Association of arterial blood pressure and vasopressor load with septic shock mortality: a post hoc analysis of a multicenter trial

INTRODUCTION: It is unclear to which level mean arterial blood pressure (MAP) should be increased during septic shock in order to improve outcome. In this study we investigated the association between MAP values of 70 mmHg or higher, vasopressor load, 28-day mortality and disease-related events in septic shock. METHODS: This is a post hoc analysis of data of the control group of a multicenter trial and includes 290 septic shock patients in whom a mean MAP > or = 70 mmHg could be maintained during shock. Demographic and clinical data, MAP, vasopressor requirements during the shock period, disease-related events and 28-day mortality were documented. Logistic regression models adjusted for the geographic region of the study center, age, presence of chronic arterial hypertension, simplified acute physiology score (SAPS) II and the mean vasopressor load during the shock period was calculated to investigate the association between MAP or MAP quartiles > or = 70 mmHg and mortality or the frequency and occurrence of disease-related events. RESULTS: There was no association between MAP or MAP quartiles and mortality or the occurrence of disease-related events. These associations were not influenced by age or pre-existent arterial hypertension (all P > 0.05). The mean vasopressor load was associated with mortality (relative risk (RR), 1.83; confidence interval (CI) 95%, 1.4-2.38; P < 0.001), the number of disease-related events (P < 0.001) and the occurrence of acute circulatory failure (RR, 1.64; CI 95%, 1.28-2.11; P < 0.001), metabolic acidosis (RR, 1.79; CI 95%, 1.38-2.32; P < 0.001), renal failure (RR, 1.49; CI 95%, 1.17-1.89; P = 0.001) and thrombocytopenia (RR, 1.33; CI 95%, 1.06-1.68; P = 0.01). CONCLUSIONS: MAP levels of 70 mmHg or higher do not appear to be associated with improved survival in septic shock. Elevating MAP >70 mmHg by augmenting vasopressor dosages may increase mortality. Future trials are needed to identify the lowest acceptable MAP level to ensure tissue perfusion and avoid unnecessary high catecholamine infusions.

A Routing Protocol Based on Energy and Link Quality for Internet of Things Applications

The Internet of Things (IoT) is attracting considerable attention from the universities, industries, citizens and governments for applications, such as healthcare, environmental monitoring and smart buildings. IoT enables network connectivity between smart devices at all times, everywhere, and about everything. In this context, Wireless Sensor Networks (WSNs) play an important role in increasing the ubiquity of networks with smart devices that are low-cost and easy to deploy. However, sensor nodes are restricted in terms of energy, processing and memory. Additionally, low-power radios are very sensitive to noise, interference and multipath distortions. In this context, this article proposes a routing protocol based on Routing by Energy and Link quality (REL) for IoT applications. To increase reliability and energy-efficiency, REL selects routes on the basis of a proposed end-to-end link quality estimator mechanism, residual energy and hop count. Furthermore, REL proposes an event-driven mechanism to provide load balancing and avoid the premature energy depletion of nodes/networks. Performance evaluations were carried out using simulation and testbed experiments to show the impact and benefits of REL in small and large-scale networks. The results show that REL increases the network lifetime and services availability, as well as the quality of service of IoT applications. It also provides an even distribution of scarce network resources and reduces the packet loss rate, compared with the performance of well-known protocols.

Transport and uptake of immunogenic lipids

An increasing number of lipid mediators have been identified as key modulators of immunity. Among these is a family of glycolipids capable of cellular uptake, loading onto the MHC-like molecule CD1d and stimulation of NKT cells. NKT cells are particularly interesting because they bridge innate and adaptive immunity by coordinating the early events of dendritic cell maturation, recruitment of NK cells, CD4 and CD8 T cells, and B cells at the site of microbial injury. As such, their therapeutic manipulation could be of the greatest interest in vaccine design or active immunotherapy. However, the use of NKT cells as cellular adjuvant of immunity in the clinic will require a better knowledge of the pharmacology of lipid agonists in order to optimize their action and avoid potential unseen off-target effects. We have been studying extracellular transport and cellular uptake of NKT agonists for the past few years. This field is confronted to a very limited prior knowledge and a small set of usable tools. New technology must be put in place and adapted to answering basic immunology questions related to NKT cells. The intimate link between the pharmacology of glycolipids and lipid metabolism makes us believe that great variations of bioactivity could be seen in the general population when NKT agonists are used therapeutically.

