Global knee function rating more strongly influences adolescent athletes that sustain a sports-related surgical ACL re-injury or contralateral ACL injury.

PURPOSE: This study evaluated differences between adolescent athletes who sustained a surgical anterior cruciate ligament (ACL) re-injury, or contralateral ACL injury following return to sports bridge programme participation (Group 1) compared to those that did not (Group 2). METHODS: At 19.9 ± 7 years of age, 198 athletes participated in this study. Groups were compared for time postsurgery, preprogramme and postprogramme Knee Outcome Survey Sports Activity Scale (KOS-SAS) and global rating of knee function (GRKF) during sports activities, postprogramme lower extremity physical function test performance and perceived sports performance compared to preinjury level. RESULTS: By 6.0 ± 3.2 years postsurgery, 11 (5.6%) sustained another ACL injury. Group 1 was younger (17.3 ± 1.7 years vs. 20.1 ± 6.8 years, p < 0.001). Postprogramme re-evaluation revealed that Group 1 had a greater GRKF compared to their programme initiation GRKF than Group 2 (32.6 ± 38 vs. 20.0 ± 23, p = 0.04). Group 1 also had a greater mean preprogramme to postprogramme GRKF change than Group 2 (51.3 ± 31 vs. 35.5 ± 21, p = 0.02) (effect size = 0.73). More Group 1 subjects also had a GRKF difference that exceeded the overall mean than Group 2 (p = 0.04). Group 1 had moderately strong relationships between preprogramme and postprogramme GRKF score change and the postprogramme GRKF score (r = 0.65, p = 0.04) and between preprogramme and postprogramme KOS-SAS score change and postprogramme GRKF score (r = 0.60, p = 0.04). CONCLUSION: Global rating scores had a stronger influence among adolescent athletes that sustained either surgical ACL re-injury or contralateral ACL injury. Since group physical function and neuromuscular control factors were similar, clinicians need to increase their awareness and understanding of other factors that may influence surgical ACL re-injury or contralateral ACL injury risk. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Repeat-associated non-AUG translation induces cytoplasmic aggregation of CAG repeat-containing RNAs.

CAG trinucleotide repeat expansions cause several neurodegenerative diseases, including Huntington's disease and spinocerebellar ataxia. RNAs with expanded CAG repeats contribute to disease in two unusual ways. First, these repeat-containing RNAs may agglomerate in the nucleus as foci that sequester several RNA-binding proteins. Second, these RNAs may undergo aberrant repeat-associated non-AUG (RAN) translation in multiple frames and produce aggregation-prone proteins. The relationship between RAN translation and RNA foci, and their relative contributions to cellular dysfunction, are unclear. Here, we show that CAG repeat-containing RNAs that undergo RAN translation first accumulate at nuclear foci and, over time, are exported to the cytoplasm. In the cytoplasm, these RNAs are initially dispersed but, upon RAN translation, aggregate with the RAN translation products. These RNA-RAN protein agglomerates sequester various RNA-binding proteins and are associated with the disruption of nucleocytoplasmic transport and cell death. In contrast, RNA accumulation at nuclear foci alone does not produce discernable defects in nucleocytoplasmic transport or cell viability. Inhibition of RAN translation prevents cytoplasmic RNA aggregation and alleviates cell toxicity. Our findings demonstrate that RAN translation-induced RNA-protein aggregation correlates with the key pathological hallmarks observed in disease and suggest that cytoplasmic RNA aggregation may be an underappreciated phenomenon in CAG trinucleotide repeat expansion disorders.

Comparison of Freshly Isolated Adipose Tissue-derived Stromal Vascular Fraction and Bone Marrow Cells in a Posterolateral Lumbar Spinal Fusion Model.

