23247928
Unexplained antepartum stillbirth: a consequence of placental aging?
Unexplained antepartum stillbirth is a major obstetric health problem. Data demonstrate a rapid rise in risk per 1000 continuing pregnancies as gestation advances beyond 40 weeks. We review the evidence that such stillbirths are a consequence of aging related changes in the late gestation placenta. We suggest that the relatively small number of continuing pregnancies after 40 completed weeks means that negative effects of genes that produce aging affect so few pregnancies that polymorphisms in genes that produce these effects are retained in the population. Aging related changes likely represent a consequence of the damaging effects of oxidative stress, increased by cigarette smoking counteracted by the mitigating effects of oxidative defence pathways. The aging related changes are likely downstream from nutrient sensing units such as mTOR and include effects on production of telomerase and consequent shortening of telomere length. The late gestation changes occur in the context of increasing fetal growth and nutrient supply demands that can produce the rapid development of a mismatch between placental supply and fetal need resulting in fetal demise. Premature aging may also play an important role in antepartum stillbirth occurring earlier in pregnancy, especially in the context of growth restriction.
7050862
The placenta, a transducer linking maternal nutrition to adult disease in the offspring?
This month’s Journal carries an article from Shanghai on the regulation of glucose transporters (GLUT) in humanplacenta(1).Thestudiesbringapossiblenewplayer into the ongoing drama of nutritional regulation of fetal growth and development. The in vitro studies by Gao et al. (1) examined the effects of CRH on mRNA and protein concentrations of GLUT1 and GLUT3. Using a variety of techniques, including small interfering RNA for the corticotrophin releasing hormone receptor type 1 (CRH-R1) receptor, antibodies to the receptor, and receptor blockers, the studies convincingly show that CRH stimulates trophoblast production of GLUT1 and inhibits the expression of GLUT3 via the CRH-R1 receptor. The area is of increasing interest as data accumulate that fetal growth is an important determinant of adult health. The Barker hypothesis posits that restricted intrauterine growth associated with the birth of a small infant leads to early onset diabetes, hypertension, and ischemic heart disease (2). This hypothesis is linked to the concept of phenotypic plasticity, a widespread phenomenon in nature whereby the environment interacts with the genome to determine an organism’s phenotype (3). In the setting of intrauterine growth restriction, it is proposed that impaired nutrient transfer to the fetus leads to the development of a metabolic phenotype that is adapted to an environment low in nutrients. The fetus adapted to low nutrients that is then born into a Western society with high-energy diets is maladapted, develops obesity, diabetes, hypertension, and early heart disease. There are strong animal data for this scenario; however, human data are more limited (4). Given the importance of optimizing fetal growth, the pathway to optimal fetal growth becomes of great interest. Unfortunately, this pathway is very poorly characterized. Worldwide, low birth weight is very common, leading to a recent Gates Foundation call for studies on the underlying mechanisms leading to impaired fetal growth (http://www. grandchallenges.org/GCGHDocs/Healthy_Growth_Rules_ and_Guidelines.pdf). Althoughconditions suchaspreeclampsia are well-known associates of impaired growth, there is little knowledge on the etiology of most cases. Major deficiencies in knowledge extend to even what might be the ideal diet for a pregnant woman to produce a healthy baby with an optimum metabolic phenotype for the 21st century. National guidelines for maternal intakes exist, but these are not founded on a sound evidence base of longitudinal studies of infant outcomes (5). Recent research on comparative nutritional intakes of protein, fat, and carbohydrate suggest that all animals have a genetically determined target intake of macronutrients (6). This work strongly suggests that an ideal target intake would exist for pregnant women, but this has not yet been defined. With an ideal maternal intake, the placenta is the port via which this nutrition is transported to the fetus. How exactly this occurs and how it is regulated again remains unclear. Nutrient sensing by the fetus may involve the IGF axis within the fetal liver (7). How is nutrient sensing performed by the placenta on behalf of the fetus? Syncytiotrophoblast expression of GLUT1 is stimulated by placental variant growth hormone, which increases across gestation as does GLUT1; so perhaps again the IGF axis is central (8). How does the placenta determine how much nutrient will be invested in placental growth and how much transferred to the fetus for fetal growth? How does the placenta regulate the nutrient mix it provides to the fetus and is the ideal nutrient mix for the mother the same for the fetus?
3424059
Alterations in the hypothalamic pituitary adrenal axis during pregnancy and the placental clock that determines the length of parturition.
Although corticotrophin releasing hormone (CRH) was initially identified as a hypothalamic peptide it is also synthesised in the placenta and secreted into both the maternal and fetal circulation. The presence of large molecular weight forms in the placenta suggest that secretion may be constitutive rather that regulated. Placental CRH is bioactive but causes only modest increases in ACTH and cortisol in the pregnant woman because of agonist induced desensitisation of pituitary CRH receptors. CRH concentrations increase exponentially in maternal plasma as gestation advances. Elevated concentrations, compared with gestational age matched controls, occur in patients in preterm labour. The exponential curve describing the CRH increase is shifted to the left in women who will subsequently deliver preterm and to the right in women who will deliver post dates indicating that CRH is linked to a placental clock which determines the length of gestation. Maternal plasma CRH concentrations may be useful in identifying women at high risk of preterm delivery and CRH antagonists may prevent preterm labour. As significant CRH production by the placenta is restricted to primates future research must take into account the species specificity of the mechanisms regulating parturition.
35241468
The effect of surgery on plasma beta-endorphin and methionine-enkephalin.
Seven women undergoing abdominal hysterectomy under halothane and nitrous oxide analgesia had plasma samples taken before, during and after surgery for assay of adrenocorticotrophin (ACTH), beta-endorphin, beta-lipotrophin and methionine (Met)-enkephalin immunoreactivity. Plasma ACTH, beta-endorphin and beta-lipotrophin all rose in parallel from the start of surgery and were unaffected by postoperative opiate analgesia. Plasma Met-enkephalin concentrations did not change significantly during the course of the surgery and immediate post-operative period, although the variance of the samples increased at the time of the first skin incision. These data indicate that the stress of surgery and post-operative pain, while producing marked elevations of proopiomelanocortin-derived peptides, are not associated with changes in plasma Met-enkephalin. These data exclude a role for circulating Met-enkephalin in the modulation of surgical pain but do not exclude such a role for beta-endorphin.
21610567
Patterns of plasma corticotropin-releasing hormone, progesterone, estradiol, and estriol change and the onset of human labor.
CONTEXT
Clinical prediction of preterm delivery is largely ineffective, and the mechanism mediating progesterone (P) withdrawal and estrogen activation at the onset of human labor is unclear.


