Creatine Protects against Excitoxicity in an In Vitro Model of Neurodegeneration

Creatine has been shown to be neuroprotective in aging, neurodegenerative conditions and brain injury. As a common molecular background, oxidative stress and disturbed cellular energy homeostasis are key aspects in these conditions. Moreover, in a recent report we could demonstrate a life-enhancing and health-promoting potential of creatine in rodents, mainly due to its neuroprotective action. In order to investigate the underlying pharmacology mediating these mainly neuroprotective properties of creatine, cultured primary embryonal hippocampal and cortical cells were challenged with glutamate or H2O2. In good agreement with our in vivo data, creatine mediated a direct effect on the bioenergetic balance, leading to an enhanced cellular energy charge, thereby acting as a neuroprotectant. Moreover, creatine effectively antagonized the H2O2-induced ATP depletion and the excitotoxic response towards glutamate, while not directly acting as an antioxidant. Additionally, creatine mediated a direct inhibitory action on the NMDA receptor-mediated calcium response, which initiates the excitotoxic cascade. Even excessive concentrations of creatine had no neurotoxic effects, so that high-dose creatine supplementation as a health-promoting agent in specific pathological situations or as a primary prophylactic compound in risk populations seems feasible. In conclusion, we were able to demonstrate that the protective potential of creatine was primarily mediated by its impact on cellular energy metabolism and NMDA receptor function, along with reduced glutamate spillover, oxidative stress and subsequent excitotoxicity

Biopsy confirmation of metastatic sites in breast cancer patients:clinical impact and future perspectives

Determination of hormone receptor (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2 status in the primary tumor is clinically relevant to define breast cancer subtypes, clinical outcome,and the choice of therapy. Retrospective and prospective studies suggest that there is substantial discordance in receptor status between primary and recurrent breast cancer. Despite this evidence and current recommendations,the acquisition of tissue from metastatic deposits is not routine practice. As a consequence, therapeutic decisions for treatment in the metastatic setting are based on the features of the primary tumor. Reasons for this attitude include the invasiveness of the procedure and the unreliable outcome of biopsy, in particular for biopsies of lesions at complex visceral sites. Improvements in interventional radiology techniques mean that most metastatic sites are now accessible by minimally invasive methods, including surgery. In our opinion, since biopsies are diagnostic and changes in biological features between the primary and secondary tumors can occur, the routine biopsy of metastatic disease needs to be performed. In this review, we discuss the rationale for biopsy of suspected breast cancer metastases, review issues and caveats surrounding discordance of biomarker status between primary and metastatic tumors, and provide insights for deciding when to perform biopsy of suspected metastases and which one (s) to biopsy. We also speculate on the future translational implications for biopsy of suspected metastatic lesions in the context of clinical trials and the establishment of bio-banks of biopsy material taken from metastatic sites. We believe that such bio-banks will be important for exploring mechanisms of metastasis. In the future,advances in targeted therapy will depend on the availability of metastatic tissue

abd-A Regulation by the iab-8 Noncoding RNA

The homeotic genes in Drosophila melanogaster are aligned on the chromosome in the order of the body segments that they affect. The genes affecting the more posterior segments repress the more anterior genes. This posterior dominance rule must be qualified in the case of abdominal-A (abd-A) repression by Abdominal-B (Abd-B). Animals lacking Abd-B show ectopic expression of abd-A in the epidermis of the eighth abdominal segment, but not in the central nervous system. Repression in these neuronal cells is accomplished by a 92 kb noncoding RNA. This “iab-8 RNA” produces a micro RNA to repress abd-A, but also has a second, redundant repression mechanism that acts only “in cis.” Transcriptional interference with the abd-A promoter is the most likely mechanism

