TDAG51 induces renal interstitial fibrosis through modulation of TGF-β receptor 1 in chronic kidney disease

Chronic kidney disease (CKD) is characterized by the gradual loss of renal function and is a major public health concern. Risk factors for CKD include hypertension and proteinuria, both of which are associated with endoplasmic reticulum (ER) stress. ER stress-induced TDAG51 protein expression is increased at an early time point in mice with CKD. Based on these findings, wild-type and TDAG51 knock-out (TDKO) mice were used in an angiotensin II/deoxycorticosterone acetate/salt model of CKD. Both wild-type and TDKO mice developed hypertension, increased proteinuria and albuminuria, glomerular injury, and tubular damage. However, TDKO mice were protected from apoptosis and renal interstitial fibrosis. Human proximal tubular cells were used to demonstrate that TDAG51 expression induces apoptosis through a CHOP-dependent mechanism. Further, a mouse model of intrinsic acute kidney injury demonstrated that CHOP is required for ER stress-mediated apoptosis. Renal fibroblasts were used to demonstrate that TGF-β induces collagen production through an IRE1-dependent mechanism; cells treated with a TGF-β receptor 1 inhibitor prevented XBP1 splicing, a downstream consequence of IRE1 activation. Interestingly, TDKO mice express significantly less TGF-β receptor 1, thus, preventing TGF-β-mediated XBP1 splicing. In conclusion, TDAG51 induces apoptosis in the kidney through a CHOP-dependent mechanism, while contributing to renal interstitial fibrosis through a TGF-β-IRE1-XBP1 pathway.Subject terms: Endoplasmic reticulum, Apoptosis, End-stage renal disease, Preclinical research, Chronic inflammation     

Embodied Subjects and Fragmented Objects: Women’s Bodies,Assisted Reproduction Technologies and the Right to Self-Determination

This article focuses on the transformation of the female reproductive body with the use of assisted reproduction technologies under neo-liberal economic globalisation, wherein the ideology of trade without borders is central, as well as under liberal feminist ideals, wherein the right to self-determination is central. Two aspects of the body in western medicine—the fragmented body and the commodified body, and the integral relation between these two—are highlighted. This is done in order to analyse the implications of local and global transactions in women’s reproductive body parts for their right to self-determination and individual agency and what this means for their embodiment. We conclude by exploring whether women can become embodied subjects by exercising their proprietary right to their bodies through directing technology to achieve their own goals, while at the same time being fragmented into parts and losing their personhood and bodily integrity. This article has been translated and adapted from the Dutch version published in the Tijdschrift voor Humanistiek, 2006; 26(7).     

Myocardial Metastases on 6-[18F] fluoro-L-DOPA PET/CT: A Retrospective Analysis of 116 Serotonin Producing Neuroendocrine Tumour Patients

Purpose

This study evaluates the prevalence of cardiac metastases in patients with serotonin producing neuroendocrine tumours (NET), examined with ¹⁸F-FDOPA PET/CT, and the relationship of these metastases to the presence of carcinoid heart disease (CHD) based on echocardiography.

Background

CHD occurs in patients with serotonin producing NET. The diagnostic method of choice remains echocardiography. The precise prevalence of cardiac metastases is unknown given the limitations of standard technologies. Nuclear medicine modalities have the potential to visualize metastases of NET.

Methods

All patients who underwent ¹⁸F-FDOPA PET/CT because of serotonin producing NET between November 2009 and May 2012 were retrospectively analyzed. The presence of cardiac metastasis was defined as myocardial tracer accumulation higher than the surrounding physiological myocardial uptake. Laboratory tests and transthoracic echocardiography (TTE) results were digitally collected.

Results

116 patients (62 male) underwent ¹⁸F-FDOPA PET/CT, mean age was 61±13 years. TTE was performed in 79 patients. Cardiac metastases were present in 15 patients, of which 10 patients also underwent TTE. One patient had both cardiac metastasis (only on ¹⁸F-FDOPA PET/CT) and echocardiographic signs of CHD. There were no differences in echocardiographic parameters for CHD between patients with and without cardiac metastases. TTE in none of the 79 patients showed cardiac metastases.

Conclusion

The prevalence of cardiac metastases detected with ¹⁸F-FDOPA PET/CT in this study is 13%. ¹⁸F-FDOPA PET/CT can visualize cardiac metastases in serotonin producing NET patients. There appears to be no relationship between the presence of cardiac metastases and TTE parameters of CHD.     

Survival after Locoregional Recurrence or Second Primary Breast Cancer: Impact of the Disease-Free Interval

The association between the disease-free interval (DFI) and survival after a locoregional recurrence (LRR) or second primary (SP) breast cancer remains uncertain. The objective of this study is to clarify this association to obtain more information on expected prognosis. Women first diagnosed with early breast cancer between 2003–2006 were selected from the Netherlands Cancer Registry. LRRs and SP tumours within five years of first diagnosis were examined. The five-year period was subsequently divided into three equal intervals. Prognostic significance of the DFI on survival after a LRR or SP tumour was determined using Kaplan-Meier estimates and multivariable Cox regression analysis. Follow-up was complete until January 1, 2014. A total of 37,278 women was included in the analysis. LRRs or SP tumours were diagnosed in 890 (2,4%) and 897 (2,4%) respectively. Longer DFI was strongly and independently related to an improved survival after a LRR (long versus short: HR 0.65, 95% CI 0.48–0.88; medium versus short HR 0.81, 95% CI 0.65–1.01). Other factors related to improved survival after LRR were younger age (<70 years) and surgical removal of the recurrence. No significant association was found between DFI and survival after SP tumours. This is the first study to explore the association between the DFI and survival after recurrence in a nationwide population-based cancer registry. The DFI before a LRR is an independent prognostic factor for survival, with a longer DFI predicting better prognosis.     

