Infection with Soil-Transmitted Helminths Is Associated with Increased Insulin Sensitivity

Objective

Given that helminth infections have been shown to improve insulin sensitivity in animal studies, which may be explained by beneficial effects on energy balance or by a shift in the immune system to an anti-inflammatory profile, we investigated whether soil-transmitted helminth (STH)-infected subjects are more insulin sensitive than STH-uninfected subjects.

Design

We performed a cross-sectional study on Flores island, Indonesia, an area with high prevalence of STH infections.

Methods

From 646 adults, stool samples were screened for Trichuris trichiura by microscopy and for Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale, and Strongyloides stercoralis by qPCR. No other helminth was found. We collected data on body mass index (BMI, kg/m²), waist-to-hip ratio (WHR), fasting blood glucose (FBG, mmol/L), insulin (pmol/L), high sensitive C-reactive protein (ng/ml) and Immunoglobulin E (IU/ml). The homeostatic model assessment for insulin resistance (HOMAIR) was calculated and regression models were used to assess the association between STH infection status and insulin resistance.

Results

424 (66%) participants had at least one STH infection. STH infected participants had lower BMI (23.2 vs 22.5 kg/m², p value = 0.03) and lower HOMAIR (0.97 vs 0.81, p value = 0.05). In an age-, sex- and BMI-adjusted model a significant association was seen between the number of infections and HOMAIR: for every additional infection with STH species, the HOMAIR decreased by 0.10 (p for linear trend 0.01). This effect was mainly accounted for by a decrease in insulin of 4.9 pmol/L for every infection (p for trend = 0.07).

Conclusion

STH infections are associated with a modest improvement of insulin sensitivity, which is not accounted for by STH effects on BMI alone.     

Endoscopically visible steam pop during high-energy laser pulmonary vein ablation

A 58-year-old woman with atrial fibrillation underwent laser balloon ablation at our centre. During 12 W ablation in the left superior pulmonary vein, a sudden steam pop was witnessed with displacement of the balloon catheter. Visualisation of the pulmonary vein antrum showed a red discolouration at the last ablation site.The endoscopically assisted laser balloon ablation system (EAS) is a relatively novel technique that is being used to perform pulmonary vein isolation (PVI) in the treatment of atrial fibrillation [1]. The EAS consists of a flexible, compliant balloon for sustained wall contact and a power adjustable laser beam for ablation independent of tissue contact.A 58-year-old woman underwent PVI with the EAS due to drug-refractory, symptomatic and paroxysmal atrial fibrillation. During 12 W ablation at the antrum of the left superior pulmonary vein (LSPV), a sudden steam pop was witnessed, with displacement of the EAS catheter (Fig. 1). Visualisation of the LSPV antrum showed a red discolouration, most likely a haematoma in the antral wall of the LSPV, at the last ablation site. A successful PVI was performed; the red discolouration was still present after 1 h. The patient did not develop symptoms related to the steam pop and echocardiography did not reveal any abnormalities.Open in a separate windowFig. 1Witnessed steam pop during endoscopically assisted ablation. Panel a displays the fifth ablation site in the left superior pulmonary vein (LSPV) where the steam pop occurred. The white ring of exposed tissue is a sign of optimal catheter-wall contact. Panel b displays the LSPV antrum directly after the steam pop. Note the red discolouration which was not present in panel a Steam pops are caused by overheating of myocardial tissue, exceeding 100 ℃, and are preceded by a shift in impedance levels, which cannot be measured with the EAS. Higher energy settings and higher contact force are known to increase the risk of steam pops. Steam pops can lead to tissue disruption and cardiac perforation [2]. However, steam pops appear to be a rare complication with reduced EAS energy settings, which we mostly used in 50 EAS patients, in whom no steam pops were observed [3].     

