Cardiac torsion-strain relationships in fatigued primary biliary cirrhosis patients show accelerated aging: a pilot cross-sectional study

The autoimmune liver disease primary biliary cirrhosis (PBC) is associated with life-altering fatigue in ～50% of patients. Previous work suggests that fatigued PBC subjects have evidence of autonomic dysfunction and may be at a higher risk of sudden cardiac death. The manifestation of this risk is not clear. This pilot study investigated whether alterations in cardiac torsion and strain could be detected in fatigued or nonfatigued early-stage PBC patients. We performed cardiac tissue tagging and anatomical cine-imaging in 13 early-stage PBC patients (including 7 with significant fatigue) and 10 control subjects to calculate cardiac torsion and strain throughout systole and diastole. From the cardiac tagging, we calculated the torsion-to-shortening ratio (TSR), a measure of subepicardial torsion exerting mechanical advantage over subendocardial shortening. Autonomic function testing was performed to evaluate baroreceptor effective index on standing. TSR was markedly increased in the fatigued PBC patients (0.70 ± 0.13) compared with both controls (0.46 ± 0.11, P = 0.002) and nonfatigued PBC patients (0.44 ± 0.12, P = 0.003). Decreased baroreceptor effective index on standing strongly correlated with increased TSR within the whole PBC group (r = -0.71, P = 0.007). Fatigued PBC patients demonstrate a redistribution of myocardial strain characteristic of a reduced relative contribution to contraction from the subendocardium. This is analogous to the changes found in healthy aging for subjects ～16 yr older than the fatigued PBC patients. Hence the hearts of fatigued PBC patients may be subject to processes of accelerated aging.     

Invasive fungal infections in solid organ transplant recipients

Invasive fungal infections are a major problem in solid organ transplant (SOT) recipients. Overall, the most common fungal infection in SOT is candidiasis, followed by aspergillosis and cryptococcosis, except in lung transplant recipients, where aspergillosis is most common. Development of invasive disease hinges on the interplay between host factors (e.g., integrity of anatomical barriers, innate and acquired immunity) and fungal factors (e.g., exposure, virulence and resistance to prophylaxis). In this article, we describe the epidemiology and clinical features of the most common fungal infections in organ transplantation. Within this context, we review recent advances in diagnostic modalities and antifungal chemotherapy, and their impact on evolving prophylaxis and treatment paradigms.     

Insulin and Endothelin in the Acute Regulation of Adiponectin in Vivo in Humans

Objective: In vitro, insulin and endothelin (ET) both modulate adiponectin secretion from adipocyte cell lines. The current studies were performed to assess whether endogenous ET contributes to the acute action of insulin infusions on adiponectin levels in vivo in humans. Research Methods and Procedures: We studied 17 lean and 20 obese subjects (BMI 21.8 ± 2.2 and 34.0 ± 5.0 kg/m², respectively). Hyperinsulinemic euglycemic clamp studies were performed using insulin infusion rates of 10, 30, or 300 mU/m² per minute alone or with concurrent infusion of BQ123, an antagonist of type A ET receptors. Circulating adiponectin levels were assessed at baseline and after achievement of steady‐state glucose with the insulin infusion. Results: Adiponectin levels were lower in obese than lean subjects (6.76 ± 3.66 vs. 8.37 ± 2.79 μg/mL, p = 0.0148 adjusted for differences across gender). Insulin infusions suppressed adiponectin by a mean of 7.8% (p < 0.0001). In a subset of 13 lean and 14 obese subjects for whom data with and without BQ123 were available, there was no evident effect of BQ123 to modulate clamp‐associated suppression of adiponectin (p = 0.16). Surprisingly, there was no evident relationship between steady‐state insulin concentrations and adiponectin suppression (r = 0.14, p = 0.30), and again no effect of BQ123 to modify this relationship was seen. Discussion: Despite baseline differences in adiponectin levels, we observed equal suppression of adiponectin with insulin infusions in lean and obese subjects. ET receptor antagonism with BQ123 did not modulate this effect, suggesting that endogenous ET does not have a role in modifying the acute effects of insulin on adiponectin production and/or disposition.     

