Use of big data from health insurance for assessment of cardiovascular outcomes.

Outcome research that supports guideline recommendations for primary and secondary preventions largely depends on the data obtained from clinical trials or selected hospital populations. The exponentially growing amount of real-world medical data could enable fundamental improvements in cardiovascular disease (CVD) prediction, prevention, and care. In this review we summarize how data from health insurance claims (HIC) may improve our understanding of current health provision and identify challenges of patient care by implementing the perspective of patients (providing data and contributing to society), physicians (identifying at-risk patients, optimizing diagnosis and therapy), health insurers (preventive education and economic aspects), and policy makers (data-driven legislation). HIC data has the potential to inform relevant aspects of the healthcare systems. Although HIC data inherit limitations, large sample sizes and long-term follow-up provides enormous predictive power. Herein, we highlight the benefits and limitations of HIC data and provide examples from the cardiovascular field, i.e. how HIC data is supporting healthcare, focusing on the demographical and epidemiological differences, pharmacotherapy, healthcare utilization, cost-effectiveness and outcomes of different treatments. As an outlook we discuss the potential of using HIC-based big data and modern artificial intelligence (AI) algorithms to guide patient education and care, which could lead to the development of a learning healthcare system and support a medically relevant legislation in the future.

Inferring the effect of interventions on COVID-19 transmission networks.

Countries around the world implement nonpharmaceutical interventions (NPIs) to mitigate the spread of COVID-19. Design of efficient NPIs requires identification of the structure of the disease transmission network. We here identify the key parameters of the COVID-19 transmission network for time periods before, during, and after the application of strict NPIs for the first wave of COVID-19 infections in Germany combining Bayesian parameter inference with an agent-based epidemiological model. We assume a Watts-Strogatz small-world network which allows to distinguish contacts within clustered cliques and unclustered, random contacts in the population, which have been shown to be crucial in sustaining the epidemic. In contrast to other works, which use coarse-grained network structures from anonymized data, like cell phone data, we consider the contacts of individual agents explicitly. We show that NPIs drastically reduced random contacts in the transmission network, increased network clustering, and resulted in a previously unappreciated transition from an exponential to a constant regime of new cases. In this regime, the disease spreads like a wave with a finite wave speed that depends on the number of contacts in a nonlinear fashion, which we can predict by mean field theory.

Optimizing Decision-Making Processes in Times of COVID-19: Using Reflexivity to Counteract Information-Processing Failures.

The effectiveness of policymakers' decision-making in times of crisis depends largely on their ability to integrate and make sense of information. The COVID-19 crisis confronts governments with the difficult task of making decisions in the interest of public health and safety. Essentially, policymakers have to react to a threat, of which the extent is unknown, and they are making decisions under time constraints in the midst of immense uncertainty. The stakes are high, the issues involved are complex and require the careful balancing of several interests, including (mental) health, the economy, and human rights. These circumstances render policymakers' decision-making processes vulnerable to errors and biases in the processing of information, thereby increasing the chances of faulty decision-making processes with poor outcomes. Prior research has identified three main information-processing failures that can distort group decision-making processes and can lead to negative outcomes: (1) failure to search for and share information, (2) failure to elaborate on and analyze information that is not in line with earlier information and (3) failure to revise and update conclusions and policies in the light of new information. To date, it has not yet been explored how errors and biases underlying these information-processing failures impact decision-making processes in times of crisis. In this narrative review, we outline how groupthink, a narrow focus on the problem of containing the virus, and escalation of commitment may pose real risks to decision-making processes in handling the COVID-19 crisis and may result in widespread societal damages. Hence, it is vital that policymakers take steps to maximize the quality of the decision-making process and increase the chances of positive outcomes as the crisis goes forward. We propose group reflexivity-a deliberate process of discussing team goals, processes, or outcomes-as an antidote to these biases and errors in decision-making. Specifically, we recommend several evidence-based reflexivity tools that could easily be implemented to counter these information-processing errors and improve decision-making processes in uncertain times.

Majority Decision-Making Works Best Under Conditions of Leadership Ambiguity and Shared Task Representations.

