Gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodelling

Aims: Pathological cardiac remodelling is characterized by cardiomyocyte (CM) hypertrophy and fibroblast activation, which can ultimately lead to maladaptive hypertrophy and heart failure (HF). Genome-wide expression analysis on heart tissue has been instrumental for the identification of molecular mechanisms at play. However, these data were based on signals derived from all cardiac cell types. Here, we aimed for a more detailed view on molecular changes driving maladaptive CM hypertrophy to aid in the development of therapies to reverse pathological remodelling. Methods and results: Utilizing CM-specific reporter mice exposed to pressure overload by transverse aortic banding and CM isolation by flow cytometry, we obtained gene expression profiles of hypertrophic CMs in the more immediate phase after stress, and CMs showing pathological hypertrophy. We identified subsets of genes differentially regulated and specific for either stage. Among the genes specifically up-regulated in the CMs during the maladaptive phase we found known stress markers, such as Nppb and Myh7, but additionally identified a set of genes with unknown roles in pathological hypertrophy, including the platelet isoform of phosphofructokinase (PFKP). Norepinephrine-angiotensin II treatment of cultured human CMs induced the secretion of N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP) and recapitulated the up-regulation of these genes, indicating conservation of the up-regulation in failing CMs. Moreover, several genes induced during pathological hypertrophy were also found to be increased in human HF, with their expression positively correlating to the known stress markers NPPB and MYH7. Mechanistically, suppression of Pfkp in primary CMs attenuated stress-induced gene expression and hypertrophy, indicating that Pfkp is an important novel player in pathological remodelling of CMs. Conclusion: Using CM-specific transcriptomic analysis, we identified novel genes induced during pathological hypertrophy that are relevant for human HF, and we show that PFKP is a conserved failure-induced gene that can modulate the CM stress response

Hypothermia predicts mortality in critically ill elderly patients with sepsis

<p>Abstract</p> <p>Background</p> <p>Advanced age is one of the factors that increase mortality in intensive care. Sepsis and multi-organ failure are likely to further increase mortality in elderly patients.</p> <p>We compared the characteristics and outcomes of septic elderly patients (> 65 years) with younger patients (≤ 65 years) and identified factors during the first 24 hours of presentation that could predict mortality in elderly patients.</p> <p>Methods</p> <p>This study was conducted in a Level III intensive care unit with a case mix of medical and surgical patients excluding cardiac and neurosurgical patients.</p> <p>We performed a retrospective review of all septic patients admitted to our ICU between July 2004 and May 2007. In addition to demographics and co-morbidities, physiological and laboratory variables were analysed to identify early predictors of mortality in elderly patients with sepsis.</p> <p>Results</p> <p>Of 175 patients admitted with sepsis, 108 were older than 65 years. Elderly patients differed from younger patients with regard to sex, temperature (37.2°C VS 37.8°C p < 0.01), heart rate, systolic blood pressure, pH, HCO₃, potassium, urea, creatinine, APACHE III and SAPS II. The ICU and hospital mortality was significantly higher in elderly patients (10.6% Vs 23.14% (p = 0.04) and 19.4 Vs 35.1 (p = 0.02) respectively). Elderly patients who died in hospital had a significant difference in pH, HCO₃, mean blood pressure, potassium, albumin, organs failed, lactate, APACHE III and SAPS II compared to the elderly patients who survived while the mean age and co-morbidities were comparable. Logistic regression analysis identified temperature (OR [per degree centigrade decrease] 0.51; 95% CI 0.306- 0.854; p = 0.010) and SAPS II (OR [per point increase]: 1.12; 95% CI 1.016-1.235; p = 0.02) during the first 24 hours of admission to independently predict increased hospital mortality in elderly patients.</p> <p>Conclusions</p> <p>The mortality in elderly patients with sepsis is higher than the younger patients. Temperature (hypothermia) and SAPS II scores during the first 24 hours of presentation independently predict hospital mortality.</p

The Ups and Downs of Mutation Frequencies during Aging Can Account for the Apert Syndrome Paternal Age Effect

