Does the environment affect menopause? A review of the effects of endocrine disrupting chemicals on menopause.

Endocrine disrupting chemicals are widely distributed in our environment. Humans are exposed to these compounds not only through their occupations, but also through dietary consumption and exposure to contaminated water, personal care products and textiles. Chemicals that are persistent in the body and in our environment include dioxins and polychlorinated biphenyls. Non-persistent chemicals including bisphenol A, phthalates and parabens are equally as important because they are ubiquitous in our environment. Heavy metals, including lead and cadmium, can also have endocrine disrupting properties. Although difficult to study due to their variety of sources of exposures and mechanisms of action, these chemicals have been associated with early menopause, increased frequency of vasomotor symptoms, altered steroid hormone levels and markers of diminished ovarian reserve. Understanding the impacts of these exposures is important given the potential for epigenetic modification, which can alter gene function and result in multi-generational effects. This review summarizes findings in humans and animals or cell-based models from the past decade of research. Continued research is needed to assess the effects of mixtures of chemicals, chronic exposures and new compounds that are continuously being developed as replacements for toxic chemicals that are being phased out.

Defining sepsis on the wards: results of a multi-centre point-prevalence study comparing two sepsis definitions.

Our aim was to prospectively determine the predictive capabilities of SEPSIS-1 and SEPSIS-3 definitions in the emergency departments and general wards. Patients with National Early Warning Score (NEWS) of 3 or above and suspected or proven infection were enrolled over a 24-h period in 13 Welsh hospitals. The primary outcome measure was mortality within 30 days. Out of the 5422 patients screened, 431 fulfilled inclusion criteria and 380 (88%) were recruited. Using the SEPSIS-1 definition, 212 patients had sepsis. When using the SEPSIS-3 definitions with Sequential Organ Failure Assessment (SOFA) score ≥ 2, there were 272 septic patients, whereas with quickSOFA score ≥ 2, 50 patients were identified. For the prediction of primary outcome, SEPSIS-1 criteria had a sensitivity (95%CI) of 65% (54-75%) and specificity of 47% (41-53%); SEPSIS-3 criteria had a sensitivity of 86% (76-92%) and specificity of 32% (27-38%). SEPSIS-3 and SEPSIS-1 definitions were associated with a hazard ratio (95%CI) 2.7 (1.5-5.6) and 1.6 (1.3-2.5), respectively. Scoring system discrimination evaluated by receiver operating characteristic curves was highest for Sequential Organ Failure Assessment score (0.69 (95%CI 0.63-0.76)), followed by NEWS (0.58 (0.51-0.66)) (p < 0.001). Systemic inflammatory response syndrome criteria (0.55 (0.49-0.61)) and quickSOFA score (0.56 (0.49-0.64)) could not predict outcome. The SEPSIS-3 definition identified patients with the highest risk. Sequential Organ Failure Assessment score and NEWS were better predictors of poor outcome. The Sequential Organ Failure Assessment score appeared to be the best tool for identifying patients with high risk of death and sepsis-induced organ dysfunction.

Viscoelastometric-guided early fibrinogen concentrate replacement during postpartum haemorrhage: OBS2, a double-blind randomized controlled trial.

BACKGROUND: Postpartum haemorrhage (PPH) can be exacerbated by haemostatic failure. We hypothesized that early fibrinogen replacement, guided by viscoelastometric testing, reduces blood product usage and bleed size. METHODS: Women with PPH 1000-1500 ml were enrolled. If Fibtem A5 was ≤15 mm and bleeding continued, subjects were randomized to fibrinogen concentrate or placebo. The primary outcome compared the number of units of red blood cells, plasma, cryoprecipitate and platelets transfused. RESULTS: Of 663 women enrolled 55 were randomized. The adjusted incidence rate ratio (IRR) (95% CI) for the number of allogeneic units transfused in the fibrinogen group compared with placebo was 0.72 (0.3-1.7), P =0.45. In pre-specified subgroup analyses, subjects who had a Fibtem A5 ≤12 mm at the time of randomization and who received fibrinogen concentrate received a median (25th-75th centile) of 1 (0-4.5) unit of allogeneic blood products and had an additional 300 (100-350) ml blood loss whereas those who received placebo also received 3 (0-6) units of allogeneic blood products and had 700 (200-1550) ml additional blood loss; these differences were not statistically significantly different. There was one thrombotic event in each group. CONCLUSIONS: Infusion of fibrinogen concentrate triggered by Fibtem A5 ≤15 mm did not improve outcomes in PPH. Pre-specified subgroup analyses suggest that fibrinogen replacement is not required if the Fibtem A5 is > 12 mm or Clauss fibrinogen >2 g litre -1 , but an effect below these levels cannot be excluded. The raised fibrinogen at term appears to be a physiological buffer rather than required for haemostasis. TRIAL REGISTRATION: ISRCTN46295339 ( http://www.isrctn.com/ISRCTN46295339 , last accessed 5 July 2017), EudraCT 2012-005511-11 ( https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-005511-11 , last accessed 5 July 2017).

