OXIDATIVE STRESS BIOMARKER RESPONSES TO AN ACUTE SESSION OF HYPERTROPHY-RESISTANCE TRADITIONAL INTERVAL TRAINING AND CIRCUIT TRAINING

Deminice, R, Sicchieri, T, Mialich, MS, Milani, F, Ovidio, PP, and Jordao, AA. Oxidative stress biomarker responses to an acute session of hypertrophy-resistance traditional interval training and circuit training. J Strength Cond Res 25(3): 798-804, 2011-We have studied circuit resistance schemes with high loads as a time-effective alternative to hypertrophy-traditional resistance training. However, the oxidative stress biomarker responses to high-load circuit training are unknown. The aim of the present study was to compare oxidative stress biomarker response with an acute session of hypertrophy-resistance circuit training and traditional interval training. A week after the 1 repetition maximum (1RM) test, 11 healthy and well-trained male participants completed hypertrophy-resistance acute sessions of traditional interval training (3 x 10 repetitions at 75% of the 1RM, with 90-second passive rest) and circuit training (3 x 10 repetitions at 75% of the 1RM, in alternating performance of 2 exercises with different muscle groups) in a randomized and cross-over design. Venous blood samples were collected before (pre) and 10 minutes after (post) the resistance training sessions for oxidative stress biomarker assays. As expected, the time used to complete the circuit training (20.2 +/- 1.6) was half of that needed to complete the traditional interval training (40.3 +/- 1.8). Significant increases (p < 0.05) in thiobarbituric acid reactive substances (40%), creatine kinase (CK) (67%), glutathione (14%), and uric acid (25%) were detected posttraditional interval training session in relation to pre. In relation to circuit training, a significant increase in CK (33%) activity postsession in relation to pre was observed. Statistical analysis did not reveal any other change in the oxidative stress biomarker after circuit training. In conclusion, circuit resistance-hypertrophy training scheme proposed in the current study promoted lower oxidative stress biomarkers and antioxidant modulations compared with resistance traditional interval training.

Efficacy of Marigold Extract-Loaded Formulations Against UV-induced Oxidative Stress

The present study investigated the potential use of topical formulations containing marigold extract (ME) (Calendula officinalis extract) against ultraviolet (UV) B irradiation-induced skin damage. The physical and functional stabilities, as well as the skin penetration capacity, of the different topical formulations developed were evaluated. In addition, the in vivo capacity to prevent/treat the UVB irradiation-induced skin damage, in hairless mice, of the formulation with better skin penetration capacity was investigated. All of the formulations were physically and functionally stable. The gel formulation [Formulation 3 (F3)] was the most effective for the topical delivery of ME, which was detected as 0.21 mu g/cm(2) of narcissin and as 0.07 mu g/cm(2) of the rutin in the viable epidermis. This formulation was able to maintain glutathione reduced levels close to those of nonirradiated animals, but did not affect the gelatinase-9 and myeloperoxidase activities increased by exposure to UVB irradiation. In addition, F3 reduced the histological skin changes induced by UVB irradiation that appear as modifications of collagen fibrils. Therefore, the photoprotective effect in hairless mice achieved with the topical application of ME in gel formulation is most likely associated with a possible improvement in the collagen synthesis in the subepidermal connective tissue. (C) 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:2182-2193, 2011

Can the nitrogenous composition of xylem sap be used to assess salinity stress in Casuarina glauca?

It is predicted that dryland salinity will affect up to 17 Mha of the Australian landscape by 2050, and therefore, monitoring the health of tree plantings and remnant native vegetation in saline areas is increasingly important. Casuarina glauca Sieber ex Spreng. has considerable salinity tolerance and is commonly planted in areas with a shallow, saline water table. To evaluate the potential of using the nitrogenous composition of xylem sap to assess salinity stress in C. glauca, the responses of trees grown with various soil salinities in a greenhouse were compared with those of trees growing in field plots with different water table depths and groundwater salinities. In the greenhouse, increasing soil salinity led to increased allocation of nitrogen (N) to proline and arginine in both stem and root xylem sap, with coincident decreases in citrulline and asparagine. Although the field plots were ranked as increasingly saline-based on ground water salinity and depth-only the allocation of N to citrulline differed significantly between the field plots. Within each plot, temporal variation in the composition of the xylem sap was related to rainfall, rainfall infiltration and soil salinity. Periods of low rainfall and infiltration and higher soil salinity corresponded with increased allocation of N to proline and arginine in the xylem sap. The allocation of N to citrulline and asparagine increased following rainfall events where rain was calculated to have infiltrated sufficiently to decrease soil salinity. The relationship between nitrogenous composition of the xylem sap of C. glauca and soil salinity indicates that the analysis of xylem sap is an effective method for assessing changes in salinity stress in trees at a particular site over time. However, the composition of the xylem sap proved less useful as a comparative index of salinity stress in trees growing at different sites.

