Preventing hyperhomocysteinemia using vitamin B6 supplementation in Givosiran-treated acute intermittent porphyria: Highlights from a case report and brief literature review.

Acute hepatic porphyrias are inherited metabolic disorders of heme biosynthesis characterized by the accumulation of toxic intermediate metabolites responsible for disabling acute neurovisceral attacks. Givosiran is a newly approved siRNA-based treatment of acute hepatic porphyria targeting the first and rate-limiting δ-aminolevulinic acid synthase 1 (ALAS1) enzyme of heme biosynthetic pathway. We described a 72-year old patient who presented with severe inaugural neurological form of acute intermittent porphyria evolving for several years which made her eligible for givosiran administration. On initiation of treatment, the patient developed a major hyperhomocysteinemia (>400 µmol/L) which necessitated to discontinue the siRNA-based therapy. A thorough metabolic analysis in the patient suggests that hyperhomocysteinemia could be attributed to a functional deficiency of cystathionine ß-synthase (CBS) enzyme induced by givosiran. Long-term treatment with vitamin B6, a cofactor of CBS, allowed to normalize homocysteinemia while givosiran treatment was maintained. We review the recently published cases of hyperhomocysteinemia in acute hepatic porphyria and its exacerbation under givosiran therapy. We also discuss the benefits of vitamin B6 supplementation in the light of hypothetic pathophysiological mechanisms responsible for hyperhomocysteinemia in these patients. Our results confirmed the importance of monitoring homocysteine metabolism and vitamin status in patients with acute intermittent porphyria in order to improve management by appropriate vitamin supplementation during givosiran treatment.

Adrenal insufficiency revealing bilateral adrenal hemorrhage related to JAK2 V617F-positive essential thrombocythemia: about two cases.

Bilateral adrenal hemorrhage is a rare cause of adrenal insufficiency which has been rarely associated with myeloproliferative neoplasms. Here, we report two cases of bilateral adrenal hemorrhage revealed by abdominal pain, malaise, and fatigue in two octogenarian males previously diagnosed with JAK2 V617F-positive essential thrombocythemia. Both patients were on long-term direct oral anticoagulant treatment for atrial fibrillation. Evolution was favorable under steroid replacement therapy, associated with cytoreduction, aspirin, and switch of direct oral anticoagulants for vitamin K antagonists.

Pilot study on accelerated aging in lupus using epigenetic biomarkers of age.

OBJECTIVE: Despite an important increase in lifespan over the last decades, patients with systemic lupus erythematosus (SLE) still have to face a high morbi-mortality, particularly related to cardiovascular diseases, infections and cancers. Such events are more commonly found during old age in the general population, raising the hypothesis of an acceleration of the aging process in SLE patients. In this pilot study, we wanted to test the hypothesis that SLE would be associated with an accelerated biological aging measured by the epigenetic clocks models. METHODS: We applied DNA methylation-based biomarkers of age in publicly available datasets of SLE patients. For every SLE patient and control included in the dataset, we calculated their epigenetic age and a measure of epigenetic age acceleration, according to Horvath's epigenetic clock model. RESULTS: We included in our analysis two distinct DNA methylation datasets of 30 subjects (among which 15 with SLE) and 55 subjects (among which 30 with SLE), respectively. In both datasets, there was a statistically significant correlation between chronological age and epigenetic age. We did not observe any statistically significant difference in the measure of epigenetic age acceleration between SLE patients and controls. CONCLUSION: We did not observe any evidence of an accelerated biological aging in SLE patients, according to Horvath's epigenetic clock model.

Knowledge of Nutrition and Physical Activity Guidelines is Not Associated with Physical Function in Dutch Older Adults Attending a Healthy Ageing Public Engagement Event.

Purpose: Evidence-based guidelines on nutrition and physical activity are used to increase knowledge in order to promote a healthy lifestyle. However, actual knowledge of guidelines is limited and whether it is associated with health outcomes is unclear. Participants and Methods: This inception cohort study aimed to investigate the association of knowledge of nutrition and physical activity guidelines with objective measures of physical function and physical activity in community-dwelling older adults attending a public engagement event in Amsterdam, The Netherlands. Knowledge of nutrition and physical activity according to Dutch guidelines was assessed using customized questionnaires. Gait speed and handgrip strength were proxies of physical function and the Minnesota Leisure Time Physical Activity Questionnaire was used to assess physical activity in minutes/week. Linear regression analysis, stratified by gender and adjusted for age, was used to study the association between continuous and categorical knowledge scores with outcomes. Results: In 106 older adults (mean age=70.1 SD=6.6, years) who were highly educated, well-functioning, and generally healthy, there were distinct knowledge gaps in nutrition and physical activity which did not correlate with one another (R2=0.013, p=0.245). Knowledge of nutrition or physical activity guidelines was not associated with physical function or physical activity. However, before age-adjustment nutrition knowledge was positively associated with HGS in males (B= 0.64 (95% CI: 0.05, 1.22)) and having knowledge above the median was associated with faster gait speed in females (B=0.10 (95% CI: 0.01, 0.19)). Conclusion: Our findings may represent a ceiling effect of the impact knowledge has on physical function and activity in the this high performing and educated population and that there may be other determinants of behavior leading to health status such as attitude and perception to consider in future studies.

