A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivo

Polyglutamine (polyQ) disorders, including Huntington's disease (HD), are caused by expansion of polyQ-encoding repeats within otherwise unrelated gene products. In polyQ diseases, the pathology and death of affected neurons are associated with the accumulation of mutant proteins in insoluble aggregates. Several studies implicate polyQ-dependent aggregation as a cause of neurodegeneration in HD, suggesting that inhibition of neuronal polyQ aggregation may be therapeutic in HD patients. We have used a yeast-based high-throughput screening assay to identify small-molecule inhibitors of polyQ aggregation. We validated the effects of four hit compounds in mammalian cell-based models of HD, optimized compound structures for potency, and then tested them in vitro in cultured brain slices from HD transgenic mice. These efforts identified a potent compound (IC50=10 nM) with long-term inhibitory effects on polyQ aggregation in HD neurons. Testing of this compound in a Drosophila HD model showed that it suppresses neurodegeneration in vivo, strongly suggesting an essential role for polyQ aggregation in HD pathology. The aggregation inhibitors identified in this screen represent four primary chemical scaffolds and are strong lead compounds for the development of therapeutics for human polyQ diseases.     

Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation

Toxicity of aggregation-prone proteins is thought to play an important role in aging and age-related neurological diseases like Parkinson and Alzheimer's diseases. Here, we identify tryptophan 2,3-dioxygenase (tdo-2), the first enzyme in the kynurenine pathway of tryptophan degradation, as a metabolic regulator of age-related α-synuclein toxicity in a Caenorhabditis elegans model. Depletion of tdo-2 also suppresses toxicity of other heterologous aggregation-prone proteins, including amyloid-β and polyglutamine proteins, and endogenous metastable proteins that are sensors of normal protein homeostasis. This finding suggests that tdo-2 functions as a general regulator of protein homeostasis. Analysis of metabolite levels in C. elegans strains with mutations in enzymes that act downstream of tdo-2 indicates that this suppression of toxicity is independent of downstream metabolites in the kynurenine pathway. Depletion of tdo-2 increases tryptophan levels, and feeding worms with extra l-tryptophan also suppresses toxicity, suggesting that tdo-2 regulates proteotoxicity through tryptophan. Depletion of tdo-2 extends lifespan in these worms. Together, these results implicate tdo-2 as a metabolic switch of age-related protein homeostasis and lifespan. With TDO and Indoleamine 2,3-dioxygenase as evolutionarily conserved human orthologs of TDO-2, intervening with tryptophan metabolism may offer avenues to reducing proteotoxicity in aging and age-related diseases.     

Evidence-based, interdisciplinary guidelines for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis

Uveitis in juvenile idiopathic arthritis (JIA) is frequently associated with the development of complications and visual loss. Topical corticosteroids are the first-choice therapy, and immunosuppression is commonly used. However, treatment has not been standardized. Representatives from the German Ophthalmological Society, Society for Childhood and Adolescent Rheumatology, and the German Society for Rheumatology reached consensus on a standardized treatment strategy according to disease severity in the individual patient. The recommendations were based on a systematic literature analysis in MEDLINE and consensus expert meetings. Evidence and recommendations were graded, and an algorithm for anti-inflammatory treatment and final statements confirmed in a Delphi method. An interdisciplinary, evidence-based treatment guideline for JIA uveitis is presented.     

Randomized Controlled Trial to Compare Two Bone Substitutes in the Treatment of Bony Dehiscences

Aim: This in vivo split‐mouth randomized controlled trial compared a synthetic bone substitute with a bovine bone mineral to cover bone dehiscences after implant insertion. Materials and Methods: Fourteen patients received four to six implants to support an overdenture. Two comparable dehiscences within the same patient were first covered with a layer of autogenous bone, followed by a layer of either Bio‐Oss® (group 1; Geistlich Pharma AG, Wolhusen, Switzerland) or Straumann BoneCeramic® (group 2; Institut Straumann AG, Basel, Switzerland) and sealed by a resorbable membrane. The change in vertical dimension of the defect was measured at implant placement and at abutment connection (6.5 months). Clinical and radiological parameters were evaluated up to 1 year of loading. Results: The vertical size of the defect at surgery was 6.4 ± 1.6 mm for group 1 and 6.4 ± 2.2 mm for group 2 sites, measured from the implant shoulder. After 6.5 months, the depth of the defect was reduced to 1.5 ± 1.2 mm and 1.9 ± 1.2 mm for group 1 and group 2 sites, respectively (p > 0.05). No implants failed during follow‐up. Mean marginal bone loss over the SLActive surface was 0.94 mm (group 1), 0.81 mm (group 2), and 0.93 mm (group 3, no dehiscence) after 1 year of loading. Conclusion: Both bone substitutes behaved equally effectively.     

Stimulation of the intra-cardiac vagal nerves innervating the AV-node to control ventricular rate during AF: specificity, parameter optimization and chronic use up to 3?months

Background  

Stimulation of the intra-cardiac vagal nerves innervating the AV-node (AVNS) is a promising approach to slow down ventricular rate (VR) during atrial fibrillation (AF). Our purpose was to demonstrate that effects on R-R-interval during stable AF can be maintained for several months once optimized and that AVNS affects specifically the nerves innervating the AV-node.     

Why do studies show different associations between intrauterine exposure to maternal smoking and age at menarche?

Purpose

Studies suggests that intrauterine exposure to maternal smoking both accelerates or delays age at menarche. We hypothesize that these opposing findings relate to different infant and childhood growth patterns across cohorts.