Relationship between abnormal maternal inflammation and insulin resistance during pregnancy

Abnormal maternal inflammation during pregnancy is linked to complications such as preeclampsia and fetal growth restriction. There is growing evidence that insulin resistance is also associated with a heightened inflammatory state, and is linked to pregnancy complications such as gestational diabetes. This study tested the hypothesis that abnormal inflammation during pregnancy is causally linked to elevations in blood glucose and insulin resistance. To induce a state of abnormal systemic inflammation, bacterial lipopolysaccharide (LPS) was administered to pregnant rats on gestational days (GD) 13.5-16.5. Dams treated with LPS exhibited an abnormal immune response characterized by an elevation in white blood cells, which was linked to reduced fetal weight and increased glucose levels over pregnancy. Abnormal inflammation is characterized by increased levels of circulating pro-inflammatory cytokines such as tumour necrosis factor alpha (TNF) and interleukin-6, which contribute to insulin resistance by inhibiting the insulin signalling pathway. TNF in particular induces a serine phosphorylation (pSer307) of insulin receptor substrate 1 (IRS-1). In our model, insulin resistance was assessed by measuring the extent of pSer307 of IRS-1 and total IRS-1 expression in skeletal muscle, as well as changes in metabolic parameters and pancreas tissue morphology associated with insulin resistance. LPS-treated dams exhibited a significant reduction in IRS-1 expression, elevation in fasting glucose levels, and reduction in insulin sensitivity indices. There were also biologically relevant increases in fasting plasma insulin levels and insulin resistance indices, but not pSer307 of IRS-1 and pancreatic islet size. To determine whether inflammation plays a role in reducing insulin signalling and the other changes associated with LPS administration, etanercept, a TNF antagonist, was administered on GDs 13.5 and 15.5 prior to LPS injections. With the exception of IRS-1 expression, in rats treated with etanercept all of the measured parameters remained at the levels observed in saline controls, indicating a link between abnormal inflammation and insulin resistance. The results of this study support the practice of monitoring the inflammatory conditions of the mother prior to and during pregnancy, and support further investigation into the potential use of anti-inflammatory agents during pregnancy in women at risk of insulin resistance and gestational diabetes.

Stabilization of zinc electrodes with a conducting polymer

The reversibility of zinc anode in alkaline medium was enhanced by electrostatic deposition of a conducting polymer (polypyrrole). Electropolymerization of pyrrole onto zinc in aqueous medium using an organic acid as dopant is feasible and preferred as zinc is less corrosive in this medium. The structure of the polymer film was analyzed by FT-IR spectroscopy and scanning electron microscopy. The effect of the polypyrrole deposit on the zinc electrode was studied by cyclic voltammetry and charge–discharge cycling.

Optimizing The Nasal Allergen Challenge Model For The Study Of Allergic Rhinitis

Background The Allergic Rhinitis Clinical Investigator Collaborative (AR-CIC) uses a Nasal Allergen Challenge (NAC) model to study the pathophysiology of AR and provides proof of concept for novel therapeutics. The NAC model needs to ensure optimal participant qualification, allergen challenge, clinical symptoms capture and biological samples collection. Repeatability of the protocol is key to ensuring unbiased efficacy analysis of novel therapeutics. The effect of allergen challenge on IL-33 gene expression and its relation to IL1RL1 receptor and cytokine secretion was investigated. Methods Several iterations of the NAC protocol was tested, comparing variations of qualifying criteria based on the Total Nasal Symptom Score (TNSS) and Peak Nasal Inspiratory Flow (PNIF). The lowest allergen concentration was delivered and TNSS and PNIF recorded 15 minutes later. Participants qualified if the particular criteria for the protocol were met, otherwise the next higher allergen concentration (4-fold increase), was administered until the targets were reached. Participants returned for a NAC visit and received varying allergen challenge concentrations depending on the protocol, TNSS/PNIF were recorded at 15 minutes, 30 minutes, 1 hour, and hourly up to 12 hours, a 24 hour time point was added in later iterations. Repeatability was evaluated using a 3-4week interval between screening, NAC1, and NAC2 visits. Various biomarker samples were collected. Results A combined TNSS and PNIF criterion was more successful in qualifying participants. The cumulative allergen challenge (CAC) protocol proved more reliable in producing a robust clinical and biomarker response. Repeatability of the CAC protocol was achieved with a 3-week interval between visits, on a clinical and biological basis. IL-33 cytokine is an important biomarker in initiating the inflammatory response in AR in humans. IL-33 and IL1RL1 expression might employ a negative feedback mechanism in human nasal epithelial cells. Comparing the clinical and biological response to ragweed vs cat allergen challenge, proved the CAC protocol’s suitability for use employing different allergens. Conclusion The AR-CIC’s CAC protocol is an effective method of studying AR, capable of generating measurable and repeatable clinical and biomarker responses, enabling better understanding of AR pathophysiology and ensuring that any change would be purely due to medication under investigation in a clinical trial setting.

