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.
11517691
Pathological interactions with the timing of birth and uterine activation.
The physiological processes that regulate the onset of parturition and birth are slowly being elucidated, and the points at which pathology can intervene are becoming more apparent. The data support the view that multiple pathways lead to myometrial activation. The clinical corollary is that combinations of tocolytics that operate via different mechanisms may be more effective than single agents. It may also be necessary to divide preterm labour into groups based on underlying mechanisms and to tailor therapy accordingly.
29843044
Hormone trajectories leading to human birth
The mechanisms regulating human parturition and labor remain unknown. This ignorance is expensive as preterm birth is responsible for 70% of neonatal mortality and 50% of cerebral palsy. Methods for the prediction of preterm birth and treatments for women in preterm labor have poor efficacy reflecting our limited knowledge of the mechanisms involved. Recent research has supported the view that parturition is a cascade of events that commences early in pregnancy and involves the mother, fetus, placenta, membranes, cervix and myometrium. Although a number of the key hormones and proteins involved have been identified, the relationships between these factors in time and tissues remain unclear. Placental production of Corticotropin-releasing hormone (CRH) is proposed as an early event regulating the cascade of events. Central to the onset of parturition will be a mechanism for progesterone withdrawal and estrogen activation in human. Two forms of progesterone receptor with opposing actions exist in the human myometrium. Progesterone receptor A (PR-A) is a dominant negative repressor of progesterone receptor B (PR-B). Preliminary studies strongly support the hypothesis that the onset of human parturition is initiated by rising concentrations of PR-A in the myometrium.
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.
40275488
The nonsuppressibility of plasma cortisol persists after pregnancy.
To determine if normal balance is restored to the hypothalamic-pituitary-adrenal axis after pregnancy, we compared the dexamethasone suppressibility of plasma cortisol in women four days after delivery of their infant, with that of nonpregnant women. Plasma concentrations of cortisol before dexamethasone administration were similar in the post-partum women and in women taking oestrogen contraceptives, but both were higher than in normally cycling women. After dexamethasone, plasma cortisol in the post-partum women was significantly higher than in both oestrogen-taking and normally cycling nonpregnant women. The reduced dexamethasone-suppressibility of plasma cortisol, which is characteristic of pregnancy, extends into the post-partum period.
205100912
Mutant huntingtin interacts with {beta}-tubulin and disrupts vesicular transport and insulin secretion.
Huntington's disease is a severe progressive neurodegenerative disorder caused by a CAG expansion in the IT15 gene, which encodes huntingtin. The disease primarily affects the neostriatum and cerebral cortex and also associates with increased incidence of diabetes. Here, we show that mutant huntingtin disrupts intracellular transport and insulin secretion by direct interference with microtubular beta-tubulin. We demonstrate that mutant huntingtin impairs glucose-stimulated insulin secretion in insulin-producing beta-cells, without altering stored levels of insulin. Using VSVG-YFP, we show that mutant huntingtin retards post-Golgi transport. Moreover, we demonstrate that the speed of insulin vesicle trafficking is reduced. Using immunoprecipitation of mutant and wild-type huntingtin in combination with mass spectrometry, we reveal an enhanced and aberrant interaction between mutant huntingtin and beta-tubulin, implying the underlying mechanism of impaired intracellular transport. Thus, our findings have revealed a novel pathogenetic process by which mutant huntingtin may disrupt hormone exocytosis from beta-cells and possibly impair vesicular transport in any cell that expresses the pathogenic protein.
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.
 

41256785
It's not just what you do, it's the way that you do it: the effect of different payment card formats and survey administration on willingness to pay for health gain.
A general population sample of 314 Australian respondents were randomly allocated to complete a contingent valuation survey administered by face-to-face or telephone ('phone-mail-phone') interview. Although the telephone interview was quicker to complete, no significant difference was found in values obtained through either method. Within each sub-sample, respondents were also randomly allocated to the three different versions of the payment card (PC) questionnaire format: values listed from high-to-low, values listed from low-to-high and values randomly shuffled. The high-to-low version resulted in significantly higher values than the other versions. Further analyses indicate that the randomly shuffled PC version may produce the most 'valid' values.
15927414
LC-MS alignment in theory and practice: a comprehensive algorithmic review
Liquid chromatography-mass spectrometry is widely used for comparative replicate sample analysis in proteomics, lipidomics and metabolomics. Before statistical comparison, registration must be established to match corresponding analytes from run to run. Alignment, the most popular correspondence approach, consists of constructing a function that warps the content of runs to most closely match a given reference sample. To date, dozens of correspondence algorithms have been proposed, creating a daunting challenge for practitioners in algorithm selection. Yet, existing reviews have highlighted only a few approaches. In this review, we describe 50 correspondence algorithms to facilitate practical algorithm selection. We elucidate the motivation for correspondence and analyze the limitations of current approaches, which include prohibitive runtimes, numerous user parameters, model limitations and the need for reference samples. We suggest and describe a paradigm shift for overcoming current correspondence limitations by building on known liquid chromatography-mass spectrometry behavior.
19926226
Sensitivity to scale in contingent valuation: the importance of the budget constraint.
The possible insensitivity of willingness-to-pay (WTP) values to changes in scale continues to cause concern within the contingent valuation (CV) literature. Although several reasons for this phenomenon have been suggested, empirical evidence both supports and refutes insensitivity. This paper presents data that suggest that insensitivity may be significantly determined by the individual's budget constraint: the higher the proportion of income the expressed WTP represents, the greater the insensitivity of that WTP to changes in the scale of the good, irrespective of changes in underlying marginal utility. The methodological implication for CV studies in health care is outlined.