Laboratory evaluation of a novel anaesthesia delivery device.

Here, we describe proof of concept of a novel method for delivering volatile anaesthetics, where the liquid anaesthetic (sevoflurane or isoflurane) is formulated into an emulsion that is contained in a compact, lightweight device through which carrier gas flows. Release of anaesthetic is achieved by stirring of the formulation, allowing controlled and responsive release of anaesthetic at a variety of fixed flow rates between 0.5 l.min-1 and 5 l.min-1 , with ventilated, non-ventilated and draw-over breathing systems. Anaesthetic release was evaluated using target anaesthetic concentrations ranging from 0.5% v/v to 8% v/v to mimic those typically required for induction and maintenance of anaesthesia, and lower concentrations suitable for sedation. Under all conditions, output could be maintained within 0.1% v/v of the intended setting, and the device could deliver a controlled level of anaesthetic for at least 60 min, with compensation for different ambient temperatures (10-30 °C) and carrier gas flow rates. This device offers a simple, inexpensive method of delivering safe concentrations of volatile anaesthetics for a wide range of applications.

A forward modelling approach for the estimation of oxygen extraction fraction by calibrated fMRI.

The measurement of the absolute rate of cerebral metabolic oxygen consumption (CMRO2) is likely to offer a valuable biomarker in many brain diseases and could prove to be important in our understanding of neural function. As such there is significant interest in developing robust MRI techniques that can quantify CMRO2 non-invasively. One potential MRI method for the measurement of CMRO2 is via the combination of fMRI and cerebral blood flow (CBF) data acquired during periods of hypercapnic and hyperoxic challenges. This method is based on the combination of two, previously independent, signal calibration techniques. As such analysis of the data has been approached in a stepwise manner, feeding the results of one calibration experiment into the next. Analysing the data in this manner can result in unstable estimates of the output parameter (CMRO2), due to the propagation of errors along the analysis pipeline. Here we present a forward modelling approach that estimates all the model parameters in a one-step solution. The method is implemented using a regularized non-linear least squares approach to provide a robust and computationally efficient solution. The proposed framework is compared with previous analytical approaches using modelling studies and in vivo acquisitions in healthy volunteers (n=10). The stability of parameter estimates is demonstrated to be superior to previous methods (both in vivo and in simulation). In vivo estimates made with the proposed framework also show better agreement with expected physiological variation, demonstrating a strong negative correlation between baseline CBF and oxygen extraction fraction. It is anticipated that the proposed analysis framework will increase the reliability of absolute CMRO2 measurements made with calibrated BOLD.

Effect of early tracheostomy on resource utilization and clinical outcomes in critically ill patients: meta-analysis of randomized controlled trials.

BACKGROUND: Early tracheostomy may decrease the duration of mechanical ventilation, sedation exposure, and intensive care stay, possibly resulting in improved clinical outcomes, but the evidence is conflicting. METHODS: Systematic review and meta-analysis of randomized trials in patients allocated to tracheostomy within 10 days of start of mechanical ventilation was compared with placement of tracheostomy after 10 days if still required. Medline, EMBASE, the Cochrane Controlled Clinical Trials Register, and Google Scholar were searched for eligible trials. The co-primary outcomes were mortality within 60 days, and duration of mechanical ventilation, sedation, and intensive care unit stay. Secondary outcomes were the number of tracheostomy procedures performed, and incidence of ventilator-associated pneumonia (VAP). Outcomes are described as relative risk or weighted mean difference with 95% confidence intervals. RESULTS: Of note, 4482 publications were identified and 14 trials enrolling 2406 patients were included. Tracheostomy within 10 days was not associated with any difference in mortality [risk ratio (RR): 0.93 (0.83-1.05)]. There were no differences in duration of mechanical ventilation [-0.19 days (-1.13-0.75)], intensive care stay [-0.83 days (-2.05-0.40)], or incidence of VAP. However, duration of sedation was reduced in the early tracheostomy groups [-2.78 days (-3.68 to -1.88)]. More tracheostomies were performed in patients randomly assigned to receive early tracheostomy [RR: 2.53 (1.18-5.40)]. CONCLUSION: We found no evidence that early (within 10 days) tracheostomy reduced mortality, duration of mechanical ventilation, intensive care stay, or VAP. Early tracheostomy leads to more procedures and a shorter duration of sedation.