Personalidade e percepção de stress em bombeiros

RESUMO: O objectivo deste estudo consistiu na obtenção de dados que ajudem a melhor compreender as diversas correlações entre traços de personalidade e a percepção de stress em bombeiros, de modo a que seja possível identificar factores desencadeantes de stress, bem como traços de personalidade que reforcem positiva ou negativamente esses mesmos factores . A amostra é constituída por 302 bombeiros pertencentes a corporações das regiões do Ribatejo e da Extremadura, sendo que todos os participantes desempenham funções de bombeiro voluntário ou profissional/efectivo. De entre os bombeiros participantes 238 são do sexo masculino e 64 são do sexo feminino tendo idades compreendidas entre os 17 e os 73 anos (m= 32,75 ; dp=9,309). As medidas utilizadas neste estudo são as seguintes: Marlow-Crowne Social Desirability Scale – Short Form C (MCSDS-C) de Ballard (1992), para a avaliação da desejabilidade social; Perceived Stress Scale (PSS) de Cohen, Kamarck & Mermelstein (1983), para a avaliação do stress e o Revised NEO Personality Inventory (NEO PI-R) de Costa & McCrae (1992) , para a avaliação da personalidade. Os resultados obtidos demonstraram associações significativas entre as dimensões da personalidade, nomeadamente o neuroticismo, a extroversão, a abertura à experiência e a conscienciosidade, e o stress. Verificaram-se correlações positivas entre as dimensões de neuroticismo e abertura à experiência relativamente ao stress, ao invés das dimensões de extroversão e conscienciosidade que por sua vez se correlacionaram negativamente com o stress. Este estudo demonstra também que os bombeiros profissionais(efectivos apresentam um mais elevado nível de stress comparativamente aos bombeiros pertencentes à categoria de voluntários, tal como os bombeiros com nove ou menos anos na função comparativamente aos bombeiros com mais de nove anos na função. Verificou-se também que os bombeiros do sexo masculino apresentam menos índices de stress comparativamente aos do sexo feminino. ABSTRACT: The purpose of this study was to obtain data can help us to better understand the various correlations between personality traits and the perception of stress in firefighters in order to identify trigger stress factors and personality traits which increase positively or negatively these same factors. The sample consists of 302 firefighters belonging to corporations within the regions of Ribatejo and Extremadura, being that all participants are either professional/effective or volunteer firefighters. Among the participating firefighters 238 are males and 64 are females, having aged between 17 and 73 years (m=32.75; dp=9.309). The measures used in this study are the following: Marlow-Crowne Social Desirability Scale – Short Form C (MCSDS-C) by Ballard (1992), for the assessment of social desirability; Perceived Stress Scale (PSS) by Cohen, Kamarck & Mermelstein (1983), for the assessment of stress and the Revised NEO Personality Inventory (NEO PI-R) by Costa & McCrae (1992) , for the assessment of personality. The results obtained showed significant associations between the personality dimensions of neuroticism, extraversion, openness and conscientiousness, and stress. The dimensions of neuroticism and openness are positively correlated to stress, on the other hand, the dimensions of extraversion and conscientiousness are negatively correlated to stress. Results also show that professional/effective firefighters have a higher level of stress as compared to volunteer firefighters as do firefighters with nine or fewer years in function compared with firefighters with more than nine years in function. It was also noted that male fire fighters present minor stress levels comparatively to female firefighters.