STUDY DESIGN: Rat posterolateral lumbar fusion model. OBJECTIVE: The aim of this study was to compare the efficacy of freshly isolated adipose tissue-derived stromal vascular fraction (A-SVF) and bone marrow cells (BMCs) cells in achieving spinal fusion in a rat model. SUMMARY OF BACKGROUND DATA: Adipose tissue-derived stromal cells (ASCs) offer advantages as a clinical cell source compared to bone marrow-derived stromal cells (BMSCs), including larger available tissue volumes and reduced donor site morbidity. While pre-clinical studies have shown that ex vivo expanded ASCs can be successfully used in spinal fusion, the use of A-SVF cells better allows for clinical translation. METHODS: A-SVF cells were isolated from the inguinal fat pads, whereas BMCs were isolated from the long bones of syngeneic 6- to 8-week-old Lewis rats and combined with Vitoss (Stryker) bone graft substitute for subsequent transplantation. Posterolateral spinal fusion surgery at L4-L5 was performed on 36 female Lewis rats divided into three experimental groups: Vitoss bone graft substitute only (VO group); Vitoss + 2.5 × 106 A-SVF cells/side; and, Vitoss + 2.5 × 106 BMCs/side. Fusion was assessed 8 weeks post-surgery via manual palpation, micro-computed tomography (µCT) imaging, and histology. RESULTS: µCT imaging analyses revealed that fusion volumes and µCT fusion scores in the A-SVF group were significantly higher than in the VO group; however, they were not significantly different between the A-SVF group and the BMC group. The average manual palpation score was highest in the A-SVF group compared with the BMC and VO groups. Fusion masses arising from cell-seeded implants yielded better bone quality than nonseeded bone graft substitute. CONCLUSION: In a rat model, A-SVF cells yielded a comparable fusion mass volume and radiographic rate of fusion to BMCs when combined with a clinical-grade bone graft substitute. These results suggest the feasibility of using freshly isolated A-SVF cells in spinal fusion procedures.Level of Evidence: N/A.

Analysis of morphological measurements of the trigeminal nerve in the linac stereotactic radiosurgery simulation targeting the root entry zone in trigeminal neuralgia / Análisis de las mediciones morfológicas del nervio trigémino en la simulación de radiocirugía estereotáctica con LINAC considerando como blanco la zona de entrada de la raíz en neuralgia trigeminal

Purpose: To describe the anatomical measurements of the trigeminal nerve in patients with trigeminal neuralgia (TN) during Linac (linear accelerator)-based stereotactic radiosurgery (SRS) simulation, targeting the root entry zone (REZ), with a 30% isodose line tangential to the pons, using 4-mm and 6-mm collimators. Methods: In this retrospective study, 53 TN patients, who underwent Fiesta sequence scanning prior to any treatment modality, were assessed. Bilateral measurements were obtained from the cisternal segment of the trigeminal nerve, the trigeminal-pontine angle, and the lateral width of the pontine cistern on the Fiesta MRI sequence. Linac-based SRS simulations were estimated with a radiation dosage of 90Gy to 30% isodose line tangential to the pons, with both 4- and 6-mm collimators. Distances from the calculated targets to the pons and the Gasserian ganglion were measured for later analysis. The statistical analysis was performed comparing the affected side against the unaffected side. Results: Right trigeminal nerve was affected in 36 patients (67.9%), and left one in 17 (32.1%) patients. The mean length of the trigeminal nerve was 9.8mm (range: 4.6-16.8mm) on the affected side, and 10.5mm (range: 5.6-18.4mm) on the unaffected side (p=.02). The mean trigeminal-pontine angle was 12.5° (range: 5.4° to 19.5°) on the affected side, and 10.2° (range: 5.0° to 30.5°) on the unaffected side (p=.01). In the simulations, the distances from the estimated targets to the pons and the Gasserian ganglion were not statistically different between sides. The variation of target-pons and target-ganglion distances was statistically significant on the affected side with the change of collimators (p<.001). Conclusions: In this anatomical study, significant differences were identified in the length of the affected trigeminal nerve and trigeminal-pontine angle compared to the unaffected side in TN patients in Fiesta sequences prior to surgery or radiosurgery. Significant variation of the target location was found on the REZ between the 4- and 6-collimators during the Linac-based SRS simulations with the estimated radiation dosage of 90Gy and 30% isodose line tangential to the pons