The effectiveness of decision-making teams depends largely on their ability to integrate and make sense of information. Consequently, teams which more often use majority decision-making may make better quality decisions, but particularly so when they also have task representations which emphasize the elaboration of information relevant to the decision, in the absence of clear leadership. In the present study we propose that (a) majority decision-making will be more effective when task representations are shared, and that (b) this positive effect will be more pronounced when leadership ambiguity (i.e., team members' perceptions of the absence of a clear leader) is high. These hypotheses were put to the test using a sample comprising 81 teams competing in a complex business simulation for seven weeks. As predicted, majority decision-making was more effective when task representations were shared, and this positive effect was more pronounced when there was leadership ambiguity. The findings extend and nuance earlier research on decision rules, the role of shared task representations, and leadership clarity.

Metreleptin therapy for nonalcoholic steatohepatitis: Open-label therapy interventions in two different clinical settings.

BACKGROUND: Recombinant leptin therapy reverses nonalcoholic steatohepatitis (NASH) in leptin-deficient lipodystrophy. We inquired if leptin therapy would improve nonalcoholic steatohepatitis in more common forms of this heterogeneous condition. METHODS: Nine male patients with relative leptin deficiency (level < 25th percentile of body mass index- and gender-matched United States population) and biopsy-proven NASH and 23 patients with partial lipodystrophy and NASH were recruited for two distinctive open-label trials. Participants received leptin therapy in the form of metreleptin for 12 months. The primary endpoints were the global nonalcoholic steatohepatitis scores from paired liver biopsies scored blindly. FINDINGS: Of 9 participants recruited in the relative leptin deficiency treatment study, 7 completed 12-months of therapy. Mean global NASH scores were reduced from 8 ± 3 to 5 ± 2 (range: from 1 to 6, P = 0.004). In the partial lipodystrophy study, 19 of 22 subjects completed 12 months of treatment, and 18 completed a second liver biopsy. Global NASH scores also reduced significantly from 6 ± 2 to 5 ± 2 (range: from -2 to 4, P = 0.008). In both studies, the predominant changes were in steatosis and hepatic injury scores. CONCLUSION: Our findings show that patients with NASH associated with both relative leptin deficiency and partial lipodystrophy have reductions in hepatic steatosis and injury in response to exogenous leptin therapy. Moreover, leptin deficiency may have regulatory effects in mediating fat deposition and ensuing injury in the liver.TRIAL REGISTRATION. ClinicalTrials.gov NCT00596934 and NCT01679197.

Executive Functions and Emotion Regulation in Attention-Deficit/Hyperactivity Disorder and Borderline Intellectual Disability.

The main objective of this study is to investigate the multiple relations and to determine the differences between executive functions (EFs), emotion regulation, and behavioral and emotional problems in children with attention-deficit/hyperactivity disorder (ADHD), borderline intellectual disability (ID), and typical development (TD). The sample included 85 children aged 6 to 11 years, 42 with typical development (TD), 27 with ADHD, and 16 with borderline ID. The results emphasized a positive correlation between adaptive emotion regulation strategies and EFs, and no significant relations between the maladaptive emotion regulation strategies and EFs. In addition, the executive function of planning correlated negatively with anxiety, ADHD symptoms, and conduct problems. The performance of both clinical groups regarding EFs was significantly lower than that of the TD group, and they differed significantly from each other only on visual attention. The presence of oppositional-defiant and conduct problems was higher in both clinical groups than in the TD group, and more anxiety symptoms were reported in children with ADHD. This study supports the idea that emotion regulation, Efs, and clinical symptoms are interconnected. It also profiles the deficits in cognitive functioning and emotion regulation in two clinical groups, thus helping future intervention programs.

The complicated clinical course in a case of atypical lipodystrophy after development of neutralizing antibody to metreleptin: treatment with setmelanotide.