Role of Shp2 in forebrain neurons in regulating metabolic and cardiovascular functions and responses to leptin.

OBJECTIVE: We examined whether deficiency of Src homology 2 containing phosphatase (Shp2) signaling in forebrain neurons alters metabolic and cardiovascular regulation under various conditions and if it attenuates the anorexic and cardiovascular effects of leptin. We also tested whether forebrain Shp2 deficiency alters blood pressure (BP) and heart rate (HR) responses to acute stress. DESIGN: Forebrain Shp2(-/-) mice were generated by crossing Shp2(flox/flox) mice with CamKIIα-cre mice. At 22-24 weeks of age, the mice were instrumented for telemetry for measurement of BP, HR and body temperature (BT). Oxygen consumption (VO2), energy expenditure and motor activity were monitored by indirect calorimetry. RESULTS: Shp2/CamKIIα-cre mice were heavier (46±3 vs 32±1 g), hyperglycemic, hyperleptinemic, hyperinsulinemic and hyperphagic compared to Shp2(flox/flox) control mice. Shp2/CamKIIα-cre mice exhibited reduced food intake responses to fasting/refeeding and impaired regulation of BT when exposed to 15 and 30 °C ambient temperatures. Despite being obese and having many features of metabolic syndrome, Shp2/CamKIIα-cre mice had similar daily average BP and HR compared to Shp2(flox/flox) mice (112±2 vs 113±1 mm Hg and 595±34 vs 650±40 b.p.m.), but exhibited increased BP and HR responses to cold exposure and acute air-jet stress test. Leptin's ability to reduce food intake and to raise BP were markedly attenuated in Shp2/CamKIIα-cre mice. CONCLUSION: These results suggest that forebrain Shp2 signaling regulates food intake, appetite responses to caloric deprivation and thermogenic control of body temperature during variations in ambient temperature. Deficiency of Shp2 signaling in the forebrain is associated with augmented cardiovascular responses to cold and acute stress but attenuated BP responses to leptin.

Global consensus statement on menopausal hormone therapy.

The following Consensus Statement is endorsed by The American Society for Reproductive Medicine, The Asia Pacific Menopause Federation, The Endocrine Society, The European Menopause and Andropause Society, The International Menopause Society, The International Osteoporosis Foundation and The North American Menopause Society.

Investigation of phthalate release from tracheal tubes.

Phthalates are chemicals used extensively in the manufacture of plastics for their desirable physical characteristics. In addition to enhancing the performance of plastics, phthalates have a number of undesirable effects, principally endocrine disruptor effects, that may have adverse effects on reproductive development and functioning. As a result, they have been banned from the manufacture of children's toys. Despite this, they continue to be used in the manufacture of medical devices, including anaesthetic equipment. This study aimed to assess phthalate release from five brands of tracheal tube. Using gas chromatography-mass spectrometry, we analysed phthalate concentrations from samples of ultra pure water in which tracheal tubes had been submerged. Phthalate concentration increased from 6.7 to 149 µg.l(-1) over a period of 4.8 days. Phthalate release from anaesthetic equipment has not previously been documented over short time periods and raises the possibility of iatrogenic endocrine disruption with routine anaesthesia.

A novel HLA-A*30 allele, HLA-A*30:36.

A novel HLA allele, HLA-A*30:36, is found in a donor from the Central German Bone Marrow Donor Registry.

Inhibition of soluble epoxide hydrolase reduces food intake and increases metabolic rate in obese mice.