Breastfeeding in Bolivia – information and attitudes

BACKGROUND: The main objective of the present study was to investigate the relationship between the attitudes of the mother and her family towards breastfeeding and the actual feeding pattern in a Bolivian population. A second objective was to study the relationship between breastfeeding information, specified according to source and timing, and feeding pattern. METHODS: Cross-sectional interviews with 420–502 Bolivian mothers with an infant less than or equal to 1 year of age. Duration of exclusive breastfeeding, use of prelacteal food and/or colostrum were the main outcome measures. RESULTS: The attitudes of the mother, her partner (the infant's father) and the infant's grandmother towards breastfeeding did not influence the infant feeding pattern. Women who had received breastfeeding information from health care personnel before birth or on the maternity ward breastfed exclusively for a longer duration (adjusted p = 0.0233) and avoided prelacteal food to a greater extent (adjusted odds ratio (AOR) = 0.42; 95% confidence interval for adjusted odds ratio (95% CI AOR) = 0.23–0.72). Information from a doctor before birth or on the maternity ward was associated with less use of prelacteal food (AOR = 0.53; 95% CI AOR = 0.31–0.93), an increased use of colostrum (AOR = 3.30; 95% CI AOR = 1.16–9.37), but was not linked to the duration of exclusive breastfeeding (p = 0.1767). CONCLUSION: The current study indicates that breastfeeding information delivered by health care personnel in a non-trial setting may affect the infant feeding pattern including the use of prelacteal foods and colostrum. There was no evidence that the attitudes of the mother, or the infant's father or grandmother influenced actual feeding behavior. The lack of a "negative or neutral attitude" towards breastfeeding in the participants of the current study does, however, diminish the chances to link attitude to feeding behavior

Waist-to-Height Ratio Is More Predictive of Years of Life Lost than Body Mass Index

Objective: Our aim was to compare the effect of central obesity (measured by waist-to-height ratio, WHtR) and total obesity (measured by body mass index, BMI) on life expectancy expressed as years of life lost (YLL), using data on British adults. Methods: A Cox proportional hazards model was applied to data from the prospective Health and Lifestyle Survey (HALS) and the cross sectional Health Survey for England (HSE). The number of years of life lost (YLL) at three ages (30, 50, 70 years) was found by comparing the life expectancies of obese lives with those of lives at optimum levels of BMI and WHtR. Results: Mortality risk associated with BMI in the British HALS survey was similar to that found in US studies. However, WHtR was a better predictor of mortality risk. For the first time, YLL have been quantified for different values of WHtR. This has been done for both sexes separately and for three representative ages. Conclusion: This study supports the simple message ‘‘Keep your waist circumference to less than half your height’’. The use of WHtR in public health screening, with appropriate action, could help add years to life

Quasi-Normal Modes of Stars and Black Holes

Perturbations of stars and black holes have been one of the main topics of relativistic astrophysics for the last few decades. They are of particular importance today, because of their relevance to gravitational wave astronomy. In this review we present the theory of quasi-normal modes of compact objects from both the mathematical and astrophysical points of view. The discussion includes perturbations of black holes (Schwarzschild, Reissner-Nordstr\"om, Kerr and Kerr-Newman) and relativistic stars (non-rotating and slowly-rotating). The properties of the various families of quasi-normal modes are described, and numerical techniques for calculating quasi-normal modes reviewed. The successes, as well as the limits, of perturbation theory are presented, and its role in the emerging era of numerical relativity and supercomputers is discussed.Comment: 74 pages, 7 figures, Review article for "Living Reviews in Relativity

Regulation of Ubx Expression by Epigenetic Enhancer Silencing in Response to Ubx Levels and Genetic Variation

For gene products that must be present in cells at defined concentrations, expression levels must be tightly controlled to ensure robustness against environmental, genetic, and developmental noise. By studying the regulation of the concentration-sensitive Drosophila melanogaster Hox gene Ultrabithorax (Ubx), we found that Ubx enhancer activities respond to both increases in Ubx levels and genetic background. Large, transient increases in Ubx levels are capable of silencing all enhancer input into Ubx transcription, resulting in the complete silencing of this gene. Small increases in Ubx levels, brought about by duplications of the Ubx locus, cause sporadic silencing of subsets of Ubx enhancers. Ubx enhancer silencing can also be induced by outcrossing laboratory stocks to D. melanogaster strains established from wild flies from around the world. These results suggest that enhancer activities are not rigidly determined, but instead are sensitive to genetic background. Together, these findings suggest that enhancer silencing may be used to maintain gene product levels within the correct range in response to natural genetic variation

The relationship between body size and mortality in the linked Scottish Health Surveys: cross-sectional surveys with follow-up

