The nuclear ubiquitin ligase adaptor SPOP is a conserved regulator of C9orf72 dipeptide toxicity.

A hexanucleotide repeat expansion in the C9orf72 gene is the most common cause of inherited amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Unconventional translation of the C9orf72 repeat produces dipeptide repeat proteins (DPRs). Previously, we showed that the DPRs PR50 and GR50 are highly toxic when expressed in Caenorhabditis elegans, and this toxicity depends on nuclear localization of the DPR. In an unbiased genome-wide RNA interference (RNAi) screen for suppressors of PR50 toxicity, we identified 12 genes that consistently suppressed either the developmental arrest and/or paralysis phenotype evoked by PR50 expression. All of these genes have vertebrate homologs, and 7 of 12 contain predicted nuclear localization signals. One of these genes was spop-1, the C. elegans homolog of SPOP, a nuclear localized E3 ubiquitin ligase adaptor only found in metazoans. SPOP is also required for GR50 toxicity and functions in a genetic pathway that includes cul-3, which is the canonical E3 ligase partner for SPOP Genetic or pharmacological inhibition of SPOP in mammalian primary spinal cord motor neurons suppressed DPR toxicity without affecting DPR expression levels. Finally, we find that knockdown of bromodomain proteins in both C. elegans and mammalian neurons, which are known SPOP ubiquitination targets, suppresses the protective effect of SPOP inhibition. Together, these data suggest a model in which SPOP promotes the DPR-dependent ubiquitination and degradation of BRD proteins. We speculate the pharmacological manipulation of this pathway, which is currently underway for multiple cancer subtypes, could also represent an entry point for therapeutic intervention to treat C9orf72 FTD/ALS.

Several Techniques Exist With Favorable Biomechanical Outcomes in Radial Meniscus Tear Repair-A Systematic Review.

PURPOSE: To compare biomechanical properties of various radial tear repair techniques in the medial and lateral menisci. METHODS: A search was performed for key words regarding mechanical properties of repair of radial meniscal tears in PubMed, Embase, CINAHL, Scopus, and Cochrane databases, yielding 1791 articles. Articles were screened using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines against inclusion criteria and underwent Methodological Index for Non-Randomized Studies (MINORS) methodologic quality assessment. Repair constructs evaluated were classified based on repair technique, use of a transtibial augmentation, and the number, orientation, and pattern of stitches. Results published across different studies were compared but not subjected to meta-analysis due to variability in testing procedures and heterogeneity of repair methods. RESULTS: We identified 20 studies that performed mechanical testing on 21 different radial meniscal tear repair techniques. The greatest reported mean load-to-failure (LtF) were the transtibial 2-tunnel + 4 horizontal inside-out sutures (191.2 N ± 17.3, cadaver) and all-inside double vertical repair (146.3 N ± 36.2, porcine). The transtibial technique improved LtF and displacement of an inside-out (IO) horizontal repair. All-inside vertical repairs demonstrated greater LtF, stiffness, and displacement compared with IO horizontal repairs in 2 studies. Compared with IO double horizontal repairs, all-inside double vertical or IO double horizontal repairs with reinforcing stitches parallel to the tear exhibited greater LtF in 3 studies and stiffness in 2 studies. Two studies reported that parallel reinforcing stitches significantly reduced suture tear-through compared with similar, nonreinforced repairs. Mean MINORS score for all studies analyzed was 19.88 ± 1.47 points. CONCLUSIONS: A systematic review demonstrated that there may be alternatives to traditional IO horizontal repairs for radial meniscus tears. Less-invasive all-inside vertical techniques reinforced with suture parallel to the tear instead of standard IO horizontal sutures may improve strength of repair. In addition, transtibial 2-tunnel augmentation may also increase strength of radial meniscus tear repairs. CLINICAL RELEVANCE: There may be alternatives to IO horizontal repairs for radial meniscus tears.

More Is Not Merrier: Increasing Numbers of All-Inside Implants Do Not Correlate with Higher Odds of Revision Surgery.