Avaliação do stress oxidativo na disfunção erétil

As sequelas fisiopatológicas do stress oxidativo são difíceis de quantificar. Apesar dos obstáculos, a relevância médica do stress oxidativo tem vindo a ser cada vez mais reconhecida, sendo hoje em dia encarado como um componente chave de virtualmente todas as doenças. A disfunção erétil (DE) surge neste contexto como uma espécie de barómetro da função endotelial e do dano oxidativo. A quantificação de biomarcadores de stress oxidativo poderá apresentar um enorme impacto na avaliação de pacientes com DE. O rácio glutationa reduzida/oxidada (GSH/GSSG) e a nitrotirosina (3-NT) têm vindo a demonstrar relevância clínica. A consideração de polimorfismos genéticos constitui ainda uma abordagem promissora na avaliação destas relações no futuro. Um método altamente sensível de cromatografia líquida de alta performance (HPLC) foi desenvolvido para a determinação de 3-NT em plasma humano. As concentrações de 3-NT medidos em indivíduos com DE foram 6,6±2,1μM (média±S.D., n = 46). A medição da concentração plasmática de 3-NT poderá revelar-se útil como marcador de dano oxidativo dependente do óxido nítrico (NO). O nível de stress oxidativo pode também ser quantificado através da medição do decréscimo do rácio GSH/GSSG, que tem mostrado alterações numa miríade de patologias, como a DE e a diabetes mellitus. O método proposto para a quantificação do rácio GSH/GSSG em HPLC apresenta a vantagem de avaliação concomitante dos dois parâmetros em apenas uma corrida. O valor do rácio GSH/GSSG obtido a partir de sangue de indivíduos com DE foi 11,9±9,8 (média±S.D., n = 49). Os resultados estatísticos revelaram diferenças significativas (p<0,001) entre ambos a concentração plasmática de 3-NT e o rácio GSH/GSSG de sangue de indivíduos com DE e as respetivas medições em indivíduos saudáveis. Observaram-se ainda diferenças estatisticamente significativas (p≈0,027) entre o rácio GSH/GSSG do sangue de pacientes apenas com diagnóstico de DE e a medição respetiva em indivíduos com DE e comorbilidades cardiovasculares. Estes resultados enfatizam o papel do dano oxidativo na biopatologia da DE, elucidado com o auxílio destas duas metodologias, que poderão ter um amplo campo de aplicação no futuro, dado que se mostraram simples, não dispendiosas e rápidas, podendo eventualmente adequar-se a estudos de rastreio em larga escala.

The Role of the Endoplasmic Reticulum Stress Transducer Ire1 during Photoreceptor Differentiation in Drosophila

Dissertation presented to obtain the Ph.D degree in Biology.

AFT3 as a new therapeutic target for skin field cancerization in antagonism with compromised Notch/CSL signaling

