PPARβ/δ attenuates palmitate-induced endoplasmic reticulum stress and induces autophagic markers in human cardiac cells.

BACKGROUND: Chronic endoplasmic reticulum (ER) stress contributes to the apoptotic cell death in the myocardium, thereby playing a critical role in the development of cardiomyopathy. ER stress has been reported to be induced after high-fat diet feeding in mice and also after saturated fatty acid treatment in vitro. Therefore, since several studies have shown that peroxisome proliferator-activated receptor (PPAR)β/δ inhibits ER stress, the main goal of this study consisted in investigating whether activation of this nuclear receptor was able to prevent lipid-induced ER stress in cardiac cells. METHODS AND RESULTS: Wild-type and transgenic mice with reduced PPARβ/δ expression were fed a standard diet or a high-fat diet for two months. For in vitro studies, a cardiomyocyte cell line of human origin, AC16, was treated with palmitate and the PPARβ/δ agonist GW501516. Our results demonstrate that palmitate induced ER stress in AC16 cells, a fact which was prevented after PPARβ/δ activation with GW501516. Interestingly, the effect of GW501516 on ER stress occurred in an AMPK-independent manner. The most striking result of this study is that GW501516 treatment also upregulated the protein levels of beclin 1 and LC3II, two well-known markers of autophagy. In accordance with this, feeding on a high-fat diet or suppression of PPARβ/δ in knockout mice induced ER stress in the heart. Moreover, PPARβ/δ knockout mice also displayed a reduction in autophagic markers. CONCLUSION: Our data indicate that PPARβ/δ activation might be useful to prevent the harmful effects of ER stress induced by saturated fatty acids in the heart by inducing autophagy.

Bax-induced apoptosis in Leber's congenital amaurosis: a dual role in rod and cone degeneration.

Pathogenesis in the Rpe65(-/-) mouse model of Leber's congenital amaurosis (LCA) is characterized by a slow and progressive degeneration of the rod photoreceptors. On the opposite, cones degenerate rapidly at early ages. Retinal degeneration in Rpe65(-/-) mice, showing a null mutation in the gene encoding the retinal pigment epithelium 65-kDa protein (Rpe65), was previously reported to depend on continuous activation of a residual transduction cascade by unliganded opsin. However, the mechanisms of apoptotic signals triggered by abnormal phototransduction remain elusive. We previously reported that activation of a Bcl-2-dependent pathway was associated with apoptosis of rod photoreceptors in Rpe65(-/-) mice during the course of the disease. In this study we first assessed whether activation of Bcl-2-mediated apoptotic pathway was dependent on constitutive activation of the visual cascade through opsin apoprotein. We then challenged the direct role of pro-apoptotic Bax protein in triggering apoptosis of rod and cone photoreceptors.Quantitative PCR analysis showed that increased expression of pro-apoptotic Bax and decreased level of anti-apoptotic Bcl-2 were restored in Rpe65(-/-)/Gnat1(-/-) mice lacking the Gnat1 gene encoding rod transducin. Moreover, photoreceptor apoptosis was prevented as assessed by TUNEL assay. These data indicate that abnormal activity of opsin apoprotein induces retinal cell apoptosis through the Bcl-2-mediated pathway. Following immunohistological and real-time PCR analyses, we further observed that decreased expression of rod genes in Rpe65-deficient mice was rescued in Rpe65(-/-)/Bax(-/-) mice. Histological and TUNEL studies confirmed that rod cell demise and apoptosis in diseased Rpe65(-/-) mice were dependent on Bax-induced pathway. Surprisingly, early loss of cones was not prevented in Rpe65(-/-)/Bax(-/-) mice, indicating that pro-apoptotic Bax was not involved in the pathogenesis of cone cell death in Rpe65-deficient mice.This is the first report, to our knowledge, that a single genetic mutation can trigger two independent apoptotic pathways in rod and cone photoreceptors in Rpe65-dependent LCA disease. These results highlight the necessity to investigate and understand the specific death signaling pathways committed in rods and cones to develop effective therapeutic approaches to treat RP diseases.