A large-scale survey of genetic copy number variations among Han Chinese residing in Taiwan

Background

Winter migration of immature brown trout (Salmo trutta) into freshwater rivers has been hypothesized to result from physiologically stressful combinations of high salinity and low temperature in the sea.

Results

We sampled brown trout from two Danish populations entering different saline conditions and quantified expression of the hsp70 and Na/K-ATPases α 1b genes following acclimation to freshwater and full-strength seawater at 2°C and 10°C. An interaction effect of low temperature and high salinity on expression of both hsp70 and Na/K-ATPase α 1b was found in trout from the river entering high saline conditions, while a temperature independent up-regulation of both genes in full-strength seawater was found for trout entering marine conditions with lower salinities.

Conclusion

Overall our results support the hypothesis that physiologically stressful conditions in the sea drive sea-run brown trout into freshwater rivers in winter. However, our results also demonstrate intra-specific differences in expression of important stress and osmoregulative genes most likely reflecting adaptive differences between trout populations on a regional scale, thus strongly suggesting local adaptations driven by the local marine environment.     

XRCC1-DNA polymerase beta interaction is required for efficient base excision repair

X-ray repair cross-complementing protein-1 (XRCC1)-deficient cells are sensitive to DNA damaging agents and have delayed processing of DNA base lesions. In support of its role in base excision repair, it was found that XRCC1 forms a tight complex with DNA ligase IIIα and also interacts with DNA polymerase β (Pol β) and other base excision repair (BER) proteins. We have isolated wild-type XRCC1–DNA ligase IIIα heterodimer and mutated XRCC1–DNA ligase IIIα complex that does not interact with Pol β and tested their activities in BER reconstituted with human purified proteins. We find that a point mutation in the XRCC1 protein which disrupts functional interaction with Pol β, affected the ligation efficiency of the mutant XRCC1–DNA ligase IIIα heterodimer in reconstituted BER reactions. We also compared sensitivity to hydrogen peroxide between wild-type CHO-9 cells, XRCC1-deficient EM-C11 cells and EM-C11 cells transfected with empty plasmid vector or with plasmid vector carrying wild-type or mutant XRCC1 gene and find that the plasmid encoding XRCC1 protein, that does not interact with Pol β has reduced ability to rescue the hydrogen peroxide sensitivity of XRCC1- deficient cells. These data suggest an important role for the XRCC1–Pol β interaction for coordinating the efficiency of the BER process.     

Barley aleurone cells contain two types of vacuoles. Characterization Of lytic organelles by use of fluorescent probes

Light microscopy was used to study the structure and function of vacuoles in living protoplasts of barley (Hordeum vulgare cv Himalaya) aleurone. Light microscopy showed that aleurone protoplasts contain two distinct types of vacuole: the protein storage vacuole and a lysosome-like organelle, which we have called the secondary vacuole. Fluorescence microscopy using pH-sensitive fluorescent probes and a fluorogenic substrate for cysteine proteases showed that both protein storage vacuoles and secondary vacuoles are acidic, lytic organelles. Ratio imaging showed that the pH of secondary vacuoles was lower in aleurone protoplasts incubated in gibberellic acid than in those incubated in abscisic acid. Uptake of fluorescent probes into intact, isolated protein storage vacuoles and secondary vacuoles required ATP and occurred via at least two types of vanadate-sensitive, ATP-dependent tonoplast transporters. One transporter catalyzed the accumulation of glutathione-conjugated probes, and another transported probes not conjugated to glutathione.     

Identifying rare and common disease associated variants in genomic data using Parkinson’s disease as a model

Background

Genome-wide association studies have been successful in identifying common genetic variants for human diseases. However, much of the heritable variation associated with diseases such as Parkinson’s disease remains unknown suggesting that many more risk loci are yet to be identified. Rare variants have become important in disease association studies for explaining missing heritability. Methods for detecting this type of association require prior knowledge on candidate genes and combining variants within the region. These methods may suffer from power loss in situations with many neutral variants or causal variants with opposite effects.

