Steatogenesis in adult-onset type II citrullinemia is associated with down-regulation of PPARα

AbstractSLC25A13 (citrin or aspartate–glutamate carrier 2) is located in the mitochondrial membrane in the liver and its genetic deficiency causes adult-onset type II citrullinemia (CTLN2). CTLN2 is one of the urea cycle disorders characterized by sudden-onset hyperammonemia due to reduced argininosuccinate synthase activity. This disorder is frequently accompanied with hepatosteatosis in the absence of obesity and ethanol consumption. However, the precise mechanism of steatogenesis remains unclear. The expression of genes associated with fatty acid (FA) and triglyceride (TG) metabolism was examined using liver samples obtained from 16 CTLN2 patients and compared with 7 healthy individuals. Although expression of hepatic genes associated with lipogenesis and TG hydrolysis was not changed, the mRNAs encoding enzymes/proteins involved in FA oxidation (carnitine palmitoyl-CoA transferase 1α, medium- and very-long-chain acyl-CoA dehydrogenases, and acyl-CoA oxidase 1), very-low-density lipoprotein secretion (microsomal TG transfer protein), and FA transport (CD36 and FA-binding protein 1), were markedly suppressed in CTLN2 patients. Serum concentrations of ketone bodies were also decreased in these patients, suggesting reduced mitochondrial β-oxidation activity. Consistent with these findings, the expression of peroxisome proliferator-activated receptor α (PPARα), a master regulator of hepatic lipid metabolism, was significantly down-regulated. Hepatic PPARα expression was inversely correlated with severity of steatosis and circulating ammonia and citrulline levels. Additionally, phosphorylation of c-Jun-N-terminal kinase was enhanced in CTLN2 livers, which was likely associated with lower hepatic PPARα. Collectively, down-regulation of PPARα is associated with steatogenesis in CTLN2 patients. These findings provide a novel link between urea cycle disorder, lipid metabolism, and PPARα

The desmosome and pemphigus

Desmosomes are patch-like intercellular adhering junctions (“maculae adherentes”), which, in concert with the related adherens junctions, provide the mechanical strength to intercellular adhesion. Therefore, it is not surprising that desmosomes are abundant in tissues subjected to significant mechanical stress such as stratified epithelia and myocardium. Desmosomal adhesion is based on the Ca2+-dependent, homo- and heterophilic transinteraction of cadherin-type adhesion molecules. Desmosomal cadherins are anchored to the intermediate filament cytoskeleton by adaptor proteins of the armadillo and plakin families. Desmosomes are dynamic structures subjected to regulation and are therefore targets of signalling pathways, which control their molecular composition and adhesive properties. Moreover, evidence is emerging that desmosomal components themselves take part in outside-in signalling under physiologic and pathologic conditions. Disturbed desmosomal adhesion contributes to the pathogenesis of a number of diseases such as pemphigus, which is caused by autoantibodies against desmosomal cadherins. Beside pemphigus, desmosome-associated diseases are caused by other mechanisms such as genetic defects or bacterial toxins. Because most of these diseases affect the skin, desmosomes are interesting not only for cell biologists who are inspired by their complex structure and molecular composition, but also for clinical physicians who are confronted with patients suffering from severe blistering skin diseases such as pemphigus. To develop disease-specific therapeutic approaches, more insights into the molecular composition and regulation of desmosomes are required

Pemphigus autoimmunity: Hypotheses and realities

The goal of contemporary research in pemphigus vulgaris and pemphigus foliaceus is to achieve and maintain clinical remission without corticosteroids. Recent advances of knowledge on pemphigus autoimmunity scrutinize old dogmas, resolve controversies, and open novel perspectives for treatment. Elucidation of intimate mechanisms of keratinocyte detachment and death in pemphigus has challenged the monopathogenic explanation of disease immunopathology. Over 50 organ-specific and non-organ-specific antigens can be targeted by pemphigus autoimmunity, including desmosomal cadherins and other adhesion molecules, PERP cholinergic and other cell membrane (CM) receptors, and mitochondrial proteins. The initial insult is sustained by the autoantibodies to the cell membrane receptor antigens triggering the intracellular signaling by Src, epidermal growth factor receptor kinase, protein kinases A and C, phospholipase C, mTOR, p38 MAPK, JNK, other tyrosine kinases, and calmodulin that cause basal cell shrinkage and ripping desmosomes off the CM. Autoantibodies synergize with effectors of apoptotic and oncotic pathways, serine proteases, and inflammatory cytokines to overcome the natural resistance and activate the cell death program in keratinocytes. The process of keratinocyte shrinkage/detachment and death via apoptosis/oncosis has been termed apoptolysis to emphasize that it is triggered by the same signal effectors and mediated by the same cell death enzymes. The natural course of pemphigus has improved due to a substantial progress in developing of the steroid-sparing therapies combining the immunosuppressive and direct anti-acantholytic effects. Further elucidation of the molecular mechanisms mediating immune dysregulation and apoptolysis in pemphigus should improve our understanding of disease pathogenesis and facilitate development of steroid-free treatment of patients

