Interaction between ATM and PARP-1 in response to DNA damage and sensitization of ATM deficient cells through PARP inhibition

ATM and PARP-1 are two of the most important players in the cell's response to DNA damage. PARP-1 and ATM recognize and bound to both single and double strand DNA breaks in response to different triggers. Here we report that ATM and PARP-1 form a molecular complex in vivo in undamaged cells and this association increases after gamma-irradiation. ATM is also modified by PARP-1 during DNA damage. We have also evaluated the impact of PARP-1 absence or inhibition on ATM-kinase activity and have found that while PARP-1 deficient cells display a defective ATM-kinase activity and reduced gamma-H2AX foci formation in response to gamma-irradiation, PARP inhibition on itself is able to activate ATM-kinase. PARP inhibition induced gamma H2AX foci accumulation, in an ATM-dependent manner. Inhibition of PARP also induces DNA double strand breaks which were dependent on the presence of ATM. As consequence ATM deficient cells display an increased sensitivity to PARP inhibition. In summary our results show that while PARP-1 is needed in the response of ATM to gamma irradiation, the inhibition of PARP induces DNA double strand breaks (which are resolved in and ATM-dependent pathway) and activates ATM kinase.

Proceso de inspección

En la port.: Secretaría General de Salud Pública y Participación

Effectiveness of olive oil for the prevention of pressure ulcers caused in immobilized patients within the scope of primary health care: study protocol for a randomized controlled trial.

BACKGROUND Pressure ulcers are considered an important issue, mainly affecting immobilized older patients. These pressure ulcers increase the care burden for the professional health service staff as well as pharmaceutical expenditure. There are a number of studies on the effectiveness of different products used for the prevention of pressure ulcers; however, most of these studies were carried out at a hospital level, basically using hyperoxygenated fatty acids (HOFA). There are no studies focused specifically on the use of olive-oil-based products and therefore this research is intended to find the most cost-effective treatment and achieve an alternative treatment. METHODS/DESIGN The main objective is to assess the effectiveness of olive oil, comparing it with HOFA, to treat immobilized patients at home who are at risk of pressure ulcers. As a secondary objective, the cost-effectiveness balance of this new application with regard to the HOFA will be assessed. The study is designed as a noninferiority, triple-blinded, parallel, multi-center, randomized clinical trial. The scope of the study is the population attending primary health centers in Andalucía (Spain) in the regional areas of Malaga, Granada, Seville, and Cadiz. Immobilized patients at risk of pressure ulcers will be targeted. The target group will be treated by application of an olive-oil-based formula whereas the control group will be treated by application of HOFA to the control group. The follow-up period will be 16 weeks. The main variable will be the presence of pressure ulcers in the patient. Secondary variables include sociodemographic and clinical information, caregiver information, and whether technical support exists. Statistical analysis will include the Kolmogorov-Smirnov test, symmetry and kurtosis analysis, bivariate analysis using the Student's t and chi-squared tests as well as the Wilcoxon and the Man-Whitney U tests, ANOVA and multivariate logistic regression analysis. DISCUSSION The regular use of olive-oil-based formulas should be effective in preventing pressure ulcers in immobilized patients, thus leading to a more cost-effective product and an alternative treatment. TRIAL REGISTRATION Clinicaltrials.gov identifier: NCT01595347.

Factores asociados a insulinemia en población general adolescente.

Objectives: To identify factors that correlate with insulin values and to examine its independent associations among adolescents. Methods: A cross-sectional population-based study was conducted among adolescents aged 12-16,9 years old. A multi-stage stratified cluster random sampling method was employed. Anthropometric measurements and nutritional survey were performed, and fasting blood samples for insulin were obtained. Statistics: Multiple lineal regression. Results: 379 adolescents were included. Mean age was 14.08 ± 1.30 years. Factors associated with higher fasting insulin levels were puberty [ 4.55 (95% IC 0.42-8.69)], abdominal obesity [ 6.11 (95% IC 3.93-8.29)] and to be born small for gestational age (SGA) [ 7.45 (95% IC 2.47-12.44)]. It was observed a negative association between the regular intake of olive oil at home and insulin values [ -4.14 (95% IC -7.31- -0.98)]. Conclusions: Abdominal obesity and SGA were factors associated with higher fasting insulin values. In contrast, the regular intake of olive oil at home was an independent protective factor.

Infección por virus pandémico (H1N1) 2009 en Andalucía

In April 2009, in response to the WHO's alert due to the existence of human infection cases with a new AH1N1 influenza virus, known as swine flu, Andalusian Health Authorities trigger an specific action plan. The surveillance actions developped provided us with appropriate clinical, epidemiological and virological characteristics of the disease. During the first few days, contingency plans were set up based on epidemiological surveillance and outbreak control measures were adopted through early alert and rapid response systems. After phase 6 was declared, influenza sentinel and severe cases surveillance were used in order to plan healthcare services, to reduce transmission and to identify and protect the most vulnerable population groups. Behaviour of pandemic influenza in Andalusia was similar to that observed in the rest of the world. Atack rate was similar to a seasonal flu and the peak was reached at the 46th/2009 week. Most of them were mild cases and affected particularly to young people. The average age of hospitalised patients was 32. Prior pulmonary disease, smoking and morbid obesity (BMI>40) were the most common pathologies and risk factors in severe cases. An impact scenario of pandemic wave in Andalusia, with an expected attack rate from 2 to 5%, was prepared considering watt observed in the southern hemisphere. Characteristics of the epidemic concerning its extent, severity and mortality rate were adjusted to this scenario.