Development of LRFD Procedures for Bridge Pile Foundations in Iowa, Volume I: An Electronic Database for PIle LOad Tests (PILOT), TR-573, 2011

For well over 100 years, the Working Stress Design (WSD) approach has been the traditional basis for geotechnical design with regard to settlements or failure conditions. However, considerable effort has been put forth over the past couple of decades in relation to the adoption of the Load and Resistance Factor Design (LRFD) approach into geotechnical design. With the goal of producing engineered designs with consistent levels of reliability, the Federal Highway Administration (FHWA) issued a policy memorandum on June 28, 2000, requiring all new bridges initiated after October 1, 2007, to be designed according to the LRFD approach. Likewise, regionally calibrated LRFD resistance factors were permitted by the American Association of State Highway and Transportation Officials (AASHTO) to improve the economy of bridge foundation elements. Thus, projects TR-573, TR-583 and TR-584 were undertaken by a research team at Iowa State University’s Bridge Engineering Center with the goal of developing resistance factors for pile design using available pile static load test data. To accomplish this goal, the available data were first analyzed for reliability and then placed in a newly designed relational database management system termed PIle LOad Tests (PILOT), to which this first volume of the final report for project TR-573 is dedicated. PILOT is an amalgamated, electronic source of information consisting of both static and dynamic data for pile load tests conducted in the State of Iowa. The database, which includes historical data on pile load tests dating back to 1966, is intended for use in the establishment of LRFD resistance factors for design and construction control of driven pile foundations in Iowa. Although a considerable amount of geotechnical and pile load test data is available in literature as well as in various State Department of Transportation files, PILOT is one of the first regional databases to be exclusively used in the development of LRFD resistance factors for the design and construction control of driven pile foundations. Currently providing an electronically organized assimilation of geotechnical and pile load test data for 274 piles of various types (e.g., steel H-shaped, timber, pipe, Monotube, and concrete), PILOT (http://srg.cce.iastate.edu/lrfd/) is on par with such familiar national databases used in the calibration of LRFD resistance factors for pile foundations as the FHWA’s Deep Foundation Load Test Database. By narrowing geographical boundaries while maintaining a high number of pile load tests, PILOT exemplifies a model for effective regional LRFD calibration procedures.

Increased salt sensitivity of ambulatory blood pressure in women with a history of severe preeclampsia.

Cardiovascular diseases are the principal cause of death in women in developed countries and are importantly promoted by hypertension. The salt sensitivity of blood pressure (BP) is considered as an important cardiovascular risk factor at any BP level. Preeclampsia is a hypertensive disorder of pregnancy that arises as a risk factor for cardiovascular diseases. This study measured the salt sensitivity of BP in women with a severe preeclampsia compared with women with no pregnancy hypertensive complications. Forty premenopausal women were recruited 10 years after delivery in a case-control study. Salt sensitivity was defined as an increase of >4 mm Hg in 24-hour ambulatory BP on a high-sodium diet. The ambulatory BP response to salt was significantly increased in women with a history of preeclampsia compared with that of controls. The mean (95% confidence interval) daytime systolic/diastolic BP increased significantly from 115 (109-118)/79 (76-82) mm Hg on low-salt diet to 123 (116-130)/80 (76-84) on a high-salt diet in women with preeclampsia, but not in the control group (from 111 [104-119]/77 [72-82] to 111 [106-116]/75 [72-79], respectively, P<0.05). The sodium sensitivity index (SSI=Δmean arterial pressure/Δurinary Na excretion×1000) was 51.2 (19.1-66.2) in women with preeclampsia and 6.6 (5.8-18.1) mm Hg/mol per day in controls (P=0.015). The nocturnal dip was blunted on a high-salt diet in women with preeclampsia. Our study shows that women who have developed preeclampsia are salt sensitive before their menopause, a finding that may contribute to their increased cardiovascular risk. Women with a history of severe preeclampsia should be targeted at an early stage for preventive measures of cardiovascular diseases.

Role of JNK in neurodegenerative diseases

The c-Jun N-terminal kinases (JNK) are members of the MAPK family and can be activated by different stimuli such as cellular stress, heat shock and ultra-violet irradiation. JNKs have different physiological functions and they have been linked to apoptosis in different cell types. Therefore, the JNK signalling pathway is an important target to prevent cell death. In the present chapter, the role of JNKs in neurodegenerative diseases will be discussed, as well as the pharmacological compounds that inhibit this signalling pathway as therapeutic intervention to prevent neuronal death.