Objetivo: Describir las mediciones anatómicas del nervio trigémino en pacientes con neuralgia del trigémino (NT) en la simulación para radiocirugía estereotáctica (SRS) con acelerador lineal (LINAC), utilizando como blanco la zona de entrada de la raíz (REZ), con una línea de isodosis del 30% tangencial al puente, usando colimadores de 4 y 6mm. Métodos: En este estudio retrospectivo, fueron evaluados 53 pacientes con NT con una secuencia FIESTA de RM previo a recibir alguna modalidad de tratamiento. Las mediciones obtenidas bilateralmente fueron la longitud de la porción cisternal del nervio trigémino, del ángulo trigémino-pontino y la anchura lateral de la cisterna pontina. Las simulaciones de SRS con LINAC fueron estimadas con una dosis de radiación de 90Gy a una línea de isodosis del 30% tangencial al puente, tanto con colimadores de 4 y 6mm. Las distancias desde los blancos calculados al puente y al ganglio de Gasser, bajo estos parámetros, fueron medidas. El análisis estadístico fue realizado comparando el lado afectado contra el lado no afectado. Resultados: El nervio trigémino derecho se encontró afectado en 36 pacientes (67,9%), y el izquierdo en 17 (32,1%) pacientes. La longitud media del nervio trigémino fue 9,8mm (rango: 4,6-16,8mm) en el lado afectado, y 10,5mm (rango: 5,6-18,4mm) en el lado no afectado, con una diferencia media estadísticamente significativa (p=0,02). El ángulo trigémino-pontino fue 12,5° (rango: 5,4-19,5°) en el lado afectado y 10,2° (rango: 5,0-30,5°) en el lado no afectado, con una diferencia media significativa (p=0,01). En las simulaciones, las distancias desde los blancos estimados al puente y al ganglio de Gasser no fueron significativamente diferentes entre ambos lados. La variación de las distancias blanco-puente y blanco-ganglio fue estadísticamente significativa en el lado afectado con el cambio de colimadores (p<0,001). Conclusiones: En este estudio anatómico, diferencias significativas fueron identificadas en la longitud del nervio trigémino y el ángulo trigémino-pontino en el lado afectado al compararse con el lado no afectado en pacientes con NT idiopática en secuencias FIESTA previo a cirugía o radiocirugía. Se observó variación en la localización del blanco sobre la REZ en las simulaciones de SRS con LINAC entre los colimadores de 4 y 6mm, con una dosis de radiación estimada de 90Gy y una línea de isodosis del 30% paralela al puente

α-Sheet secondary structure in amyloid ß-peptide drives aggregation and toxicity in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the deposition of ß-sheet-rich, insoluble amyloid ß-peptide (Aß) plaques; however, plaque burden is not correlated with cognitive impairment in AD patients; instead, it is correlated with the presence of toxic soluble oligomers. Here, we show, by a variety of different techniques, that these Aß oligomers adopt a nonstandard secondary structure, termed "α-sheet." These oligomers form in the lag phase of aggregation, when Aß-associated cytotoxicity peaks, en route to forming nontoxic ß-sheet fibrils. De novo-designed α-sheet peptides specifically and tightly bind the toxic oligomers over monomeric and fibrillar forms of Aß, leading to inhibition of aggregation in vitro and neurotoxicity in neuroblastoma cells. Based on this specific binding, a soluble oligomer-binding assay (SOBA) was developed as an indirect probe of α-sheet content. Combined SOBA and toxicity experiments demonstrate a strong correlation between α-sheet content and toxicity. The designed α-sheet peptides are also active in vivo where they inhibit Aß-induced paralysis in a transgenic Aß Caenorhabditis elegans model and specifically target and clear soluble, toxic oligomers in a transgenic APPsw mouse model. The α-sheet hypothesis has profound implications for further understanding the mechanism behind AD pathogenesis.

Analysis of morphological measurements of the trigeminal nerve in the linac stereotactic radiosurgery simulation targeting the root entry zone in trigeminal neuralgia.