Genomic stability, anti-inflammatory phenotype, and up-regulation of the RNAseH2 in cells from centenarians.

Current literature agrees on the notion that efficient DNA repair favors longevity across evolution. The DNA damage response machinery activates inflammation and type I interferon signaling. Both pathways play an acknowledged role in the pathogenesis of a variety of age-related diseases and are expected to be detrimental for human longevity. Here, we report on the anti-inflammatory molecular make-up of centenarian's fibroblasts (low levels of IL-6, type 1 interferon beta, and pro-inflammatory microRNAs), which is coupled with low level of DNA damage (measured by comet assay and histone-2AX activation) and preserved telomere length. In the same cells, high levels of the RNAseH2C enzyme subunit and low amounts of RNAseH2 substrates, i.e. cytoplasmic RNA:DNA hybrids are present. Moreover, RNAseH2C locus is hypo-methylated and RNAseH2C knock-down up-regulates IL-6 and type 1 interferon beta in centenarian's fibroblasts. Interestingly, RNAseH2C locus is hyper-methylated in vitro senescent cells and in tissues from atherosclerotic plaques and breast tumors. Finally, extracellular vesicles from centenarian's cells up-regulate RNAseH2C expression and dampen the pro-inflammatory phenotype of fibroblasts, myeloid, and cancer cells. These data suggest that centenarians are endowed with restrained DNA damage-induced inflammatory response, that may facilitate their escape from the deleterious effects of age-related chronic inflammation.

Molecular Aging of Human Liver: An Epigenetic/Transcriptomic Signature.

The feasibility of liver transplantation from old healthy donors suggests that this organ is able to preserve its functionality during aging. To explore the biological basis of this phenomenon, we characterized the epigenetic profile of liver biopsies collected from 45 healthy liver donors ranging from 13 to 90 years old using the Infinium HumanMethylation450 BeadChip. The analysis indicates that a large remodeling in DNA methylation patterns occurs, with 8,823 age-associated differentially methylated CpG probes. Notably, these age-associated changes tended to level off after the age of 60, as confirmed by Horvath's clock. Using stringent selection criteria, we further identified a DNA methylation signature of aging liver including 75 genomic regions. We demonstrated that this signature is specific for liver compared to other tissues and that it is able to detect biological age-acceleration effects associated with obesity. Finally, we combined DNA methylation measurements with available expression data. Although the intersection between the two omic characterizations was low, both approaches suggested a previously unappreciated role of epithelial-mesenchymal transition and Wnt-signaling pathways in the aging of human liver.

OX40L/OX40 axis impairs follicular and natural Treg function in human SLE.

Tregs are impaired in human systemic lupus erythematosus (SLE) and contribute to effector T cell activation. However, the mechanisms responsible for the Treg deficiency in SLE remain unclear. We hypothesized that the OX40L/OX40 axis is implicated in Treg and regulatory follicular helper T (Tfr) cell dysfunction in human SLE. OX40L/OX40 axis engagement on Tregs and Tfr cells not only specifically impaired their ability to regulate effector T cell proliferation, but also their ability to suppress T follicular helper (Tfh) cell-dependent B cell activation and immunoglobulin secretion. Antigen-presenting cells from patients with active SLE mediated Treg dysfunction in an OX40L-dependent manner, and OX40L-expressing cells colocalized with Foxp3+ cells in active SLE skin lesions. Engagement of the OX40L/OX40 axis resulted in Foxp3 downregulation in Tregs, and expression in SLE Tregs correlated with the proportion of circulating OX40L-expressing myeloid DCs. These data support that OX40L/OX40 signals are implicated in Treg dysfunction in human SLE. Thus, blocking the OX40L/OX40 axis appears to be a promising therapeutic strategy.

Predictive biological markers of systemic lupus erythematosus flares: a systematic literature review.

BACKGROUND: The aim of this study was to identify the most reliable biomarkers in the literature that could be used as flare predictors in systemic lupus erythematosus (SLE). METHODS: A systematic review of the literature was performed using two databases (MEDLINE and EMBASE) through April 2015 and congress abstracts from the American College of Rheumatology and the European League Against Rheumatism were reviewed from 2010 to 2014. Two independent reviewers screened titles and abstracts and analysed selected papers in detail, using a specific questionnaire. Reports addressing the relationships between one or more defined biological test(s) and the occurrence of disease exacerbation were included in the systematic review. RESULTS: From all of the databases, 4668 records were retrieved, of which 69 studies or congress abstracts were selected for the systematic review. The performance of seven types of biomarkers performed routinely in clinical practice and nine types of novel biological markers was evaluated. Despite some encouraging results for anti-double-stranded DNA antibodies, anti-C1q antibodies, B-lymphocyte stimulator and tumour necrosis factor-like weak inducer of apoptosis, none of the biomarkers stood out from the others as a potential gold standard for flare prediction. The results were heterogeneous, and a lack of standardized data prevented us from identifying a powerful biomarker. CONCLUSIONS: No powerful conclusions could be drawn from this systematic review due to a lack of standardized data. Efforts should be undertaken to optimize future research on potential SLE biomarkers to develop validated candidates. Thus, we propose a standardized pattern for future studies.