OBJECTIVES
Our objectives were to determine associations of rates of change of circulating maternal CRH in midpregnancy with preterm delivery, CRH with estriol (E3) concentrations in late pregnancy, and predelivery changes in the ratios of E3, estradiol (E2), and P.


DESIGN AND SETTING
A cohort of 500 pregnant women was followed from first antenatal visits to delivery during the period 2000-2004 at John Hunter Hospital, New South Wales, Australia, a tertiary care obstetric hospital.


PATIENTS
Unselected subjects were recruited (including women with multiple gestations) and serial blood samples obtained.


MAIN OUTCOME MEASURES
CRH daily percentage change in term and preterm singletons at 26 wk, ratios E3/E2, P/E3, and P/E2 and the association between E3 and CRH concentrations in the last month of pregnancy (with spontaneous labor onset) were assessed.


RESULTS
CRH percentage daily change was significantly higher in preterm than term singletons at 26 wk (medians 3.09 and 2.73; P = 0.003). In late pregnancy, CRH and E3 concentrations were significantly positively associated (P = 0.003). E3/E2 increased, P/E3 decreased, and P/E2 was unchanged in the month before delivery (medians: E3/E2, 7.04 and 10.59, P < 0.001; P/E3, 1.55 and 0.98, P < 0.001; P/E2, 11.78 and 10.79, P = 0.07).