Objective: To investigate the relationship between body mass index (BMI), waist circumference (WC) or waist–hip ratio (WHR) and all-cause mortality or cause-specific mortality. Design: Cross-sectional surveys linked to hospital admissions and death records. Subjects: In total, 20 117 adults (aged 18–86 years) from a nationally representative sample of the Scottish population. Measurements: Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause, or cause-specific, mortality. The three anthropometric measurements BMI, WC and WHR were the main variables of interest. The following were adjustment variables: age, gender, smoking status, alcohol consumption, survey year, social class and area of deprivation. Results: BMI-defined obesity (greater than or equal to30 kg m−2) was not associated with increased risk of mortality (HR=0.93; 95% confidence interval=0.80–1.08), whereas the overweight category (25–&#60;30 kg m−2) was associated with a decreased risk (0.80; 0.70–0.91). In contrast, the HR for a high WC (mengreater than or equal to102 cm, womengreater than or equal to88 cm) was 1.17 (1.02–1.34) and a high WHR (mengreater than or equal to1, women&#8805;0.85) was 1.34 (1.16–1.55). There was an increased risk of cardiovascular disease (CVD) mortality associated with BMI-defined obesity, a high WC and a high WHR categories; the HR estimates for these were 1.36 (1.05–1.77), 1.41 (1.11–1.79) and 1.44 (1.12–1.85), respectively. A low BMI (&#60;18.5 kg m−2) was associated with elevated HR for all-cause mortality (2.66; 1.97–3.60), for chronic respiratory disease mortality (3.17; 1.39–7.21) and for acute respiratory disease mortality (11.68; 5.01–27.21). This pattern was repeated for WC but not for WHR. Conclusions: It might be prudent not to use BMI as the sole measure to summarize body size. The alternatives WC and WHR may more clearly define the health risks associated with excess body fat accumulation. The lack of association between elevated BMI and mortality may reflect the secular decline in CVD mortality.</p

The C. elegans H3K27 Demethylase UTX-1 Is Essential for Normal Development, Independent of Its Enzymatic Activity

Epigenetic modifications influence gene expression and provide a unique mechanism for fine-tuning cellular differentiation and development in multicellular organisms. Here we report on the biological functions of UTX-1, the Caenorhabditis elegans homologue of mammalian UTX, a histone demethylase specific for H3K27me2/3. We demonstrate that utx-1 is an essential gene that is required for correct embryonic and postembryonic development. Consistent with its homology to UTX, UTX-1 regulates global levels of H3K27me2/3 in C. elegans. Surprisingly, we found that the catalytic activity is not required for the developmental function of this protein. Biochemical analysis identified UTX-1 as a component of a complex that includes SET-16(MLL), and genetic analysis indicates that the defects associated with loss of UTX-1 are likely mediated by compromised SET-16/UTX-1 complex activity. Taken together, these results demonstrate that UTX-1 is required for many aspects of nematode development; but, unexpectedly, this function is independent of its enzymatic activity

A self-rating scale for patient-perceived side effects of inhaled corticosteroids

BACKGROUND: Patient-reported side effect questionnaires offer a simple method for the systematic measurement of drug-related side effects. In order to measure patients' inhaled corticosteroids (ICS) related side effect perceptions the 14-day retrospective Inhaled Corticosteroid Questionnaire (ICQ) was developed. In this research we aim to assess the construct validity and reliability of the ICQ and test its responsiveness to dose changes in adult asthma patients. METHODS: In a cross-sectional study, current inhaler users with asthma completed the ICQ (27 with non ICS inhaler; 61 BDP equivalent daily ICS low dose ≤400 μg; 62 mid dose 401–800 μg; and 105 with high dose >800 μg). We generated 3 construct validity hypotheses: 1) a hierarchical dose-response pattern for scoring of the individual items on the ICQ, and statistically significant differences in the scores of each of the 15 ICQ domains by ICS dose group 2) an association between ICS dose and ICQ scoring after adjusting for appropriate confounders in multiple regression; 3) greater convergence between local side effect domains than between systemic and local domains of the scale. Test-retest reliability was assessed on a randomly selected subgroup of patients (n = 73) who also completed the ICQ a second time after 7 days. In a separate longitudinal study, 61 patients with asthma completed the ICQ at baseline and after changing their daily ICS dose, at 2- and 6- months, in order to test the ICQ's responsiveness. RESULTS: All three construct validity hypotheses were well supported: 1) a statistically significant difference existed in scores for 14 domains, the high ICS dose group scoring highest; 2) ICS dose independently predicted ICQ scoring after adjusting for confounders; 3) greater convergence existed between local ICQ domains than between local and systemic domains. The ICQ had good reproducibility: test-retest intraclass correlation coefficients were ≥0.69 for all but the 'Facial Oedema' domain. In the longitudinal study, ICQ scores for 'Voice Problems' changed significantly at 2- and 6-months from baseline and other ICQ domains displayed trends in scoring change accordant with dose modulation at 6-months. CONCLUSION: The ICQ has good dose-related discriminative properties, is valid, reliable, and shows potential responsiveness to ICS dose change