Effect of N-acetylcysteine on pulmonary cell death in a controlled hemorrhagic shock model in rats

PURPOSE: To evaluate the effect of N-acetylcysteine (NAC) combined with fluid resuscitation on pulmonary cell death in rats induced with controlled hemorrhagic shock (HS). METHODS: Two arteries (MAP calculation and exsanguination) and one vein (treatments) were catheterized in 22 anesthetized rats. Two groups of male albino rats were induced with controlled HS at 35mmHg MAP for 60 min. After this period, the RL group was resuscitated with Ringer's lactate and the RL+NAC group was resuscitated with Ringer's lactate combined with 150mg/Kg NAC. The control group animals were cannulated only. The animals were euthanized after 120 min of fluid resuscitation. Lung tissue samples were collected to evaluate the following: histopathology, TUNEL and imunohistochemical expression of caspase 3. RESULTS: RL showed a greater number of cells stained by TUNEL than RL + NAC, but there was no change in caspase 3 expression in any group. CONCLUSION: N-acetylcysteine associate to fluid resuscitation, after hemorrhagic shock, decreased cell death attenuating lung injury.

In-hospital death in acute coronary syndrome was related to admission glucose in men but not in women

Background: Admission hyperglycaemia is associated with mortality in patients with acute coronary syndrome (ACS), but controversy exists whether hyperglycaemia uniformly affects both genders. We evaluated coronary risk factors, gender, hyperglycaemia and their effect on hospital mortality. Methods: 959 ACS patients (363 women and 596 men) were grouped based on glycaemia >= or < 200 mg/dL and gender: men with glucose < 200 mg/dL (menG-); women with glucose < 200 mg/dL (womenG-); men with glucose >= 200 mg/dL (menG+); and women with glucose >= 200 mg/dL (womenG+). A logistic regression analysis compared the relation between gender and glycaemia groups and death, adjusted for coronary risk factors and laboratory data. Results group: menG- had lower mortality than menG+ (OR = 0.172, IC95% 0.062-0.478), and womenG+ (OR = 0.275, IC95% 0.090-0.841); womenG- mortality was lower than menG+ (OR = 0.230, IC95% 0.074-0.717). No difference was found between menG+ vs womenG+ (p = 0.461), or womenG- vs womenG+ (p = 0.110). Age (OR = 1.067, IC95% 1.031-1.104), EF (OR = 0.942, IC95% 0.915-0.968), and serum creatinine (OR = 1.329, IC95% 1.128-1.566) were other independent factors related to in-hospital death. Conclusions: Death was greater in hyperglycemic men compared to lower blood glucose men and women groups, but there was no differences between women groups in respect to glycaemia after adjustment for coronary risk factors.

The Effects of High Pressure on the Point of No Return in Simulated Penalty Kicks

We investigated the effects of high pressure on the point of no return or the minimum time required for a kicker to respond to the goalkeeper's dive in a simulated penalty kick task. The goalkeeper moved to one side with different times available for the participants to direct the ball to the opposite side in low-pressure (acoustically isolated laboratory) and high-pressure situations (with a participative audience). One group of participants showed a significant lengthening of the point of no return under high pressure. With less time available, performance was at chance level. Unexpectedly, in a second group of participants, high pressure caused a qualitative change in which for short times available participants were inclined to aim in the direction of the goalkeeper's move. The distinct effects of high pressure are discussed within attentional control theory to reflect a decreasing efficiency of the goal-driven attentional system, slowing down performance, and a decreasing effectiveness in inhibiting stimulus-driven behavior.

Quantitative proteomic analysis and functional studies reveal that nucleophosmin is involved in cell death in glioblastoma cell line transfected with siRNA

Previously, we reported that nucleophosmin (NPM) was increased in glioblastoma multiforme (GBM). NPM is a phosphoprotein related to apoptosis, ribosome biogenesis, mitosis, and DNA repair, but details about its function remain unclear. We treated U87MG and A172 cells with small interference RNA (siRNA) and obtained a reduction of 80% in NPM1 expression. Knockdown at the protein level was evident after the 4th day and was maintained until the 7th day of transfection that was investigated by quantitative proteomic analysis using isobaric tags. The comparison of proteomic analysis of NPM1-siRNA against controls allowed the identification of 14 proteins, two proteins showed increase and 12 presented a reduction of expression levels. Gene ontology assigned most of the hypoexpressed proteins to apoptosis regulation, including GRP78. NPM1 silencing did not impair cell proliferation until the 7th day after transfection, but sensitized U87MG cells to temozolomide (TMZ), culminating with an increase in cell death and provoking at a later period a reduction of colony formation. In a large data set of GBM patients, both GRP78 and NPM1 genes were upregulated and presented a tendency to shorter overall survival time. In conclusion, NPM proved to participate in the apoptotic process, sensitizing TMZ-treated U87MG and A172 cells to cell death, and in association with upregulation of GRP78 may be helpful as a predictive factor of poor prognosis in GBM patients.