SUMMARY: A patient with atypical partial lipodystrophy who had a transient initial response to metreleptin experienced acute worsening of her metabolic state when neutralizing antibodies against metreleptin appeared. Because her metabolic status continued to deteriorate, a therapeutic trial with melanocortin-4 receptor agonist setmelanotide, that is believed to function downstream from leptin receptor in the leptin signaling system, was undertaken in an effort to improve her metabolic status for the first time in a patient with lipodystrophy. To achieve this, a compassionate use (investigational new drug application; IND) was initiated (NCT03262610). Glucose control, body fat by dual-energy X-ray absorptiometry and MRI, and liver fat by proton density fat fraction were monitored. Daily hunger scores were assessed by patient filled questionnaires. Although there was a slight decrease in hunger scales and visceral fat, stimulating melanocortin-4 receptor by setmelanotide did not result in any other metabolic benefit such as improvement of hypertriglyceridemia or diabetes control as desired. Targeting melanocortin-4 receptor to regulate energy metabolism in this setting was not sufficient to obtain a significant metabolic benefit. However, complex features of our case make it difficult to generalize these observations to all cases of lipodystrophy. It is still possible that melanocortin-4 receptor agonistic action may offer some therapeutic benefits in leptin-deficient patients. LEARNING POINTS: A patient with atypical lipodystrophy with an initial benefit with metreleptin therapy developed neutralizing antibodies to metreleptin (Nab-leptin), which led to substantial worsening in metabolic control. The neutralizing activity in her serum persisted for longer than 3 years. Whether the worsening in her metabolic state was truly caused by the development of Nab-leptin cannot be fully ascertained, but there was a temporal relationship. The experience noted in our patient at least raises the possibility for concern for substantial metabolic worsening upon emergence and persistence of Nab-leptin. Further studies of cases where Nab-leptin is detected and better assay systems to detect and characterize Nab-leptin are needed. The use of setmelanotide, a selective MC4R agonist targeting specific neurons downstream from the leptin receptor activation, was not effective in restoring metabolic control in this complex patient with presumed diminished leptin action due to Nab-leptin. Although stimulating the MC4R pathway was not sufficient to obtain a significant metabolic benefit in lowering triglycerides and helping with her insulin resistance as was noted with metreleptin earlier, there was a mild reduction in reported food intake and appetite. Complex features of our case make it difficult to generalize our observation to all leptin-deficient patients. It is possible that some leptin-deficient patients (especially those who need primarily control of food intake) may still theoretically benefit from MC4R agonistic action, and further studies in carefully selected patients may help to tease out the differential pathways of metabolic regulation by the complex network of leptin signaling system.

Differences in the Inflammatory Response of White Adipose Tissue and Adipose-Derived Stem Cells.

The application of liposuctioned white adipose tissue (L-WAT) and adipose-derived stem cells (ADSCs) as a novel immunomodulatory treatment option is the currently subject of various clinical trials. Because it is crucial to understand the underlying therapeutic mechanisms, the latest studies focused on the immunomodulatory functions of L-WAT or ADSCs. However, studies that examine the specific transcriptional adaptation of these treatment options to an extrinsic inflammatory stimulus in an unbiased manner are scarce. The aim of this study was to compare the gene expression profile of L-WAT and ADSCs, when subjected to tumor necrosis factor alpha (TNFα), and to identify key factors that might be therapeutically relevant when using L-WAT or ADSCs as an immuno-modulator. Fat tissue was harvested by liposuction from five human donors. ADSCs were isolated from the same donors and shortly subjected to expansion culture. L-WAT and ADSCs were treated with human recombinant TNFα, to trigger a strong inflammatory response. Subsequently, an mRNA deep nextgeneration sequencing was performed to evaluate the different inflammatory responses of L-WAT and ADSCs. We found significant gene expression changes in both experimental groups after TNFα incubation. However, ADSCs showed a more homogenous gene expression profile by predominantly expressing genes involved in immunomodulatory processes such as CCL19, CCL5, TNFSF15 and IL1b when compared to L-WAT, which reacted rather heterogeneously. As RNA sequencing between L-WAT and ADSCS treated with TNFα revealed that L-WAT responded very heterogeneously to TNFα treatment, we therefore conclude that ADSCs are more reliable and predictable when used therapeutically. Our study furthermore yields insight into potential biological processes regarding immune system response, inflammatory response, and cell activation. Our results can help to better understand the different immunomodulatory effects of L-WAT and ADSCs.

