Reconsidering fear of birth: Language matters.

Interest in fear of childbirth has grown exponentially since the 1980s, but the landscape of birth has shifted considerably since then, with evolving feminism; moving from a patriarchal environment in a biomedical model of care to a holistic model which recognizes the birth and sexuality rights of women and birthing people. Distinguishing the spectrum of fear from low to high and severe is important rather than aggregating all individuals with fear of childbirth. However, the terms 'fear of childbirth' and 'tocophobia' have been used interchangeably. In this paper we urge clinicians to use the term 'tocophobia' with caution since it may be construed negatively and there is a limited understanding of the underpinning aetiology of tocophobia. Furthermore, using the label may be disempowering for women and birthing people making decisions about their birth. Further research is warranted to better understand the experience, refine and define the issue and meet the individual needs of people with fear of childbirth and tocophobia.

Poor adherence to integral daily tasks limits the efficacy of CSII in youth.

INTRODUCTION/AIMS: Many young people experience improved glycemia with continuous subcutaneous insulin infusion (CSII) regimens; however, sustained glycemic benefit eludes a significant proportion. Our aims were to assess adherence to recommended CSII-related behaviors in a representative pediatric cohort and to identify potentially modifiable behaviors that impact on HbA1c in youth. RESEARCH DESIGN AND METHODS: Data uploaded from insulin pump devices of 100 youth with type 1 diabetes were analyzed. RESULTS: Ability to translate recommended behaviors into daily self-management varied widely in youth. Mean bolus frequency was 6.1/d; however, 69/100 entered <4 blood glucose levels (BGL)/d. HbA1c decreased by 0.2% for each additional BGL (p=0.001) and bolus event (p<0.001) per day. Prandial insulin omission was common and associated with significantly increased HbA1c. On average, if breakfast insulin was missed ≥4 times per fortnight, HbA1c increased 1.0% (p<0.001). If one or more days per fortnight with ≤2 food boluses/d were recorded, then HbA1c increased 0.8% (p=0.001). Increasing age and duration of CSII correlated with poorer adherence to recommended behaviors. CONCLUSIONS: Glycemic advantage obtained with CSII regimens is closely related to the manner in which CSII is employed. Poor adherence to integral CSII-related tasks is frequently encountered in adolescents and limits the efficacy of CSII in these youth.

Glycaemic impact of patient-led use of sensor-guided pump therapy in type 1 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: The objective of this study was to assess the impact of patient-led sensor-guided pump management on glycaemic control, and compare the effect with that of standard insulin pump therapy. METHODS: An open multicentre parallel randomised controlled trial was conducted at five tertiary diabetes centres. Participants aged 13.0-40.0 years with well-controlled type 1 diabetes were randomised 1:1 to either study group for 3 months. Randomisation was carried out using a central computer-generated schedule. Participants in the intervention group used sensor-guided pump management; no instructive guidelines in interpreting real-time data were provided ('patient-led' use). Participants in the control group continued their original insulin pump regimen. Continuous glucose monitoring (CGM) and HbA(1c) level were used to assess outcomes. The primary outcome was the difference in the proportion of time in the target glycaemic range during the 3 month study period (derived from CGM, target range 4-10 mmol/l). Secondary outcomes were difference in HbA(1c), time in hypoglycaemic (< or =3.9 mmol/l) and hyperglycaemic (> or =10.1 mmol/l) ranges and glycaemic variability. RESULTS: Sixty-two participants were recruited and randomised; 5/31 and 2/31 withdrew from intervention and control groups, respectively, leaving 26/31 and 29/31 for the intention-to-treat analyses. When adjusted for baseline values, the mean end-of-study HbA(1c) was 0.43% lower in the intervention group compared with the control group (95% CI 0.19 to 0.75%; p = 0.009). No difference was observed in CGM-derived time in target (measured difference 1.72; 95% CI -5.37 to 8.81), hypoglycaemic (0.54; 95% CI -3.48 to 4.55) or hyperglycaemic (-2.18; 95% CI -10.0 to 5.69) range or in glycaemic variability (-0.29; 95% CI -0.34 to 0.28). Within the intervention group, HbA(1c) was 0.51% lower in participants with sensor use > or =70% compared with participants with sensor use <70% (95% CI -0.98 to -0.04, p = 0.04). Five episodes of device malfunction occurred. CONCLUSIONS/INTERPRETATION: Individuals established on insulin pump therapy can employ sensor-guided pump management to improve glycaemic control. An apparent dose-dependent effect of sensor usage was noted; however, frequent use of this technology (> or =70%) was not universally acceptable. TRIAL REGISTRATION: ACTRN12606000049572

Curcumin: potential for hepatic fibrosis therapy?