Les interactions épithélio-mésenchymateuses jouent un rôle important dans le contrôle du développement normal de la peau, son homéostasie et sa tumorigenèse. Les fibroblastes dermiques (DFs) représentent la catégorie cellulaire la plus abondante dans le stroma et leur rôle est de plus en plus considéré. En ce qui concerne particulièrement la tumorigenèse, des facteurs diffusibles produits par les fibroblastes entourant les tumeurs épithéliales, appelés 'fibroblastes associés au cancer (CAF)', interagissent au niveau de l'inflammation impliquée directement ou indirectement dans la signalisation paracrine, entre le stroma et les cellules épiéliales cancéreuses. Le risque de cancer de la peau augmente de façon exponentielle avec l'âge. Comme un lien probable entre les deux, la sénescence des fibroblastes résulte de la production du sécrétome favorisant la sénescence (SMS), un groupe de facteurs diffusibles induisant une stimulation paracrine de la croissance, l'inflammation et le remodelage de la matrice. De façon fort intéressante, l'induction de ces gènes est aussi une caractéristique des CAFs. Cependant, le lien entre les deux événements cellulaires sénescence et activation des CAFs reste en grande partie inexploré. L'ATF3 (Activating Transcription Factor 3) est un facteur de transcription induit en réponse au stress, dont les fonctions sont hautement spécifiques du type cellulaire. Bien qu'il ait été découvert dans notre laboratoire en tant que promoteur de tumeurs dans les kératinocytes, ses fonctions biologique et biochimique dans le derme n'ont pas encore été étudiées. Récemment, nous avons constaté que, chez la souris, l'abrogation de la voie de signalisation de Notch/CSL dans les DFs, induisait la formation de tumeurs kératinocytaires multifocales. Ces dernières proviennent de la cancérisation en domaine, un phénomène associé à une atrophie du stroma, des altérations de la matrice et de l'inflammation. D'autres études ont montré que CSL agissait comme un régulateur négatif de gènes impliqués dans sénescence des DFs et dans l'activation des CAFs. Ici, nous montrons que la suppression ou l'atténuation de l'expression de ATF3 dans les DFs induit la sénescence et l'expression des gènes liés aux CAFs, de façon similaire à celle déclenchée par la perte de CSL, tandis que la surexpression de ATF3 supprime ces changements. Nous émettons l'hypothèse que ATF3 joue un rôle suppresseur dans l'activation des CAFs et dans la progression des tumeurs kératinocytaires, en surmontant les conséquences de l'abrogation de la voie de signalisation Notch/CSL. En concordance avec cette hypothèse, nous avons constaté que la perte de ATF3 dans les DFs favorisait la tumorigénicité des kératinocytes via le contrôle négatif de cytokines, des enzymes de la matrice de remodelage et de protéines associées au cancer, peut-être par liaison directe des effecteurs de la voie Notch/CSL : IL6 et les gènes Hes. Enfin, dans les échantillons cliniques humains, le stroma sous-jacent aux lésions précancéreuses de kératoses actiniques montre une diminution significative de l'expression de ATF3 par rapport au stroma jouxtant la peau normale. La restauration de l'expression de ATF3 pourrait être utilisée comme un outil thérapeutique en recherche translationnelle pour prévenir ou réprimer le processus de cancérisation en domaine. - Epithelial-mesenchymal interactions play an important role in control of normal skin development, homeostasis and tumorigenesis. The role of dermal fibroblasts (DFs) as the most abundant cell type in stroma is increasingly appreciated. Especially during tumorigenesis, fibroblasts surrounding epithelial tumors, called Cancer Associated Fibroblasts (CAFs), produce diffusible factors (growth factors, inflammatory cytokines, chemokines and enzymes, and matrix metalloproteinases) that mediate inflammation either directly or indirectly through paracrine signaling between stroma and epithelial cancer cells. The risk of skin cancer increases exponentially with age. As a likely link between the two, senescence of fibroblasts results in production of the senescence-messaging-secretome (SMS), a panel of diffusible factors inducing paracrine growth stimulation, inflammation, and matrix remodeling. Interestingly, induction of these genes is also a characteristic of Cancer Associated Fibroblasts (CAFs). However, the link between the two cellular events, senescence and CAF activation is largely unexplored. ATF3 is a key stress response transcription factor with highly cell type specific functions, which has been discovered as a tumor promoter in keratinocytes in our lab. However, the biological and biochemical function of ATF3 in the dermal compartment of the skin has not been studied yet. Recently, we found that compromised Notch/CSL signaling in dermal fibroblasts (DFs) in mice is a primary cause of multifocal keratinocyte tumors called field cancerization associated with stromal atrophy, matrix alterations and inflammation. Further studies showed that CSL functions as a negative regulator of genes involved in DFs senescence and CAF activation. Here, we show that deletion or silencing of the ATF3 gene in DFs activates senescence and CAF-related gene expression similar to that triggered by loss of CSL, while increased ATF3 suppresses these changes. We hypothesize that ATF3 plays a suppressing role in CAF activation and keratinocyte tumor progression, overcoming the consequences of compromised Notch/CSL signaling. In support of this hypothesis, we found that loss of ATF3 in DFs promotes tumorigenic behavior of keratinocytes via negative control of cytokines, matrix-remodeling enzymes and cancer-associated proteins, possibly through direct binding to Notch/CSL targets, IL6 and Hes genes. On the other hand, in human clinical samples, stromal fields underlying premalignant actinic keratosis lesions showed significantly decreased ATF3 expression relative to stroma of flanking normal skin. Restoration of ATF3, which is lost in cancer development, may be used as a therapeutic tool for translational research to prevent or suppress the field cancerization process.

Angiotensin II receptor blockade prevents acute renal sodium retention induced by low levels of orthostatic stress.

