36391510
Effect of histamine infusion on circulating methionine-enkephalin and catecholamine concentrations
In 5 normal adult men, histamine was infused i.v. for 5 min at 20 micrograms/kg/h and at 80 micrograms/kg/h on two occasions one week apart. Diastolic blood pressure fell and heart rate, plasma adrenaline and noradrenaline all rose in a dose-dependent manner, but plasma methionine-enkephalin (Met-Enk) concentrations were unchanged. These results indicate that while Met-Enk may be co-stored with catecholamines (CAs) in the adrenal medulla in at least this paradigm, circulating concentrations of CAs may be altered without similar changes in plasma Met-Enk immunoreactivity.
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.
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?
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.
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.
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.
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.
31702390
The role of 'reference goods' in contingent valuation: should we help respondents to 'construct' their willingness to pay?
A general population sample of 135 Australian respondents completed one of four contingent valuation surveys that asked them to value health benefits either in the absence of an explicit reference good or in the presence of one of three different forms of reference good. Results suggest that respondents have a 'ball-park' figure that is then challenged by the reference good. For values that appear far lower than, or similar to, this 'ball-park' figure, the reference good has little quantitative effect, but qualitatively appears to help respondents in their confidence in this value being their actual WTP. The implications for CV research in health care are outlined in the discussion.
23464544
A macroeconomic approach to evaluating policies to contain antimicrobial resistance
BackgroundAntimicrobial resistance (AMR) is, at least in part, associated with high antimicrobial usage and causes increased morbidity, mortality and healthcare costs. However, policies to contain AMR focus on ‘micro’ interventions — typically in one institution (usually a hospital). Furthermore, in evaluating these interventions, economists tend to concentrate on the economic impact to the healthcare sector alone, which may give an incorrect estimation of the social costs and benefits of a disease or intervention.MethodsThis study outlines and illustrates a macroeconomic approach to tackling AMR through the evaluation of three ‘macro’ policies: regulation, permits and taxes/charges. In addition to effects on the healthcare sector, the effect of AMR (and these three policies to contain it) on labour productivity, GDP, household income, government transfers, tax revenues, unemployment, inflation and social services are estimated for the UK using the specific context of methicillin-resistant Staphylococcus aureus (MRSA).ResultsAMR is likely to have a far greater impact on the national economy than would be estimated by concentrating on the healthcare sector alone.ConclusionThe permit system appears to offer the most efficient ‘solution’ to optimising antimicrobial consumption and, hence, reducing the development of resistance.
27343241
Novel algorithms and the benefits of comparative validation
Contact: 2robsmith@gmail.com, jtprince@chem.byu.edu Bioinformatic research has produced a large volume of proposed algorithmic solutions to a host of problems. Whether presented as a processing step in a clinical experiment or treated in a stand-alone publication, novel bioinformatic algorithms are often not subjected to the thorough comparative evaluation endured by their counterparts in other closely related fields—such as computer science—where an algorithm unevaluated against extant methods is considered unpublishable. Two audiences are interested in algorithmic publications: the practitioner, who may use the algorithm, and the researcher, who will work to develop solutions superior to those extant. We argue that failure during the review/publication process to require comparative evaluation for novel algorithms is detrimental to both parties. To demonstrate the dilemma, we conducted a case study of novel LC-MS alignment algorithms. Of the 48 publications from 2001 to 2012 that present alignment algorithms of which we are aware, 60% include no comparison to other methods. Another 20%
15592441
Genomics knowledge and equity: a global public goods perspective of the patent system.
Genomics, the comprehensive examination of an organism's entire set of genes and their interactions, will have a major impact on the way disease is diagnosed, prevented and treated in the new millennium. Despite the tremendous potential it holds for improving global health, genomics challenges policy-makers to ensure that its benefits are harnessed equitably across populations and nations. The classification of genomics as a global public good and the inequity encountered in the development and application of genomics knowledge are outlined in this paper, We examine the effect of the current patent system on the distribution of costs and benefits relating to genomics knowledge between countries of different economic strength. The global public goods concept provides a normative economic rationale for the modification of certain aspects of the current patent system and for the creation of complementary mechanisms to respond to the health needs of low-income and middle-income countries.