ATN classification and clinical progression in subjective cognitive decline

Objective: To investigate the relationship between the ATN classification system (amyloid, tau, neurodegeneration) and risk of dementia and cognitive decline in individuals with subjective cognitive decline (SCD). / Methods: We classified 693 participants with SCD (60 ± 9 years, 41% women, Mini-Mental State Examination score 28 ± 2) from the Amsterdam Dementia Cohort and Subjective Cognitive Impairment Cohort (SCIENCe) project according to the ATN model, as determined by amyloid PET or CSF β-amyloid (A), CSF p-tau (T), and MRI-based medial temporal lobe atrophy (N). All underwent extensive neuropsychological assessment. For 342 participants, follow-up was available (3 ± 2 years). As a control population, we included 124 participants without SCD. / Results: Fifty-six (n = 385) participants had normal Alzheimer disease (AD) biomarkers (A–T–N–), 27% (n = 186) had non-AD pathologic change (A–T–N+, A–T+N–, A–T+N+), 18% (n = 122) fell within the Alzheimer continuum (A+T–N–, A+T–N+, A+T+N–, A+T+N+). ATN profiles were unevenly distributed, with A–T+N+, A+T–N+, and A+T+N+ containing very few participants. Cox regression showed that compared to A–T–N–, participants in A+ profiles had a higher risk of dementia with a dose–response pattern for number of biomarkers affected. Linear mixed models showed participants in A+ profiles showed a steeper decline on tests addressing memory, attention, language, and executive functions. In the control group, there was no association between ATN and cognition. / Conclusions: Among individuals presenting with SCD at a memory clinic, those with a biomarker profile A–T+N+, A+T–N–, A+T+N–, and A+T+N+ were at increased risk of dementia, and showed steeper cognitive decline compared to A–T–N– individuals. These results suggest a future where biomarker results could be used for individualized risk profiling in cognitively normal individuals presenting at a memory clinic

Nuclear Factor (NF) κB polymorphism is associated with heart function in patients with heart failure

<p>Abstract</p> <p>Background</p> <p>Cardiac remodeling is generally an adverse sign and is associated with heart failure (HF) progression. NFkB, an important transcription factor involved in many cell survival pathways, has been implicated in the remodeling process, but its role in the heart is still controversial. Recently, a promoter polymorphism associated with a lesser activation of the <it>NFKB1 </it>gene was also associated with Dilated Cardiomyopathy. The purpose of this study was to evaluate the association of this polymorphism with clinical and functional characteristics of heart failure patients of different etiologies.</p> <p>Methods</p> <p>A total of 493 patients with HF and 916 individuals from a cohort of individuals from the general population were investigated. The <it>NFKB1 </it>-94 insertion/deletion ATTG polymorphism was genotyped by High Resolution Melt discrimination. Allele and genotype frequencies were compared between groups. In addition, frequencies or mean values of different phenotypes associated with cardiovascular disease were compared between genotype groups. Finally, patients were prospectively followed-up for death incidence and genotypes for the polymorphism were compared regarding disease onset and mortality incidence in HF patients.</p> <p>Results</p> <p>We did not find differences in genotype and allelic frequencies between cases and controls. Interestingly, we found an association between the ATTG₁/ATTG₁genotype with right ventricle diameter (<it>P </it>= 0.001), left ventricle diastolic diameter (P = 0.04), and ejection fraction (EF) (P = 0.016), being the genotype ATTG₁/ATTG₁more frequent in patients with EF lower than 50% (<it>P </it>= 0.01). Finally, we observed a significantly earlier disease onset in ATTG1/ATTG₁carriers.</p> <p>Conclusion</p> <p>There is no genotype or allelic association between the studied polymorphism and the occurrence of HF in the tested population. However, our data suggest that a diminished activation of <it>NFKB1</it>, previously associated with the ATTG₁/ATTG₁genotype, may act modulating on the onset of disease and, once the individual has HF, the genotype may modulate disease severity by increasing cardiac remodeling and function deterioration.</p

Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS.

Ischaemia-reperfusion injury occurs when the blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death and aberrant immune responses through the generation of mitochondrial reactive oxygen species (ROS). Although mitochondrial ROS production in ischaemia reperfusion is established, it has generally been considered a nonspecific response to reperfusion. Here we develop a comparative in vivo metabolomic analysis, and unexpectedly identify widely conserved metabolic pathways responsible for mitochondrial ROS production during ischaemia reperfusion. We show that selective accumulation of the citric acid cycle intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase, which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. After reperfusion, the accumulated succinate is rapidly re-oxidized by succinate dehydrogenase, driving extensive ROS generation by reverse electron transport at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo ischaemia-reperfusion injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of ischaemia-reperfusion injury. Furthermore, these findings reveal a new pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation after subsequent reperfusion is a potential therapeutic target to decrease ischaemia-reperfusion injury in a range of pathologies

Choosing to live with home dialysis-patients' experiences and potential for telemedicine support: a qualitative study