Activation of heat shock and antioxidant responses by the natural product celastrol: transcriptional signatures of a thiol-targeted molecule.

Stress response pathways allow cells to sense and respond to environmental changes and adverse pathophysiological states. Pharmacological modulation of cellular stress pathways has implications in the treatment of human diseases, including neurodegenerative disorders, cardiovascular disease, and cancer. The quinone methide triterpene celastrol, derived from a traditional Chinese medicinal herb, has numerous pharmacological properties, and it is a potent activator of the mammalian heat shock transcription factor HSF1. However, its mode of action and spectrum of cellular targets are poorly understood. We show here that celastrol activates Hsf1 in Saccharomyces cerevisiae at a similar effective concentration seen in mammalian cells. Transcriptional profiling revealed that celastrol treatment induces a battery of oxidant defense genes in addition to heat shock genes. Celastrol activated the yeast Yap1 oxidant defense transcription factor via the carboxy-terminal redox center that responds to electrophilic compounds. Antioxidant response genes were likewise induced in mammalian cells, demonstrating that the activation of two major cell stress pathways by celastrol is conserved. We report that celastrol's biological effects, including inhibition of glucocorticoid receptor activity, can be blocked by the addition of excess free thiol, suggesting a chemical mechanism for biological activity based on modification of key reactive thiols by this natural product.

Psychometric and biohormonal indices of dental anxiety in children. A prospective cohort study.

The stress of dental treatment often elicits negative emotions in children, expressed as dental fear or anxiety. Highly anxious children obstruct treatment and avoid therapy, further amplifying oral health problems. The aim of this study was to examine the neuroendocrine and autonomic nervous system responses to dental treatment and their possible interactions and associations with psychometric indices of anxiety, caries, previous dental experience, anesthesia, age and gender in school children. Upon informed consent, saliva was obtained from 97 children (59% males, mean age ±  SD: 89.73 ± 15 months) in the Clinic of pediatric dentistry before treatment, immediately post-treatment and at the recall visit to determine cortisol and salivary alpha-amylase (sAA) levels. Dental and general anxiety was assessed through specific questionnaires completed by the children. Compared to pre-treatment, cortisol levels were increased following treatment, while sAA levels were higher at the recall. Pre- and post-treatment cortisol and sAA responses were positively correlated. Dental and general anxiety questionnaire scores were also significantly correlated with each other. The integrated autonomic and neuroendocrine responses prior to treatment were correlated with state anxiety and those following treatment with dental anxiety. However, univariable and multivariable linear regression analysis associated post-treatment cortisol, but not sAA, levels with dental anxiety. No associations of cortisol or sAA responses with caries, age, gender, previous dental experience or anesthesia were detected. These data provide some evidence that both sAA and cortisol levels are altered in children in anticipation or during dental treatment, but only cortisol levels are associated to dental anxiety.

Diagnosis and interdisciplinary treatment of a botryoid odontogenic cyst in the posterior mandible: report of a case.

Botryoid odontogenic cysts (BOC) are considered to be rare polycystic variants of lateral periodontal cysts characterized by a multilocular growth pattern. The most frequent location of BOC is the mandible, predominantly the premolar-canine area, followed by the anterior region of the maxilla. The cyst shows a slight female predilection. This case report of a BOC demonstrates a treatment with initial fenestration and decompression of the cyst in order to prevent damage to adjacent structures such as the inferior alveolar nerve. The present case report emphasizes the importance of accurate clinical, radiographic, and histologic diagnostic procedures of unspecific radiolucent lesions in the jaws to establish a firm diagnosis and avoid inappropriate treatment strategies.