Comorbidities and Survival in Patients With Lipodystrophy: An International Chart Review Study.

CONTEXT: Limited natural history data are available in patients with non-HIV-related lipodystrophy syndromes who never received disease-specific therapies, making interpretation of benefits of therapies in lipodystrophy syndromes challenging. OBJECTIVE: We assessed the natural history of non-HIV-related generalized lipodystrophy (GL) and partial lipodystrophy (PL) in patients who have never received leptin or other lipodystrophy-specific therapies. DESIGN/SETTING/PATIENTS: We conducted an international chart review of 230 patients with confirmed GL or PL at five treatment centers who never received leptin or other lipodystrophy-specific therapies. Patients were observed from birth to loss to follow-up, death, or date of chart abstraction. OUTCOME MEASURES: Lifetime prevalence of diabetes/insulin resistance and select organ abnormalities, time to diabetes/insulin resistance, first organ abnormality, disease progression, and mortality were described. RESULTS: Diabetes/insulin resistance was identified in 58.3% of patients. Liver abnormalities were the most common organ abnormality (71.7%), followed by kidney (40.4%), heart (30.4%), and pancreatitis (13.0%). Kaplan-Meier estimates of mean (SE) time to first organ abnormality were 7.7 years (0.9) in GL and 16.1 years (1.5) in PL (P < 0.001). Mean time to diabetes/insulin resistance was 12.7 years (1.2) in GL and 19.1 years (1.7) in PL (P = 0.131). Mean time to disease progression was 7.6 years (0.8) and comparable between GL and PL subgroups (P = 0.393). Mean time to death was 51.2 years (3.5) in GL and 66.6 years (1.0) in PL (P < 0.001). CONCLUSIONS: This large-scale study provides comprehensive, long-term data across multiple countries on the natural history of non-HIV-related lipodystrophy.

On Ethically Solvent Leaders: The Roles of Pride and Moral Identity in Predicting Leader Ethical Behavior.

The popular media has repeatedly pointed to pride as one of the key factors motivating leaders to behave unethically. However, given the devastating consequences that leader unethical behavior may have, a more scientific account of the role of pride is warranted. The present study differentiates between authentic and hubristic pride and assesses its impact on leader ethical behavior, while taking into consideration the extent to which leaders find it important to their self-concept to be a moral person. In two experiments we found that with higher levels of moral identity, authentically proud leaders are more likely to engage in ethical behavior than hubristically proud leaders, and that this effect is mediated by leaders' motivation to act selflessly. A field survey among organizational leaders corroborated that moral identity may bring the positive effect of authentic pride and the negative effect of hubristic pride on leader ethical behavior to the forefront.

Inhibition of IKKɛ and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes.

Numerous studies indicate an inflammatory link between obesity and type 2 diabetes. The inflammatory kinases IKKɛ and TBK1 are elevated in obesity; their inhibition in obese mice reduces weight, insulin resistance, fatty liver and inflammation. Here we studied amlexanox, an inhibitor of IKKɛ and TBK1, in a proof-of-concept randomized, double-blind, placebo-controlled study of 42 obese patients with type 2 diabetes and nonalcoholic fatty liver disease. Treatment of patients with amlexanox produced a statistically significant reduction in Hemoglobin A1c and fructosamine. Interestingly, a subset of drug responders also exhibited improvements in insulin sensitivity and hepatic steatosis. This subgroup was characterized by a distinct inflammatory gene expression signature from biopsied subcutaneous fat at baseline. They also exhibited a unique pattern of gene expression changes in response to amlexanox, consistent with increased energy expenditure. Together, these data suggest that dual-specificity inhibitors of IKKɛ and TBK1 may be effective therapies for metabolic disease in an identifiable subset of patients.

Cross-sector cooperation in health-enhancing physical activity policymaking: more potential than achievements?

