RESUMO
Alzheimer's disease (AD) is characterized by the progressive accumulation of amyloid-ß and hyperphosphorylated tau (pTau), which can spread throughout the brain via extracellular vesicles (EVs). Membrane ceramide enrichment regulated by the enzyme neutral sphingomyelinase 2 (nSMase2) is a critical component of at least one EV biogenesis pathway. Our group recently identified 2,6-Dimethoxy-4-(5-Phenyl-4-Thiophen-2-yl-1H-Imidazol-2-yl)-Phenol (DPTIP), the most potent (30 nM) and selective inhibitor of nSMase2 reported to date. However, DPTIP exhibits poor oral pharmacokinetics (PK), modest brain penetration, and rapid clearance, limiting its clinical translation. To enhance its PK properties, we conjugated DPTIP to a hydroxyl-PAMAM dendrimer delivery system, creating dendrimer-DPTIP (D-DPTIP). In an acute brain injury model, orally administered D-DPTIP significantly reduced the intra-striatal IL-1ß-induced increase in plasma EVs up to 72 h post-dose, while oral DPTIP had a limited effect. In a mouse tau propagation model, where a mutant hTau (P301L/S320F) containing adeno-associated virus was unilaterally seeded into the hippocampus, oral D-DPTIP (dosed 3× weekly) significantly inhibited brain nSMase2 activity and blocked the spread of pTau to the contralateral hippocampus. These data demonstrate that dendrimer conjugation of DPTIP improves its PK properties, resulting in significant inhibition of EV propagation of pTau in mice. Dendrimer-based delivery of DPTIP has the potential to be an exciting new therapeutic for AD.
RESUMO
OBJECTIVE: A posterior dynamic deformity correction (PDDC) system was used to correct adolescent idiopathic scoliosis (AIS) without fusion. The preliminary outcomes of bridging only 3-4 discs in patients with variable curve severity have previously been reported. This paper examines a subgroup of patients with the authors' proposed current indications for this device who were also treated with a longer construct. METHODS: Inclusion criteria included a single AIS structural curve between 40° and 60°, curve flexibility ≤ 30°, PDDC spanning 5-6 levels, and minimum 2-year follow-up. A retrospective review was conducted and demographic and radiographic data were recorded. A successful outcome was defined as a curve magnitude of ≤ 30° at final follow-up. Any serious adverse events and reoperations were recorded. RESULTS: Twenty-two patients who met the inclusion criteria were operated on with the PDDC in 5 medical centers. There were 19 girls and 3 boys, aged 13-17 years, with Risser grades ≥ 2. Thirteen had Lenke type 1 curves and 9 had type 5 curves. The mean preoperative curve was 47° (range 40°-55°). At a minimum of 2 years' follow-up, the mean major curve measured 25° (46% correction, p < 0.05). In 18 (82%) of 22 patients, the mean final Cobb angle measured ≤ 30° (range 15°-30°). Trunk shift was corrected by 1.5 cm (range 0.4-4.3 cm). The mean minor curve was reduced from 27° to 17° at final follow-up (35% correction, p < 0.05). For Lenke type 1 patterns, the mean 2D thoracic kyphosis was 24° preoperatively versus 27° at final follow-up (p < 0.05), and for Lenke type 5 curves, mean lumbar lordosis was 47° preoperatively versus 42° at final follow-up (p < 0.05). The mean preoperative Scoliosis Research Society-22 questionnaire score improved from 2.74 ± 0.3 at baseline to 4.31 ± 0.4 at 2 years after surgery (p < 0.0001). The mean preoperative self-image score and satisfaction scores improved from preoperative values, while other domain scores did not change significantly. Four patients (18%) underwent revision surgery because of nut loosening (n = 2), pedicle screw backup (n = 1), and ratchet malfunction (n = 1). CONCLUSIONS: In AIS patients with a single flexible major curve up to 60°, the fusionless PDDC device achieved a satisfactory result as 82% had residual curves ≤ 30°. These findings suggest that the PDDC device may serve as an alternative to spinal fusion in select patients.