Inhibition of 4-aminobutyrate aminotransferase protects against injury-induced osteoarthritis in mice

Recently we demonstrated that ablation of the DNA methyltransferase enzyme, Dnmt3b, resulted in catabolism and progression of osteoarthritis (OA) in murine articular cartilage through a mechanism involving increased mitochondrial respiration. In this study, we identify 4-aminobutyrate aminotransferase (Abat) as a downstream target of Dnmt3b. Abat is an enzyme that metabolizes γ-aminobutyric acid to succinate, a key intermediate in the tricarboxylic acid cycle. We show that Dnmt3b binds to the Abat promoter, increases methylation of a conserved CpG sequence just upstream of the transcriptional start site, and inhibits Abat expression. Dnmt3b deletion in articular chondrocytes results in reduced methylation of the CpG sequence in the Abat promoter, which subsequently increases expression of Abat. Increased Abat expression in chondrocytes leads to enhanced mitochondrial respiration and elevated expression of catabolic genes. Overexpression of Abat in murine knee joints via lentiviral injection results in accelerated cartilage degradation following surgical induction of OA. In contrast, lentiviral-based knockdown of Abat attenuates the expression of IL-1β-induced catabolic genes in primary murine articular chondrocytes in vitro and also protects against murine articular cartilage degradation in vivo. Strikingly, treatment with the FDA-approved small-molecule Abat inhibitor, vigabatrin, significantly prevents the development of injury-induced OA in mice. In summary, these studies establish Abat as an important new target for therapies to prevent OA

Child outcomes after placement of a cervical pessary in women with a multiple pregnancy : A 4-year follow-up of the ProTWIN trial

Acknowledgements We like to thank the research nurses of the Dutch Consortium for Healthcare Evaluation and Research in Obstetrics and Gynecology for their help in finding contact details of the parents.Peer reviewedPublisher PD

Evolution of sex-specific pace-of-life syndromes: genetic architecture and physiological mechanisms

Sex differences in life history, physiology, and behavior are nearly ubiquitous across taxa, owing to sex-specific selection that arises from different reproductive strategies of the sexes. The pace-of-life syndrome (POLS) hypothesis predicts that most variation in such traits among individuals, populations, and species falls along a slow-fast pace-of-life continuum. As a result of their different reproductive roles and environment, the sexes also commonly differ in pace-of-life, with important consequences for the evolution of POLS. Here, we outline mechanisms for how males and females can evolve differences in POLS traits and in how such traits can covary differently despite constraints resulting from a shared genome. We review the current knowledge of the genetic basis of POLS traits and suggest candidate genes and pathways for future studies. Pleiotropic effects may govern many of the genetic correlations, but little is still known about the mechanisms involved in trade-offs between current and future reproduction and their integration with behavioral variation. We highlight the importance of metabolic and hormonal pathways in mediating sex differences in POLS traits; however, there is still a shortage of studies that test for sex specificity in molecular effects and their evolutionary causes. Considering whether and how sexual dimorphism evolves in POLS traits provides a more holistic framework to understand how behavioral variation is integrated with life histories and physiology, and we call for studies that focus on examining the sex-specific genetic architecture of this integration

Economic burden of burn injuries in the Netherlands: A 3 months follow-up study

Introduction Burn care has rapidly improved in the past decades. However, healthcare innovations can be expensive, demanding careful choices on their implementation. Obtaining knowledge on the extent of the costs of burn injuries is an essential first step for economic evaluations within burn care. The objective of this study was to determine the economic burden of patients with burns admitted to a burn centre and to identify important cost categories until 3 months post-burn. Patients and methods A prospective cohort study was conducted in the burn centre of Maasstad Hospital Rotterdam, the Netherlands, including all patients with acute burn related injuries from August 2011 until July 2012. Total costs were calculated from a societal perspective, until 3 months post injury. Subgroup analyses were performed to examine whether the mean total costs per patient differed by age, aetiology or percentage total body surface area (TBSA) burned. Results In our population, with a mean burn size of 8%, mean total costs were €26,540 per patient varying from €742 to €235,557. Most important cost categories were burn centre days (62%), surgical interventions (5%) and work absence (20%). Flame burns were significantly more costly than other types of burns, adult patients were significantly more costly than children and adolescents and a higher percentage TBSA burned also corresponded to significantly higher costs. Discussion and conclusion Mean total costs of burn care in the first 3 months post injury were estimated at €26,540 and depended on age, aetiology and TBSA. Mean total costs in our population probably apply to other high-income countries as well, although we should realise that patients with burn injuries are diverse and represent a broad range of total costs. To reduce costs of burn care, future intervention studies should focus on a timely wound healing, reducing length of stay and enabling an early return to work