Combined aerobic exercise and enzyme replacement therapy rejuvenates the mitochondrial-lysosomal axis and alleviates autophagic blockage in Pompe disease.

A unifying feature in the pathogenesis of aging, neurodegenerative disease, and lysosomal storage disorders is the progressive deposition of macromolecular debris impervious to enzyme catalysis by cellular waste disposal mechanisms (e.g., lipofuscin). Aerobic exercise training (AET) has pleiotropic effects and stimulates mitochondrial biogenesis, antioxidant defense systems, and autophagic flux in multiple organs and tissues. Our aim was to explore the therapeutic potential of AET as an ancillary therapy to mitigate autophagic buildup and oxidative damage and rejuvenate the mitochondrial-lysosomal axis in Pompe disease (GSD II/PD). Fourteen weeks of combined recombinant acid α-glucosidase (rhGAA) and AET polytherapy attenuated mitochondrial swelling, fortified antioxidant defense systems, reduced oxidative damage, and augmented glycogen clearance and removal of autophagic debris/lipofuscin in fast-twitch skeletal muscle of GAA-KO mice. Ancillary AET potently augmented the pool of PI4KA transcripts and exerted a mild restorative effect on Syt VII and VAMP-5/myobrevin, collectively suggesting improved endosomal transport and Ca(2+)- mediated lysosomal exocytosis. Compared with traditional rhGAA monotherapy, AET and rhGAA polytherapy effectively mitigated buildup of protein carbonyls, autophagic debris/lipofuscin, and P62/SQSTM1, while enhancing MnSOD expression, nuclear translocation of Nrf-2, muscle mass, and motor function in GAA-KO mice. Combined AET and rhGAA therapy reactivates cellular clearance pathways, mitigates mitochondrial senescence, and strengthens antioxidant defense systems in GSD II/PD. Aerobic exercise training (or pharmacologic targeting of contractile-activity-induced pathways) may have therapeutic potential for mitochondrial-lysosomal axis rejuvenation in lysosomal storage disorders and related conditions (e.g., aging and neurodegenerative disease).

Open reduction and plate fixation versus nonoperative treatment for displaced midshaft clavicular fractures: a multicenter, randomized, controlled trial.

BACKGROUND: There is a growing trend to treat displaced midshaft clavicular fractures with primary open reduction and plate fixation; whether such treatment results in improved patient outcomes is debatable. The aim of this multicenter, single-blinded, randomized controlled trial was to compare union rates, functional outcomes, and economic costs for displaced midshaft clavicular fractures that were treated with either primary open reduction and plate fixation or nonoperative treatment. METHODS: In a prospective, multicenter, stratified, randomized controlled trial, 200 patients between sixteen and sixty years of age who had an acute displaced midshaft clavicular fracture were randomized to receive either primary open reduction and plate fixation or nonoperative treatment. Functional assessment was conducted at six weeks, three months, six months, and one year with use of the Disabilities of the Arm, Shoulder and Hand (DASH) and Constant scores. Union was evaluated with use of three-dimensional computed tomography. Complications were recorded, and an economic evaluation was performed. RESULTS: The rate of nonunion was significantly reduced after open reduction and plate fixation (one nonunion) as compared with nonoperative treatment (sixteen nonunions) (relative risk = 0.07; p = 0.007). Group allocation to nonoperative treatment was independently predictive of the development of nonunion (p = 0.0001). Overall, DASH and Constant scores were significantly better after open reduction and plate fixation than after nonoperative treatment at the time of the one-year follow-up (DASH score, 3.4 versus 6.1 [p = 0.04]; Constant score, 92.0 versus 87.8 [p = 0.01]). However, when patients with nonunion were excluded from analysis, there were no significant differences in the Constant scores or DASH scores at any time point. Patients were less dissatisfied with symptoms of shoulder droop, local bump at the fracture site, and shoulder asymmetry in the open reduction and plate fixation group (p < 0.0001). The cost of treatment was significantly greater after open reduction and plate fixation (p < 0.0001). CONCLUSIONS: Open reduction and plate fixation reduces the rate of nonunion after acute displaced midshaft clavicular fracture compared with nonoperative treatment and is associated with better functional outcomes. However, the improved outcomes appear to result from the prevention of nonunion by open reduction and plate fixation. Open reduction and plate fixation is more expensive and is associated with implant-related complications that are not seen in association with nonoperative treatment. The results of the present study do not support routine primary open reduction and plate fixation for the treatment of displaced midshaft clavicular fractures.

Sinonasal T-Cell lymphomas: A clinicopathologic study of a possibly distinct entity.

BACKGROUND: Most cases of sinonasal lymphomas reported in the literature which show positive expression for Epstein-Barr virus are CD2+, CD3-, CD43+ and CD56+, and also show a germ-line T-cell receptor genotype. Five-year survival is usually around 50%. We report a group of patients with T-cell sinonasal lymphoma that showed distinct immunophenotypic and molecular profiles and a more aggressive behavior. PATIENTS AND METHODS: Nineteen cases representing approximately 75% of sinonasal lymphoma diagnosed and treated at our institution between 1988 and 1997 were studied. They comprised 12 males and 7 females, with an age range of 10 to 73 years (median 46 years). The remaining cases (about 25%) were B-cell lymphomas. The morphology of the cases was evaluated together with a limited immunophenotyping. In situ hybridization for EBV mRNA was performed in 18 cases. Polymerase chain reaction (PCR) for T-cell receptor (TCR) gene rearrangement was performed in 15 cases. Clinical follow-up information was available on 14 patients. All cases showed a pattern of large-cell lymphoma, and three exhibited an immunoblastic morphology. The tumors showed extensive soft tissue invasion, necrosis and ulceration. While perineural invasion was a prominent feature, perivascular invasion was not noticed. RESULTS: Seventeen tumors (84%) were CD3 positive. PCR analysis showed TCR gene rearrangement in 7 of 15 cases (46%). Fifteen cases (79%) were positive for EBV. The 14 patients with available clinical information had extensive local diseases, with stages ranging from IE to IIIE, where none showed positive bone marrow involvement. The 14 patients received chemotherapy with or without radiation therapy. Ten of the 14 patients (71%) died of the disease after a median of seven months, including all seven patients with positive TCR gene rearrangement. CONCLUSION: Our findings suggest that sinonasal T-cell lymphoma represents a heterogeneous group of diseases with different phenotypic, genotypic and biological characteristics. Cases that show TCR gene rearrangement may represent a more aggressive subtype of the disease.

Progress toward the synthesis of nonionic oligonucleotide analogues with sulfonate and sulfonamide internucleotide linkages.

The synthesis of building blocks for the preparation of nonionic oligonucleotide analogues with sulfonate and sulfonamide internucleotide linkages is described. Coupling conditions for the conversion of several of these monomers to dimers are also described.