The purpose of this study was to evaluate the relationship between the number of all-inside meniscal repair implants placed and the risk of repair failure. We hypothesized that the use of higher numbers of all-inside meniscus repair implants would be associated with increased failure risk. A retrospective chart review identified 351 patients who underwent all-inside meniscus repair between 2006 and 2013 by a sports medicine fellowship-trained orthopaedic surgeon at a single institution. Patient demographics (age, body mass index [BMI], sex) and surgical data (number of implants used, concomitant anterior cruciate ligament reconstruction [cACLR], and tear type/size/location) were recorded. Patients who received repairs in both menisci or who had follow-up < 1-year postoperatively were excluded. Repair failure was identified through chart review or patient interviews defined as a revision surgery on the index knee such as partial meniscectomy, total knee arthroplasty, meniscus transplant, or repeat repair. Logistic regression modeling was utilized to evaluate the relationship between the number of implants used and repair failure. A total of 227 all-inside meniscus repairs were included with a mean follow-up of 5.0 ± 3.0 years following surgery. Repair failure was noted in 68 knees (30.3%)-in 28.1% of knees with fewer than four implants and in 35.8% of knees with four or more implants (p = 0.31). No significant increase in failure was observed with increasing number of all-inside medial (odds ratio [OR]: 1.15; 95% confidence interval [CI]: 0.79-1.7; p = 0.46) or lateral (OR: 0.86; 95% CI: 0.47-1.57; p = 0.63) implants after controlling for patient age, BMI, cACLR, tear type, or size. Tears of the lateral meniscus located in the red-white and white-white zones had lower odds of failure (OR: 0.14; 95% CI: 0.02-0.88; p = 0.036) than tears within the red-red zone, and patients with cACLR had lower odds of repair failure (OR: 0.40; 95% CI: 0.18-0.86, p = 0.024) than those without. The number of all-inside implants placed during meniscus tear repair did not affect the likelihood of repair failure leading to reoperation after controlling for BMI, age, tear type, size, location, and cACLR. LEVEL OF EVIDENCE: III.

Static Cage Morphology in Short-Segment Transforaminal Lumbar Interbody Fusions Is Associated With Alterations in Foraminal Height But Not Clinical Outcomes.

INTRODUCTION: Steerable "banana" cages have been posited to increase segmental lordosis in short-segment transforaminal lumbar interbody fusions (TLIF). The same is not necessarily true for straight "bullet" cages. Although increased lordosis is generally thought to be advantageous, a potential complication is decreased foraminal height. Here we evaluate for any association between cage type and change in foraminal height and clinical outcomes following short-segment TLIFs. METHODS: We retrospectively reviewed consecutive 1- and 2-level TLIFs with bilateral facetectomies with minimum 1-year clinical and radiographic follow-up. Two cohorts were based on cage morphology: steerable "banana" cage or straight "bullet" cage. Patient reported outcome measures (PROMs), radiographic measurements, and revision rates were compared. RESULTS: A total of 46 patients with 53 straight and 95 patients with 131 steerable cage levels were included. Steerable cages showed increased segmental lordosis (9.1° vs. 13.5°, P < 0.001) and decreased foraminal height (20.3 vs. 18.5 mm, P < 0.001) after surgery. Straight cages demonstrated similar segmental lordosis (8.7° vs 8.1°, P = 0.30) and foraminal height (19.4 vs 20.0 mm, P < 0.065). Both cohorts showed improved PROMs at last follow-up (P ≤ 0.005). Subanalysis comparing patients who had increased or decreased foraminal height revealed similarly improved PROMs between cohorts. Revision rates at 1 year were similar between cohorts (4.3% for straight and 3.2% for steerable group, P = 0.72). CONCLUSIONS: Although the increased segmental lordosis afforded by placement of steerable cages may decrease foraminal height after short segment TLIF, clinical outcomes are not negatively affected by this association.

Radiographic and clinical outcomes in one- and two-level transforaminal lumbar interbody fusions: a comparison of bullet versus banana cages.

OBJECTIVE: The aim of this study was to determine whether cage morphology influences clinical and radiographic outcomes following short-segment transforaminal lumbar interbody fusion (TLIF) procedures. METHODS: The authors retrospectively reviewed one- and two-level TLIFs at a single tertiary care center between August 2012 and November 2019 with a minimum 1-year radiographic and clinical follow-up. Two cohorts were compared based on interbody cage morphology: steerable "banana" cage or straight "bullet" cage. Patient-reported outcome measures (PROMs), radiographs, and complications were analyzed. RESULTS: A total of 135 patients with 177 interbody levels were identified; 45 patients had 52 straight cages and 90 patients had 125 steerable cages. Segmental lordosis increased with steerable cages, while it decreased with straight cages (+3.8 ± 4.6 vs -1.9 ± 4.3, p < 0.001). Conversely, the mean segmental lordosis of adjacent lumbar levels decreased in the former group, while it increased in the latter group (-0.52 ± 1.9 vs +0.52 ± 2.1, p = 0.004). This reciprocal relationship results in global sagittal parameters, including pelvic incidence minus lumbar lordosis and lumbar distribution index, which did not change after surgery with either cage morphology. Multivariate analysis confirmed that steerable cage morphology, anterior cage positioning, and less preoperative index-level segmental lordosis were associated with greater improvement in index-level segmental lordosis. PROMs were improved after surgery with both cage types, and the degree of improvement did not differ between cohorts (p > 0.05). Perioperative and radiographic complications were similar between cohorts (p > 0.05). Overall reoperation rates, as well as reoperation rates for adjacent-segment disease within 2 years of surgery, were not significantly different between cohorts. CONCLUSIONS: Steerable cages are more likely to lie within the anterior disc space, thus increasing index-level segmental lordosis, which is accompanied by a reciprocal change in segmental alignment at the adjacent lumbar levels. The converse relationship occurs for straight cages, with a kyphotic change at the index levels and reciprocal lordosis occurring at adjacent levels.