The beneficial antioxidative, anti-inflammatory and antitumorigenic effects of curcumin have been well documented in relation to cancer and other chronic diseases. Recent evidence suggests that it may be of therapeutic interest in chronic liver disease. Hepatic fibrosis (scarring) occurs in advanced liver disease, where normal hepatic tissue is replaced with collagen-rich extracellular matrix and, if left untreated, results in cirrhosis. Curcumin inhibits liver cirrhosis in a rodent model and exerts multiple biological effects in hepatic stellate cells (HSCs), which play a central role in the pathogenesis of hepatic fibrosis. In response to liver injury, these cells proliferate producing pro-inflammatory mediators and extracellular matrix. Curcumin induces apoptosis and suppresses proliferation in HSCs. In addition, it inhibits extracellular matrix formation by enhancing HSC matrix metalloproteinase expression via PPARgamma and suppressing connective tissue growth factor (CTGF) expression. In this issue, Chen and co-workers propose that curcumin suppresses CTGF expression in HSC by inhibiting ERK and NF-kappaB activation. These studies suggest that curcumin modulates several intracellular signalling pathways in HSC and may be of future interest in hepatic fibrosis therapy.

Major increase in Type 1 diabetes: no support for the Accelerator Hypothesis.

BACKGROUND: The Accelerator Hypothesis postulates that the apparent increase in incidence of Type 1 diabetes mellitus (T1DM) is related to an acceleration of disease onset by weight-related insulin resistance. Our diabetes clinic has experienced a major recent increase in newly diagnosed diabetes. The Accelerator Hypothesis predicts that this increase should be associated with younger age and increased body mass at diagnosis, with youngest children having the highest body mass index (BMI). AIM: To test the Accelerator Hypothesis in the context of the major increase in T1DM at our centre. METHODS: Data from all young people diagnosed with T1DM between 1992 and 2003 were reviewed. Height and weight measurements from initial outpatient review were used to calculate BMI. RESULTS: The mean increase in BMI standard deviation score (SDS) is 0.03 per year (P = 0.01). Age at diagnosis has also increased by a mean of 0.11 years annually (P = 0.003). There was no association between BMI SDS and age at diagnosis (P = 0.7). A significant difference in BMI SDS between age-banded subgroups was evident (P = 0.04); however, youngest children had the lowest SDS. CONCLUSION: Our results do not support increased body mass as an accelerator of diabetes presentation.

The impact of long chain n-3 polyunsaturated fatty acid supplementation on inflammation, insulin sensitivity and CVD risk in a group of overweight women with an inflammatory phenotype.

BACKGROUND: Inflammation is strongly related to obesity and the risk of cardiovascular disease (CVD). The metabolic benefits of long chain (LC) n-3 polyunsaturated fatty acid (PUFA) may be attributable to its anti-inflammatory properties. OBJECTIVE: To investigate whether an individual's habitual inflammatory status influences the impact of a LC n-3 PUFA intervention on CVD risk. DESIGN: The study was a randomized crossover design. Subjects received LC n-3 PUFA capsules or a placebo for 12 weeks, with 4-week washout between phases. Thirty women, in the top and bottom tertiles of baseline sialic acid concentration, formed raised inflammatory status (top, n = 12) and reference (bottom, n = 18) groups. Baseline data were analysed using one-way anova, differences between treatment phases were calculated at each timepoint and analysed using a random effects model. RESULTS: At baseline, the raised inflammatory status group had significantly higher body mass index and area under the curve (AUC) insulin than the reference group. With LC n-3 PUFA supplementation, both groups showed significantly higher plasma eicosapentaenoic acid and docosahexaenoic acid at 4 and 12 weeks (p < 0.001), and lower triacylglycerols (4 weeks p < 0.01 and 12 weeks p < 0.05). The difference in AUC insulin between the two treatment phases at 12 weeks was significantly greater in the raised inflammatory status group compared to the reference group (p < 0.05). Inflammatory markers were significantly lower after 12 weeks LC n-3 PUFA supplementation compared to baseline (C-reactive protein p < 0.05 and interleukin-6 p < 0.01), but there was no significant group effect. CONCLUSIONS: Habitual inflammatory status influences the impact of LC n-3 PUFA supplementation, but it is not clear whether the effect of LC n-3 PUFA on AUC insulin is mediated through inflammatory mechanisms.

Moderate alcohol consumption and increased bone mineral density: potential ethanol and non-ethanol mechanisms.