BACKGROUND: Depending on its magnitude, lower body negative pressure (LBNP) has been shown to induce a progressive activation of neurohormonal, renal tubular, and renal hemodynamic responses, thereby mimicking the renal responses observed in clinical conditions characterized by a low effective arterial volume such as congestive heart failure. Our objective was to evaluate the impact of angiotensin II receptor blockade with candesartan on the renal hemodynamic and urinary excretory responses to a progressive orthostatic stress in normal subjects. METHODS: Twenty healthy men were submitted to three levels of LBNP (0, -10, and -20 mbar or 0, -7.5, and -15 mm Hg) for 1 hour according to a crossover design with a minimum of 2 days between each level of LBNP. Ten subjects were randomly allocated to receive a placebo and ten others were treated with candesartan 16 mg orally for 10 days before and during the three levels of LBNP. Systemic and renal hemodynamics, renal sodium excretions, and the hormonal response were measured hourly before, during, and for 2 hours after LBNP. RESULTS: During placebo, LBNP induced no change in systemic and renal hemodynamics, but sodium excretion decreased dose dependently with higher levels of LBNP. At -20 mbar, cumulative 3-hour sodium balance was negative at -2.3 +/- 2.3 mmol (mean +/- SEM). With candesartan, mean blood pressure decreased (76 +/- 1 mm Hg vs. 83 +/- 3 mm Hg, candesartan vs. placebo, P < 0.05) and renal plasma flow increased (858 +/- 52 mL/min vs. 639 +/- 36 mL/min, candesartan vs. placebo, P < 0.05). Glomerular filtration rate (GFR) was not significantly higher with candesartan (127 +/- 7 mL/min in placebo vs. 144 +/- 12 mL/min in candesartan). No significant decrease in sodium and water excretion was found during LBNP in candesartan-treated subjects. At -20 mbar, the 3-hour cumulative sodium excretion was + 4.6 +/- 1.4 mmol in the candesartan group (P= 0.02 vs. placebo). CONCLUSION: Selective blockade of angiotensin II type 1 (AT1) receptors with candesartan increases renal blood flow and prevents the antinatriuresis during sustained lower body negative pressure despite a modest decrease in blood pressure. These results thus provide interesting insights into potential benefits of AT1 receptor blockade in sodium-retaining states such as congestive heart failure.

Control of the adaptive response of the heart to stress via the Notch1 receptor pathway.

In the damaged heart, cardiac adaptation relies primarily on cardiomyocyte hypertrophy. The recent discovery of cardiac stem cells in the postnatal heart, however, suggests that these cells could participate in the response to stress via their capacity to regenerate cardiac tissues. Using models of cardiac hypertrophy and failure, we demonstrate that components of the Notch pathway are up-regulated in the hypertrophic heart. The Notch pathway is an evolutionarily conserved cell-to-cell communication system, which is crucial in many developmental processes. Notch also plays key roles in the regenerative capacity of self-renewing organs. In the heart, Notch1 signaling takes place in cardiomyocytes and in mesenchymal cardiac precursors and is activated secondary to stimulated Jagged1 expression on the surface of cardiomyocytes. Using mice lacking Notch1 expression specifically in the heart, we show that the Notch1 pathway controls pathophysiological cardiac remodeling. In the absence of Notch1, cardiac hypertrophy is exacerbated, fibrosis develops, function is altered, and the mortality rate increases. Therefore, in cardiomyocytes, Notch controls maturation, limits the extent of the hypertrophic response, and may thereby contribute to cell survival. In cardiac precursors, Notch prevents cardiogenic differentiation, favors proliferation, and may facilitate the expansion of a transient amplifying cell compartment.

Expanding view of phenotype and oxidative stress in Friedreich's ataxia patients with and without idebone.

Friedreich's ataxia (FRDA), the most common autosomal recessive ataxia, is characterised by progressive ataxia with dysarthria of speech, loss of deep-tendon reflexes, impaired vibratory and proprioceptive sensations and corticospinal weakness with a Babinski's sign. Patients eventually also develop kyphoscoliosis, cardiomyopathy and diabetes mellitus. The disease is a GAA repeat disorder resulting in severely reduced levels of frataxin, with secondary increased sensitivity to oxidative stress. The anti-oxidative drug, idebenone, is effective against FRDA-associated cardiomyopathy. We provide detailed clinical, electrophysiological and biochemical data from 20 genetically confirmed FRDA patients and have analysed the relationship between phenotype, genotype and malondialdehyde (MDA), which is a marker of superoxide formation. We assessed the effects of idebenone biochemically by measuring blood MDA and clinically by serial measurements of the International Cooperative Ataxia Rating Scale (ICARS). The GAA repeat length influenced the age at onset (p <0.001), the severity of ataxia (p = 0.02), the presence of cardiomyopathy (p = 0.04) and of low-frequency hearing loss (p = 0.009). Multilinear regression analysis showed (p = 0.006) that ICARS was dependent on the two variables of disease duration (p = 0.01) and size of the GAA expansion (p = 0.02). We found no correlation to bilateral palpebral ptosis, visual impairment, diabetes mellitus or skeletal deformities, all of which appear to be signs of disease progression rather than severity. We discuss more thoroughly two underrecognised clinical findings: palpebral ptosis and GAA length-dependent low-frequency hearing loss. The average ICARS remained unchanged in 10 patients for whom follow-up on treatment was available (mean 2.9 years), whereas most patients treated with idebenone reported an improvement in dysarthria (63%), hand dexterity (58%) and fatigue (47%) after taking the drug for several weeks or months. Oxidative stress analysis showed an unexpected increase in blood MDA levels in patients on idebenone (p = 0.04), and we discuss the putative underlying mechanism for this result, which could then explain the unique efficacy of idebenone in treating the FRDA-associated cardiomyopathy, as opposed to other antioxidative drugs. Indeed, idebenone is not only a powerful stimulator of complexes II and III of the respiratory chain, but also an inhibitor of complex I activity, then promoting superoxide formation. Our preliminary clinical observations are the first to date supporting an effect of idebenone in delaying neurological worsening. Our MDA results point to the dual effect of idebenone on oxidative stress and to the need for controlled studies to assess its potential toxicity at high doses on the one hand, and to revisit the exact mechanisms underlying the physiopathology of Friedreich's ataxia on the other hand, while recent reports suggest non-oxidative pathophysiology of the disease.

