27058025
Mammalian labor: variations on a theme by amniota.
In this month’s issue of Endocrinology, Wada et al (1) report on the “Role of vascular endothelial growth factor (VEGF) in maintenance of pregnancy in mice.” It’s a beautifully written report of a carefully performed series of experiments that strongly implicate a fall in the corpus luteum production of VEGF in the onset of labor in mice. However, the most intriguing and insightful aspect is the focus within the title on pregnancy maintenance. Maintaining the fertilized egg within the reproductive tract is a key issue for all amniotes. Before the evolution of the amniote egg, most vertebrate females laid their eggs in water and fertilization was achieved by the male depositing sperm in the vicinity (2). The ability to be fully terrestrial required the evolution of the amniote egg that was covered with membranes that were impervious to water so they did not dry out, yet permeable to oxygen and carbon dioxide allowing respiration. However, the membranes and shell of the amniote egg are formed inside the reproductive tract and the formed coverings are impermeable not only to water but also to sperm. The physiological consequence of the internal creation of the egg coverings is the need also for internal fertilization before the formation of the impenetrable membranes. Movement of the ovum from the ovary to the exterior down the reproductive tract is seen in fish and amphibians in anticipation of external fertilization. This transport is effected by both peristaltic contraction and cilial motion (3). In contrast, for all amniotes, a central requirement is a female reproductive tract that allows the penetration of the sperm against the usual peristaltic and cilial transport toward the exterior. Once fertilization has occurred within the reproductive tract of the amniote, the fertilized ovum must be retained to allow formation of the membranes and in some species the shell or outer covering. A critical evolutionary step for the amniote is the development of a mechanism to retain the zygote within the reproductive tract. Although direct studies of early amniotes are impossible, the physiology of extant members of the group may provide clues. Extant amniotes include birds, reptiles, and mammals. In these diverse classes of vertebrates, the endocrinological processes that arrest contractions of the reproductive tract or uterus have been examined. In the chicken, progesterone plays a key role in retaining the egg within the oviduct. Equally, in the lizard and other reptiles, corpus luteum production of progesterone is critical (4). Within mammalia, the role of progesterone has been examined in many species. In the sheep, murides, marsupials (5), and in humans, progesterone withdrawal is associated with the onset of labor indicating a role for progesterone in reducing contractile activity of the myometrium. Therefore, progesterone as an agent for the inhibition of uterine or reproductive tract activity is found in members of all extant classes of amniotes. This is evidence that progesterone was used to maintain reproductive tract quiescence in the ancestral root amniote. This view is also supported by genome comparison studies that support the evolution of the progesterone receptor (PR) before the evolution of amniotes (6). The data indicate that progesterone allows the amniote to delay the passage of the zygote through the reproductive passage to permit additional parental investment. In some amniotes, the investment of the mother is in the form of egg yolk and the formation of a shell. In placental mammals, retention of the zygote allows additional development of the embryo and fetal growth before release into the exter-
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.
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.
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.
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?
1484363
Public health evaluation in the twenty-first century: time to see the wood as well as the trees.
This paper argues that concepts, methodologies and practices within public health need further development if they are to be sufficient to allow us to develop, undertake and evaluate interventions in the twenty-first century. The public health profession, and the disciplines that contribute to it, maintains the historical focus upon detailed micro analysis (individual and health sector) and not broader macro analysis (societal and system). This brief paper suggests why this is and outlines three challenges it poses: specifying and evaluating outcomes; specifying and understanding complex causal pathways in social interventions and the development of multisector evaluation, to meet information demands from multiple stakeholders. While there is general agreement that public health evaluation needs development, this paper argues that the focus needs to be more upon a broader evaluative space than is currently practiced. There is a need to move beyond primary and secondary health-related effects upon individuals, and focus more on evaluation of the wider range and distribution of direct and indirect effects upon individuals, communities and populations. That is, those involved in public health evaluation need to step back and first consider the wood before focusing in on specific trees.
660912
Cholinergic neuronal defect without cell loss in Huntington's disease.
Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG-repeat expansion in the huntingtin (IT15) gene. The striatum is one of the regions most affected by neurodegeneration, resulting in the loss of the medium-sized spiny neurons. Traditionally, the large cholinergic striatal interneurons are believed to be spared. Recent studies demonstrate that neuronal dysfunction without cell death also plays an important role in early and mid-stages of the disease. Here, we report that cholinergic transmission is affected in a HD transgenic mouse model (R6/1) and in tissues from HD patients. Stereological analysis shows no loss of cholinergic neurons in the striatum or septum in R6/1 mice. In contrast, the levels of mRNA and protein for vesicular acetylcholine transporter (VAChT) and choline acetyltransferase (ChAT) are decreased in the striatum and cortex, and acetylcholine esterase activity is lowered in the striatum of R6/1 mice already at young ages. Accordingly, VAChT is also reduced in striatal tissue from patients with HD. The decrease of VAChT in the patient samples studied is restricted to the striatum and does not occur in the hippocampus or the spinal cord. The expression and localization of REST/NRSF, a transcriptional regulator for the VAChT and ChAT genes, are not altered in cholinergic neurons. We show that the R6/1 mice exhibit severe deficits in learning and reference memory. Taken together, our data show that the cholinergic system is dysfunctional in R6/1 and HD patients. Consequently, they provide a rationale for testing of pro-cholinergic drugs in this disease.
7096884
Foreign direct investment and trade in health services: a review of the literature.
Globalization is a key challenge facing health policy-makers. A significant aspect of this is direct trade in health services, a result of the rise of transnational corporations, challenges in health care financing, porous borders and improved technology creating the scope for increased 'foreign direct investment' (FDI) in health care. This has gathered momentum with the General Agreement on Trade in Services (GATS), which aims to further liberalize trade in services, and within which FDI has been noted as perhaps the most critical area for trade negotiation. Given the rapid development of this area, there are little empirical data. This paper therefore seeks to provide the first comprehensive and systematic review of evidence concerning FDI and health services. This process included electronic bibliographic database searches, website searches and correspondence with experts in the area of trade in health services, from which 76 papers, books and reports were reviewed. Perhaps due to the rapid developments in this area, most of the literature is speculative, polarized between those arguing for the benefits of liberalization and those arguing against. However, there seem to be three issues which emerge as of most importance: (i) the extent to which a national health system is commercialized per se is of more significance than whether investment in it is foreign or domestic; (ii) the national regulatory environment and its 'strength' will significantly determine the economic and health impact of FDI, the effectiveness of safeguard measures, and the stability of GATS commitments; and (iii) any negotiations will depend upon parties having a common understanding of what is being negotiated, and the interpretation of key definitions is thus critical. Each of these issues is explored in some depth, with the overall conclusion that countries should take a step back and first think through the risks and benefits of commercialization of their health sector, rather than being sidetracked in to considering the level of foreign investment.
205696369
Impact of HIV severity on cognitive and adaptive functioning during childhood and adolescence.
BACKGROUND
The influence of disease severity on cognitive and adaptive functioning in perinatally HIV-infected youth with (PHIV+/C) and without (PHIV+/NoC) a previous AIDS-defining illness (Centers for Disease Control and Prevention Class C event), compared with perinatally HIV-exposed but uninfected youth (PHEU) is not well understood.