Apert syndrome is almost always caused by a spontaneous mutation of paternal origin in one of two nucleotides in the fibroblast growth factor receptor 2 gene (FGFR2). The incidence of this disease increases with the age of the father (paternal age effect), and this increase is greater than what would be expected based on the greater number of germ-line divisions in older men. We use a highly sensitive PCR assay to measure the frequencies of the two causal mutations in the sperm of over 300 normal donors with a wide range of ages. The mutation frequencies increase with the age of the sperm donors, and this increase is consistent with the increase in the incidence rate. In both the sperm data and the birth data, the increase is non-monotonic. Further, after normalizing for age, the two Apert syndrome mutation frequencies are correlated within individual sperm donors. We consider a mathematical model for germ-line mutation which reproduces many of the attributes of the data. This model, with other evidence, suggests that part of the increase in both the sperm data and the birth data is due to selection for mutated premeiotic cells. It is likely that a number of other genetic diseases have similar features

MSH3 polymorphisms and protein levels affect CAG repeat instability in huntington's disease mice

Expansions of trinucleotide CAG/CTG repeats in somatic tissues are thought to contribute to ongoing disease progression through an affected individual's life with Huntington's disease or myotonic dystrophy. Broad ranges of repeat instability arise between individuals with expanded repeats, suggesting the existence of modifiers of repeat instability. Mice with expanded CAG/CTG repeats show variable levels of instability depending upon mouse strain. However, to date the genetic modifiers underlying these differences have not been identified. We show that in liver and striatum the R6/1 Huntington's disease (HD) (CAG)~100 transgene, when present in a congenic C57BL/6J (B6) background, incurred expansion-biased repeat mutations, whereas the repeat was stable in a congenic BALB/cByJ (CBy) background. Reciprocal congenic mice revealed the Msh3 gene as the determinant for the differences in repeat instability. Expansion bias was observed in congenic mice homozygous for the B6 Msh3 gene on a CBy background, while the CAG tract was stabilized in congenics homozygous for the CBy Msh3 gene on a B6 background. The CAG stabilization was as dramatic as genetic deficiency of Msh2. The B6 and CBy Msh3 genes had identical promoters but differed in coding regions and showed strikingly different protein levels. B6 MSH3 variant protein is highly expressed and associated with CAG expansions, while the CBy MSH3 variant protein is expressed at barely detectable levels, associating with CAG stability. The DHFR protein, which is divergently transcribed from a promoter shared by the Msh3 gene, did not show varied levels between mouse strains. Thus, naturally occurring MSH3 protein polymorphisms are modifiers of CAG repeat instability, likely through variable MSH3 protein stability. Since evidence supports that somatic CAG instability is a modifier and predictor of disease, our data are consistent with the hypothesis that variable levels of CAG instability associated with polymorphisms of DNA repair genes may have prognostic implications for various repeat-associated diseases

Symptoms of anxiety and depression are related to cardiovascular responses to active, but not passive, coping tasks

Objective: Anxiety and depression have been linked to blunted blood pressure (BP) and heart rate (HR) reactions to mental stress tests; however, most studies have not included indices of underlying hemodynamics nor multiple stress tasks. This study sought to examine the relationships of anxiety and depression with hemodynamic responses to acute active and passive coping tasks. Methods: A total of 104 participants completed the Hospital Anxiety and Depression Scales and mental arithmetic, speech, and cold pressor tasks while BP, HR, total peripheral resistance, and cardiac output (CO) were assessed. Results: After adjustment for traditional risk factors and baseline cardiovascular activity, depression scores were negatively associated with systolic BP, HR, and CO responses to the mental arithmetic task, while anxiety scores were inversely related to the systolic BP response to mental arithmetic. Conclusion: High anxiety or depression scores appear to be associated with blunted cardiac reactions to mental arithmetic (an active coping task), but not to the cold pressor test or speech tasks. Future research should further examine potential mechanisms and longitudinal pathways relating depression and anxiety to cardiovascular reactivity

Assessing Quality of Care of Elderly Patients Using the ACOVE Quality Indicator Set: A Systematic Review