Genetic analysis of white facial and leg markings in the Swiss Franches-Montagnes Horse Breed

White markings and spotting patterns in animal species are thought to be a result of the domestication process. They often serve for the identification of individuals but sometimes are accompanied by complex pathological syndromes. In the Swiss Franches-Montagnes horse population, white markings increased vastly in size and occurrence during the past 30 years, although the breeding goal demands a horse with as little depigmented areas as possible. In order to improve selection and avoid more excessive depigmentation on the population level, we estimated population parameters and breeding values for white head and anterior and posterior leg markings. Heritabilities and genetic correlations for the traits were high (h(2) > 0.5). A strong positive correlation was found between the chestnut allele at the melanocortin-1-receptor gene locus and the extent of white markings. Segregation analysis revealed that our data fit best to a model including a polygenic effect and a biallelic locus with a dominant-recessive mode of inheritance. The recessive allele was found to be the white trait-increasing allele. Multilocus linkage disequilibrium analysis allowed the mapping of the putative major locus to a chromosomal region on ECA3q harboring the KIT gene.

To eat or not to eat—relationship of lichen herbivory by snails with secondary compounds and field frequency of lichens

Aims The biochemical defense of lichens against herbivores and its relationship to lichen frequency are poorly understood. Therefore, we tested whether chemical compounds in lichens act as feeding defense or rather as stimulus for snail herbivory among lichens and whether experimental feeding by snails is related to lichen frequency in the field. Methods In a no-choice feeding experiment, we fed 24 lichen species to snails of two taxa from the Clausilidae and Enidae families and compared untreated lichens and lichens with compounds removed by acetone rinsing. Then, we related experimental lichen consumption with the frequency of lichen species among 158 forest plots in the field (Schwäbische Alb, Germany), where we had also sampled snail and lichen species. Important findings In five lichen species, snails preferred treated samples over untreated controls, indicating chemical feeding defense, and vice versa in two species, indicating chemical feeding stimulus. Interestingly, compared with less frequent lichen species, snails consumed more of untreated and less of treated samples of more frequent lichen species. Removing one outlier species resulted in the loss of a significant positive relationship when untreated samples were analyzed separately. However, the interaction between treatment and lichen frequency remained significant when excluding single species or including snail genus instead of taxa, indicating that our results were robust and that lumping the species to two taxa was justified. Our results imply lichen-feeding snails to prefer frequent lichens and avoid less frequent ones because of secondary compound recognition. This supports the idea that consumers adapt to the most abundant food source.

Do Information, Price, or Morals Influence Ethical Consumption? A Natural Field Experiment and Customer Survey on the Purchase of Fair Trade Coffee

We address ethical consumption using a natural field experiment on the actual purchase of Fair Trade (FT) coffee in three supermarkets in Germany. Based on a quasi-experimental before-and-after design the effects of three different treatments – information, 20% price reduction, and a moral appeal – are analyzed. Sales data cover actual ethical purchase behavior and avoid problems of social desirability. But they offer only limited insights into the motivations of individual consumers. We therefore complemented the field experiment with a customer survey that allows us to contrast observed (ethical) buying behavior with self-reported FT consumption. Results from the experiment suggest that only the price reduction had the expected positive and statistically significant effect on FT consumption.