Differences in Abdominal and Liver Fat Accumulation Between Obesity-Matched Adults With and Without Type 2 Diabetes

Despite attempts to identify the mechanisms by which obesity leads to the development of Type 2 Diabetes (T2D), it remains unclear why some but not all adults with obesity develop T2D. Given the established associations between visceral adipose tissue (VAT) and liver fat with insulin resistance, we hypothesized that compared to age and obesity matched adults who were non-diabetic (NT2D), adults with T2D would have greater amounts of VAT and liver fat. The International Study of Prediction of Intra-Abdominal Adiposity and Its Relationship with Cardiometabolic Risk/Intra-Abdominal Adiposity (INSPIRE ME IAA) aims to study the associations between VAT and liver fat and risk of developing T2D and cardiovascular disease. Four thousand, five hundred and four participants were initially recruited; from this, 2383 White and Asian adults were selected for this ancillary analysis. The NT2D and T2D groups were matched for age, body mass index (BMI) and waist circumference (WC). The T2D and NT2D groups were also compared to participants with either impaired fasting glucose (IFG) or impaired glucose tolerance (IGT; IFG/IGT)). Abdominal adipose tissue was measured by computed tomography; liver fat was estimated using computed tomography-derived mean attenuation. Secondary analysis determined whether differences existed between NT2D and T2D groups in VAT and liver fat accumulation within selected BMI categories for Whites and Asians. We report across sex and race, T2D and IFG/IGT groups had elevated VAT and liver fat compared to the NT2D group (p<0.05). VAT was not different between IFG/IGT and T2D groups (p>0.05), however liver fat was greater in the T2D group compared to the IFG/IGT group in both Whites and Asians (p<0.05). Within each BMI category, the T2D group had elevated VAT and liver fat compared to the age and anthropometrically matched NT2D group in both Whites and Asians (p<0.05). With few exceptions, abdominal subcutaneous adipose tissue was not different in the T2D or IFG/IGT groups compared to the NT2D group independent of sex and race. Compared to age and obesity-matched adults who are NT2D, we observe that White and Asian adults with T2D, and those with IFG/IGT, present with greater levels of both VAT and liver fat.

Long-term hydroclimatic change and interannual variability in water sources, Apex River (Iqaluit), Baffin Island, Nunavut

The eastern Canadian Arctic is home to Canada’s largest Indigenous population, which depends on local freshwater sources for drinking water. However, small watersheds have rarely been analyzed for long-term hydrologic response to changing climate. This study aims to address this issue by examining the Apex River, a small watershed with a long hydroclimatic record, near Iqaluit, Nunavut. Particular emphasis was placed on the long-term changes in climate and river discharge, and the seasonal variability of water sources between two snapshots in time, 1983 and 2013. Long-term hydrological data were obtained from gauge station 10UH002, operated by Environment and Climate Change Canada, and long-term meteorological data were acquired from Environment Canada–operated stations near Iqaluit Airport. Breakpoint analysis suggested that long-term mean annual surface air temperatures have increased since 1994. In contrast, no long-term total precipitation or annual discharge changes were observed. However, river flow initiation and cessation analyses of the Apex River flow season indicates that flow extended into the autumn since the 2000s. The 2013 flow season lasted 44 days longer than the 1983 flow season. Systematic river sampling was undertaken throughout the 2013 thaw season to determine contributing proportions of event (snowmelt or rainfall) and pre-event (baseflow) water to river runoff. Results from the stable isotope hydrograph separation for 2013 were compared to findings for 1983. Snow was the main source of water to the river during the snowmelt period in 1983 and 2013, however baseflow was still an important contributor. Although there was high similarity of water sources early in the season in 1983 and 2013, the two years differed during the autumn. In 2013 there was a high rainfall runoff response that was not present in 1983, suggesting high release of late-season sub-surface water storage and an increased sensitivity to late-season rainfall events in 2013. This research provides insights into the hydrologic response of the Apex River to long-term climatic change, and highlights the need for high-quality precipitation and discharge data for effective long-term hydrological assessment.