Comparison of oxidative stress markers in HIV-infected patients on efavirenz or atazanavir/ritonavir-based therapy.

INTRODUCTION Chronic low-grade inflammation and immune activation may persist in HIV patients despite effective antiretroviral therapy (ART). These abnormalities are associated with increased oxidative stress (OS). Bilirubin (BR) may have a beneficial role in counteracting OS. Atazanavir (ATV) inhibits UGT1A1, thus increasing unconjugated BR levels, a distinctive feature of this drug. We compared changes in OS markers in HIV patients on ATV/r versus efavirenz (EFV)-based first-line therapies. MATERIALS AND METHODS Cohort of the Spanish Research Network (CoRIS) is a multicentre, open, prospective cohort of HIV-infected patients naïve to ART at entry and linked to a biobank. We identified hepatitis C virus/hepatitis B virus (HCV/HBV) negative patients who started first-line ART with either ATV/r or EFV, had a baseline biobank sample and a follow-up sample after at least nine months of ART while maintaining initial regimen and being virologically suppressed. Lipoprotein-associated Phospholipase A2 (Lp-PLA2), Myeloperoxidase (MPO) and Oxidized LDL (OxLDL) were measured in paired samples. Marker values at one year were interpolated from available data. Multiple imputations using chained equations were used to deal with missing values. Change in the OS markers was modelled using multiple linear regressions adjusting for baseline marker values and baseline confounders. Correlations between continuous variables were explored using Pearson's correlation tests. RESULTS 145 patients (97 EFV; 48 ATV/r) were studied. Mean (SD) baseline values for OS markers in EFV and ATV/r groups were: Lp-PLA2 [142.2 (72.8) and 150.1 (92.8) ng/mL], MPO [74.3 (48.2) and 93.9 (64.3) µg/L] and OxLDL [76.3 (52.3) and 82.2 (54.4) µg/L]. After adjustment for baseline variables patients on ATV/r had a significant decrease in Lp-PLA2 (estimated difference -16.3 [CI 95%: -31.4, -1.25; p=0.03]) and a significantly lower increase in OxLDL (estimated difference -21.8 [-38.0, -5.6; p<0.01] relative to those on EFV, whereas no differences in MPO were found. Adjusted changes in BR were significantly higher for the ATV/r group (estimated difference 1.33 [1.03, 1.52; p<0.01]). Changes in BR and changes in OS markers were significantly correlated. CONCLUSIONS In virologically suppressed patients on stable ART, OS was lower in ATV/r-based regimens compared to EFV. We hypothesize these changes could be in part attributable to increased BR plasma levels.

Targeting Notch signaling in pancreatic cancer.

IMPORTANCE OF THE FIELD: With some 220,000 new cases/year in the world, pancreatic adenocarcinoma is the fourth highest cause of death by cancers. Among newly diagnosed patients about 210,000 will die within 9 months following diagnosis. Therefore, effective adjuncts to current treatment strategies are necessary. Because embryological signaling pathways are upregulated in pancreatic adenocarcinoma, they represent potential targets for future therapies. AREAS COVERED IN THIS REVIEW: Our aim is to present the Notch pathway, and to describe its involvement in pancreatic pathophysiology/carcinogenesis. This pathway appeared as a prime target for pancreatic cancer therapy. In the light of the crosstalk of Notch with other survival/embryologic pathways, drugs affecting more than one pathway may have to be combined. WHAT THE READER WILL GAIN: Drugs against gamma-secretases could thus serve in cancer treatment and can be combined with drugs targeting survival pathways interplaying with Notch such as Hedgehog. TAKE HOME MESSAGE: Downregulation of Notch contributes to the inhibition and apoptosis of pancreatic cancer cells whereas Hedgehog inhibition will allow for enhanced delivery of drugs to the tumor. Both pathway inhibitors appear to have synergistic effects for future therapeutics for pancreatic adenocarcinoma, once safety issues of compounds are overcome.