Role of JNK in neurodegenerative diseases

The c-Jun N-terminal kinases (JNK) are members of the MAPK family and can be activated by different stimuli such as cellular stress, heat shock and ultra-violet irradiation. JNKs have different physiological functions and they have been linked to apoptosis in different cell types. Therefore, the JNK signalling pathway is an important target to prevent cell death. In the present chapter, the role of JNKs in neurodegenerative diseases will be discussed, as well as the pharmacological compounds that inhibit this signalling pathway as therapeutic intervention to prevent neuronal death.

An epidemiological study of dental agenesis in a primary health area in Spain: estimated prevalence and associated factors

Objectives: To evaluate the prevalence of dental agenesis and its possible association with other developmental dental anomalies and systemic entities. Setting and Sample Population: Descriptive transversal study, for which 1518 clinical records, of patients visited by the Odontological Service of the Primary Health Centre of Cassà de la Selva (Girona-Spain) between December 2002 and February 2006 were reviewed. The data were recorded in relation to the oral and dental anomalies and the associated systemic entities, between the ones referred as concomitant in literature. Results: Values of 9.48% (7.25% excluding the third molars) for dental agenesis and 0.39% for oligodontia were obtained. The presence of dental agenesis concomitant with some other forms of oral and dental anomalies was observed. Attention must be drawn to the fact that a greater number of concomitant systemic entities were observed in those patients that presented a severe phenotypical pattern of dental agenesis. Conclusions: The results of the present study do not differ from the ones reported in studies of similar characteristics among Occidental and Spanish populations. The relationship observed between certain systemic entities and developmental dental anomalies suggest a possible common genetic etiology

Distinctive role of integrin-mediated adhesion in TNF-induced PKB/Akt and NF-kappaB activation and endothelial cell survival.

Tumor necrosis factor (TNF) is a pro-inflammatory cytokine exerting pleiotropic effects on endothelial cells. Depending on the vascular context it can induce endothelial cell activation and survival or death. The microenvironmental cues determining whether endothelial cells will survive or die, however, have remained elusive. Here we report that integrin ligation acts permissive for TNF-induced protein kinase B (PKB/Akt) but not nuclear factor (NF)-kappaB activation. Concomitant activation of PKB/Akt and NF-kappaB is essential for the survival of endothelial cells exposed to TNF. Active PKB/Akt strengthens integrin-dependent endothelial cell adhesion, whereas disruption of actin stress fibers abolishes the protective effect of PKB/Akt. Integrin-mediated adhesion also represses TNF-induced JNK activation, but JNK activity is not required for cell death. The alphaVbeta3/alphaVbeta5 integrin inhibitor EMD121974 sensitizes endothelial cells to TNF-dependent cytotoxicity and active PKB/Akt attenuates this effect. Interferon gamma synergistically enhanced TNF-induced endothelial cell death in all conditions tested. Taken together, these observations reveal a novel permissive role for integrins in TNF-induced PKB/Akt activation and prevention of TNF-induced death distinct of NF-kappaB, and implicate the actin cytoskeleton in PKB/Akt-mediated cell survival. The sensitizing effect of EMD121974 on TNF cytotoxicity may open new perspectives to the therapeutic use of TNF as anticancer agent.

Association of early repolarization with risk of cardiac mortality in the general population

Early repolarization, which is characterized by an elevation of the J-point on 12-lead electrocardiography, is a common finding that has been considered as benign for decades. However, in the last years, it has been related with vulnerability to idiopathic ventricular fibrillation and with cardiac mortality in the general population. Recently, 4 potential ECG predictors that could differentiate the benign from the malignant form of early repolarization have been suggested. Any previous study about early repolarization has been done in Spain. Aim. To ascertain whether the presence of early repolarization pattern in a resting electrocardiogram is associated with a major risk of cardiac death in a Spanish general population and to determine whether the presence of potential predictors of malignancy in a resting electrocardiogram increases the risk of cardiac mortality in patients with early repolarization pattern. Methods. We will analyse the presence of early repolarization and the occurrence of cardiac mortality in a retrospective cohort study of 4,279 participants aged 25 to 74 years in the province of Girona. This cohort has been followed during a mean of 9.8 years. Early repolarization will be stratified according to the degree of J-point elevation (≥0.1 mV or ≥0.2 mV), the morphology of the J-wave (slurring, notching or any of these two), the ST-segment pattern (ascending or descending) and the localization (inferior leads, lateral leads, or both). Association of early repolarization with cardiac death will be assessed by adjusted Cox-proportional hazards models

Partial cricotracheal resection for congenital subglottic stenosis in children: the effect of concomitant anomalies.