BACKGROUND: The cooperation of actors across policy fields and the need for cross-sector cooperation as well as recommendations on how to implement cross-sector cooperation have been addressed in many national and international policies that seek to solve complex issues within societies. For such a purpose, the relevant governance structure between policy sectors is cross-sector cooperation. Therefore, cross-sector cooperation and its structures need to be better understood for improved implementation. This article reports on the governance structures and processes of cross-sector cooperation in health-enhancing physical activity (HEPA) policies in six European Union (EU) member states. METHODS: Qualitative content analysis of HEPA policies and semi-structured interviews with key policymakers in six European countries. RESULTS: Cross-sector cooperation varied between EU member states within HEPA policies. The main issues of the cross-sector policy process can be divided into stakeholder involvement, governance structures and coordination structures and processes. Stakeholder involvement included citizen hearings and gatherings of stakeholders from various non-governmental organisations and citizen groups. Governance structures with policy and political discussions included committees, working groups and consultations for HEPA policymaking. Coordination structures and processes included administrative processes with various stakeholders, such as ministerial departments, research institutes and private actors for HEPA policymaking. Successful cross-sector cooperation required joint planning and evaluation, financial frameworks, mandates based on laws or agreed methods of work, communication lines, and valued processes of cross-sector cooperation. CONCLUSIONS: Cross-sector cooperation required participation with the co-production of goals and sharing of resources between stakeholders, which could, for example, provide mechanisms for collaborative decision-making through citizen hearing. Clearly stated responsibilities, goals, communication, learning and adaptation for cross-sector cooperation improve success. Specific resources allocated for cross-sector cooperation could enhance the empowerment of stakeholders, management of processes and outcomes of cross-sector cooperation.

Paediatric head injuries treated in a children's emergency department from Cluj-Napoca, Romania.

The aim of the study was to describe paediatric head injuries and identify factors that led to advanced care. Incident cases of head injuries that sought care from December 2008 to October 2010 at Children's Emergency Hospital Cluj-Napoca were evaluated. The main outcome was transfer or admission to advanced care. From a total of 3053 children treated for an injury, 1541 (50.4%) presented with head injury. A total of 960 (62.3%) of the children with a head injury required advanced care treatment. Young children were more likely to suffer a head injury than older children, but a higher proportion of older children required advanced care (70.3%). Children who suffered a head injury as a consequence of road traffic were almost five times more likely to require advanced care (OR: 4.97; 3.09-8.06) than being released. Our results suggest that data on injuries provide evidence-based information on the nature of injuries children are prone to, and what activity, type, and mechanism of injury impact Romanian children.

Epidemiology of pedestrian-MVCs by road type in Cluj, Romania.

OBJECTIVE: Pedestrian-motor vehicle (PMV) crash rates in Romania are among the highest in all of Europe. The purpose of this study was to examine the characteristics of pedestrian-MVCs in Cluj County, Romania, on the two major types of roadways: national or local. METHODS: Cluj County police crash report data from 2010 were used to identify pedestrian, driver and crash characteristics of pedestrian-MVCs. Crashes with available location data were geocoded and road type (national or local) for each crash was determined. Distributions of crash characteristics were examined by road type and multivariable logistic regression models were built to determine predictors of crash road type. RESULTS: Crashes occurring on national roads involved more teenagers and adults, while those on local roads involved more young children (0-12) and older adults (65+) (p<0.01). Crashes on national roads were more likely to have marked pedestrian crossings and shoulders compared with local crashes. Pedestrian-MVCs that involved a moving violation by the motorist were more likely to occur on national roadways (adjusted OR=1.93, 95% CI 1.07 to 3.49). CONCLUSIONS: Pedestrian-MVCs pose a considerable health burden in Romania. Results from this study suggest that factors leading to PMV crashes on national roads are more likely to involve driver-related causes compared with local roads. Intervention priorities to reduce pedestrian crashes on national roads should be directed towards driver behaviour on national roads. Further examination of driver and pedestrian behaviours related to crash risk on both national and local roads, such as distraction and speeding, is warranted.

Risk factors associated with nicotine dependence in a sample of Romanian pregnant smokers.

