Haptoglobin genotype predicts development of coronary artery calcification in a prospective cohort of patients with type 1 diabetes

<p>Abstract</p> <p>Background</p> <p>Coronary artery disease has been linked with genotypes for haptoglobin (Hp) which modulates extracorpuscular hemoglobin. We hypothesized that the Hp genotype would predict progression of coronary artery calcification (CAC), a marker of subclinical atherosclerosis.</p> <p>Methods</p> <p>CAC was measured three times in six years among 436 subjects with type 1 diabetes and 526 control subjects participating in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. Hp typing was performed on plasma samples by polyacrylamide gel electrophoresis.</p> <p>Results</p> <p>The Hp 2-2 genotype predicted development of significant CAC only in subjects with diabetes who were free of CAC at baseline (OR: 1.95, 95% CI: 1.07-3.56, p = 0.03), compared to those without the Hp 2-2 genotype, controlling for age, sex, blood pressure and HDL-cholesterol. Hp 2 appeared to have an allele-dose effect on development of CAC. Hp genotype did not predict CAC progression in individuals without diabetes.</p> <p>Conclusions</p> <p>Hp genotype may aid prediction of accelerated coronary atherosclerosis in subjects with type 1 diabetes.</p

Identification of a Conserved Anti-Apoptotic Protein That Modulates the Mitochondrial Apoptosis Pathway

Here we identified an evolutionarily highly conserved and ubiquitously expressed protein (C9orf82) that shows structural similarities to the death effector domain of apoptosis-related proteins. RNAi knockdown of C9orf82 induced apoptosis in A-549 and MCF7/casp3-10b lung and breast carcinoma cells, respectively, but not in cells lacking caspase-3, caspase-10 or both. Apoptosis was associated with activated caspases-3, -8, -9 and -10, and inactivation of caspases 10 or 3 was sufficient to block apoptosis in this pathway. Apoptosis upon knockdown of C9orf82 was associated with increased caspase-10 expression and activation, which was required for the generation of an 11 kDa tBid fragment and activation of Caspase-9. These data suggest that C9orf82 functions as an anti-apoptotic protein that modulates a caspase-10 dependent mitochondrial caspase-3/9 feedback amplification loop. We designate this ubiquitously expressed and evolutionarily conserved anti-apoptotic protein Conserved Anti-Apoptotic Protein (CAAP). We also demonstrated that treatment of MCF7/casp3-10b cells with staurosporine and etoposides induced apoptosis and knockdown of CAAP expression. This implies that the CAAP protein could be a target for chemotherapeutic agents

Volume Density, Distribution, and Ultrastructure of Secretory and Basolateral Membranes and Mitochondria Predict Parietal Cell Secretory (Dys)function

Acid secretion in gastric parietal cells requires highly coordinated membrane transport and vesicle trafficking. Histologically, consensus defines acid secretion as the ratio of the volume density (Vd) of canalicular and apical membranes (CAMs) to tubulovesicular (TV) membranes, a value which varies widely under normal conditions. Examination of numerous achlorhydric mice made it clear that this paradigm is discrepant when used to assess most mice with genetic mutations affecting acid secretion. Vd of organelles in parietal cells of 6 genetically engineered mouse strains was obtained to identify a stable histological phenotype of acid secretion. We confirmed that CAM to TV ratio fairly represented secretory activity in untreated and secretion-inhibited wild-type (WT) mice and in NHE2−/− mice as well, though the response was significantly attenuated in the latter. However, high CAM to TV ratios wrongly posed as active acid secretion in AE2−/−, GHKAα−/−, and NHE4−/− mice. Achlorhydric genotypes also had a significantly higher Vd of basolateral membrane than WT mice, and reduced Vd of mitochondria and canaliculi. The Vd of mitochondria, and ratio of the Vd of basolateral membranes/Vd of mitochondria were preferred predictors of the level of acid secretion. Alterations in acid secretion, then, cause significant changes not only in the Vd of secretory membranes but also in mitochondria and basolateral membranes

25-Hydroxyvitamin D Depletion Does Not Exacerbate MPTP-Induced Dopamine Neuron Damage in Mice