BACKGROUND AND AIMS: This study evaluated the responses to soluble epoxide hydrolase (s-EH) inhibition, an essential enzyme in the metabolism of arachidonic acid, on food intake, body weight and metabolic parameters in mice fed a high fat-high fructose diet (HFD) for 10 weeks. METHODS AND RESULTS: After 5 weeks of HFD, mice were divided into two groups: 1) s-EH inhibitor (AR9281, 200mg/kg/day by gavage twice daily), and 2) vehicle (0.3ml per gavage). Food intake, body weight, oxygen consumption (VO(2)), carbon dioxide production (VCO(2)), respiratory quotient (RQ), and motor activity were measured weekly for more 5 weeks. HFD increased body weight (37±1 vs. 26±1g), and plasma of glucose (316±8 vs. 188±27mg/dl), insulin (62.1±8.1 vs. 15.5±5.0µU/ml), and leptin levels (39.4±3.6 vs. 7.5±0.1ng/ml) while reducing VO(2), VCO(2) and motor activity. s-EH inhibition for 5 weeks decreased caloric intake by ~32% and increased VO(2) by ~17% (42.8±1.4 vs. 50.2±1.5ml/kg/min) leading to significant weight loss. Inhibition of s-EHi also caused significant reductions in plasma leptin levels and visceral fat content. Uncoupling protein 1 (UCP1) content in brown adipose tissue was also elevated by ~50% during s-EH inhibition compared to vehicle treatment. CONCLUSION: These results suggest that s-EH inhibition with AR9281 promotes weight loss by reducing appetite and increasing metabolic rate, and that increased UCP1 content may contribute to the increase in energy expenditure.

Complement takes its Toll: an inflammatory crosstalk between Toll-like receptors and the receptors for the complement anaphylatoxin C5a.

The innate immune system is responsible for a rapid inflammatory response to pathogens that is essential for the clearance of infections. Although this response is vital, it is nonetheless potentially harmful, and dysregulated inflammation is a feature of many disease states. Thus, the mechanisms that regulate the release of soluble mediators of inflammation are an active focus of investigation. The activation by infections of two key components of the innate immune system, the Toll-like receptors (TLRs) and complement, leading to the release of soluble mediators of inflammation, is critical to microbial killing and clearance. Both TLRs and complement are independently capable of triggering pro-inflammatory responses, but their synergistic interaction resulting from a substantial crosstalk markedly amplifies those responses and may contribute to the pathophysiology of diseases such as sepsis.

Differential effects of aging on estrogen negative and positive feedback.

Recent studies have demonstrated an age-related decline in gonadotropins and a decrease in pituitary responsiveness to GnRH, indicating that aging influences the neuroendocrine components of the female reproductive axis independently of changes in ovarian function. To determine whether aging might also affect the luteinizing hormone (LH) negative and positive feedback responses to gonadal steroids, we administered a controlled, graded sex steroid infusion to 11 younger (45-56 yr) and nine older (70-80 yr) postmenopausal women (PMW) in whom endogenous ovarian steroids and peptides are uniformly low. The doses of estradiol (E(2)) and progesterone (P) were chosen to mimic levels across the normal follicular phase and have been shown previously to induce negative followed by positive feedback on LH. Similar E(2) and P levels were achieved in younger and older PMW (P = 0.4 and 0.3, respectively) and produced a biphasic LH response in all subjects. The early decline in LH to 53% of baseline was not different in older vs. younger PMW. However, the positive feedback effect was attenuated in older compared with younger PMW (peak LH 144.4 ± 19.5 vs. 226.8 ± 22.3 IU/l, respectively, P = 0.01). In conclusion, these studies in PMW demonstrate preservation of short-term steroid negative and positive feedback in response to exogenous E(2) and P with aging. Attenuation of positive feedback in older compared with younger PMW is consistent with previous reports of declining GnRH responsiveness with aging.

A novel HLA-A*03 allele, HLA-A*03:71.

A novel HLA-A*03 allele, HLA-A*03:71, was identified by PCR sequence-based typing.

The effect of desflurane on filtration performance of breathing system filters.

This study assessed the effect of desflurane on the filtration performance of six breathing system filters intended for use with adults. Three filters contained an electrostatic filter material and three contained a pleated glass fibre filter material. Five samples of each model of filter were exposed to 6% v/v of desflurane for 1 h, 12% v/v of desflurane for 1 h, 12% v/v of desflurane for 4 h and air only for 1 h. Five samples of each filter were also tested without exposure to any vapour or air. The filtration performance was measured by challenging each filter with an aerosol of sodium chloride particles using a Moore's test rig. Penetration of particles through the electrostatic filters increased following exposure to a higher concentration of desflurane for a longer duration (p < 0.001). The effect on two of the pleated filters was not significant (p = 0.55 and p = 0.64). The effect on the remaining pleated filter was significant (p < 0.001) but small. The efficiency of some filters decreases when they are exposed to high concentrations of desflurane for a long duration. This effect appears more marked in electrostatic filters compared with pleated filters.

Efficacy of the novel diamidine compound 2,5-Bis(4-amidinophenyl)- furan-bis-O-Methlylamidoxime (Pafuramidine, DB289) against Trypanosoma brucei rhodesiense infection in vervet monkeys after oral administration.

