Gene therapy for follistatin mitigates systemic metabolic inflammation and post-traumatic arthritis in high-fat diet-induced obesity

Obesity-associated inflammation and loss of muscle function play critical roles in the development of osteoarthritis (OA); thus, therapies that target muscle tissue may provide novel approaches to restoring metabolic and biomechanical dysfunction associated with obesity. Follistatin (FST), a protein that binds myostatin and activin, may have the potential to enhance muscle formation while inhibiting inflammation. Here, we hypothesized that adeno-associated virus 9 (AAV9) delivery of FST enhances muscle formation and mitigates metabolic inflammation and knee OA caused by a high-fat diet in mice. AAV-mediated FST delivery exhibited decreased obesity-induced inflammatory adipokines and cytokines systemically and in the joint synovial fluid. Regardless of diet, mice receiving FST gene therapy were protected from post-traumatic OA and bone remodeling induced by joint injury. Together, these findings suggest that FST gene therapy may provide a multifactorial therapeutic approach for injury-induced OA and metabolic inflammation in obesity

J-R FRACTURE TOUGHNESS OF NUCLEAR PIPING MATERIALS UNDER EXCESSIVE SEISMIC LOADING CONDITION

ABSTRACT This study investigated the loading rate effect on the fracture resistance under cyclic loading conditions to clearly understand the fracture behavior of piping materials under excessive seismic conditions. J-R fracture toughness tests were conducted under monotonic and cyclic loading conditions at various displacement rates at room temperature (RT) and the operating temperature of nuclear power plants (NPPs), i.e., 316°C. SA508 Gr. 1a low-alloy steel (LAS) and SA312 TP316 stainless steel (SS) piping materials were used for the tests. The fracture resistance under a reversible cyclic load was considerably lower than that under monotonic load regardless of test temperature, material, and loading rate. Under both cyclic and monotonic loading conditions, the fracture behavior of SA312 TP316 SS was independent of the loading rate at both RT and 316°C. For SA508 Gr. 1a LAS, the loading rate effect on the fracture behavior was appreciable at 316°C under both cyclic and monotonic loading conditions. However, the loading rate effect diminished when the cyclic load ratio (R) was -1. Thus, it was recognized that the fracture behavior of piping materials, including seismic loading characteristics, can be evaluated when tested under a cyclic load of R = -1 at a quasi-static loading rate

One-Bone Forearm Procedure for Acquired Pseudoarthrosis of the Ulna Combined with Radial Head Dislocation in a Child: A Case with 20 Years Follow-Up

This report describes a 6 year-old boy who was treated with one-bone forearm procedure for acquired pseudoarthrosis of the ulna combined with radial head dislocation after radical ulna debridement for osteomyelitis. At more than 20 years of follow-up, the patient had a nearly full range of elbow movements with a few additional surgical procedures. Pronation and supination was restricted by 45°, but the patient had near-normal elbow and hand functions without the restriction of any daily living activity. This case shows that one-bone forearm formation is a reasonable option for forearm stability in longstanding pseudoarthrosis of the ulna with radial head dislocation in a child

Correction of Long Standing Proximal Interphalangeal Flexion Contractures with Cross Finger Flaps and Vigorous Postoperative Exercises

PURPOSE: We reviewed the results of cross finger flaps after surgical release and vigorous postoperative exercises for long-standing, severe flexion contractures of the Proximal Interphalangeal (PIP) joints of fingers. MATERIALS AND METHODS: In 9 patients, all contracted tissue was sequentially released and the resultant skin defect was covered with a cross-finger flap. The cause of the contracture was contact burn in 4, skin graft in 3, and a previous operation in 2. The mean followup period was 41.2 months. RESULTS: The mean flexion contracture/further flexion in the joints were improved from 73.4/87.8 degrees to 8.4/95.4 degrees at the last follow-up. A mean of 19.5 degrees of extension was achieved with vigorous extension exercise after the operation. The mean gain in range of motion (ROM) was 79.4 degrees. Near full ROM was achieved in 3 cases. There were no major complications. CONCLUSION: In severe flexion contractures with scarring of the PIP joints of fingers, cross finger flaps after sufficient release and vigorous postoperative exercise seems to be a reasonable option to obtain satisfactory ROM of the jointsope

A genome-engineered bioartificial implant for autoregulated anticytokine drug delivery

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Impacts of coexisting bronchial asthma on severe exacerbations in mild-to-moderate COPD : results from a national database