Recent clinical evidence supports a link between 25-hydroxyvitamin D insufficiency (serum 25-hydroxyvitamin D [25(OH)D] levels <30 ng/mL) and Parkinson’s disease. To investigate the effect of 25(OH)D depletion on neuronal susceptibility to toxic insult, we induced a state of 25(OH)D deficiency in mice and then challenged them with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We found there was no significant difference between control and 25(OH)D-deficient animals in striatal dopamine levels or dopamine transporter and tyrosine hydroxylase expression after lesioning with MPTP. Additionally, we found no difference in tyrosine hydroxylase expression in the substantia nigra pars compacta. Our data suggest that reducing 25(OH)D serum levels in mice has no effect on the vulnerability of nigral dopaminergic neurons in vivo in this model system of parkinsonism

QCD at small x and nucleus-nucleus collisions

At large collision energy sqrt(s) and relatively low momentum transfer Q, one expects a new regime of Quantum Chromo-Dynamics (QCD) known as "saturation". This kinematical range is characterized by a very large occupation number for gluons inside hadrons and nuclei; this is the region where higher twist contributions are as large as the leading twist contributions incorporated in collinear factorization. In this talk, I discuss the onset of and dynamics in the saturation regime, some of its experimental signatures, and its implications for the early stages of Heavy Ion Collisions.Comment: Plenary talk given at QM2006, Shanghai, November 2006. 8 pages, 8 figure

Hydration and nutrition care practices in stroke: findings from the UK and Australia

BACKGROUND: Dehydration and malnutrition are common in hospitalised patients following stroke leading to poor outcomes including increased mortality. Little is known about hydration and nutrition care practices in hospital to avoid dehydration or malnutrition, and how these practices vary in different countries. This study sought to capture how the hydration and nutrition needs of patients' post-stroke are assessed and managed in the United Kingdom (UK) and Australia (AUS).AIM: To examine and compare current in-hospital hydration and nutrition care practice for patients with stroke in the UK and Australia.METHODS: A cross-sectional survey was conducted between April and November 2019. Questionnaires were mailed to stroke specialist nurses in UK and Australian hospitals providing post-stroke inpatient acute care or rehabilitation. Non-respondents were contacted up to five times.RESULTS: We received 150/174 (86%) completed surveys from hospitals in the UK, and 120/162 (74%) in Australia. Of the 270 responding hospitals, 96% reported undertaking assessment of hydration status during an admission, with nurses most likely to complete assessments (85%). The most common methods of admission assessment were visual assessment of the patient (UK 62%; AUS 58%), weight (UK 52%; AUS 52%), and body mass index (UK 47%; AUS 42%). Almost all (99%) sites reported that nutrition status was assessed at some point during admission, and these were mainly completed by nurses (91%). Use of standardised nutrition screening tools were more common in the UK (91%) than Australia (60%). Similar proportions of hydration management decisions were made by physicians (UK 84%; AUS 83%), and nutrition management decisions by dietitians (UK 98%; AUS 97%).CONCLUSION: Despite broadly similar hydration and nutrition care practices after stroke in the UK and Australia, some variability was identified. Although nutrition assessment was more often informed by structured screening tools, the routine assessment of hydration was generally not. Nurses were responsible for assessment and monitoring, while dietitians and physicians undertook decision-making regarding management. Hydration care could be improved through the development of standardised assessment tools. This study highlights the need for increased implementation and use of evidence-based protocols in stroke hydration and nutrition care to improve patient outcomes.</p

Histone Acetylation-Mediated Regulation of the Hippo Pathway

The Hippo pathway is a signaling cascade recently found to play a key role in tumorigenesis therefore understanding the mechanisms that regulate it should open new opportunities for cancer treatment. Available data indicate that this pathway is controlled by signals from cell-cell junctions however the potential role of nuclear regulation has not yet been described. Here we set out to verify this possibility and define putative mechanism(s) by which it might occur. By using a luciferase reporter of the Hippo pathway, we measured the effects of different nuclear targeting drugs and found that chromatin-modifying agents, and to a lesser extent certain DNA damaging drugs, strongly induced activity of the reporter. This effect was not mediated by upstream core components (i.e. Mst, Lats) of the Hippo pathway, but through enhanced levels of the Hippo transducer TAZ. Investigation of the underlying mechanism led to the finding that cancer cell exposure to histone deacetylase inhibitors induced secretion of growth factors and cytokines, which in turn activate Akt and inhibit the GSK3 beta associated protein degradation complex in drug-affected as well as in their neighboring cells. Consequently, expression of EMT genes, cell migration and resistance to therapy were induced. These processes were suppressed by using pyrvinium, a recently described small molecule activator of the GSK 3 beta associated degradation complex. Overall, these findings shed light on a previously unrecognized phenomenon by which certain anti-cancer agents may paradoxically promote tumor progression by facilitating stabilization of the Hippo transducer TAZ and inducing cancer cell migration and resistance to therapy. Pharmacological targeting of the GSK3 beta associated degradation complex may thus represent a unique approach to treat cancer. © 2013 Basu et al