Calibration of EMG to force for knee muscles is applicable with submaximal voluntary contractions.

PURPOSE: In this study, the influence of using submaximal isokinetic contractions about the knee compared to maximal voluntary contractions as input to obtain the calibration of an EMG-force model for knee muscles is investigated. METHODS: Isokinetic knee flexion and extension contractions were performed by healthy subjects at five different velocities and at three contraction levels (100%, 75% and 50% of MVC). Joint angle, angular velocity, joint moment and surface EMG of five knee muscles were recorded. Individual calibration values were calculated according to [C.A.M. Doorenbosch, J. Harlaar, A clinically applicable EMG-force model to quantify active stabilization of the knee after a lesion of the anterior cruciate ligament, Clinical Biomechanics 18 (2003) 142-149] for each contraction level. RESULTS: First, the output of the model, calibrated with the 100% MVC was compared to the actually exerted net knee moment at the dynamometer. Normalized root mean square errors were calculated [A.L. Hof, C.A.N. Pronk, J.A. van Best, Comparison between EMG to force processing and kinetic analysis for the calf muscle moment in walking and stepping, Journal of Biomechanics 20 (1987) 167-187] to compare the estimated moments with the actually exerted moments. Mean RMSD errors ranged from 0.06 to 0.21 for extension and from 0.12 to 0.29 for flexion at the 100% trials. Subsequently, the calibration results of the 50% and 75% MVC calibration procedures were used. A standard signal, representing a random EMG level was used as input in the EMG force model, to compare the three models. Paired samples t-tests between the 100% MVC and the 75% MVC and 50% MVC, respectively, showed no significant differences (p>0.05). CONCLUSION: The application of submaximal contractions of larger than 50% MVC is suitable to calibrate a simple EMG to force model for knee extension and flexion. This means that in clinical practice, the EMG to force model can be applied by patients who cannot exert maximal force.     

Biofungicides as alternative to synthetic fungicide control of grey mould (Botrytis cinerea) – prospects and challenges

Botrytis cinerea is one of the most destructive pathogens of ve?getables and fruits both in the field and storage. There have been several research activities focused on developing biocontrol strategies for the pathogen due to its resistance to the commonly used synthetic fungicides. Additionally, concerns have been raised over residual effect of current synthetic fungicides used for its control. Most of these research activities have focused on Trichoderma spp., Ulocladium spp., Bacillus subtilis, plant extracts and their essential oils with some commercial products available on the market for the control of B. cinerea disease. This review summarises some of the current published information on the use of biocontrol agents and plant-based compounds for B. cinerea control. Some limitations and future prospects were also mentioned.     

A high-resolution anatomical ontology of the developing murine genitourinary tract

Cataloguing gene expression during development of the genitourinary tract will increase our understanding not only of this process but also of congenital defects and disease affecting this organ system. We have developed a high-resolution ontology with which to describe the subcompartments of the developing murine genitourinary tract. This ontology incorporates what can be defined histologically and begins to encompass other structures and cell types already identified at the molecular level. The ontology is being used to annotate in situ hybridisation data generated as part of the Genitourinary Development Molecular Anatomy Project (GUDMAP), a publicly available data resource on gene and protein expression during genitourinary development. The GUDMAP ontology encompasses Theiler stage (TS) 17-27 of development as well as the sexually mature adult. It has been written as a partonomic, text-based, hierarchical ontology that, for the embryological stages, has been developed as a high-resolution expansion of the existing Edinburgh Mouse Atlas Project (EMAP) ontology. It also includes group terms for well-characterised structural and/or functional units comprising several sub-structures, such as the nephron and juxtaglomerular complex. Each term has been assigned a unique identification number. Synonyms have been used to improve the success of query searching and maintain wherever possible existing EMAP terms relating to this organ system. We describe here the principles and structure of the ontology and provide representative diagrammatic, histological, and whole mount and section RNA in situ hybridisation images to clarify the terms used within the ontology. Visual examples of how terms appear in different specimen types are also provided.     

Male Mating Tactics in Captive Rhesus Macaques (Macaca mulatta): The Influence of Dominance, Markets, and Relationship Quality

Male mating success in a multimale–multifemale group can depend on several variables: body condition, dominance, coalitions, “friendship,” or an exchange of services for mating access. Exchange patterns may also be determined by market effects or social relationships. We studied the mating tactics of males in a captive, multimale–multifemale group of rhesus macaques and the resulting patterns of mating and paternity to determine the influence of dominance rank, mating markets, and relationship quality on their mating tactics. Male rank was positively related to the total number of copulations and the number of mating partners, but did not explain male mating distribution completely. Moreover, male fertilization success was not related to male rank. Males did not exchange grooming for mating access on the same day and neither the supply nor the rank (as a proxy for quality) of receptive females affected the amount of male grooming, suggesting that market effects did not explain male mating access. However, there was a positive correlation between long-term grooming patterns of both males and females and mating access, indicating that social relationships were important for male mating access. Paternity data revealed that these social relationships were also important for male reproductive success. We conclude that both male rank and male–female “friendship” determined male mating access in these rhesus macaques, but that “friendship” was more important in determining paternity, emphasizing the importance of intersex social bonds in male mating success in multimale primate societies.