Results

We propose a method capable of scanning genetic variants to identify the region most likely harbouring disease gene with rare and/or common causal variants. Our method assigns a score at each individual variant based on our scoring system. It uses aggregate scores to identify the region with disease association. We evaluate performance by simulation based on 1000 Genomes sequencing data and compare with three commonly used methods. We use a Parkinson’s disease case–control dataset as a model to demonstrate the application of our method.Our method has better power than CMC and WSS and similar power to SKAT-O with well-controlled type I error under simulation based on 1000 Genomes sequencing data. In real data analysis, we confirm the association of α-synuclein gene (SNCA) with Parkinson’s disease (p = 0.005). We further identify association with hyaluronan synthase 2 (HAS2, p = 0.028) and kringle containing transmembrane protein 1 (KREMEN1, p = 0.006). KREMEN1 is associated with Wnt signalling pathway which has been shown to play an important role for neurodegeneration in Parkinson’s disease.

Conclusions

Our method is time efficient and less sensitive to inclusion of neutral variants and direction effect of causal variants. It can narrow down a genomic region or a chromosome to a disease associated region. Using Parkinson’s disease as a model, our method not only confirms association for a known gene but also identifies two genes previously found by other studies. In spite of many existing methods, we conclude that our method serves as an efficient alternative for exploring genomic data containing both rare and common variants.

Electronic supplementary material

The online version of this article (doi:10.1186/s12929-014-0088-9) contains supplementary material, which is available to authorized users.     

Impact of temperature on Na2Sr(PO4)F:Eu3+ phosphor

In this article, we report the synthesis of Na₂Sr_1‐x(PO₄)F:Eu_x phosphor via a combustion method. The influence of different annealing temperatures on the photoluminescence properties was investigated. The phosphor was excited at both 254 and 393 nm. Na₂Sr_1‐x(PO₄)F:Eu_x³⁺ phosphors emit strong orange and red color at 593 and 612 nm, respectively, under both excitation wavelengths. Na₂Sr_1‐x(PO₄)F:Eu_x³⁺ phosphors annealed at 1050°C showed stronger emission intensity compared with 600, 900 and 1200°C. Moreover, Na₂Sr_1‐x(PO₄)F:Eu_x³⁺ phosphor was found to be more intense when compared with commercial Y₂O₃:Eu³⁺ phosphor. Copyright © 2013 John Wiley & Sons, Ltd.     

Role of Endogenous ET‐1 in the Regulation of Myocardial Blood Flow in Lean and Obese Humans

Endothelin is an important determinant of peripheral vascular tone, and increased endogenous endothelin activity contributes to peripheral vascular dysfunction in human obesity. The contributions of endothelin to the regulation of coronary vascular tone in health in humans have not been well studied. We hypothesized that the contribution of endothelin to the regulation of myocardial perfusion would be augmented in human obesity. Using [NH₃]ammonia positron emission tomography (PET), we measured myocardial perfusion under resting and adenosine‐stimulated conditions on two separate days, with and without concurrent exposure to BQ123, an antagonist of type A endothelin receptors (1 µmol/min IV beginning 90 min before measurement). We studied 10 lean and 9 obese subjects without hypertension, hyperlipidemia, or diabetes mellitus. We observed a BQ123‐induced increase in resting myocardial perfusion of ～40%, not different between lean and obese subjects (BQ123‐induced increase in flow: lean 0.12 ± 0.20, obese 0.32 ± 0.51 ml/g/min, P = 0.02 BQ123 effect, P = 0.27 comparing response across groups). Although basal flow rates varied by region of the myocardium, the BQ123 effect was seen in all regions. BMI and cholesterol were significantly related to BQ123‐induced increases in basal tone in multivariable analysis. There was no baseline difference in the adenosine‐stimulated increase in blood flow between lean and obese subjects, and BQ123 failed to augment these responses in either group. These observations suggest that endothelin is an important contributor to the regulation of myocardial perfusion under resting conditions in healthy lean and obese humans, with increased contributions in proportion to increasing obesity.     

Erratum

Neurotransmitter receptor trafficking and the regulation of synaptic strength. Traffic 2001:2(7):437–448.