and lifetime follow-up is required. We report the preliminary results of the first 20 patients with Cushing's disease operated on at our hospital using nadir cortisol levels less than 2 mcg/dl as remission criterion.     

Stable HIV-1 integrase diversity during initial HIV-1 RNA Decay suggests complete blockade of plasma HIV-1 replication by effective raltegravir-containing salvage therapy

Background

There is legitimate concern that minority drug-resistant mutants may be selected during the initial HIV-1 RNA decay phase following antiretroviral therapy initiation, thus undermining efficacy of treatment. The goal of this study was to characterize viral resistance emergence and address viral population evolution during the first phase of viral decay after treatment containing initiation.

Findings

454 sequencing was used to characterize viral genetic diversity and polymorphism composition of the HIV-1 integrase gene during the first two weeks following initiation of raltegravir-containing HAART in four ART-experienced subjects. No low-prevalence Raltegravir (RAL) drug resistance mutations (DRM) were found at baseline. All patients undergoing treatment received a fully active ART according to GSS values (GSS?≥?3.5). No emergence of DRM after treatment initiation was detected. Longitudinal analysis showed no evidence of any other polymorphic mutation emergence or variation in viral diversity indexes.

Conclusions

This suggests that fully active salvage antiretroviral therapy including raltegravir achieves a complete blockade of HIV-1 replication in plasma. It is unlikely that raltegravir-resistant HIV-1 may be selected in plasma during the early HIV-1 RNA decay after treatment initiation if the administered therapy is active enough.

     

Bystander Responses to a Violent Incident in an Immersive Virtual Environment

Under what conditions will a bystander intervene to try to stop a violent attack by one person on another? It is generally believed that the greater the size of the crowd of bystanders, the less the chance that any of them will intervene. A complementary model is that social identity is critical as an explanatory variable. For example, when the bystander shares common social identity with the victim the probability of intervention is enhanced, other things being equal. However, it is generally not possible to study such hypotheses experimentally for practical and ethical reasons. Here we show that an experiment that depicts a violent incident at life-size in immersive virtual reality lends support to the social identity explanation. 40 male supporters of Arsenal Football Club in England were recruited for a two-factor between-groups experiment: the victim was either an Arsenal supporter or not (in-group/out-group), and looked towards the participant for help or not during the confrontation. The response variables were the numbers of verbal and physical interventions by the participant during the violent argument. The number of physical interventions had a significantly greater mean in the in-group condition compared to the out-group. The more that participants perceived that the Victim was looking to them for help the greater the number of interventions in the in-group but not in the out-group. These results are supported by standard statistical analysis of variance, with more detailed findings obtained by a symbolic regression procedure based on genetic programming. Verbal interventions made during their experience, and analysis of post-experiment interview data suggest that in-group members were more prone to confrontational intervention compared to the out-group who were more prone to make statements to try to diffuse the situation.     

Air Passive Sampling for the Screening of Inhalation Risks of POPs Near an Incineration Plant

The use of passive air samplers (PAS) in recent years to monitor the occurrence of persistent organic pollutants (POPs) in air has been increasing, not only globally, but also at regional and/or local scales. The present study was aimed at analyzing the airborne concentrations of the POPs: polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and polychlorinated naphthalenes (PCNs) in the vicinity of a municipal solid waste incinerator (MSWI) in Tarragona (Catalonia, Spain). Mean air levels of PCBs, PBDEs, and PCNs were 44.1, 65.0, and 6.65 pg/m³, respectively. No differences were noted according to the distance or direction from the plant for any chemical. Furthermore, this information was used to estimate the air inhalation of POPs for the local population. Environmental exposure to POPs through air accounted for only <2% of the total when compared with the dietary intake. The overall results indicate that the MSWI here assessed does not mean a relevant increase on human health risks derived from inhalation of POPs. PAS can also be utilized for human health risk assessment studies, being also suitable tools to control the environmental burden of non-regulated chemicals, for which no emission thresholds have yet been derived.     

Plasma kisspeptin levels are elevated in cord blood and present sexual dimorphism in the adult population: relation with leptin, gonadotropins and anthropometrical data

Kisspeptin, the product of the hypothalamic KISS1 gene, is a main regulator of the hypothalamic-pituitary-gonadal axis and could be a link between metabolism and reproduction through its interaction with leptin. Kisspeptin could be involved in gonadotropin regulation and responsive to leptin levels from the first stages of life, exhibiting, as does leptin, sexual dimorphism. To test our hypothesis, we have analyzed plasma kisspeptin levels and their possible relationship with gonadotropins and leptin in a cohort composed of newborns (n = 86) and adults (n = 55). Plasma kisspeptin, gonadotropin and leptin levels were measured by RIA and multiplexed bead immunoassays, respectively. We have built a multivariate linear regression model (analyzing kisspeptin and LH separately as dependent variables) by stepwise analysis, incorporating the variables that had shown significant correlation in the univariate analysis. Cord blood samples exhibited high kisspeptin levels 127.01(113-141.02 pmol/l), but these were not sexually dimorphic. The adult population exhibited sexual dimorphism (3.72(2.95-4.49) vs. 1.77(1.23-2.31) pmol/l women vs. men, p < 0.05). Leptin levels showed sexual dimorphism in cord blood samples and also in the adult population. Furthermore, there was a significant interaction between LH and kisspeptin levels and kisspeptin was negatively correlated with age. The high kisspeptin levels observed in cord blood, with no sexual dimorphism, suggest a placental source. The sexual dimorphism exhibited in adulthood supports the notion that there are different sources and/or differential kisspeptin regulation between men and women.     