Mounting epidemiological evidence indicates an association between the moderate ingestion of alcoholic beverages and higher bone mineral density (v. abstainers). More limited findings provide some evidence for translation of this association into reduced fracture risk, but further studies are required. Here, these data are reviewed and caveats in their assimilation, comparison and interpretation as well as in the use and application of bone health indices are discussed. Whilst it is concluded that evidence is now strong for the moderate alcohol-bone health association, at least in relation to bone mineral density, mechanisms are less clear. Both ethanol and non-ethanol components have been implicated as factors that positively affect bone health in the light of moderate consumption of alcoholic beverages, and four particular areas are discussed. First, recent findings suggest that moderate ethanol consumption acutely inhibits bone resorption, in a non-parathyroid hormone- and non-calcitonin-dependent fashion, which can only partly be attributed to an energy effect. Second, critical review of the literature does not support a role for moderate ethanol consumption affecting oestrogen status and leading to a knock-on effect on bone. Third, Si is present at high levels in certain alcoholic beverages, especially beer, and may have a measurable role in promoting bone formation. Fourth, a large body of work indicates that phytochemicals (e.g. polyphenols) from alcoholic beverages could influence bone health, but human data are lacking. With further work it is hoped to be able to model epidemiological observations and provide a clear pathway between the magnitude of association and the relative contribution of these mechanisms for the major classes of alcoholic beverage.

Dexamphetamine use for management of obesity and hypersomnolence following hypothalamic injury.

UNLABELLED: Unrelenting weight gain, morbid obesity and disturbance of the sleep-wake cycle are well-recognized sequelae of hypothalamic injury. These health problems and their risk of significant associated co-morbidity drive the search for potential treatment modalities. OBJECTIVE: To report effects on weight change and wakefulness in a cohort of 12 patients with structural hypothalamic lesions treated with low-dose dexamphetamine. METHOD: Retrospective review of case notes. RESULTS: Twelve patients received dexamphetamine 5 mg twice daily (median duration 13 months in males, 15 months in females). Ten of 12 patients experienced either stabilisation of weight or weight loss on treatment (median loss -0.7 SDS in males, -0.44 SDS in females). Eleven patients reported improvement in daytime wakefulness and/or concentration and exercise tolerance. CONCLUSION: Low-dose dexamphetamine therapy has a positive impact on inexorable weight gain and daytime somnolence following hypothalamic injury.

Cleavage of dsRNAs hyper-edited by ADARs occurs at preferred editing sites.

Long double-stranded RNAs (dsRNAs) may undergo covalent modification (hyper-editing) by adenosine deaminases that act on RNA (ADARs), whereby up to 50-60% of adenosine residues are converted to inosine. Previously, we have described a ribonuclease activity in various cell extracts that specifically targets dsRNAs hyper-edited by ADARs. Such a ribonuclease may play an important role in viral defense, or may alternatively be involved in down-regulation of other RNA duplexes. Cleavage of hyper-edited dsRNA occurs within sequences containing multiple IU pairs but not in duplexes that contain either isosteric GU pairs or Watson-Crick base pairs. Here, we describe experiments aimed at further characterizing cleavage of hyper-edited dsRNA. Using various inosine-containing dsRNAs we show that cleavage occurs preferentially at a site containing both IU and UI pairs, and that inclusion of even a single GU pair inhibits cleavage. We also show that cleavage occurs on both strands within a single dsRNA molecule and requires a 2'-OH group. Strikingly, we show that ADAR1, ADAR2 or dADAR all preferentially generate the preferred cleavage site when hyper-editing a long dsRNA.

A bioinformatic screen for novel A-I RNA editing sites reveals recoding editing in BC10.

MOTIVATION: Recent studies have demonstrated widespread adenosine-inosine RNA editing in non-coding sequence. However, the extent of editing in coding sequences has remained unknown. For many of the known sites, editing can be observed in multiple species and often occurs in well-conserved sequences. In addition, they often occur within imperfect inverted repeats and in clusters. Here we present a bioinformatic approach to identify novel sites based on these shared features. Mismatches between genomic and expressed sequences were filtered to remove the main sources of false positives, and then prioritized based on these features. This protocol is tailored to identifying specific recoding editing sites, rather than sites in non-coding repeat sequences. RESULTS: Our protocol is more sensitive for identifying known coding editing sites than any previously published mammalian screen. A novel multiply edited transcript, BC10, was identified and experimentally verified. BC10 is highly conserved across a range of metazoa and has been implicated in two forms of cancer.

Haem oxygenase-1: a target for dietary antioxidants.