CONCLUSIONS
The very rapid rise of CRH in late pregnancy is associated with an E3 surge and critically altered P/E3 and E3/E2 ratios that create an estrogenic environment at the onset of labor. Our evidence provides a rationale for the use of CRH in predicting preterm birth and informs approaches to delaying labor using P supplementation.
37019249
Acute hemorrhagic stress in conscious sheep elevates immunoreactive beta-endorphin in plasma but not in cerebrospinal fluid.
The effects of acute hemorrhagic stress on the concentrations of immunoreactive beta-endorphin (IR beta EP) in cerebrospinal fluid (CSF) and blood plasma were investigated in conscious sheep in which the cisterna magna, a carotid artery, and a jugular vein were chronically cannulated. Serial samples of CSF and jugular venous blood were collected before and after acute arterial hemorrhage and in control experiments. Basal concentrations of IR beta EP were higher in plasma than in CSF. Plasma concentrations of cortisol and IR beta EP increased within 45 min of the commencement of hemorrhage and returned to near baseline levels within 2.25 h. The concentrations of cortisol and IR beta EP in plasma observed after hemorrhage were significantly different from those observed in controls (analysis of variance). Neither the molar nor the relative changes from initial concentrations of IR beta EP in CSF were significantly different between hemorrhage-stressed and controls by analysis of variance. These results show that hemorrhagic stress in conscious sheep elevates concentrations of IR beta EP in plasma but not in CSF, indicating that pituitary beta EP secreted into blood does not enter CSF in significant amounts.
23578107
Synaptic dysfunction in Huntington’s disease: a new perspective
Abstract.Huntington’s disease (HD) is caused by a polyglutamine expansion in the protein huntingtin and is characterized by intraneuronal inclusions and widespread neuronal death at the late stage of the disease. In research, most of the emphasis has been on understanding the cell death and its mechanisms. Until recently, it was believed that the vast majority, if not all, of the symptoms in HD are a direct consequence of neurodegeneration. However, increasing evidence shows that subtle alterations in synaptic function could underlie the early symptoms. It is of particular interest to understand the nature of this neuronal dysfunction. Normal huntingtin interacts with various cytoskeletal and synaptic vesicle proteins that are essential for exocytosis and endocytosis. Altered interactions of mutant huntingtin with its associated partners could contribute to abnormal synaptic transmission in HD. This review describes recent advances in understanding synaptic dysfunction in HD.
10131027
Simvastatin Inhibits Glucose Metabolism and Legumain Activity in Human Myotubes
Simvastatin, a HMG-CoA reductase inhibitor, is prescribed worldwide to patients with hypercholesterolemia. Although simvastatin is well tolerated, side effects like myotoxicity are reported. The mechanism for statin-induced myotoxicity is still poorly understood. Reports have suggested impaired mitochondrial dysfunction as a contributor to the observed myotoxicity. In this regard, we wanted to study the effects of simvastatin on glucose metabolism and the activity of legumain, a cysteine protease. Legumain, being the only known asparaginyl endopeptidase, has caspase-like properties and is described to be involved in apoptosis. Recent evidences indicate a regulatory role of both glucose and statins on cysteine proteases in monocytes. Satellite cells were isolated from the Musculus obliquus internus abdominis of healthy human donors, proliferated and differentiated into polynuclear myotubes. Simvastatin with or without mevalonolactone, farnesyl pyrophosphate or geranylgeranyl pyrophosphate were introduced on day 5 of differentiation. After 48 h, cells were either harvested for immunoblotting, ELISA, cell viability assay, confocal imaging or enzyme activity analysis, or placed in a fuel handling system with [14C]glucose or [3H]deoxyglucose for uptake and oxidation studies. A dose-dependent decrease in both glucose uptake and oxidation were observed in mature myotubes after exposure to simvastatin in concentrations not influencing cell viability. In addition, simvastatin caused a decrease in maturation and activity of legumain. Dysregulation of glucose metabolism and decreased legumain activity by simvastatin points out new knowledge about the effects of statins on skeletal muscle, and may contribute to the understanding of the myotoxicity observed by statins.
45170668
The relative sensitivity of willingness-to-pay and time-trade-off to changes in health status: an empirical investigation.
This paper directly compares the relative sensitivity of time-trade-off (TTO) and willingness-to-pay (WTP) values obtained for various levels of change in health status. This was achieved by administering a TTO and WTP survey to a population of 50 subjects, assessing their valuation of various degrees of change in health status. It was found that, overall, WTP is more sensitive than TTO in distinguishing between different dimensions of health at the same nominal level of health status (only four WTP values not significantly different, compared with eight TTO values). In addition, WTP was also more sensitive to differences in quality of life between different levels of health within each dimension (all values significantly different from each other, with TTO yielding three insignificant relationships). These results tentatively suggest, therefore, that WTP seems to be a more sensitive measure of change in health status than TTO.
6543991
Rubabel: wrapping open Babel with Ruby
BackgroundThe number and diversity of wrappers for chemoinformatic toolkits suggests the diverse needs of the chemoinformatic community. While existing chemoinformatics libraries provide a broad range of utilities, many chemoinformaticians find compiled language libraries intimidating, time-consuming, arcane, and verbose. Although high-level language wrappers have been implemented, more can be done to leverage the intuitiveness of object-orientation, the paradigms of high-level languages, and the extensibility of languages such as Ruby. We introduce Rubabel, an intuitive, object-oriented suite of functionality that substantially increases the accessibily of the tools in the Open Babel chemoinformatics library.ResultsRubabel requires fewer lines of code than any other actively developed wrapper, providing better object organization and navigation, and more intuitive object behavior than extant solutions. Moreover, Rubabel provides a convenient interface to the many extensions currently available in Ruby, greatly streamlining otherwise onerous tasks such as creating web applications that serve up Rubabel functionality.ConclusionsRubabel is powerful, intuitive, concise, freely available, cross-platform, and easy to install. We expect it to be a platform of choice for new users, Ruby users, and some users of current solutions.
11081915
Estimating the economic impact of pandemic influenza: An application of the computable general equilibrium model to the UK