OBJECTIVE: To review the surgical outcomes of partial cricotracheal resection in children with severe congenital subglottic stenosis and define the effect of concomitant anomalies or syndromes affecting outcome. METHODS: Forty-one children with subglottic stenosis of congenital and mixed (acquired on congenital) etiologies who underwent partial cricotracheal resection were identified from a prospectively collected database. Children with congenital subglottic stenosis and concomitant anomalies/syndromes were compared to children with congenital subglottic stenosis with no syndromes or concomitant anomalies. Operation-specific decannulation rates and complication rates were the primary outcome measures. We performed a two-sample test of proportion using the STATA-10 software for categorical variables to detect differences in proportions. Significance was set at p value<0.05. RESULTS: Twenty-seven (66%) of 41 children had concomitant anomalies/syndromes and 14 (34%) had congenital subglottic stenosis without concomitant anomalies/syndromes. Four patients needed revision surgery in the concomitant anomaly group and two patients needed revision surgery in the non concomitant anomaly group before achieving decannulation. The operation-specific decannulation rate in the concomitant anomaly group was 85% and 86% in the non anomaly group. When compared to children without concomitant anomaly, children with concomitant anomalies were more likely to have delayed decannulation following partial cricotracheal resection. However, this difference was not found to be statistically significant. The complication and operation-specific decannulation rates after partial cricotracheal resection were comparable to children without concomitant anomalies. Mortality rate was 11% (three of 27 patients) in the group with associated congenital anomalies or syndromes. Two patients succumbed to the primary pathology and one patient died due to tracheostomy-tube obstruction. There was no post-operative death in the non anomaly group. CONCLUSION: Partial cricotracheal resection can be done safely and effectively in children with concomitant anomalies/syndromes to achieve decannulation. The post-operative course may be prolonged but the decannulation and the complication rates are comparable to those children with congenital subglottic stenosis without concomitant anomalies.

Transitoriness in cancer patients: a cross-sectional survey of lung and gastrointestinal cancer patients.

Despite earlier diagnosis and advancements in treatment, cancer remains a leading cause of death in the world (13% of all deaths according to the World Health Organization) among men and women. Cancer accounts for approximately 20% of the deaths in the USA every year. Here, we report the findings from a cross-sectional survey of psychosocial factors in lung and gastrointestinal cancer patients. The aim of the study was to explore the associations among transitoriness, uncertainty, and locus of control (LOC) with quality of life. Transitoriness is defined as a person's confrontation with life's finitude due to a cancer diagnosis. A total of 126 patients with lung or gastrointestinal cancer completed eight self-reporting questionnaires addressing demographics, spiritual perspective, symptom burden, transitoriness, uncertainty, LOC, and quality of life. Transitoriness, uncertainty, and LOC were significantly associated with one another (r = 0.3267, p = 0.0002/r = 0.1994, p = 0.0252, respectively). LOC/belief in chance has a significant inverse relationship with patients' quality of life (r = -0.2505, p = 0.0047). Transitoriness, uncertainty, and LOC were found to have a significant inverse relationship with patients' quality of life (transitoriness state: r = -0.5363, p = 0.0000/trait: r = -0.4629, p = 0.0000/uncertainty: r = -0.4929, p = 0.0000/internal LOC: r = 0.1759, p = 0.0489/chance LOC: r = -0.2505, p = 0.0047). Transitoriness, uncertainty, and LOC are important concepts as they adversely influence patients' quality of life. Incorporating this finding into the care of cancer patients may provide them with the support they need to cope with treatment and maintenance of a positive quality of life.

Respiratory failure in a mouse model of myotonic dystrophy does not correlate with the CTG repeat length.

Myotonic dystrophy (DM1) is a multisystemic disease caused by an expansion of CTG repeats in the region of DMPK, the gene encoding DM protein kinase. The severity of muscle disability in DM1 correlates with the size of CTG expansion. As respiratory failure is one of the main causes of death in DM1, we investigated the correlation between respiratory impairment and size of the (CTG)n repeat in DM1 animal models. Using pressure plethysmography the respiratory function was assessed in control and transgenic mice carrying either 600 (DM600) or >1300 CTG repeats (DMSXL). The statistical analysis of respiratory parameters revealed that both DM1 transgenic mice sub-lines show respiratory impairment compared to control mice. In addition, there is no significant difference in breathing functions between the DM600 and DMSXL mice. In conclusion, these results indicate that respiratory impairment is present in both transgenic mice sub-lines, but the severity of respiratory failure is not related to the size of the (CTG)n expansion.