Mood and nonmood components of perceived stress and exacerbation of Crohn's disease.

BACKGROUND: Diverse psychological factors are involved in the pathophysiology of stress. In order to devise effective intervention strategies, it is important to elucidate which factors play the most important role in the association between psychological stress and exacerbation of Crohn's disease (CD). We hypothesized that the association between perceived stress and exacerbation of CD would remain after removal of mood and anxiety components, which are largely involved in stress perception. METHODS: In all, 468 adults with CD were recruited and followed in different hospitals and private practices of Switzerland for 18 months. At inclusion, patients completed the Perceived Stress Questionnaire and anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. During the follow-up, gastroenterologists assessed whether patients presented with a CD exacerbation. By means of binary logistic regression analysis, we estimated the factor by which one standard deviation of perceived stress would increase the odds of exacerbation of CD with and without controlling for anxiety and depression. RESULTS: The odds of exacerbation of CD increased by 1.85 times (95% confidence interval 1.43-2.40, P < 0.001) for 1 standard deviation of perceived stress. After removing the anxiety and depression components, the residuals of perceived stress were no longer associated with exacerbation of CD. CONCLUSIONS: The association between perceived stress and exacerbation of CD was fully attributable to the mood components, specifically anxiety and depression. Future interventional studies should evaluate the treatment of anxiety and depression as a strategy for potential prevention of CD exacerbations.

Expanding view of phenotype and oxidative stress in Friedreich's ataxia patients with and without idebenone

Summary: Friedreich's ataxia (FRDA), the most common autosomal recessive ataxia, is characterised by progressive ataxia with dysarthria of speech, loss of deep-tendon reflexes, impaired vibratory and proprioceptive sensations and corticospinal weakness with a Babinski's sign. Patients eventually also develop kyphoscoliosis, cardiomyopathy and diabetes mellitus. The disease is a GAA repeat disorder resulting in severely reduced levels of frataxin, with secondary increased sensitivity to oxidative stress. The anti-oxidative drug, idebenone, is effective against FRDA-associated cardiomyopathy. We provide detailed clinical, electrophysiological and biochemical data from 20 genetically confirmed FRDA patients and have analysed the relation-ship between phenotype, genotype and malondialdehyde (MDA), which is a marker of superoxide formation. We assessed the effects of idebenone biochemically by measuring blood M DA and clinically by serial measurements of the International Cooperative Ataxia Rating Scale (ICARS). The GAA repeat length influenced the age at onset (p <0.001), the severity of ataxia (p= 0.02), the presence of cardiomyopathy (p =0.04) and of low-frequency hearing loss (p = 0.009). Multilinear regression analysis showed (p = 0.006) that ICARS was dependent on the two variables of disease duration (p = 0.01) and size of the GAA expansion (p = 0.02). We found no correlation to bilateral palpebral ptosis visual impairment, diabetes mellitus or skeletal deformities, all of which appear to be signs of disease progression rather than severity. We discuss more thoroughly two underrecognised clinical findings: palpebral ptosis and GAA length-dependent low-frequency hearing loss. The average ICARS remained unchanged in 10 patients for whom follow-up on treatment was available (mean 2.9 years), whereas most patients treated with idebenone reported an improvement in dysarthria (63%), hand dexterity (.58%) and fatigue (47%) after taking the drug for several weeks or months. Oxidative stress analysis showed an unexpected increase in blood MDA levels in patients on idebenone (p = 0.04), and we discuss the putative underlying mechanism for this result, which could then explain the unique efficacy of idebenone in treating the FRDA-associated cardiomyopathy, as opposed to other antioxidative drugs. Indeed, idebenone is not only a powerful stimulator of complexes II and III of the respiratory chain, but also an inhibitor of complex I activity, then promoting superoxide formation. Our preliminary clinical observations are the first to date supporting an effect of idebenone in delaying neurological worsening. Our MDA results point to the dual effect of idebenone on oxidative stress and to the need for controlled studies to assess its potential toxicity at high doses on the one hand, and to revisit the exact mechanisms underlying the .physiopathology of Friedreich's ataxia on the other hand, while recent reports suggest non-oxidative pathophysiology of the disease.