Palliative care in UK prisons: practical and emotional challenges for staff and fellow prisoners

Despite falling crime rates in England and Wales over the past 20 years, the number of prisoners has doubled. People over the age of 50 constitute the fastest growing section of the prison population, and increasing numbers of older prisoners are dying in custody. This article discusses some of the issues raised by these changing demographics and draws on preliminary findings from a study underway in North West England. It describes the context behind the rise in the numbers of older prisoners; explores the particular needs of this growing population; and discusses some of the practical and emotional challenges for prison officers, health care staff, and fellow prisoners who are involved in caring for dying prisoners in a custodial environment

Bodyweight Perceptions among Texas Women: The Effects of Religion, Race/Ethnicity, and Citizenship Status

Despite previous work exploring linkages between religious participation and health, little research has looked at the role of religion in affecting bodyweight perceptions. Using the theoretical model developed by Levin et al. (Sociol Q 36(1):157–173, 1995) on the multidimensionality of religious participation, we develop several hypotheses and test them by using data from the 2004 Survey of Texas Adults. We estimate multinomial logistic regression models to determine the relative risk of women perceiving themselves as overweight. Results indicate that religious attendance lowers risk of women perceiving themselves as very overweight. Citizenship status was an important factor for Latinas, with noncitizens being less likely to see themselves as overweight. We also test interaction effects between religion and race. Religious attendance and prayer have a moderating effect among Latina non-citizens so that among these women, attendance and prayer intensify perceptions of feeling less overweight when compared to their white counterparts. Among African American women, the effect of increased church attendance leads to perceptions of being overweight. Prayer is also a correlate of overweight perceptions but only among African American women. We close with a discussion that highlights key implications from our findings, note study limitations, and several promising avenues for future research

Generalization of DNA microarray dispersion properties: microarray equivalent of t-distribution

BACKGROUND: DNA microarrays are a powerful technology that can provide a wealth of gene expression data for disease studies, drug development, and a wide scope of other investigations. Because of the large volume and inherent variability of DNA microarray data, many new statistical methods have been developed for evaluating the significance of the observed differences in gene expression. However, until now little attention has been given to the characterization of dispersion of DNA microarray data. RESULTS: Here we examine the expression data obtained from 682 Affymetrix GeneChips(® )with 22 different types and we demonstrate that the Gaussian (normal) frequency distribution is characteristic for the variability of gene expression values. However, typically 5 to 15% of the samples deviate from normality. Furthermore, it is shown that the frequency distributions of the difference of expression in subsets of ordered, consecutive pairs of genes (consecutive samples) in pair-wise comparisons of replicate experiments are also normal. We describe a consecutive sampling method, which is employed to calculate the characteristic function approximating standard deviation and show that the standard deviation derived from the consecutive samples is equivalent to the standard deviation obtained from individual genes. Finally, we determine the boundaries of probability intervals and demonstrate that the coefficients defining the intervals are independent of sample characteristics, variability of data, laboratory conditions and type of chips. These coefficients are very closely correlated with Student's t-distribution. CONCLUSION: In this study we ascertained that the non-systematic variations possess Gaussian distribution, determined the probability intervals and demonstrated that the K(α )coefficients defining these intervals are invariant; these coefficients offer a convenient universal measure of dispersion of data. The fact that the K(α )distributions are so close to t-distribution and independent of conditions and type of arrays suggests that the quantitative data provided by Affymetrix technology give "true" representation of physical processes, involved in measurement of RNA abundance. REVIEWERS: This article was reviewed by Yoav Gilad (nominated by Doron Lancet), Sach Mukherjee (nominated by Sandrine Dudoit) and Amir Niknejad and Shmuel Friedland (nominated by Neil Smalheiser)