Altered blood-brain barrier transport of nanotherapeutics in lysosomal storage diseases.

Treatment of neurological lysosomal storage disorders (LSDs) are limited because of impermeability of the blood-brain barrier (BBB) to macromolecules. Nanoformulations targeting BBB transcytosis are being explored, but the status of these routes in LSDs is unknown. We studied nanocarriers (NCs) targeted to the transferrin receptor (TfR), ganglioside GM1 or ICAM1, associated to the clathrin, caveolar or cell adhesion molecule (CAM) routes, respectively. We used brain endothelial cells and mouse models of acid sphingomyelinase-deficient Niemann Pick disease (NPD), and postmortem LSD patients' brains, all compared to respective controls. NC transcytosis across brain endothelial cells and brain distribution in mice were affected, yet through different mechanisms. Reduced TfR and clathrin expression were found, along with decreased transcytosis in cells and mouse brain distribution. Caveolin-1 expression and GM1 transcytosis were also reduced, yet increased GM1 levels seemed to compensate, providing similar NC brain distribution in NPD vs. control mice. A tendency to lower NHE-1 levels was seen, but highly increased ICAM1 expression in cells and human brains correlated with increased transcytosis and brain distribution in mice. Thus, transcytosis-related alterations in NPD and likely other LSDs may impact therapeutic access to the brain, illustrating the need for these mechanistic studies.

Functional outcome and complications after treatment of comminuted tibial fractures or deformities using Ilizarov bone transport: a single-center study at 15- to 30-year follow-up.

INTRODUCTION: The aim of this retrospective study was to evaluate long-term outcomes and complications of a single-center and single-surgeon patient series of isolated and comminuted tibial fractures with bone defects or tibial deformities treated by Ilizarov bone transport. MATERIALS AND METHODS: Data from a consecutive series of patients with isolated comminuted tibial fractures (Fracture Group: FG) or deformities (Deformity Group: DG) treated between 1987 and 2002 were included. For clinical assessment, the Lower Extremities Functional Scale was used; complications were recorded according to the Dindo classification and statistical analysis was performed. RESULTS: Overall, 72 patients were enrolled with a mean follow-up of 21.6 years (range 15-30) a mean LEFS of 36.4 (range 0-100). In the FG, the mean LEFS was 21.3 (range 0-98.75), and the external fixation time (EFT) lasted 7.6 months (range 3-18 months) months. In the DG, the mean LEFS was 76.7 (range 55-100), and the EFT was 10.6 months (range 3-20 months). Between the two groups, the clinical evaluation was significantly different, while the EFT was not (p = 0.14). In the FG, the worst results were obtained in the cases of open fractures with a higher percentage of complications and the need for further surgical procedures. The cumulative rate of complications was 55.6% during the first 36 months and 66.7% at the minimum follow-up of 180 months. CONCLUSIONS: Ilizarov bone transport, even at a long follow-up period, proved to be an effective technique for both definitive treatment of comminuted tibial fractures with bone defects or tibial deformities. Although our functional outcomes were lower in patients with exposed fractures, they were in line with the literature, but not influenced by the EFT when properly managed. Most complications occurred during the first 3 years; however, they could also arise much later, even until almost 30 years.

Limb lengthening for deformities in Ollier's disease: a systematic review.

BACKGROUND: The management of limb deformity, shortening, and bone defects in treatment of Ollier's disease is a major challenge. This study aims to summarize and compare the different surgical treatments, and to evaluate the outcome and possible prognostic factors of leg lengthening in these patients. MATERIALS AND METHODS: A systematic review of the literature from 1993 to 2017 was performed. Nineteen articles were found including a total of 121 patients with limb deformities because of Ollier's disease. The mean patients' age at the time of first surgery was 12 years. A total of 272 segments were surgically treated (14 segments in the upper limbs) with variable techniques including osteotomies and external fixation, intramedullary nails, as well as epiphysiodesis and lengthening over nail. We studied the bone healing index (BHI), distraction index (DI), distraction time, gained length, total treatment time, and complications. RESULTS: Available implants and techniques allowed correction of patients' deformities (lengthening and correction of angular defects) in most cases. External fixators, circular or monolateral frames were the most commonly used technique. The Ilizarov external fixator was the most commonly used frame (196 segments). The BHI was significantly better when the external fixation was combined with intramedullary nails. Epiphysiodesis was most likely to be more associated with the past than to the present. Joint stiffness, infection, early consolidation, pathological fracture, deformity recurrence, delayed union, non-union, neurapraxia, and overlengthening were the reported complications with an overall rate of 27.9%. CONCLUSIONS: There is no consensus for the optimal surgical technique and implants for correction of limbs deformities in patients with Ollier's disease. External fixators most commonly circular are the most commonly used implants; however, complications do occur.

Challenging Surgical Treatment of Displaced Articular Tibial Plateau Fractures: Do Early Knee Radiographic Features Have a Predictive Value of the Mid-Term Clinical Functional Outcomes?

OBJECTIVE: To evaluate mid-term radiographic and functional outcomes of tibial plateau fracture (TPF) patients treated with the open reduction internal fixation (ORIF) technique and to find predictive factors of clinical outcomes. METHODS: A retrospective, single-center study was performed enrolling a consecutive series of patients with diagnosis of TPF. All subjects were treated by ORIF between January 2010 and December 2015 at our level-1 healthcare trauma center. The inclusion criteria were: age between 18 and 75 years; ORIF technique used for articular TPF, type 41-B and 41-C, isolated or with associated injuries. The patients were divided in two groups, according to fracture patterns and compared. Their characteristics, radiographic and clinical outcomes were recorded. Radiographs 12 months after surgery were evaluated for reduction and alignment, and radiographs at 24 months to describe post-traumatic osteoarthritis (PTOA). Functional outcomes were assessed using the visual analog scale (VAS), the Short Form 36 (SF-36), the knee injury and osteoarthritis outcome score (KOOS), and the American Knee Society score (AKSS) questionnaires. Return to work and sport activities were also investigated. Univariate and multivariate analysis were performed, and the statistical significance was defined as two-tailed P < 0.05. RESULTS: Forty-five patients were included, 29 males and 16 females; the mean age was 54.5 years. The mean follow-up was 57.18 months (range, 26-94). There were AO 41-B fractures (partial articular fractures) in more than half of the patients (66.67%), while the remaining 15 had AO 41-C fractures (complete articular fractures). The sub-type AO 41-B3 was the most common, reported in 62.22% of patients. The mean KOOS score was 69.0. Mean AKSS and SF-36 PCS scores were 79.0 and 41.4, respectively. There were significant relationships between age and functional results (KOOS ADL, Sport, QoL, and SF-36 PCS) and between BMI and KOOS Pain, ADL, Sport, and QoL. No differences were found between the two types of fractures regarding quality of reduction and alignment. AO 41-C TPF tend to develop PTOA more frequently with respect to 41-B fractures, while type AO 41-C TPF had the worst clinical outcomes. We found that the presence of an articular step-off and the malalignment of the tibial axis after surgery were predictive of daily pain felt by patients. PTOA was predictive of a worse AKSS. The overall complication rate was 13.33%: 1 superficial wound infection, 1 deep vein thrombosis, and 4 cases of transitory deficit of the common peroneal nerve. CONCLUSION: The present study demonstrates that early radiographic features may be predictive for pain perceived by patients at mid-term follow-up.