Trends in aortic aneurysm- and dissection-related mortality in the state of Sao Paulo, Brazil, 1985-2009: multiple-cause-of-death analysis

Background: Aortic aneurysm and dissection are important causes of death in older people. Ruptured aneurysms show catastrophic fatality rates reaching near 80%. Few population-based mortality studies have been published in the world and none in Brazil. The objective of the present study was to use multiple-cause-of-death methodology in the analysis of mortality trends related to aortic aneurysm and dissection in the state of Sao Paulo, between 1985 and 2009. Methods: We analyzed mortality data from the Sao Paulo State Data Analysis System, selecting all death certificates on which aortic aneurysm and dissection were listed as a cause-of-death. The variables sex, age, season of the year, and underlying, associated or total mentions of causes of death were studied using standardized mortality rates, proportions and historical trends. Statistical analyses were performed by chi-square goodness-of-fit and H Kruskal-Wallis tests, and variance analysis. The joinpoint regression model was used to evaluate changes in age-standardized rates trends. A p value less than 0.05 was regarded as significant. Results: Over a 25-year period, there were 42,615 deaths related to aortic aneurysm and dissection, of which 36,088 (84.7%) were identified as underlying cause and 6,527 (15.3%) as an associated cause-of-death. Dissection and ruptured aneurysms were considered as an underlying cause of death in 93% of the deaths. For the entire period, a significant increased trend of age-standardized death rates was observed in men and women, while certain non-significant decreases occurred from 1996/2004 until 2009. Abdominal aortic aneurysms and aortic dissections prevailed among men and aortic dissections and aortic aneurysms of unspecified site among women. In 1985 and 2009 death rates ratios of men to women were respectively 2.86 and 2.19, corresponding to a difference decrease between rates of 23.4%. For aortic dissection, ruptured and non-ruptured aneurysms, the overall mean ages at death were, respectively, 63.2, 68.4 and 71.6 years; while, as the underlying cause, the main associated causes of death were as follows: hemorrhages (in 43.8%/40.5%/13.9%); hypertensive diseases (in 49.2%/22.43%/24.5%) and atherosclerosis (in 14.8%/25.5%/15.3%); and, as associated causes, their principal overall underlying causes of death were diseases of the circulatory (55.7%), and respiratory (13.8%) systems and neoplasms (7.8%). A significant seasonal variation, with highest frequency in winter, occurred in deaths identified as underlying cause for aortic dissection, ruptured and non-ruptured aneurysms. Conclusions: This study introduces the methodology of multiple-causes-of-death to enhance epidemiologic knowledge of aortic aneurysm and dissection in Sao Paulo, Brazil. The results presented confer light to the importance of mortality statistics and the need for epidemiologic studies to understand unique trends in our own population.

The dialogic life-death in care delivery to adolescents with cancer

This study aims to understand the experience of adolescents with cancer, family and the health team regarding death in the healthcare context, in the light of Edgar Morin's proposed theoretical framework of complexity. Participants were 12 adolescents, 14 relatives and 25 health professionals. The interview was used for data collection. The discussion of data was guided by the dialogic life-death in the context of care to adolescents with cancer. It was observed that the singularity in the way the adolescent experiences time and faces death and the possibility that the family will lose a loved one may not be in accordance with the care the health team offers, considering structural, organizational and affective aspects. It is not enough for the team just to rationally make choices on the use of diagnostic-therapeutic devices, in line with predefined moments in the disease. Instead, a contextualized and sensitive understanding of each situation is needed.

Reduced occurrence of programmed cell death and gliosis in the retinas of juvenile rabbits after short-term treatment with intravitreous bevacizumab

OBJECTIVE: Bevacizumab has been widely used as a vascular endothelial growth factor antagonist in the treatment of retinal vasoproliferative disorders in adults and, more recently, in infants with retinopathy of prematurity. Recently, it has been proposed that vascular endothelial growth factor acts as a protective factor for neurons and glial cells, particularly in developing nervous tissue. The purpose of this study was to investigate the effects of bevacizumab on the developing retinas of juvenile rabbits. METHODS: Juvenile rabbits received bevacizumab intravitreously in one eye; the other eye acted as an untreated control. Slit-lamp and fundoscopic examinations were performed both prior to and seven days after treatment. At the same time, retina samples were analyzed using immunohistochemistry to detect autophagy and apoptosis as well as proliferation and glial reactivity. Morphometric analyses were performed, and the data were analyzed using the Mann-Whitney U test. RESULTS: No clinical abnormalities were observed in either treated or untreated eyes. However, immunohistochemical analyses revealed a reduction in the occurrence of programmed cell death and increases in both proliferation and reactivity in the bevacizumab-treated group compared with the untreated group. CONCLUSIONS: Bevacizumab appears to alter programmed cell death patterns and promote gliosis in the developing retinas of rabbits; therefore, it should be used with caution in developing eyes.