The Function of Intestinal Afferent Neurons in Regulating Satiety During Health and Obesity

Background and aim: Within the gastrointestinal tract, vagal afferents regulate satiety and food intake via chemical and mechanical mechanisms. Cysteinyl Leukotrienes (CysLTs) are lipid mediators that are believed to regulate food intake and body weight. However, the involvement of vagal afferents in this effect remains to be established. Conversely, Glucagon like peptide-1 (GLP-1) is a satiety and incretin peptide hormone. The effect of obesity on GLP-1 mediated gut-brain signaling has yet to be investigated. Since intestinal vagal afferents’ activity is reduced during obesity, it is intriguing to investigate their responses to GLP-1 in such conditions. Methods: Extracellular recordings were performed on intestinal afferents from normal C57Bl6, low fat fed (LFF), and high fat fed (HFF) mice. To examine the effect on neuronal calcium signaling, calcium-imaging experiments were performed on isolated nodose ganglion neurons. Food intake experiments were conducted using LFF and HFF mice. Oral glucose tolerance tests (OGTT) were carried out. Whole cell patch clamp recordings were performed on nodose ganglion neurons from A) normal C57Bl mice to test the effect of CysLTs on membrane excitability, B) LFF and HFF mice to examine GLP-1 effect on membrane excitability during obesity. c-Fos immunohistochemical techniques were performed to measure the level of neuronal activation in the brainstem of both LFF and HFF mice in response to Ex-4. Results: CysLTs increased intestinal afferent firing rate and mechanosensitivity. In single nodose neuron experiments, CysLTs increased excitability. The GLP-1 agonist Ex-4 significantly decreased food intake in LFF but not HFF mice. However, Ex-4 markedly attenuated the rise in blood glucose in both LFF and HFF mice. The observed increase in nerve firing and mechanosensitivity following the application of GLP-1 and Ex-4 was abolished in HFF mice. Cell membrane excitability was significantly increased by Ex-4 in nodose from LFF but not HFF mice. Ex-4 significantly increased the number of activated neurons in the NTS area of LFF mice but not in their HFF counterparts. Conclusion: The previous observations indicate that the role CysLTs play in regulating satiety is likely to be vagally mediated. Also that satiety, but not incretin, effects of GLP-1 are impaired during obesity.

Recapitulation of embryological programmes in renal fibrosis - The importance of epithelial cell plasticity and developmental genes

Chronic fibrosis represents the final common pathway in progressive renal disease. Myofibroblasts deposit the constituents of renal scar, thus crippling renal function. It has recently emerged that an important source of these pivotal effector cells is the injured renal epithelium. This review concentrates on the process of epithelial-mesenchymal transition (EMT) and its regulation. The role of the developmental gene, gremlin, which is reactivated in adult renal disease, is the subject of particular focus. This member of the cysteine knot protein superfamily is critical to the process of nephrogenesis but quiescent in normal adult kidney. There is increasing evidence that gremlin expression reactivates in diabetic nephropathy, and in the diseased fibrotic kidney per se. Known to antagonize members of the bone morphogenic protein (BMP) family, gremlin may also act downstream of TGF-beta in induction of EMT. An increased understanding of the extracellular modulation of EMT and, in particular, of the gremlin-BMP axis may result in strategies that can halt or reverse the devastating progression of chronic renal fibrosis. Copyright (c) 2006 S. Karger AG, Basel.