Ovarian cancer angiogenesis, biology and therapy

The progressive growth of epithelial ovarian cancer tumor is regulated by proangiogenic molecules and growth factors released by tumor cells and the microenvironment. Previous studies showed that the expression of interleukin-8 (IL-8) directly correlates with the progression of human ovarian carcinomas implanted into the peritoneal cavity of nude mice. We examined the expression level of IL-8 in archival specimens of primary human ovarian carcinoma from patients undergoing curative surgery by in situ mRNA hybridization technique. The expression of IL-8 was significantly higher in patients with stage III disease than in patients with stage I disease. To investigate the role of IL-8 in the progressive growth of ovarian cancer, we isolated high- and low-IL-8 producing clones from parental Hey-A8 human ovarian cancer cells, and compared their proliferative activity and tumorigenicity in nude mice. The effect of exogenous IL-8 and IL-8 neutralizing antibody on ovarian cancer cell proliferation was investigated. Finally, we studied the modulation of IL-8 expression in ovarian cancer cells by sense and antisense IL-8 expression vector transfection and its effect on proliferation and tumorigenicity. We concluded that IL-8 has a direct growth potentiating activity in human ovarian cancer cells. ^ The expression level of IL-8 directly correlates with disease progression of human ovarian cancer, but the mechanism of induction is unknown. Since hypoxia and acidic pH are common features in solid tumors, we determined whether hypoxic and acidic conditions could regulate the expression of IL-8. Culturing the human ovarian cancer cells in hypoxic or acidic medium led to a significant increase in IL-8 mRNA and protein. Hypoxic- and acidosis-mediated transient increase in IL-8 expression involved both transcriptional activation of the IL-8 gene and enhanced stability of the IL-8 mRNA. Furthermore, we showed that IL-8 transcription activation by hypoxia or acidosis required the cooperation of NF-κB and AP-1 binding sites. ^ Finally, we studied novel therapies against human ovarian cancer. First, we determined whether inhibition of the catalytic tyrosine kinase activity of the receptors for vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) inhibits the formation of malignant ascites and the progressive growth of human ovarian carcinoma cells implanted into the peritoneal cavity of nude mice. Our results suggest that blockade of the VEGF/VPF receptor may be an efficient strategy to inhibit formation of malignant ascites and growth of VEGF/VPF-dependent human ovarian carcinomas. Secondly, we determined whether local sustained production of murine interferon-β could inhibit the growth of human ovarian cancer cells in the peritoneal cavity of nude mice. Our results showed that local production of IFN-β could inhibit the in vivo growth of human ovarian cancer cells by upregulating the expression of the inducible nitric oxide synthase (NOS) in host macrophages. ^

"Ripple Effects" and Forecasting Home Prices in Los Angeles, Las Vegas, and Phoenix

We examine the time-series relationship between housing prices in Los Angeles, Las Vegas, and Phoenix. First, temporal Granger causality tests reveal that Los Angeles housing prices cause housing prices in Las Vegas (directly) and Phoenix (indirectly). In addition, Las Vegas housing prices cause housing prices in Phoenix. Los Angeles housing prices prove exogenous in a temporal sense and Phoenix housing prices do not cause prices in the other two markets. Second, we calculate out-of-sample forecasts in each market, using various vector autoregessive (VAR) and vector error-correction (VEC) models, as well as Bayesian, spatial, and causality versions of these models with various priors. Different specifications provide superior forecasts in the different cities. Finally, we consider the ability of theses time-series models to provide accurate out-of-sample predictions of turning points in housing prices that occurred in 2006:Q4. Recursive forecasts, where the sample is updated each quarter, provide reasonably good forecasts of turning points.

Functional analysis of the Galpha protein, GNA -3, in the development of Neurospora crassa using biochemical and genetic studies