Antibodies against Immature Virions Are Not a Discriminating Factor for Dengue Disease Severity

Humoral immunity plays an important role in controlling dengue virus (DENV) infection. Antibodies (Abs) developed during primary infection protect against subsequent infection with the same dengue serotype, but can enhance disease following secondary infection with a heterologous serotype. A DENV virion has two surface proteins, envelope protein E and (pre)-membrane protein (pr)M, and inefficient cleavage of the prM protein during maturation of progeny virions leads to the secretion of immature and partially immature particles. Interestingly, we and others found that historically regarded non-infectious prM-containing DENV particles can become highly infectious in the presence of E- and prM-Abs. Accordingly, we hypothesized that these virions contribute to the exacerbation of disease during secondary infection. Here, we tested this hypothesis and investigated the ability of acute sera of 30 DENV2-infected patients with different grades of disease severity, to bind, neutralize and/or enhance immature DENV2. We found that a significant fraction of serum Abs bind to the prM protein and to immature virions, but we observed no significant difference between the disease severity groups. Furthermore, functional analysis of the Abs did not underscore any specific correlation between the neutralizing/enhancing activity towards immature DENV2 and the development of more severe disease. Based on our analysis of acute sera, we conclude that Abs binding to immature virions are not a discriminating factor in dengue pathogenesis.     

OmpW of Caulobacter crescentus Functions as an Outer Membrane Channel for Cations

Caulobacter crescentus is an oligotrophic bacterium that lives in dilute organic environments such as soil and freshwater. This bacterium represents an interesting model for cellular differentiation and regulation because daughter cells after division have different forms: one is motile while the other is non-motile and can adhere to surfaces. Interestingly, the known genome of C. crescentus does not contain genes predicted to code for outer membrane porins of the OmpF/C general diffusion type present in enteric bacteria or those coding for specific porins selective for classes of substrates. Instead, genes coding for 67 TonB-dependent outer membrane receptors have been identified, suggesting that active transport of specific nutrients may be the norm. Here, we report that high channel-forming activity was observed with crude outer membrane extracts of C. crescentus in lipid bilayer experiments, indicating that the outer membrane of C. crescentus contained an ion-permeable channel with a single-channel conductance of about 120 pS in 1M KCl. The channel-forming protein with an apparent molecular mass of about 20 kDa was purified to homogeneity. Partial protein sequencing of the protein indicated it was a member of the OmpW family of outer membrane proteins from Gram-negative bacteria. This channel was not observed in reconstitution experiments with crude outer membrane extracts of an OmpW deficient C. crescentus mutant. Biophysical analysis of the C. crescentus OmpW suggested that it has features that are special for general diffusion porins of Gram-negative outer membranes because it was not a wide aqueous channel. Furthermore, OmpW of C. crescentus seems to be different to known OmpW porins and has a preference for ions, in particular cations. A putative model for OmpW of C. crescentus was built on the basis of the known 3D-structures of OmpW of Escherichia coli and OprG of Pseudomonas aeruginosa using homology modeling. A comparison of the two known structures with the model of OmpW of C. crescentus suggested that it has a more hydrophilic interior and possibly a larger diameter.     

Change in HbA1c Levels between the Age of 8 Years and the Age of 12 Years in Dutch Children without Diabetes: The PIAMA Birth Cohort Study

Objective

HbA1c is associated with cardiovascular risk in persons without diabetes and cardiovascular risk accumulates over the life course. Therefore, insight in factors determining HbA1c from childhood onwards is important. We investigated (lifestyle) determinants of HbA1c at age 12 years and the effects of growth on change in HbA1c and the tracking of HbA1c between the age of 8 and 12 years.

Study Design and Methods

Anthropometric measurements were taken and HbA1c levels were assessed in 955 children without diabetes aged around 12 years participating in the PIAMA birth cohort study. In 363 of these children HbA1c was also measured at age 8 years. Data on parents and children were collected prospectively by questionnaires.

Results

We found no significant association between known risk factors for diabetes and HbA1c at age 12 years. Mean(SD) change in HbA1c between ages 8 and 12 years was 0.6(0.7) mmol/mol per year (or 0.1(0.1) %/yr). Anthropometric measures at age 8 and their change between age 8 and 12 years were not associated with the change in HbA1c. 68.9% of the children remained in the same quintile or had an HbA1c one quintile higher or lower at age 8 years compared to age 12 years.

Conclusion

The lack of association between known risk factors for diabetes and HbA1c suggest that HbA1c in children without diabetes is relatively unaffected by factors associated with glycaemia. HbA1c at age 8 years is by far the most important predictor of HbA1c at age 12. Therefore, the ranking of HbA1c levels appear to be fairly stable over time.     