HO-1 (haem oxygenase-1) is a stress-response enzyme involved in the catabolism of haem. In animal models, it plays a key protective role in vascular disease. HO-1 has anti-inflammatory effects in macrophages and is induced by a range of stimuli, including antioxidants, in various cell types. As dietary antioxidants are considered to be beneficial in vascular disease, their protective effects may occur through induction of HO-1. Emerging evidence suggests that a range of dietary and other naturally occurring antioxidants stimulate HO-1 expression in various cell types, although regulation by these compounds has not been investigated in detail. These studies suggest that HO-1 may be a target for dietary therapy in vascular disease.

Haem oxygenase-1 in inflammation.

HO-1 (haem oxygenase-1) is a stress-inducible enzyme that plays a protective role in inflammation. Pro-inflammatory mediators, including lipopolysaccharide and cytokines, induce HO-1 expression. The 5'-flanking region of the HO-1 gene contains binding sites for the transcription factors that regulate inflammation, including nuclear factor-kappaB and activator protein 1. However, these do not appear to mediate lipopolysaccharide-induced HO-1 gene expression. In response to haem and antioxidants, murine HO-1 is regulated by the transcription factor Nrf2 (NF-E2-related factor 2). This transcription factor may also be important in the regulation of HO-1 by pro-inflammatory stimuli.

Elevated sialic acid, but not CRP, predicts features of the metabolic syndrome independently of BMI in women.

AIMS: C-reactive protein (CRP) is a predictor of many diseases including type II diabetes and cardiovascular disease. Fewer studies have similarly shown sialic acid (SA) to be a predictor of obesity-related diseases, but importantly SA shows less intra-individual variability than CRP and acts as an integrated marker of the activity of a number of acute-phase proteins. This study examines the association between both CRP and SA with individual and combined features of the metabolic syndrome. SUBJECTS: In all, 257 women with a body mass index (BMI) ranging from 25.1 to 54.5 kg/m2 (geometric mean 33.1+/-5.8 kg/m2) and aged 19-71 y (mean 45.6+/-12.1 y) were studied. Subjects had no symptoms of intercurrent infection, known diabetes, treated dyslipidaemia, a chronic inflammatory condition, liver disease or malignancy. RESULTS: Linear regression demonstrates that both CRP and SA were positively associated with weight, BMI, insulin resistance, dyslipidaemia and hypertension. There was a highly significant (P<0.0001) positive association of both SA and CRP with none, one, two, three or four features of the metabolic syndrome. For a 1 s.d. (4.0 mg/l) increase in CRP, there was a significant increased risk when comparing the odds of having metabolic syndrome (defined as three or more individual features) compared with the remainder of the population (odds ratio=1.7, P<0.0001), but this was not significant after adjustment for BMI. However, for a 1 s.d. (0.34 mmol/l) increase in SA, the odds of having metabolic syndrome compared with those without metabolic syndrome was 2.5 (P<0.0001), and persisted after additional adjustment for BMI (adjusted odds ratio=1.9, P<0.0001). CONCLUSIONS: While SA and CRP are both univariately associated with individual features of the metabolic syndrome, SA, but not CRP, is significantly associated with the metabolic syndrome, independent of BMI. We conclude that SA identifies a subgroup of overweight individuals with an inflammatory phenotype, who are at the greatest risk of metabolic syndrome.

Ethnic differences in the relationship between fasting leptin and BMI in children.

OBJECTIVE: To compare the relationship between fasting serum leptin levels and body mass index (BMI) in children from different ethnic groups. SUBJECTS: Children aged 6-10 y from rural Gambia (n=471) and central Italy (n=839). MEASUREMENTS: Anthropometry (z-score of BMI) and fasting serum leptin concentrations. RESULTS: The Italian children had significantly higher mean BMI z-scores than the Gambian children (males: Italy 1.58, Gambia -1.44, P< or =0.0001; females: Italy 1.33, Gambia -1.42, P< or =0.0001) and significantly higher serum leptin concentrations (males: Italy 8.86 ng ml(-1), Gambia 1.78 ng ml(-1), P< or =0.0001; females: Italy 11.31 ng ml(-1), Gambia 2.22 ng ml(-1), P< or =0.0001). A significantly different relationship was observed between z-score of BMI and serum leptin levels in the Gambian and the Italian children for both boys and girls. CONCLUSION: A different relationship exists between z-score of BMI and leptin levels in these two groups of children from very diverse ethnic backgrounds. Future studies using detailed measures of body composition and energy balance are needed to help understand this relationship.

Leptin, malnutrition, and immune response in rural Gambian children.