Acknowledgments The authors would like to thank Kyungjoo Kim for the confident statistical analyses in this work. This study was supported by a grant (2014P3300300) from the Korea Centers for Disease Control and Prevention. The abstract of this paper was presented at the Asian Pacific Society of Respirology 20th Congress as an oral presentation with interim findings. The poster’s abstract was published in “Poster Abstracts” in Respirology.Peer reviewedPublisher PD

Pharmacological Modulation of Mitochondrial Ca2+ Content Regulates Sarcoplasmic Reticulum Ca2+ Release via Oxidation of the Ryanodine Receptor by Mitochondria-Derived Reactive Oxygen Species

In a physiological setting, mitochondria increase oxidative phosphorylation during periods of stress to meet increased metabolic demand. This in part is mediated via enhanced mitochondrial Ca2+ uptake, an important regulator of cellular ATP homeostasis. In a pathophysiological setting pharmacological modulation of mitochondrial Ca2+ uptake or retention has been suggested as a therapeutic strategy to improve metabolic homeostasis or attenuate Ca2+-dependent arrhythmias in cardiac disease states. To explore the consequences of mitochondrial Ca2+ accumulation, we tested the effects of kaempferol, an activator of mitochondrial Ca2+ uniporter (MCU), CGP-37157, an inhibitor of mitochondrial Na+/Ca2+ exchanger, and MCU inhibitor Ru360 in rat ventricular myocytes (VMs) from control rats and rats with hypertrophy induced by thoracic aortic banding (TAB). In periodically paced VMs under β-adrenergic stimulation, treatment with kaempferol (10 μmol/L) or CGP-37157 (1 μmol/L) enhanced mitochondrial Ca2+ accumulation monitored by mitochondrial-targeted Ca2+ biosensor mtRCamp1h. Experiments with mitochondrial membrane potential-sensitive dye TMRM revealed this was accompanied by depolarization of the mitochondrial matrix. Using redox-sensitive OMM-HyPer and ERroGFP_iE biosensors, we found treatment with kaempferol or CGP-37157 increased the levels of reactive oxygen species (ROS) in mitochondria and the sarcoplasmic reticulum (SR), respectively. Confocal Ca2+ imaging showed that accelerated Ca2+ accumulation reduced Ca2+ transient amplitude and promoted generation of spontaneous Ca2+ waves in VMs paced under ISO, suggestive of abnormally high activity of the SR Ca2+ release channel ryanodine receptor (RyR). Western blot analyses showed increased RyR oxidation after treatment with kaempferol or CGP-37157 vs. controls. Furthermore, in freshly isolated TAB VMs, confocal Ca2+ imaging demonstrated that enhancement of mitochondrial Ca2+ accumulation further perturbed global Ca2+ handling, increasing the number of cells exhibiting spontaneous Ca2+ waves, shortening RyR refractoriness and decreasing SR Ca2+ content. In ex vivo optically mapped TAB hearts, kaempferol exacerbated proarrhythmic phenotype. On the contrary, incubation of cells with MCU inhibitor Ru360 (2 μmol/L, 30 min) normalized RyR oxidation state, improved intracellular Ca2+ homeostasis and reduced triggered activity in ex vivo TAB hearts. These findings suggest facilitation of mitochondrial Ca2+ uptake in cardiac disease can exacerbate proarrhythmic disturbances in Ca2+ homeostasis via ROS and enhanced activity of oxidized RyRs, while strategies to reduce mitochondrial Ca2+ accumulation can be protective

Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases

Mutations in Park8, encoding for the multidomain Leucine-rich repeat kinase 2 (LRRK2) protein, comprise the predominant genetic cause of Parkinson's disease (PD). G2019S, the most common amino acid substitution activates the kinase two- to threefold. This has motivated the development of LRRK2 kinase inhibitors; however, poor consensus on physiological LRRK2 substrates has hampered clinical development of such therapeutics. We employ a combination of phosphoproteomics, genetics, and pharmacology to unambiguously identify a subset of Rab GTPases as key LRRK2 substrates. LRRK2 directly phosphorylates these both in vivo and in vitro on an evolutionary conserved residue in the switch II domain. Pathogenic LRRK2 variants mapping to different functional domains increase phosphorylation of Rabs and this strongly decreases their affinity to regulatory proteins including Rab GDP dissociation inhibitors (GDIs). Our findings uncover a key class of bona-fide LRRK2 substrates and a novel regulatory mechanism of Rabs that connects them to PD