Extracellular signals regulate fungal development and, to sense and respond to these cues, fungi evolved signal transduction pathways similar to those in mammalian systems. In fungi, heterotrimeric G proteins, composed of α, β, and γ subunits, transduce many signals, such as pheromones and nutrients, intracellularly to alter adenylyl cyclase and MAPK cascades activity. ^ Previously, the Gα proteins GNA-1 and GNA-2 were characterized in regulating development in the fungus Neurospora crassa. R. A. Baasiri isolated a third Gα, gna-3, and P. S. Rowley generated Δgna-3 mutants. GNA-3 belongs to a fungal Gα family that regulates cAMP metabolism and virulence. The Δ gna-3 sexual cycle is defective in homozygous crosses, producing inviable spores. Δgna-3 mutants have reduced aerial hyphae formation and derepressed asexual sporulation (conidiation), causing accumulation of asexual spores (conidia). These defects are similar to an adenylyl cyclase mutant, cr-1; cAMP supplementation suppressed Δ gna-3 and cr-1. Inappropriate conidiation and expression of a conidiation gene, con-10, were higher in Δ gna-3 than cr-1 submerged cultures; peptone suppressed conidiation. Adenylyl cyclase activity and expression demonstrated that GNA-3 regulates enzyme levels. ^ A Δgna-1 cr-1 was analyzed with F. D. Ivey to differentiate GNA-1 roles in cAMP-dependent and -independent pathways. Δ gna-1 cr-1 defects were worse than cr-1 and refractory to cAMP, suggesting that GNA-1 is necessary for sensing extracellular CAMP. Submerged culture conidiation was highest in Δgna-1 cr-1, and only high cell density Δgna-1 cultures conidiated, which correlated with con-10 levels. Transcription of a putative heat shock cognate protein was highest in Δgna-1 cr-1. ^ Functional relationships between the three Gαs was analyzed by constructing Δgna-1 Δgna-2 Δ gna-3, Δgna-1 Δgna-3, and Δgna-2 Δgna-3 strains. Δ gna-2 Δgna-3 strains exhibited intensified Δ gna-3 phenotypes; Δgna-1 Δgna-2 Δgna-3 and Δgna-1 Δ gna-3 strains were identical to Δgna-1 cr-1 on plates and were non-responsive to cAMP. The highest levels of conidiation and con-10 were detected in submerged cultures of Δ gna-1 Δgna-2 Δgna-3 and Δgna-1 Δgna-3 mutants, which was partially suppressed by peptone supplementation. Stimulation of adenylyl cyclase is completely deficient in Δgna-1 Δ gna-2 Δgna-3 and Δgna-1 Δ gna-3 strains. Δgna-3 and Δ gna-1 Δgna-3 aerial hyphae and conidiation defects were suppressed by mutation of a PKA regulatory subunit. ^

Perspectives on guidance and social inclusion in a global society

The world is changing rapidly. People today face numerous challenges in achieving a meaningful and fulfilling life. In many countries, there are enormous systemic barriers to address, such as: massive unemployment, HIV/AIDS, social disintegration, and inadequate infrastructure. One job for life is over. For many it never existed. Old metaphors and old models of career development no longer apply. New ways of thinking about careers are necessary, that take into account the context in which people are living, the reality of today's labour market, and the fact people's career-life journey contains many branching paths, barriers, and obstacles, but also allies and sources of assistance. Flexibility is important, as is keeping options open and making sure the journey is meaningful. Guidance professionals need to begin early, working with other professionals and those seeking assistance to develop attitudes that facilitate people taking charge of their own career-life paths. People need a vision for their life that will drive a purposeful approach to career-life planning and avoid floundering. Helping people achieve that direction can be most effectively accomplished when policy makers and practitioners work together to ensure that effective and accessible services are available for those who need them and when a large part of focus in on addressing the context in which marginalized people work and live.

Crises of social significances: adolescents and their projects for future work

This is a report on data raised through research, which has already finished, about Identification references in adolescents . Objetives : To analyze and reflect upon the collected data, adolescents' representations about the work field and their projects for future work. To conceptualize about the crises of social significances which produce and order sense and, therefore, organize our perceptions of work through social discourses and practices which have an impact on the subjectivity of adolescents and young adults. Methodology: Brief presentation of the concepts which frame the qualitative research in this area. Reading and analysis of fragments from adolescents' accounts, obtained in focal groups at different state secondary schools. Conclusions: The adolescents researched portray a self-image full of uncertainty and skepticism as regards their future possibilities. The impact produced by the fall of work as an ideal of doing and being is made evident in their accounts. Only some of them link their future project with an invested and valuable activity, even if this is not associated with economic safety and wellbeing. Others present themselves as incapable to modify the state of things, which offers a field connected with consumerist values and with the idea that "you are worth what you have (in material things)".