Background: Care of the elderly is recognized as an increasingly important segment of health care. The Assessing Care Of Vulnerable Elderly (ACOVE) quality indicators (QIs) were developed to assess and improve the care of elderly patients. Objectives: The purpose of this review is to summarize studies that assess the quality of care using QIs from or based on ACOVE, in order to evaluate the state of quality of care for the reported conditions. Methods: We systematically searched MEDLINE, EMBASE and CINAHL for English-language studies indexed by February 2010. Articles were included if they used any ACOVE QIs, or adaptations thereof, for assessing the quality of care. Included studies were analyzed and relevant information was extracted. We summarized the results of these studies, and when possible generated an overall conclusion about the quality of care as measured by ACOVE for each condition, in various settings, and for each QI. Results: Seventeen studies were included with 278 QIs (original, adapted or newly developed). The quality scores showed large variation between and within conditions. Only a few conditions showed a stable pass rate range over multiple studies. Overall, pass rates for dementia (interquartile range (IQR): 11%-35%), depression (IQR: 27%-41%), osteoporosis (IQR: 34%-43%) and osteoarthritis (IQR: 29-41%) were notably low. Medication management and use (range: 81%-90%), hearing loss (77%-79%) and continuity of care (76%-80%) scored higher than other conditions. Out of the 278 QIs, 141 (50%) had mean pass rates below 50% and 121 QIs (44%) had pass rates above 50%. Twenty-three percent of the QIs scored above 75%, and 16% scored below 25%. Conclusions: Quality of care per condition varies markedly across studies. Although there has been much effort in improving the care for elderly patients in the last years, the reported quality of care according to the ACOVE indicators is still relatively lo

A Validated Model of Serum Anti-Müllerian Hormone from Conception to Menopause

Background Anti-Müllerian hormone (AMH) is a product of growing ovarian follicles. The concentration of AMH in blood may also reflect the non-growing follicle (NGF) population, i.e. the ovarian reserve, and be of value in predicting reproductive lifespan. A full description of AMH production up to the menopause has not been previously reported. Methodology/Principal Findings By searching the published literature for AMH concentrations in healthy pre-menopausal females, and using our own data (combined ) we have generated and robustly validated the first model of AMH concentration from conception to menopause. This model shows that 34% of the variation in AMH is due to age alone. We have shown that AMH peaks at age 24.5 years, followed by a decline to the menopause. We have also shown that there is a neonatal peak and a potential pre-pubertal peak. Our model allows us to generate normative data at all ages. Conclusions/Significance These data highlight key inflection points in ovarian follicle dynamics. This first validated model of circulating AMH in healthy females describes a transition period in early adulthood, after which AMH reflects the progressive loss of the NGF pool. The existence of a neonatal increase in gonadal activity is confirmed for females. An improved understanding of the relationship between circulating AMH and age will lead to more accurate assessment of ovarian reserve for the individual woman.Publisher PDFPeer reviewe

A cross-sectional study of self-reported chemical-related sensitivity is associated with gene variants of drug-metabolizing enzymes

BACKGROUND: N-acetyltransferases (NAT) and glutathione S-transferases (GST) are involved in the metabolism of several ubiquitous chemical substances leading to the activation and detoxification of carcinogenic heterocyclic and aromatic amines. Since polymorphisms within these genes are described to influence the metabolism of ubiquitous chemicals, we conducted the present study to determine if individuals with self-reported chemical-related sensitivity differed from controls without self-reported chemical-related sensitivity with regard to the distribution of genotype frequencies of NAT2, GSTM1, GSTT1, and GSTP1 polymorphisms. METHODS: Out of 800 subjects who answered a questionnaire of ten items with regard to their severity of chemical sensitivity 521 unrelated individuals agreed to participate in the study. Subsequently, genetic variants of the NAT2, GSTM1, GSTT1, and GSTP1 genes were analyzed. RESULTS: The results show significant differences between individuals with and without self-reported chemical-related sensitivity with regard to the distribution of NAT2, GSTM1, and GSTT1 gene variants. Cases with self-reported chemical-related sensitivity were significantly more frequently NAT2 slow acetylators (controlled OR = 1.81, 95% CI = 1.27–2.59, P = 0.001). GSTM1 and GSTT1 genes were significantly more often homozygously deleted in those individuals reporting sensitivity to chemicals compared to controls (GSTM1: controlled OR 2.08, 95% CI = 1.46–2.96, P = 0.0001; GSTT1: controlled OR = 2.80, 95% CI = 1.65–4.75, P = 0.0001). Effects for GSTP1 gene variants were observed in conjunction with GSTM1, GSTT1 and NAT2 gene. CONCLUSION: The results from our study population show that individuals being slow acetylators and/or harbouring a homozygous GSTM1 and/or GSTT1 deletion reported chemical-related hypersensitivity more frequently