Association of Patients' Geographic Origins with Viral Hepatitis Co-infection

To determine if hepatitis C virus seropositivity and active hepatitis B virus infection in HIV-positive patients vary with patients' geographic origins, we studied co-infections in HIV-seropositive adults. Active hepatitis B infection was more prevalent in persons from Africa, and hepatitis C seropositivity was more common in persons from eastern Europe.

El final de la vida en la infancia y la adolescencia: aspectos éticos y jurídicos en la atención sanitaria

Coordinadores: María J. Escudero Carretero, Pablo Simón Lorda

Morbilidad psíquica, existencia de diagnóstico y consumo de psicofármacos. Diferencias por comunidades autónomas según la Encuesta Nacional de Salud de 2006

Background: Most of the studies on sychological distress in Spain have been conducted in small geographical areas or specific population groups. However, there are no studies that provide representative data for each Autonomous Community (AC). The objectives of this paper are to determine, both in Spain and in the AC, the prevalence of psychological distress, diagnosis, use of psychoactive medication, social support and self-perceived health, as well as to study the association between psychological distress and the rest of the variables. Methods: Cross-sectional study, using data from the 2006 National Health Survey, that was completed by 29,478 persons. Variables studied: sociodemographics, psychological distress (GHQ-12), self-perceived health, mental disorder diagnosis, functional social support (Duke) and use and prescription of psychoactive medication. Results: The prevalence of psychological distress in Spain was 20,1%; the highest prevalence was found in Canary Islands (28,2%) and the lowest in La Rioja (12,2%). Among those who presented psychological distress, 62,4% had never received a mental disorder diagnosis, and 71,6% had not used psychoactive medication in the last year. The highest prevalences of non-diagnosed cases (81,8%) and cases non-treated with psychoactive medication (83,1%) were found in La Rioja, whereas the lowest prevalences were found in Asturias. Eight percent of the persons who presented psychological distress had low social support and 63,8% reported bad self-perceived health. Conclusions: Psychological distress is a prevalent phenomenon, and more than half of the persons who suffer it receive neither a diagnosis nor psychoactive medication. Moreover, there are considerable differences between the AC.

Is hospital discharge administrative data an appropriate source of information for cancer registries purposes? Some insights from four Spanish registries

Background. The use of hospital discharge administrative data (HDAD) has been recommended for automating, improving, even substituting, population-based cancer registries. The frequency of false positive and false negative cases recommends local validation. Methods. The aim of this study was to detect newly diagnosed, false positive and false negative cases of cancer from hospital discharge claims, using four Spanish population-based cancer registries as the gold standard. Prostate cancer was used as a case study. Results. A total of 2286 incident cases of prostate cancer registered in 2000 were used for validation. In the most sensitive algorithm (that using five diagnostic codes), estimates for Sensitivity ranged from 14.5% (CI95% 10.3-19.6) to 45.7% (CI95% 41.4-50.1). In the most predictive algorithm (that using five diagnostic and five surgical codes) Positive Predictive Value estimates ranged from 55.9% (CI95% 42.4-68.8) to 74.3% (CI95% 67.0-80.6). The most frequent reason for false positive cases was the number of prevalent cases inadequately considered as newly diagnosed cancers, ranging from 61.1% to 82.3% of false positive cases. The most frequent reason for false negative cases was related to the number of cases not attended in hospital settings. In this case, figures ranged from 34.4% to 69.7% of false negative cases, in the most predictive algorithm. Conclusions. HDAD might be a helpful tool for cancer registries to reach their goals. The findings suggest that, for automating cancer registries, algorithms combining diagnoses and procedures are the best option. However, for cancer surveillance purposes, in those cancers like prostate cancer in which care is not only hospital-based, combining inpatient and outpatient information will be required.

Factors associated with improvement in disability-adjusted life years in patients with HIV/AIDS