Mechanism and Efficiency of Cell Death of Type II Photosensitizers: Effect of Zinc Chelation

A series of meso-substituted tetra-cationic porphyrins, which have methyl and octyl substituents, was studied in order to understand the effect of zinc chelation and photosensitizer subcellular localization in the mechanism of cell death. Zinc chelation does not change the photophysical properties of the photosensitizers (all molecules studied are type II photosensitizers) but affects considerably the interaction of the porphyrins with membranes, reducing mitochondrial accumulation. The total amount of intracellular reactive species induced by treating cells with photosensitizer and light is similar for zinc-chelated and free-base porphyrins that have the same alkyl substituent. Zinc-chelated porphyrins, which are poorly accumulated in mitochondria, show higher efficiency of cell death with features of apoptosis (higher MTT response compared with trypan blue staining, specific acridine orange/ethidium bromide staining, loss of mitochondrial transmembrane potential, stronger cytochrome c release and larger sub-G1 cell population), whereas nonchelated porphyrins, which are considerably more concentrated in mitochondria, triggered mainly necrotic cell death. We hypothesized that zinc-chelation protects the photoinduced properties of the porphyrins in the mitochondrial environment.

Proteasome inhibition and ROS generation by 4-nerolidylcatechol induces melanoma cell death

Induction of apoptotic cell death in response to chemotherapy and other external stimuli has proved extremely difficult in melanoma, leading to tumor progression, metastasis formation and resistance to therapy. A promising approach for cancer chemotherapy is the inhibition of proteasomal activity, as the half-life of the majority of cellular proteins is under proteasomal control and inhibitors have been shown to induce cell death programs in a wide variety of tumor cell types. 4-Nerolidylcatechol (4-NC) is a potent antioxidant whose cytotoxic potential has already been demonstrated in melanoma tumor cell lines. Furthermore, 4-NC was able to induce the accumulation of ubiquitinated proteins, including classic targets of this process such as Mcl-1. As shown for other proteasomal inhibitors in melanoma, the cytotoxic action of 4-NC is time-dependent upon the pro-apoptotic protein Noxa, which is able to bind and neutralize Mcl-1. We demonstrate the role of 4-NC as a potent inducer of ROS and p53. The use of an artificial skin model containing melanoma also provided evidence that 4-NC prevented melanoma proliferation in a 3D model that more closely resembles normal human skin.

Arbitrage-Free Conditions and Hedging Strategies for Markets with Penalty Costs on Short Positions

We consider a discrete-time financial model in a general sample space with penalty costs on short positions. We consider a friction market closely related to the standard one except that withdrawals from the portfolio value proportional to short positions are made. We provide necessary and sufficient conditions for the nonexistence of arbitrages in this situation and for a self-financing strategy to replicate a contingent claim. For the finite-sample space case, this result leads to an explicit and constructive procedure for obtaining perfect hedging strategies.

IL-12p40 Deficiency Leads to Uncontrolled Trypanosoma cruzi Dissemination in the Spinal Cord Resulting in Neuronal Death and Motor Dysfunction

Chagas' disease is a protozoosis caused by Trypanosoma cruzi that frequently shows severe chronic clinical complications of the heart or digestive system. Neurological disorders due to T. cruzi infection are also described in children and immunosuppressed hosts. We have previously reported that IL-12p40 knockout (KO) mice infected with the T. cruzi strain Sylvio X10/4 develop spinal cord neurodegenerative disease. Here, we further characterized neuropathology, parasite burden and inflammatory component associated to the fatal neurological disorder occurring in this mouse model. Forelimb paralysis in infected IL-12p40KO mice was associated with 60% (p<0.05) decrease in spinal cord neuronal density, glutamate accumulation (153%, p<0.05) and strong demyelization in lesion areas, mostly in those showing heavy protein nitrosylation, all denoting a neurotoxic degenerative profile. Quantification of T. cruzi 18S rRNA showed that parasite burden was controlled in the spinal cord of WT mice, decreasing from the fifth week after infection, but progressive parasite dissemination was observed in IL-12p40KO cords concurrent with significant accumulation of the astrocytic marker GFAP (317.0%, p<0.01) and 8-fold increase in macrophages/microglia (p<0.01), 36.3% (p<0.01) of which were infected. Similarly, mRNA levels for CD3, TNF-alpha, IFN-gamma, iNOS, IL-10 and arginase I declined in WT spinal cords about the fourth or fifth week after infection, but kept increasing in IL-12p40KO mice. Interestingly, compared to WT tissue, lower mRNA levels for IFN-gamma were observed in the IL-12p40KO spinal cords up to the fourth week of infection. Together the data suggest that impairments of parasite clearance mechanisms in IL-12p40KO mice elicit prolonged spinal cord inflammation that in turn leads to irreversible neurodegenerative lesions.