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Neural Oscillations and Networks in Processes Specific to Auditory Imagery

Auditory imagery is a cognitive process for generating sound in our mind. Despite the absence of external stimuli, neuroimaging studies have found overlapping neural activities within perception and imagery. While neuroimaging studies have revealed activities unique to auditory imagery, namely memory retrieval and mental manipulation, little is known about the functional oscillatory networks associated with these processes. Therefore, in this study, we aimed to distinguish between neural oscillations for memory retrieval and mental manipulation processes by building a novel experimental paradigm containing multiple imagery conditions with the goal of enabling the effective investigation of different oscillatory processes. We found that frontal and temporal gamma power was associated with mental manipulation, while frontotemporal delta phase coupling and delta-gamma phase-amplitude coupling were each associated with memory retrieval during auditory imagery. Moreover, we found that oscillations reflecting auditory-motor communication were associated with memory retrieval. Our results suggest the critical role of neural oscillations associated with imagery-specific processes and present evidence supporting the long-debated role of motor functions in auditory imagery. Our work thus adds dimension to the state of knowledge regarding functional networks within auditory imagery

Relationship between depression and risk of malnutrition among community-dwelling young-old and old-old elderly people.

This study explores the association between nutritional status and depression among healthy community-dwelling young-old (aged 65-74) and old-old elderly (aged 75 and older)

Concept Software Based on Kinect for Assessing Dual-Task Ability of Elderly People

[Objective]: Assessment of fall risk of elderly people is a critical issue. Dual-task (DT) ability is a criterion for risk assessment. We developed new concept software based on Microsoft (Redmond, WA) Kinect™ for assessing DT ability. The software is named "Dual-Task Tai Chi" (DTTC) and includes Tai Chi and number place (Sudoku) components. The purpose of this study is to validate the DTTC test for assessment of DT ability. [Subjects and Methods]: Forty-five community-dwelling elderly (mean age, 74.1±6.6 years) individuals participated in this study. They performed DTTC, locomotive, cognitive, and DT tests. DT ability was evaluated with a 10-m walk under a cognitive-task condition and a 10-m walk under a manual-task condition. The correlation between the time taken to complete the DTTC test and each function test was determined using Pearson correlation coefficients. Stepwise multiple regression analysis was conducted to assess the relationship between the DTTC test results and results of the other tests. [Results]: The time taken to complete the DTTC test was correlated with DT ability, locomotive functioning, and cognitive functioning. Results of stepwise multiple regression analysis confirmed that DT, balance, and cognitive ability are statistically significant. No statistically significant association was found for the other variables. [Conclusions]: The DTTC test quantitatively evaluates a compound function including DT, balance, and cognitive abilities

Effect of a Kinect-based exercise game on improving executive cognitive performance in community-dwelling elderly: case control study.

Background: Decrease of dual-task (DT) ability is known to be one of the risk factors for falls. We developed a new game concept, Dual-Task Tai Chi (DTTC), using Microsoft’s motion-capture device Kinect, and demonstrated that the DTTC test can quantitatively evaluate various functions that are known risk factors for falling in elderly adults. Moreover, DT training has been attracting attention as a way to improve balance and DT ability. However, only a few studies have reported that it improves cognitive performance. Objective: The purpose of this study was to demonstrate whether or not a 12-week program of DTTC training would effectively improve cognitive functions. Methods: This study examined cognitive functions in community-dwelling older adults before and after 12 weeks of DTTC training (training group [TG]) or standardized training (control group [CG]). Primary end points were based on the difference in cognitive functions between the TG and the CG. Cognitive functions were evaluated using the trail-making test (part A and part B) and verbal fluency test. Results: A total of 41 elderly individuals (TG: n=26, CG: n=15) participated in this study and their cognitive functions were assessed before and after DTTC training. Significant differences were observed between the two groups with significant group × time interactions for the executive cognitive function measure, the delta-trail-making test (part B−part A; F1,36=4.94, P=.03; TG: pre mean 48.8 [SD 43.9], post mean 42.2 [SD 29.0]; CG: pre mean 49.5 [SD 51.8], post mean 64.9 [SD 54.7]). Conclusions: The results suggest that DTTC training is effective for improving executive cognitive functions