Project Success through Effective Decisions: Case Studies on Project Goal Setting, Success Evaluation and Managerial Decision Making

The objective of the thesis is to structure and model the factors that contribute to and can be used in evaluating project success. The purpose of this thesis is to enhance the understanding of three research topics. The goal setting process, success evaluation and decision-making process are studied in the context of a project, business unitand its business environment. To achieve the objective three research questionsare posed. These are 1) how to set measurable project goals, 2) how to evaluateproject success and 3) how to affect project success with managerial decisions.The main theoretical contribution comes from deriving a synthesis of these research topics which have mostly been discussed apart from each other in prior research. The research strategy of the study has features from at least the constructive, nomothetical, and decision-oriented research approaches. This strategy guides the theoretical and empirical part of the study. Relevant concepts and a framework are composed on the basis of the prior research contributions within the problem area. A literature review is used to derive constructs of factors withinthe framework. They are related to project goal setting, success evaluation, and decision making. On the basis of this, the case study method is applied to complement the framework. The empirical data includes one product development program, three construction projects, as well as one organization development, hardware/software, and marketing project in their contexts. In two of the case studiesthe analytic hierarchy process is used to formulate a hierarchical model that returns a numerical evaluation of the degree of project success. It has its origin in the solution idea which in turn has its foundation in the notion of projectsuccess. The achieved results are condensed in the form of a process model thatintegrates project goal setting, success evaluation and decision making. The process of project goal setting is analysed as a part of an open system that includes a project, the business unit and its competitive environment. Four main constructs of factors are suggested. First, the project characteristics and requirements are clarified. The second and the third construct comprise the components of client/market segment attractiveness and sources of competitive advantage. Together they determine the competitive position of a business unit. Fourth, the relevant goals and the situation of a business unit are clarified to stress their contribution to the project goals. Empirical evidence is gained on the exploitation of increased knowledge and on the reaction to changes in the business environment during a project to ensure project success. The relevance of a successful project to a company or a business unit tends to increase the higher the reference level of project goals is set. However, normal performance or sometimes performance below this normal level is intentionally accepted. Success measures make project success quantifiable. There are result-oriented, process-oriented and resource-oriented success measures. The study also links result measurements to enablers that portray the key processes. The success measures can be classified into success domains determining the areas on which success is assessed. Empiricalevidence is gained on six success domains: strategy, project implementation, product, stakeholder relationships, learning situation and company functions. However, some project goals, like safety, can be assessed using success measures that belong to two success domains. For example a safety index is used for assessing occupational safety during a project, which is related to project implementation. Product safety requirements, in turn, are connected to the product characteristics and thus to the product-related success domain. Strategic success measures can be used to weave the project phases together. Empirical evidence on their static nature is gained. In order-oriented projects the project phases are oftencontractually divided into different suppliers or contractors. A project from the supplier's perspective can represent only a part of the ¿whole project¿ viewed from the client's perspective. Therefore static success measures are mostly used within the contractually agreed project scope and duration. Proof is also acquired on the dynamic use of operational success measures. They help to focus on the key issues during each project phase. Furthermore, it is shown that the original success domains and success measures, their weights and target values can change dynamically. New success measures can replace the old ones to correspond better with the emphasis of the particular project phase. This adjustment concentrates on the key decision milestones. As a conclusion, the study suggests a combination of static and dynamic success measures. Their linkage to an incentive system can make the project management proactive, enable fast feedback and enhancethe motivation of the personnel. It is argued that the sequence of effective decisions is closely linked to the dynamic control of project success. According to the used definition, effective decisions aim at adequate decision quality and decision implementation. The findings support that project managers construct and use a chain of key decision milestones to evaluate and affect success during aproject. These milestones can be seen as a part of the business processes. Different managers prioritise the key decision milestones to a varying degree. Divergent managerial perspectives, power, responsibilities and involvement during a project offer some explanation for this. Finally, the study introduces the use ofHard Gate and Soft Gate decision milestones. The managers may use the former milestones to provide decision support on result measurements and ad hoc critical conditions. In the latter milestones they may make intermediate success evaluation also on the basis of other types of success measures, like process and resource measures.