An assessment of the earth pressure coefficient in overconsolidated clays

The determination of the earth pressure coefficient K 0 in a natural clay deposit is a problem of considerable significance in geotechnical engineering. While the methods for evaluation of K 0 are reliable for normally consolidated soils, significant difficulties still exist in evaluating K 0 in overconsolidated clays, given that it is influenced by the stress history of the material, together with the age, structure, mineralogical composition and depositional environment. Indeed, some of these factors are responsible for the soil becoming anisotropic. The existing framework for prediction of K 0 in overconsolidated soils does not account for any influences caused by anisotropy. The work reported in this paper evaluates the validity of a revised relationship between K 0oc and OCR (overconsolidation ratio) using data obtained from laboratory investigations. The tests were performed on reconstituted and undisturbed samples of Belfast Upper Boulder Clay, London Clay and Gault Clay. Tests were also performed on reconstituted samples of kaolin. The values of K 0oc were determined using various approaches, including on-sample measurements. The results have confirmed that reliable predictions of K 0oc can be made using the proposed relationship.

A novel reciprocal and biphasic relationship between membrane cholesterol and beta-secretase activity in SH-SY5Y cells and in human platelets.

Research into the cause of Alzheimer's disease (AD) has identified strong connections to cholesterol. Cholesterol and cholesterol esters can modulate amyloid precursor protein (APP) processing, thus altering production of the A beta peptides that deposit in cortical amyloid plaques. Processing depends on the encounter between APP and cellular secretases, and is thus subject to the influence of cholesterol-dependent factors including protein trafficking, and distribution between membrane subdomains. We have directly investigated endogenous membrane beta-secretase activity in the presence of a range of membrane cholesterol levels in SH-SY5Y human neuroblastoma cells and human platelets. Membrane cholesterol significantly influenced membrane beta-secretase activity in a biphasic manner, with positive correlations at higher membrane cholesterol levels, and negative correlations at lower membrane cholesterol levels. Platelets from individuals with AD or mild cognitive impairment (n = 172) were significantly more likely to lie within the negative correlation zone than control platelets (n = 171). Pharmacological inhibition of SH-SY5Y beta-secretase activity resulted in increased membrane cholesterol levels. Our findings are consistent with the existence of a homeostatic feedback loop between membrane cholesterol level and membrane beta-secretase activity, and suggest that this regulatory mechanism is disrupted in platelets from individuals with cognitive impairment.

Credit Unions: A Theoretical and Empirical Overview

In 2009 there were over 49,330 credit unions across 98 countries with more than 184 million members and approximately $1,354 billion in assets. There is a great diversity within the credit union movement across these countries. This reflects the various economic, historic and cultural contexts within which credit unions operate. This paper traces the evolution of the credit union movement. It examines credit union objectives, and considers issues relating to efficiency, technology adoption, product diversification, merger, failure and demutualization. The regulatory environment within which credit unions operate is also explored under the themes of interest rate regulation, common bond requirements, taxation, deposit insurance and capital regulation. The overview also considers demutualization and the costs and benefits to credit unions of altering their organizational form.

Measurement of DNA damage by electrons with energies between 25 and 4000 eV.

All ionizing radiations deposit energy stochastically along their tracks. The resulting distribution of energies deposited in a small target such as the DNA helix leads to a corresponding spectrum in the severity of damage produced. So far, most information about the probable spectra of DNA lesion complexity has come from Monte Carlo studies which endeavour to model the relationship between the energy deposited in DNA and the damage induced. The aim of this paper is to establish methods of determining this relationship by irradiating pBR322 plasmid DNA using low energy electrons with energies comparable with the minimum energy thought to produce critical damage. The technique of agarose gel electrophoresis has been used to ascertain the fraction of DNA single- and double-strand breaks induced by monoenergetic electrons with energies as low as 25 eV. Our data show that the threshold electron energy for induction of single-strand breaks is