Neuroimaging in acute liver failure

Acute liver failure (ALF) is frequently complicated by the development of brain edema that can lead to intracranial hypertension and severe brain injury. Neuroimaging techniques allow a none-invasive assessment of brain tissue and cerebral hemodynamics by means of transcranial Doppler ultrasonography, magnetic resonance and nuclear imaging with radioligands. These methods have been very helpful to unravel the pathogenesis of this process and have been applied to patients and experimental models. They allow monitoring the outcome of patients with ALF and neurological manifestations. The increase in brain water can be detected by observing changes in brain volume and disturbances in diffusion weighted imaging. Neurometabolic changes are detected by magnetic resonance spectroscopy, which provides a pattern of abnormalities characterized by an increase in glutamine and a decrease in myo-inositol. Disturbances in cerebral blood flow are depicted by SPECT or PET and can be monitored and the bedside by assessing the characteristics of the waveform provided by transcranial Doppler ultrasonography. Neuroimaging methods, which are rapidly evolving, will undoubtedly lead to future diagnostic and therapeutic progress that could be very helpful for patients with ALF.     

Reprint of: Neuroimaging in acute liver failure

Acute liver failure (ALF) is frequently complicated by the development of brain edema that can lead to intracranial hypertension and severe brain injury. Neuroimaging techniques allow a none-invasive assessment of brain tissue and cerebral hemodynamics by means of transcranial Doppler ultrasonography, magnetic resonance and nuclear imaging with radioligands. These methods have been very helpful to unravel the pathogenesis of this process and have been applied to patients and experimental models. They allow monitoring the outcome of patients with ALF and neurological manifestations. The increase in brain water can be detected by observing changes in brain volume and disturbances in diffusion weighted imaging. Neurometabolic changes are detected by magnetic resonance spectroscopy, which provides a pattern of abnormalities characterized by an increase in glutamine and a decrease in myo-inositol. Disturbances in cerebral blood flow are depicted by SPECT or PET and can be monitored and the bedside by assessing the characteristics of the waveform provided by transcranial Doppler ultrasonography. Neuroimaging methods, which are rapidly evolving, will undoubtedly lead to future diagnostic and therapeutic progress that could be very helpful for patients with ALF.     

Cytochrome P450-catalysed reactive oxygen species production mediates the (-)schisandrin B-induced glutathione and heat shock responses in AML12 hepatocytes

Sch B (schisandrin B), the most abundant dibenzocyclooctadiene lignan in Fructus schisandrae, can induce glutathione antioxidant and heat shock responses, as well as protect against oxidant-induced injury in various tissues, including the liver in rodents and AML12 (alpha mouse liver 12) hepatocytes. (-)Sch B is the most potent stereoisomer of Sch B in its cytoprotective action on AML12 hepatocytes. To define the role of ROS (reactive oxygen species) arising from CYP (cytochrome P450)-catalysed metabolism of (-)Sch B in triggering glutathione antioxidant and heat shock responses, the effects of a CYP inhibitor [ABT (aminobenzotriazole)] and antioxidants [DMTU (dimethylthiouracil) and TRX (trolox)] on (-)Sch B-induced ROS production and associated increases in cellular GSH level, as well as Hsp25/70 (heat-shock protein 25/70) production, were investigated in AML12 hepatocytes. The results indicated that (-)Sch B causes a dose dependent and sustained increase in ROS production over 6 h in AML12 hepatocytes, which was completely suppressed by pre-/co-treatment with ABT or DTMU/TRX. Incubation with (-)Sch B for 6 h caused optimal and dose-dependent increases in cellular GSH level and Hsp25/70 production at 16 h post-drug exposure in AML12 hepatocytes. These cellular responses were associated with protection against menadione-induced apoptosis. Pre-/co-treatment with ABT or antioxidants completely abrogated the (-)Sch B-induced glutathione antioxidant and heat shock responses, as well as protection against menadione-induced apoptosis. Experimental evidence obtained thus far supports the causal role of ROS arising from the CYP-catalysed metabolism of (-)Sch B in eliciting glutathione antioxidant and heat shock responses in AML12 hepatocytes.     

Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer

Antibodies against epidermal growth factor receptor (EGFR)--cetuximab and panitumumab--are widely used to treat colorectal cancer. Unfortunately, patients eventually develop resistance to these agents. We describe an acquired EGFR ectodomain mutation (S492R) that prevents cetuximab binding and confers resistance to cetuximab. Cells with this mutation, however, retain binding to and are growth inhibited by panitumumab. Two of ten subjects studied here with disease progression after cetuximab treatment acquired this mutation. A subject with cetuximab resistance harboring the S492R mutation responded to treatment with panitumumab.