The use of severity indexes to estimate the risk of death in Intensive Care

The Simplified Acute Physiology Score II (SAPS II) and Logistic Organ Dysfunction System (LODS) are instruments used to classify Intensive Care Unit (ICU) inpatients according to the severity of their condition and risk of death, and evaluate the quality of nursing care. The objective of this study is to evaluate and compare the performance of SAPS II and LODS to predict the mortality of patients admitted to the ICU. The participants were 600 patients from four ICUs located in Sao Paulo, Brazil. Receiver Operator Characteristic (ROC) curves were used to compare the performance of the indexes. Results: The areas under the ROC curves of LODS (0.69) and SAPS II (0.71) indicated moderate discriminatory capacity to identify death or survival. No statistically significant differences were found between these areas (p=0.26). In conclusion, there was equivalence between SAPS II and LODS to estimate the risk of death of ICU patients.

Phoneutria nigriventer spider toxin Tx2-6 causes priapism and death: A histopathological investigation in mice

Phoneutria nigriventer spider bite causes priapism, an effect attributed to the peptide toxins Tx2-5 and Tx2-6 and involving nitric oxide. Tx2-6 (MW = 5287) is known to delay the inactivation of Sodium channels in the same fashion as many other venom toxins. In the present study we evaluated the i.p. dose that induces priapism and the other symptoms in mice. Animals killed by the toxin or crude venom (0.85 mg/kg) were autopsied and a pathological study of brain, lung, kidney, liver and heart was undertaken using standard techniques. The same protocol was employed with animals injected with crude venom. Results showed that priapism is the first sign of intoxication, followed by piloerection, abundant salivation and tremors. An i.p. injection of about 0.3 mu g/kg induced only priapism with minimal side-effects. The most remarkable histological finding was a general vascular congestion in all organs studied. Penis showed no necrosis or damage. Lungs showed vascular congestion and alveolar hemorrhage. Heart showed also sub-endothelial hemorrhage. Brain showed only a mild edema and vascular congestion. Results obtained with crude venom closely resemble those of purified toxin. We conclude that Tx2-6 have profound effects on the vascular bed especially in lungs and heart, which may be the cause of death. Interestingly brain tissue was less affected and the observed edema may be attributed to respiratory impairment. To the best of our knowledge this is the first histopathological investigation on this toxin and venom suggesting a possible cause of death. (C) 2012 Elsevier Ltd. All rights reserved.

Fhos encodes a Drosophila Formin-Like Protein participating in autophagic programmed cell death

Larval tissues undergo programmed cell death (PCD) during Drosophila metamorphosis. PCD is triggered in a stage and tissue-specific fashion in response to ecdysone pulses. The understanding of how ecdysone induces the stage and tissue-specificity of cell death remains obscure. Several steroid-regulated primary response genes have been shown to act as key regulators of cellular responses to ecdysone by inducing a cascade of transcriptional regulation of late responsive genes. In this article, the authors identify Fhos as a gene that is required for Drosophila larval salivary gland destruction. Animals with a P-element mutation in Fhos possess persistent larval salivary glands, and precise excisions of this P-element insertion resulted in reversion of this salivary gland mutant phenotype. Fhos encodes the Drosophila homolog of mammalian Formin Fhos. Fhos is differentially transcribed during development and responds to ecdysone in a method that is similar to other cell death genes. Similarly to what has been shown for its mammalian counterpart, FHOS protein is translocated to the nucleus at later stages of cell death. Fhos mutants posses disrupted actin cytoskeleton dynamics in persistent salivary glands. Together, our data indicate that Fhos is a new ecdysone-regulated gene that is crucial for changes in the actin cytoskeleton during salivary gland elimination in Drosophila. genesis 50:672684, 2012. (c) 2012 Wiley Periodicals, Inc.

Brazilian guidelines for the application of transcranial ultrasound as a diagnostic test for the confirmation of brain death

Neurosonological studies, specifically transcranial Doppler (TCD) and transcranial color-coded duplex (TCCD), have high level of specificity and sensitivity and they are used as complementary tests for the diagnosis of brain death (BD). A group of experts, from the Neurosonology Department of the Brazilian Academy of Neurology, created a task force to determine the criteria for the following aspects of diagnosing BD in Brazil: the reliability of TCD methodology; the reliability of TCCD methodology; neurosonology training and skills; the diagnosis of encephalic circulatory arrest; and exam documentation for BD. The results of this meeting are presented in the current paper.