OBJECTIVES: To fill the gap in assessing nicotine dependence during pregnancy in an unexplored population in Central and Eastern Europe and to analyze the associations of maternal characteristics and prenatal risk factors with moderate-heavy nicotine dependence among pregnant smokers. STUDY DESIGN: A questionnaire was applied to pregnant smokers in Romania to assess nicotine dependence and other related risks poorly documented in Central and Eastern Europe. The response rate was >80% and the valid sample included 137 pregnant smokers. Descriptive statistics and logistic regressions were used to assess nicotine dependence and to analyze the associations of maternal characteristic and prenatal risk factors with moderate-heavy nicotine dependence. RESULTS: Approximately 43% of the pregnant smokers in our sample (59 of 137) had moderate to heavy nicotine dependence. Depressive symptoms were associated with moderate-heavy nicotine dependence among pregnant smokers (OR=3.07, p<0.05). Women carrying an unwanted pregnancy had higher odds of moderate-heavy nicotine dependence (OR=2.59, p<0.05) compared to other pregnant women. High stress, lack of social support, and socioeconomic status were not associated with nicotine dependence. CONCLUSIONS: A large proportion of women had moderate-heavy nicotine dependence in a sample of Romanian pregnant smokers. The more dependent pregnant smokers were more likely to have depressive symptoms. Prenatal care should include brief nicotine dependence assessments and mental health screening and referrals for pregnant women who smoke. Special and intensive efforts, including psychosocial components, may be needed for the nicotine dependent pregnant smokers.

Epidemiology of assault and self-harm injuries treated in a large Romanian Emergency Department.

OBJECTIVES: Intentional injury, including interpersonal violence and self-harm, is one of the world's leading causes of preventable injury. In Europe alone, nearly 1.5 million individuals receive medical treatment each year for a violence-related injury. We examined violent injuries treated in the largest Emergency Department (ED) in Tîrgu Mures County, Romania, with a catchment area of approximately 580 000 residents to describe the epidemiology of assault and self-harm injuries. METHODS: Data were collected as part of the European Injury Database project, from a sample of patients who presented with a violence-related injury and received care from the ED of the Mures County Emergency Hospital, Romania. The data were collected for 9 months by two trained emergency physicians. Information about individual demographics; mechanism, nature, place, and activity of injury; injury types, and body regions affected; and discharge state were compared for assault and self-harm injuries. RESULTS: Of the 380 patients treated for violence-related injuries, 88.7% were for assault and 11.3% were for self-harm. For both types of injuries, the majority of patients were between the ages of 15 and 44. Assaults frequently occurred in the home, on streets and highways, or in public places; and men (80.4%) were far more likely than women (19.6%) to be treated for this type of injury; a slightly higher proportion of men (55.8%) than women (44.2%) were treated for self-harm, most of which occurred in homes. DISCUSSION: Of all injuries treated in the Tîrgu Mures ED, one out of five was violence related. One out of 10 patients that suffered an injury as a consequence of a violent event and treated in the ED required admission to a hospital for further medical care, leading to a significant health care burden. These data suggest that prevention strategies should focus on young adults, and particularly men. Interventions that focus on detection and treatment of psychological illness, reduction of alcohol use and associated aggression, and family and intimate partner violence are suggested as priorities.

Smoking during pregnancy and associated risk factors in a sample of Romanian women.

BACKGROUND: Smoking during pregnancy is one of the most modifiable risk factor for poor birth outcomes. This study assesses the prevalence and correlates of smoking during pregnancy. METHODS: A questionnaire was applied to pregnant women in two urban clinics in Romania to assess smoking prevalence, attitudes and knowledge about smoking, and other risks poorly documented in Romania, such as depressive symptoms, stress and social support. The response rate was >80% and the valid sample comprised of 916 women. Descriptive statistics and logistic regressions were used to estimate the prevalence of smoking and other risk factors and to identify correlates of smoking during pregnancy. RESULTS: Approximately 15% of the women continued smoking during pregnancy, and 26% of all women said they smoked prior to pregnancy, but quit upon finding out they were pregnant. Depressive symptoms and stress were not associated with smoking during pregnancy. Women with no social support had higher odds of continued smoking vs. non-smoking (OR = 2.3, P < 0.01), and vs. quitting (OR = 2.3, P < 0.05). Roma women had 5.2 times the odds (P < 0.01) of continued smoking vs. non-smoking. Lack of awareness about the benefits of quitting smoking and about the risks of smoking light cigarettes were associated with continued smoking during pregnancy. CONCLUSIONS: Smoking was common in a sample of Romanian pregnant women. Smoking cessation programs in Romania should include components to raise the awareness about the risks of smoking during pregnancy and the benefits of quitting at any time during pregnancy. More targeted interventions are needed in Roma communities.