<p>Abstract</p> <p>Background</p> <p>This study examines the patients' need for information and guidance in the selection of dialysis modality, and in establishing and practicing home dialysis. The study focuses on patients' experiences living with home dialysis, how they master the treatment, and their views on how to optimize communication with health services and the potential of telemedicine.</p> <p>Methods</p> <p>We used an inductive research strategy and conducted semi-structured interviews with eleven patients established in home dialysis. Our focus was the patients' experiences with home dialysis, and our theoretical reference was patients' empowerment through telemedicine solutions. Three informants had home haemodialysis (HHD); eight had peritoneal dialysis (PD), of which three had automated peritoneal dialysis (APD); and five had continuous ambulatory peritoneal dialysis (CAPD). The material comprises all PD-patients in the catchment area capable of being interviewed, and all known HHD-users in Norway at that time.</p> <p>Results</p> <p>All of the interviewees were satisfied with their choice of home dialysis, and many experienced a normalization of daily life, less dominated by disease. They exhibited considerable self-management skills and did not perceive themselves as ill, but still required very close contact with the hospital staff for communication and follow-up. When choosing a dialysis modality, other patients' experiences were often more influential than advice from specialists. Information concerning the possibility of having HHD, including knowledge of how to access it, was not easily available. Especially those with dialysis machines, both APD and HHD, saw a potential for telemedicine solutions.</p> <p>Conclusions</p> <p>As home dialysis may contribute to a normalization of life less dominated by disease, the treatment should be organized so that the potential for home dialysis can be fully exploited. Pre-dialysis information should be unbiased and include access to other patients' experiences. Telemedicine may potentially facilitate a communication-based follow-up and improve safety within the home setting, making it easier to choose and live with home dialysis.</p

Clusters of Basic Amino Acids Contribute to RNA Binding and Nucleolar Localization of Ribosomal Protein L22

The ribosomal protein L22 is a component of the 60S eukaryotic ribosomal subunit. As an RNA-binding protein, it has been shown to interact with both cellular and viral RNAs including 28S rRNA and the Epstein-Barr virus encoded RNA, EBER-1. L22 is localized to the cell nucleus where it accumulates in nucleoli. Although previous studies demonstrated that a specific amino acid sequence is required for nucleolar localization, the RNA-binding domain has not been identified. Here, we investigated the hypothesis that the nucleolar accumulation of L22 is linked to its ability to bind RNA. To address this hypothesis, mutated L22 proteins were generated to assess the contribution of specific amino acids to RNA binding and protein localization. Using RNA-protein binding assays, we demonstrate that basic amino acids 80–93 are required for high affinity binding of 28S rRNA and EBER-1 by L22. Fluorescence localization studies using GFP-tagged mutated L22 proteins further reveal that basic amino acids 80–93 are critical for nucleolar accumulation and for incorporation into ribosomes. Our data support the growing consensus that the nucleolar accumulation of ribosomal proteins may not be mediated by a defined localization signal, but rather by specific interaction with established nucleolar components such as rRNA

The Prometastatic Microenvironment of the Liver

The liver is a major metastasis-susceptible site and majority of patients with hepatic metastasis die from the disease in the absence of efficient treatments. The intrahepatic circulation and microvascular arrest of cancer cells trigger a local inflammatory reaction leading to cancer cell apoptosis and cytotoxicity via oxidative stress mediators (mainly nitric oxide and hydrogen peroxide) and hepatic natural killer cells. However, certain cancer cells that resist or even deactivate these anti-tumoral defense mechanisms still can adhere to endothelial cells of the hepatic microvasculature through proinflammatory cytokine-mediated mechanisms. During their temporary residence, some of these cancer cells ignore growth-inhibitory factors while respond to proliferation-stimulating factors released from tumor-activated hepatocytes and sinusoidal cells. This leads to avascular micrometastasis generation in periportal areas of hepatic lobules. Hepatocytes and myofibroblasts derived from portal tracts and activated hepatic stellate cells are next recruited into some of these avascular micrometastases. These create a private microenvironment that supports their development through the specific release of both proangiogenic factors and cancer cell invasion- and proliferation-stimulating factors. Moreover, both soluble factors from tumor-activated hepatocytes and myofibroblasts also contribute to the regulation of metastatic cancer cell genes. Therefore, the liver offers a prometastatic microenvironment to circulating cancer cells that supports metastasis development. The ability to resist anti-tumor hepatic defense and to take advantage of hepatic cell-derived factors are key phenotypic properties of liver-metastasizing cancer cells. Knowledge on hepatic metastasis regulation by microenvironment opens multiple opportunities for metastasis inhibition at both subclinical and advanced stages. In addition, together with metastasis-related gene profiles revealing the existence of liver metastasis potential in primary tumors, new biomarkers on the prometastatic microenvironment of the liver may be helpful for the individual assessment of hepatic metastasis risk in cancer patients

An optimized clearing protocol for the quantitative assessment of sub-epidermal ovule tissues within whole cereal pistils

Background: Seed development in the angiosperms requires the production of a female gametophyte (embryo sac) within the ovule. Many aspects of female reproductive development in cereal crops are yet to be described, largely due to the technical difficulty in obtaining phenotypic information at the cellular or sub-cellular level. Hoyer’s solution is currently well established as a solution for clearing thin tissues samples, such as sections or whole tissues of bryophytes, mycorrhizal fungi, and small model organisms (e.g. Arabidopsis thaliana). Results: Here we report a Hoyer’s solution-based clearing method to facilitate clearing of the whole barley pistil, with high reproducibility. The clearing process takes 10 days from fixation to visualisation, whereupon tissue is sufficiently clear to obtain multiple phenotypic measurements from sub-epidermal tissues and cells within the ovule. Conclusion: Visualisation of cereal ovules that have not been dissected from the pistil allows an unprecedented capability to collect quantitative morphological information from the developing ovule, integument, nucellus and embryo sac. This will enable comparisons with genetic data to reveal the contribution of pre-fertilisation ovule tissues towards downstream seed development.Laura G. Wilkinson and Matthew R. Tucke

Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery

To commemorate the auspicious occasion of the 30th anniversary of IPC, leading pioneers in the field of cardioprotection gathered in Barcelona in May 2016 to review and discuss the history of IPC, its evolution to IPost and RIC, myocardial reperfusion injury as a therapeutic target, and future targets and strategies for cardioprotection. This article provides an overview of the major topics discussed at this special meeting and underscores the huge importance and impact, the discovery of IPC has made in the field of cardiovascular research