METHODS
This was a cross-sectional analysis of cognitive and adaptive functioning in PHIV+/C (n = 88), PHIV+/NoC (n = 270) and PHEU (n = 200) youth aged 7-16 years, from a multisite prospective cohort study. Youth and caregivers completed the Wechsler Intelligence Scale for Children, Fourth Edition and the Adaptive Behavior Assessment System, Second Edition, respectively. We compared means and rates of impairment between groups, and examined associations with other psychosocial factors.


RESULTS
Overall mean scores on measures of cognitive and adaptive functioning were in the low average range for all 3 groups. After adjustment for covariates, mean full-scale intelligence quotient scores were significantly lower for the PHIV+/C group than the PHIV+/NoC and PHEU groups (mean = 77.8 versus 83.4 and 83.3, respectively), whereas no significant differences were observed between the PHEU and PHIV+/NoC groups in any domain. Lower cognitive performance for the PHIV+/C group was primarily attributable to a prior diagnosis of encephalopathy. No significant differences between groups were observed in adaptive functioning.


CONCLUSION
For long-term survivors, youth with HIV infection and a prior Centers for Disease Control and Prevention Class C event have higher risk for cognitive but not adaptive impairment regardless of current health status; this finding appears attributable to a previous diagnosis of encephalopathy. Early preventive therapy may be critical in reducing risk of later neurodevelopmental impairments.
11851126
Communicable disease control: a 'Global Public Good' perspective.
Despite the increasing 'globalization' of health, the responsibility for it remains primarily national, generating a potential mismatch between global health problems and current institutions and mechanisms to deal with them. The 'Global Public Good' (GPG) concept has been suggested as a framework to address this mismatch in different areas of public policy. This paper considers the application of the GPG concept as an organizing principle for communicable disease control (CDC), considering in particular its potential to improve the health and welfare of the developing world. The paper concludes that there are significant limitations to the GPG concept's effectiveness as an organizing principle for global health priorities, with respect to CDC. More specifically, there are few areas of CDC which qualify as GPG, and even among those that can be considered GPGs, it is not necessarily appropriate to provide everything which can be considered a GPG. It is therefore suggested that it may be more useful to focus instead on the failure of 'collective action', where the GPG concept may then: (1) provide a rationale to raise funds additional to aid from developed countries' domestic budgets; (2) promote investment by developed countries in the health systems of developing countries; (3) promote strategic partnerships between developed and developing countries to tackle major global communicable diseases; and (4) guide the political process of establishing, and mechanisms for providing and financing, global CDC programmes with GPG characteristics, and GPGs which have benefits for CDC. In short, the GPG concept is not without limitations and weaknesses as an organizing principle, but does provide, at least in some areas, guidance in improving collective action at the international level for the improvement of global CDC.