Information disclosure and depositor discipline in the Chinese banking sector

We investigate the relationship between information disclosure and depositor behaviour in the Chinese banking sector. Specifically, we enquire whether enhanced information disclosure enables investors to more effectively infer a banking institution's risk profile, thereby influencing their deposit decisions. Utilising an unbalanced panel, incorporating financial data from 169 Chinese banks over the 1998–2009 period, we employ generalised-method-of-moments (GMM) estimation procedures to control for potential endogeneity, unobserved heterogeneity, and persistence in the dependent variable. We uncover evidence that: (i) the growth rate of deposits is sensitive to bank fundamentals after controlling for macroeconomic factors, diversity in ownership structure, and government intervention; (ii) a bank publicly disclosing more transparent information in its financial reports, is more likely to experience growth in its deposit base; and (iii) banks characterised by high information transparency, well-capitalised and adopted international accounting standards, are more able to attract funds by offering higher interest rates.

Missing Links, Cultural Modernity and the Dead: Anatomically Modern Humans in the Great Cave of Niah (Sarawak, Borneo)

The Great Cave of Niah in Sarawak (northern Borneo) came into the gaze of Western Science through the work of Alfred Russell Wallace, who came to Sarawak in the 1850s to search for ‘missing links’ in his pioneering studies of evolution and the natural history of Island Southeast Asia and Australasia. The work of Tom and Barbara Harrisson in the 1950s and 1960s placed the Great Cave, and particularly their key find, the ‘Deep Skull’, at the nexus of the evolving archaeological framework for the region: for decades the skull, dated in 1958 by adjacent charcoal to c.40,000 BP, was the oldest fossil of an anatomically modern human anywhere in the world and thus critical to ideas about human evolution and dispersal. Although several authorities later questioned the provenance and antiquity of the Deep Skull, renewed investigations of the Harrisson excavations since 2000 have shown that it can be attributed securely to a specific location in the Pleistocene stratigraphy, with direct U-series dating on a piece of the skull indicating an age for it of c.37,500 BP and the first evidence for associated human activity at the site going back to c.50,000 BP. The new work also indicates that the skull is part of a cultural deposit, perhaps a precursor to the long tradition in Borneo of processing of the dead and secondary burial. These indicators of cultural complexity chime with the complexity of the subsistence behaviour of the early users of the caves discussed by Philip Piper and Ryan Rabett in chapter ten of this volume.

Deriving the Railway Mania

This article argues that the promotion boom which occurred in the railway industry during the mid 1840s was amplified by the issue of derivative-like assets, which let investors take highly leveraged positions in the shares of new railway companies. The partially paid shares which the new railway companies issued allowed investors to obtain exposure to an asset by paying only a small initial deposit. The consequence of this arrangement was that investor returns were substantially amplified, and many schemes could be financed simultaneously. However, when investors were required to make further payments it put a negative downward pressure on prices.

Identification of last interglacial deposits in eastern Beringia: a cautionary note from the Palisades, interior Alaska

Last interglacial sediments in unglaciated Alaska and Yukon (eastern Beringia) are commonly identified by palaeoecological indicators and stratigraphic position ~2-5m above the regionally prominent Old Crow tephra (124±10ka). We demonstrate that this approach can yield erroneous age assignments using data from a new exposure at the Palisades, a site in interior Alaska with numerous exposures of last interglacial sediments. Tephrochronology, stratigraphy, plant macrofossils, pollen and fossil insects from a prominent wood-rich organic silt unit are all consistent with a last interglacial age assignment. However, six 14C dates on plant and insect macrofossils from the organic silt range from non-finite to 4.0 14C ka BP, indicating that the organic silt instead represents a Holocene deposit with a mixed-age assemblage of organic material. In contrast, wood samples from presumed last interglacial organic-rich sediments elsewhere at the Palisades, in a similar stratigraphic position with respect to Old Crow tephra, yield non-finite 14C ages. Given that local permafrost thaw since the last interglaciation may facilitate reworking of older sediments into new stratigraphic positions, minimum constraining ages based on 14C dating or other methods should supplement age assignments for last interglacial sediments in eastern Beringia that are based on palaeoecology and stratigraphic association with Old Crow tephra.