"In vitro" comparative experimental study of antimicrobial action of mouth washing products

Regular use of mouth rinses modifies the oral habitat, since bacterial populations are submitted to a high selective pressure during the treatment exercised by the active presence of the disinfectant. Mostly mouth rinses are based on the antibacterial effect of Chlorhexidine, Triclosan, essential oils and other antibacterials although other pharmaceutical characteristics can also affect their effectiveness. In this paper we compare"in vitro" the antibacterial effect of different oral rinsing solutions. Minimal Inhibitory Concentrations (MIC) and Minimal Bactericidal Concentrations (MBC) were determined as well as the kinetics of bacterial death in the presence of letal concentrations of the mouth rinses. MIC values expressed as Maximal Inhibitory Dilution (MID) of the mouth rinse ranged from 1 to 1/2048 depending on the microorganism and product, whereas Minimal Biocidal Concentration (MBC), expressed as Maximal Biocidal Dilution (MBD) ranged from 1 to 1/1024, being in general one dilution less than MIC. Maximal Biocidal Dilution is a good tool to measure the actual efficiency of mouth washing solutions. However, kinetics of death seems to be better in our work killing curves demonstrate that bacterial populations are mostly eliminated during the first minute after the contact of bacterial suspension and the mouth-washing solution. In all tested bacterial species mouth-washing solutions tested were able to reduce until suspension treated except 1 and 5

Breast cancer in younger women in Switzerland 1996-2009 : a longitudinal population-based study

BACKGROUND: Breast cancer (BC) is the most commonly diagnosed cancer and a leading cause of death in younger women. METHODS: We analysed incidence, mortality and relative survival (RS) in women with BC aged 20-49 years at diagnosis, between 1996 and 2009 in Switzerland. Trends are reported as estimated annual percentage changes (EAPC). RESULTS: Our findings confirm a slight increase in the incidence of BC in younger Swiss women during the period 1996-2009. The increase was largest in women aged 20-39 years (EAPC 1.8%). Mortality decreased in both age groups with similar EAPCs. Survival was lowest among women 20-39 years (10-year RS 73.4%). We observed no notable differences in stage of disease at diagnosis that might explain these differences. CONCLUSIONS: The increased incidence and lower survival in younger women diagnosed with BC in Switzerland indicates possible differences in risk factors, tumour biology and treatment characteristics that require additional examination.

Low C-reactive protein values at admission predict mortality in patients with severe community-acquired pneumonia caused by Streptococcus pneumoniae that require intensive care management.

PURPOSE: To identify risk factors associated with mortality in patients with severe community-acquired pneumonia (CAP) caused by S. pneumoniae who require intensive care unit (ICU) management, and to assess the prognostic values of these risk factors at the time of admission. METHODS: Retrospective analysis of all consecutive patients with CAP caused by S. pneumoniae who were admitted to the 32-bed medico-surgical ICU of a community and referral university hospital between 2002 and 2011. Univariate and multivariate analyses were performed on variables available at admission. RESULTS: Among the 77 adult patients with severe CAP caused by S. pneumoniae who required ICU management, 12 patients died (observed mortality rate 15.6 %). Univariate analysis indicated that septic shock and low C-reactive protein (CRP) values at admission were associated with an increased risk of death. In a multivariate model, after adjustment for age and gender, septic shock [odds ratio (OR), confidence interval 95 %; 4.96, 1.11-22.25; p = 0.036], and CRP (OR 0.99, 0.98-0.99 p = 0.034) remained significantly associated with death. Finally, we assessed the discriminative ability of CRP to predict mortality by computing its receiver operating characteristic curve. The CRP value cut-off for the best sensitivity and specificity was 169.5 mg/L to predict hospital mortality with an area under the curve of 0.72 (0.55-0.89). CONCLUSIONS: The mortality of patients with S. pneumoniae CAP requiring ICU management was much lower than predicted by severity scores. The presence of septic shock and a CRP value at admission <169.5 mg/L predicted a fatal outcome.