Development of surface plasmon resonance biosensor assays for primary and secondary screening of acetylcholine binding protein ligands

Surface plasmon resonance (SPR) biosensors recently gained an important place in drug discovery. Here we present a primary and secondary SPR biosensor screening methodology. The primary screening method is based on a direct binding assay with covalent immobilized drug target proteins. For the secondary screening method, a sequential competition assay has been developed where the captured protein is first exposed to an unknown test compound, followed directly by an exposure to a high-molecular-weight reporter ligand. Using the high-molecular-weight reporter ligand to probe the remaining free binding site on the sensor, a significant signal enhancement is obtained. Furthermore, this assay format allows the validation of the primary direct binding assay format, efficiently revealing false positive data. As a model system, acetylcholine binding protein (AChBP), which is a soluble model protein for neuronal nicotinic acetylcholine receptors, has been used. The secondary assay is lower in throughput than the primary assay; however, the signal-to-noise ratio is two times higher compared with the direct assay, and it has a z′ factor of 0.96. Using both assays, we identified the compound tacrine as a ligand for AChBP.     

Efficacy of hyaluronic acid binding assay in selecting motile spermatozoa with normal morphology at high magnification

Background  

The present study aimed to evaluate the efficacy of the hyaluronic acid (HA) binding assay in the selection of motile spermatozoa with normal morphology at high magnification (8400x).     

Effects of cattle and rabbit grazing on clonal expansion of spiny shrubs in wood-pastures

Spiny shrubs protect non-defended plants against herbivores. Therefore, they play a role for the diversity in grazed ecosystems. While the importance of these keystone nurse shrubs is presently recognized, little is known about the factors controlling them. This knowledge is required to understand the functioning of grazed ecosystems and for sustainable management.We studied effects of cattle and rabbits on clonal expansion of Prunus spinosa in two ancient wood-pastures in the Netherlands. At each site we set up five blocks in grassland perpendicular to the edges of mature Prunus thickets, each block containing three herbivore treatments: (1) open-to-cattle-and-rabbits, (2) open to rabbits, cattle excluded, (3) cattle and rabbits excluded. We monitored the number and volume of Prunus ramets from 1998 to 2000 and again in 2003, 3 years after exclosure-removal to restore grazing.For 1998–2000 ramet volume, but not ramet number, differed between treatments. Ramet volume was highest when both cattle and rabbits were excluded. Ramet volume did not differ between grazing by rabbits or cattle and rabbits combined, indicating that rabbits alone may be as effective in inhibiting clonal expansion as cattle and rabbits combined. Three years after exclosure-removal ramet number and volume had increased in all treatments. Number of ramets remained unaffected by (former) treatments. Ramet volume remained highest in the former cattle-plus-rabbits exclusion treatment, differing significantly from the ‘open-to-cattle-and-rabbits’ treatment. So, once successfully established during herbivore absence, further expansion is not prevented by cattle and rabbit grazing.This study shows that vertebrate herbivory controls the keystone nurse-shrub in wood-pastures: combined cattle and rabbit grazing, and notably rabbits alone, inhibit expansion. Temporary herbivore absence allows expansion of ramets, which persists after herbivore-reappearance. Sustainable management of wood-pastures should allow spatial-temporal fluctuations of herbivore densities, leading to increased vegetation structure and associated biodiversity.     

Epidermal growth factor receptor fate is controlled by Hrs tyrosine phosphorylation sites that regulate Hrs degradation

Hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) is an endosomal protein essential for the efficient sorting of activated growth factor receptors into the lysosomal degradation pathway. Hrs undergoes ligand-induced tyrosine phosphorylation on residues Y329 and Y334 downstream of epidermal growth factor receptor (EGFR) activation. It has been difficult to investigate the functional roles of phosphoHrs, as only a small proportion of the cellular Hrs pool is detectably phosphorylated. Using an HEK 293 model system, we found that ectopic expression of the protein Cbl enhances Hrs ubiquitination and increases Hrs phosphorylation following cell stimulation with EGF. We exploited Cbl's expansion of the phosphoHrs pool to determine whether Hrs tyrosine phosphorylation controls EGFR fate. In structure-function studies of Cbl and EGFR mutants, the level of Hrs phosphorylation and rapidity of apparent Hrs dephosphorylation correlated directly with EGFR degradation. Differential expression of wild-type versus Y329,334F mutant Hrs in Hrs-depleted cells revealed that one or both tyrosines regulate ligand-dependent Hrs degradation, as well as EGFR degradation. By modulating Hrs ubiquitination, phosphorylation, and protein levels, Cbl may control the composition of the endosomal sorting machinery and its ability to target EGFR for lysosomal degradation.