Hyperoxia during colon surgery is associated with a reduction of xanthine oxidase activity and oxidative stress in colonic mucosa.

BACKGROUND: Gut manipulation during surgery may induce local oxidative stress. Supplemental inspired oxygen increases arterial and tissue oxygen partial pressures. This study examined whether a 0.80 fraction of inspired oxygen (FiO(2)) attenuates the oxidative stress, reducing xanthine oxidase (XO) activity in colonic mucosa as a possible mechanism during colon surgery. METHODS: Twenty-four cancer patients who underwent elective colon resection were randomly assigned to either 0.30 FiO(2) or 0.80 FiO(2) during surgery. Malondialdehyde (MDA) and oxidized glutathione (GSSG) levels were measured in blood plasma. We also determined the enzymatic activities of XO and xanthine dehydrogenase (XDH) in the colonic mucosa after resection of the piece of colon. RESULTS: Oxygen partial pressure in arterial blood was higher in the 0.80 FiO(2) group than in the 0.30 FiO(2) group (P<0.001). MDA and GSSG levels measured in blood plasma as well as MDA measured in colonic mucosa were lower in the 0.80 FiO(2) group than in the 0.30 FiO(2) group. Otherwise, XO enzymatic activity and XO/(XO+XDH) ratio in colonic mucosa were lower in the 0.80 FiO(2) group than in the 0.30 FiO(2) group. CONCLUSIONS: XO may be a major source of reactive oxygen species in patients during colon surgery. Inspiring 0.80 oxygen during colon surgery increases arterial partial pressure and this treatment was associated with reduced XO activity and levels of oxidative stress in colonic mucosa.

Inheritance of epigenetic chromatin silencing.

Maintenance of alternative chromatin states through cell divisions pose some fundamental constraints on the dynamics of histone modifications. In this paper, we study the systems biology of epigenetic inheritance by defining and analyzing general classes of mathematical models. We discuss how the number of modification states involved plays an essential role in the stability of epigenetic states. In addition, DNA duplication and the consequent dilution of marked histones act as a large perturbation for a stable state of histone modifications. The requirement that this large perturbation falls into the basin of attraction of the original state sometimes leads to additional constraints on effective models. Two such models, inspired by two different biological systems, are compared in their fulfilling the requirements of multistability and of recovery after DNA duplication. We conclude that in the presence of multiple histone modifications that characterize alternative epigenetic stable states, these requirements are more easily fulfilled.

Induction of mitochondrial xanthine oxidase activity during apoptosis in the rat mammary gland.

Oxidative stress is an important signal for apoptosis to start. So far the mitochondrial respiratory chain has been considered as the major, if not the only, cause of such stress. Here we report that this is not the case. Xanthine oxidase, a O2(-) and H2O2 generating enzyme which is important in causing significant oxidative stress in the cytosol, is also present in the mitochondrial fraction of rat mammary gland. After weaning, during the involution of the mammary gland, massive apoptosis occurs. Mitochondrial xanthine oxidase activity increases and high mitochondrial H2O2 production takes place. Inhibition of xanthine oxidase activity by allopurinol, a specific inhibitor of xanthine oxidase activity, slows down the involution of the mammary gland due to the decrease in the number of apoptotic cells and prevents the production of H2O2 that occurs during apoptosis. Thus, mitochondrial xanthine oxidase by means of its production of O2(-) and H2O2 can maintain the apoptotic machinery during the involution of the mammary gland after weaning and could be considered necessary to maintain the apoptotic cascade during the physiological involution of tissues. Oxidative stress generated during apoptosis by mitochondria is not only due to the respiratory chain.