BACKGROUND: The adipocyte derived hormone, leptin, has cytokine like function and may mediate the effects of starvation on immunity. Mice with congenital leptin deficiency (ob/ob) have small hypocellular thymuses and impaired cellular immunity. In humans leptin influences the differentiation of naïve and memory cells in vitro, and genetic leptin deficiency has been associated with an ill defined susceptibility to infection. AIMS: To describe the in vivo relation of leptin and immune function in children. METHODS: Fasting plasma leptin concentrations, immune function (T and B cell mediated vaccine responses and delayed type hypersensitivity), and mucosal function (dual sugar permeability test and salivary sIgA concentrations) were measured in a cohort of 472 moderately undernourished rural Gambian children. RESULTS: Leptin concentrations correlated with body fat assessed by mid upper arm circumference or BMI for age Z scores, and were very low compared to well nourished European norms (males 1.8 v 11.1 ng/ml; females 2.4 v 13.8 ng/ml). No detectable relations were found between leptin concentrations and any of the measures of immune or mucosal function. CONCLUSIONS: The data confirm that leptin acts as a peripheral signal of energy restriction, but do not support an association between fasting plasma leptin levels and immune function in children of this age.

The many roles of an RNA editor.

The availability of complete genome sequences has made it clear that gene number is not the sole determinant of the complexity of the proteome. Additional complexity that is not readily detected by genome analysis is present in the number and types of RNA transcript that can be derived from each locus. Although alternative splicing is a well-recognized method of generating diversity, the more subtle mechanism of RNA editing is less familiar.

Soluble adhesion molecules in inflammatory bowel disease.

BACKGROUND: Soluble adhesion molecules are elevated in a number of inflammatory conditions. AIMS: To investigate the correlation of soluble intercellular adhesion molecule-1 (sICAM-1) and sE-selectin with the activity of inflammatory bowel disease (IBD). METHODS: sICAM-1 and sE-selectin were measured by an enzyme-linked immunosorbent assay (ELISA) in 53 patients with ulcerative colitis (UC) and 38 patients with Crohn's disease (CD). RESULTS: Patients with active UC and CD had significantly higher sICAM-1 than patients with inactive disease and controls. Patients with pancolitis had significantly higher levels than patients with distal colitis. There was a significant difference in sE-selectin levels between patients with active CD and control sICAM-1. sE-selectin did not correlate with the Harvey Bradshaw index (HBI). C-reactive protein (CRP) and microalbuminuria were better markers than sICAM-1 or sE-selectin which correlated with serum tumour necrosis factor (TNF)-alpha. CONCLUSION: sICAM-1 and sE-selectin are elevated in the serum of patients with IBD but CRP and microalbuminuria reflect clinical disease activity more accurately. This study does not support the routine use of soluble adhesion molecules as disease activity markers in IBD.

Lipopolysaccharide activation of the MEK-ERK1/2 pathway in human monocytic cells mediates tissue factor and tumor necrosis factor alpha expression by inducing Elk-1 phosphorylation and Egr-1 expression.

Lipopolysaccharide (LPS) induces human monocytes to express many proinflammatory mediators, including the procoagulant molecule tissue factor (TF) and the cytokine tumor necrosis factor alpha (TNF-alpha). The TF and TNF-alpha genes are regulated by various transcription factors, including nuclear factor (NF)-kappaB/Rel proteins and Egr-1. In this study, the role of the MEK-ERK1/2 mitogen-activated protein kinase (MAPK) pathway in LPS induction of TF and TNF-alpha gene expression in human monocytic cells was investigated. The MAPK kinase (MEK)1 inhibitor PD98059 reduced LPS induction of TF and TNF-alpha expression in a dose-dependent manner. PD98059 did not affect LPS-induced nuclear translocation of NF-kappaB/Rel proteins and minimally affected LPS induction of kappaB-dependent transcription. In contrast, PD98059 and dominant-negative mutants of the Ras-Raf1-MEK-ERK (extacellular signal-regulated kinase) pathway strongly inhibited LPS induction of Egr-1 expression. In kinetic experiments LPS induction of Egr-1 expression preceded induction of TF expression. In addition, mutation of the Egr-1 sites in the TF and TNF-alpha promoters reduced expression of these proinflammatory genes. It was demonstrated that LPS induction of the Egr-1 promoter was mediated by 3 SRE sites, which bound an LPS-inducible complex containing serum response factor and Elk-1. LPS stimulation transiently induced phosphorylation of Elk-1 and increased the functional activity of a GAL4-Elk-1TA chimeric protein via the MEK-ERK1/2 pathway. The data indicate that LPS induction of Egr-1 gene expression is required for maximal induction of the TNF-alpha and TF genes in human monocytic cells.