PURPOSE: To describe the anatomical measurements of the trigeminal nerve in patients with trigeminal neuralgia (TN) during Linac (linear accelerator)-based stereotactic radiosurgery (SRS) simulation, targeting the root entry zone (REZ), with a 30% isodose line tangential to the pons, using 4-mm and 6-mm collimators. METHODS: In this retrospective study, 53 TN patients, who underwent Fiesta sequence scanning prior to any treatment modality, were assessed. Bilateral measurements were obtained from the cisternal segment of the trigeminal nerve, the trigeminal-pontine angle, and the lateral width of the pontine cistern on the Fiesta MRI sequence. Linac-based SRS simulations were estimated with a radiation dosage of 90Gy to 30% isodose line tangential to the pons, with both 4- and 6-mm collimators. Distances from the calculated targets to the pons and the Gasserian ganglion were measured for later analysis. The statistical analysis was performed comparing the affected side against the unaffected side. RESULTS: Right trigeminal nerve was affected in 36 patients (67.9%), and left one in 17 (32.1%) patients. The mean length of the trigeminal nerve was 9.8mm (range: 4.6-16.8mm) on the affected side, and 10.5mm (range: 5.6-18.4mm) on the unaffected side (p=.02). The mean trigeminal-pontine angle was 12.5° (range: 5.4° to 19.5°) on the affected side, and 10.2° (range: 5.0° to 30.5°) on the unaffected side (p=.01). In the simulations, the distances from the estimated targets to the pons and the Gasserian ganglion were not statistically different between sides. The variation of target-pons and target-ganglion distances was statistically significant on the affected side with the change of collimators (p<.001). CONCLUSIONS: In this anatomical study, significant differences were identified in the length of the affected trigeminal nerve and trigeminal-pontine angle compared to the unaffected side in TN patients in Fiesta sequences prior to surgery or radiosurgery. Significant variation of the target location was found on the REZ between the 4- and 6-collimators during the Linac-based SRS simulations with the estimated radiation dosage of 90Gy and 30% isodose line tangential to the pons.

In vivo induction of membrane damage by ß-amyloid peptide oligomers.

Exposure to the ß-amyloid peptide (Aß) is toxic to neurons and other cell types, but the mechanism(s) involved are still unresolved. Synthetic Aß oligomers can induce ion-permeable pores in synthetic membranes, but whether this ability to damage membranes plays a role in the ability of Aß oligomers to induce tau hyperphosphorylation, or other disease-relevant pathological changes, is unclear. To examine the cellular responses to Aß exposure independent of possible receptor interactions, we have developed an in vivo C. elegans model that allows us to visualize these cellular responses in living animals. We find that feeding C. elegans E. coli expressing human Aß induces a membrane repair response similar to that induced by exposure to the CRY5B, a known pore-forming toxin produced by B. thuringensis. This repair response does not occur when C. elegans is exposed to an Aß Gly37Leu variant, which we have previously shown to be incapable of inducing tau phosphorylation in hippocampal neurons. The repair response is also blocked by loss of calpain function, and is altered by loss-of-function mutations in the C. elegans orthologs of BIN1 and PICALM, well-established risk genes for late onset Alzheimer's disease. To investigate the role of membrane repair on tau phosphorylation directly, we exposed hippocampal neurons to streptolysin O (SLO), a pore-forming toxin that induces a well-characterized membrane repair response. We find that SLO induces tau hyperphosphorylation, which is blocked by calpain inhibition. Finally, we use a novel biarsenical dye-tagging approach to show that the Gly37Leu substitution interferes with Aß multimerization and thus the formation of potentially pore-forming oligomers. We propose that Aß-induced tau hyperphosphorylation may be a downstream consequence of induction of a membrane repair process.

Chiari Malformation and Hydrocephalus Masking Neurocysticercosis.

BACKGROUND: Various diagnostic characteristics associated with neurocysticercosis have been well studied; however, their potential to be implicated in other differential diagnoses has not been well demonstrated. CASE DESCRIPTION: We report the case of a 55-year-old Hispanic man who underwent a Chiari decompression surgery, which was complicated with hydrocephalus. Despite a ventriculoperitoneal shunt placement, he continued to have headaches and was soon found to have several skull base subarachnoid lesions, which were later diagnosed as the sequelae of an active neurocysticercosis infection. CONCLUSION: This case report highlights the importance of overlapping symptoms between diseases in a short temporal context.