Owing to the lack of oral drugs for human African trypanosomiasis, patients have to be hospitalized for 10 to 30 days to facilitate treatment with parenterally administered medicines. The efficacy of a novel orally administered prodrug, 2,5-bis(4-amidinophenyl)-furan-bis-O-methlylamidoxime (pafuramidine, DB289), was tested in the vervet monkey (Chlorocebus [Cercopithecus] aethiops) model of sleeping sickness. Five groups of three animals each were infected intravenously with 10(4) Trypanosoma brucei rhodesiense KETRI 2537 cells. On the seventh day postinfection (p.i.) in an early-stage infection, animals in groups 1, 2, and 3 were treated orally with pafuramidine at dose rates of 1, 3, or 10 mg/kg of body weight, respectively, for five consecutive days. The animals in groups 4 and 5 were treated with 10 mg/kg for 10 consecutive days starting on the 14th day p.i. (group 4) or on the 28th day p.i. (group 5), when these animals were in the late stage of the disease. In the groups treated in the early stage, 10 mg/kg of pafuramidine completely cured all three monkeys, whereas lower doses of 3 mg/kg and 1 mg/kg cured only one of three and zero of three monkeys, respectively. Treatment of late-stage infections resulted in cure rates of one of three (group 4) and zero of three (group 5) monkeys. These studies demonstrated that pafuramidine was orally active in monkeys with early-stage T. brucei rhodesiense infections at dose rates above 3 mg/kg for 5 days. It was also evident that the drug attained only minimal efficacy against late-stage infections, indicating the limited ability of the molecule to cross the blood-brain barrier. This study has shown that oral diamidines have potential for the treatment of early-stage sleeping sickness.

The structural organization and protein composition of lens fiber junctions.

The structural organization and protein composition of lens fiber junctions isolated from adult bovine and calf lenses were studied using combined electron microscopy, immunolocalization with monoclonal and polyclonal anti-MIP and anti-MP70 (two putative gap junction-forming proteins), and freeze-fracture and label-fracture methods. The major intrinsic protein of lens plasma membranes (MIP) was localized in single membranes and in an extensive network of junctions having flat and undulating surface topologies. In wavy junctions, polyclonal and monoclonal anti-MIPs labeled only the cytoplasmic surface of the convex membrane of the junction. Label-fracture experiments demonstrated that the convex membrane contained MIP arranged in tetragonal arrays 6-7 nm in unit cell dimension. The apposing concave membrane of the junction displayed fracture faces without intramembrane particles or pits. Therefore, wavy junctions are asymmetric structures composed of MIP crystals abutted against particle-free membranes. In thin junctions, anti-MIP labeled the cytoplasmic surfaces of both apposing membranes with varying degrees of asymmetry. In thin junctions, MIP was found organized in both small clusters and single membranes. These small clusters also abut against particle-free apposing membranes, probably in a staggered or checkerboard pattern. Thus, the structure of thin and wavy junctions differed only in the extent of crystallization of MIP, a property that can explain why this protein can produce two different antibody-labeling patterns. A conclusion of this study is that wavy and thin junctions do not contain coaxially aligned channels, and, in these junctions, MIP is unlikely to form gap junction-like channels. We suggest MIP may behave as an intercellular adhesion protein which can also act as a volume-regulating channel to collapse the lens extracellular space. Junctions constructed of MP70 have a wider overall thickness (18-20 nm) and are abundant in the cortical regions of the lens. A monoclonal antibody raised against this protein labeled these thicker junctions on the cytoplasmic surfaces of both apposing membranes. Thick junctions also contained isolated clusters of MIP inside the plaques of MP70. The role of thick junctions in lens physiology remains to be determined.

The sleep-inducing lipid oleamide deconvolutes gap junction communication and calcium wave transmission in glial cells.

Oleamide is a sleep-inducing lipid originally isolated from the cerebrospinal fluid of sleep-deprived cats. Oleamide was found to potently and selectively inactivate gap junction-mediated communication between rat glial cells. In contrast, oleamide had no effect on mechanically stimulated calcium wave transmission in this same cell type. Other chemical compounds traditionally used as inhibitors of gap junctional communication, like heptanol and 18beta-glycyrrhetinic acid, blocked not only gap junctional communication but also intercellular calcium signaling. Given the central role for intercellular small molecule and electrical signaling in central nervous system function, oleamide- induced inactivation of glial cell gap junction channels may serve to regulate communication between brain cells, and in doing so, may influence higher order neuronal events like sleep induction.