Background The epidemic of HIV/AIDS and treatments that have emerged to alleviate, have brought about a shift in the burden of disease from death to quality of life/disability. The aim was to determine which factors are associated with improvements in the level of health of male and female patients with HIV/AIDS in Andalusia, in terms of disability-adjusted life years. Methods Descriptive study based on a sample group of 8800 people on the Andalusian AIDS register between 1983 and 2004. Dependent variables: Life lost due to premature mortality (YLL), years lost due to disability (YLD) and disability-adjusted life years (DALY). Independent variables: vital state, sex, age at the time of diagnosis, age at the time of death, transmission category, province of residence, AIDS-indicator disease and the period of diagnosis. A bivariate analysis was carried out to find out if the health level variables changed in accordance with the independent variables. Using the independent variables which had a statistically significant link with the level of health variables, a multivariate linear regression model, disaggregated by gender, was constructed. Results Amongst the women, we found a model which explained the level of health of 64.9%: a link was found between a higher level of health (lower DALYs) and not intravenous drug use, the province of residence, being diagnosed during the HAART era and older age at the time of diagnosis. Amongst the men, we found a model which explained the level of health of 64.4%: a link was found between a higher level of health (lower DALYs) and intravenous drug use, the province of residence, being diagnosed during the HAART era and older age at the time of diagnosis. Conclusion A higher level of health (lower DALY) amongst both men and women was found to be linked to not be intravenous drug user, the province of residence, being diagnosed during the HAART era and older age at the time of diagnosis.

Eficacia de un programa de entrenamiento intradiálisis de fuerza-resistencia en combinación con electroestimulación neuromuscular: mejora en la capacidad funcional, fuerza, y calidad de vida

The purpose of this study was to determine the efficacy of a programme of strength-stamina exercises during haemodialysis, in improving muscular strength, quality of life and functional capacity to carry out everyday activities. A quantitative, experimental pre-test and post-test study was carried out. A programme of strength-stamina exercises in combination with neuromuscular electrostimulation was applied to 10 patients undergoing haemodialysis. These were three simple exercises adapted to the position in which haemodialysis was carried out. All the patients showed a significant improvement in strength, measured using functional tests to carry out everyday activities: walking (6-MWT) and sit-to-stand tests (10-STS). These tests were measured before and after the training programme. They also showed an improvement in the physical dimension of the quality of life measured using the specific questionnaire for renal patients, KDQOL-SFTM.

Regulation of Placental Leptin Expression by Cyclic Adenosine 5 '-Monophosphate Involves Cross Talk between Protein Kinase A and Mitogen-Activated Protein Kinase Signaling Pathways

Leptin, a 16-kDa protein mainly produced by adipose tissue, has been involved in the control of energy balance through its hypothalamic receptor. However, pleiotropic effects of leptin have been identified in reproduction and pregnancy, particularly in placenta, where it was found to be expressed. In the current study, we examined the effect of cAMP in the regulation of leptin expression in trophoblastic cells. We found that dibutyryl cAMP [(Bu)(2)cAMP], a cAMP analog, showed an inducing effect on endogenous leptin expression in BeWo and JEG-3 cell lines when analyzed by Western blot analysis and quantitative RT-PCR. Maximal effect was achieved at 100 microM. Leptin promoter activity was also stimulated, evaluated by transient transfection with a reporter plasmid construction. Similar results were obtained with human term placental explants, thus indicating physiological relevance. Because cAMP usually exerts its actions through activation of protein kinase A (PKA) signaling, this pathway was analyzed. We found that cAMP response element-binding protein (CREB) phosphorylation was significantly increased with (Bu)(2)cAMP treatment. Furthermore, cotransfection with the catalytic subunit of PKA and/or the transcription factor CREB caused a significant stimulation on leptin promoter activity. On the other hand, the cotransfection with a dominant negative mutant of the regulatory subunit of PKA inhibited leptin promoter activity. We determined that cAMP effect could be blocked by pharmacologic inhibition of PKA or adenylyl ciclase in BeWo cells and in human placental explants. Thereafter, we decided to investigate the involvement of the MAPK/ERK signaling pathway in the cAMP effect on leptin induction. We found that 50 microm PD98059, a MAPK kinase inhibitor, partially blocked leptin induction by cAMP, measured both by Western blot analysis and reporter transient transfection assay. Moreover, ERK 1/2 phosphorylation was significantly increased with (Bu)(2)cAMP treatment, and this effect was dose dependent. Finally, we observed that 50 microm PD98059 inhibited cAMP-dependent phosphorylation of CREB in placental explants. In summary, we provide some evidence suggesting that cAMP induces leptin expression in placental cells and that this effect seems to be mediated by a cross talk between PKA and MAPK signaling pathways.

Peripheral inflammation increases the damage in animal models of nigrostriatal dopaminergic neurodegeneration: possible implication in Parkinson's disease incidence.

Inflammatory processes described in Parkinson’s disease (PD) and its animal models appear to be important in the progression of the pathogenesis, or even a triggering factor. Here we review that peripheral inflammation enhances the degeneration of the nigrostriatal dopaminergic system induced by different insults; different peripheral inflammations have been used, such as IL-1β and the ulcerative colitis model, as well as insults to the dopaminergic system such as 6-hydroxydopamine or lipopolysaccharide. In all cases, an increased loss of dopaminergic neurons was described; inflammation in the substantia nigra increased, displaying a great activation of microglia along with an increase in the production of cytokines such as IL-1β and TNF-α. Increased permeability or disruption of the BBB, with overexpression of the ICAM-1 adhesion molecule and infiltration of circulating monocytes into the substantia nigra, is also involved, since the depletion of circulating monocytes prevents the effects of peripheral inflammation. Data are reviewed in relation to epidemiological studies of PD.