 Abstract
 
 There is concern regarding the impact that a global infectious disease pandemic might have, especially the economic impact in the current financial climate. However, preparedness planning concentrates more upon population health and maintaining a functioning health sector than on the wider economic impact. We developed a single country Computable General Equilibrium model to estimate the economic impact of pandemic influenza (PI) and associated policies. While the context for this development was the United Kingdom, there are lessons to be drawn for application of this methodology, as well as indicative results, to other contexts.
 Disease scenarios were constructed from an epidemiological model which estimated case fatality rates (mild, moderate and severe) as 0.06%, 0.18% and 0.35%. A clinical attack rate of 35% was also used to produce influenza scenarios, together with preparedness policies, including antivirals and school closure, and the possible prophylactic absence of workers.
 UK cost estimates (in Sterling) are presented, together with relative percentage impacts applicable to similar large economies. Percentage/cost estimates suggest PI would reduce GDP by 0.3% (£3.5bn), 0.4% (£5bn) and 0.6% (£7.4bn) respectively for the three disease scenarios. However, the impact of PI itself is smaller than disease mitigation policies: combining school closure with prophylactic absenteeism yields percentage/cost effects of 1.1% (£14.7bn), 1.3% (£16.3bn) and 1.4% (£18.5bn) respectively for the three scenarios. Sensitivity analysis shows little variability with changes in disease parameters but notable changes with variations in school closure and prophylactic absenteeism. The most severe sensitivity scenario results in a 2.9% (£37.4bn), 3.2% (£41.4bn) and 3.7% (£47.5bn) loss to GDP respectively for the three scenarios.
 
