A cell-ECM mechanism for connecting the ipsilateral eye to the brain.

Information about features in the visual world is parsed by circuits in the retina and is then transmitted to the brain by distinct subtypes of retinal ganglion cells (RGCs). Axons from RGC subtypes are stratified in retinorecipient brain nuclei, such as the superior colliculus (SC), to provide a segregated relay of parallel and feature-specific visual streams. Here, we sought to identify the molecular mechanisms that direct the stereotyped laminar targeting of these axons. We focused on ipsilateral-projecting subtypes of RGCs (ipsiRGCs) whose axons target a deep SC sublamina. We identified an extracellular glycoprotein, Nephronectin (NPNT), whose expression is restricted to this ipsiRGC-targeted sublamina. SC-derived NPNT and integrin receptors expressed by ipsiRGCs are both required for the targeting of ipsiRGC axons to the deep sublamina of SC. Thus, a cell-extracellular matrix (ECM) recognition mechanism specifies precise laminar targeting of ipsiRGC axons and the assembly of eye-specific parallel visual pathways.

Complement-dependent loss of inhibitory synapses on pyramidal neurons following Toxoplasma gondii infection.

The apicomplexan parasite Toxoplasma gondii has developed mechanisms to establish a central nervous system infection in virtually all warm-blooded animals. Acute T. gondii infection can cause neuroinflammation, encephalitis, and seizures. Meanwhile, studies in humans, nonhuman primates, and rodents have linked chronic T. gondii infection with altered behavior and increased risk for neuropsychiatric disorders, including schizophrenia. These observations and associations raise questions about how this parasitic infection may alter neural circuits. We previously demonstrated that T. gondii infection triggers the loss of inhibitory perisomatic synapses, a type of synapse whose dysfunction or loss has been linked to neurological and neuropsychiatric disorders. We showed that phagocytic cells (including microglia and infiltrating monocytes) contribute to the loss of these inhibitory synapses. Here, we show that these phagocytic cells specifically ensheath excitatory pyramidal neurons, leading to the preferential loss of perisomatic synapses on these neurons and not those on cortical interneurons. Moreover, we show that infection induces an increased expression of the complement C3 gene, including by populations of these excitatory neurons. Infecting C3-deficient mice with T. gondii revealed that C3 is required for the loss of perisomatic inhibitory synapses. Interestingly, loss of C1q did not prevent the loss of perisomatic synapses following infection. Together, these findings provide evidence that T. gondii induces changes in excitatory pyramidal neurons that trigger the selective removal of inhibitory perisomatic synapses and provide a role for a nonclassical complement pathway in the remodeling of inhibitory circuits in the infected brain.

Complete loss of the X-linked gene CASK causes severe cerebellar degeneration.

BACKGROUND: Heterozygous loss of X-linked genes like CASK and MeCP2 (Rett syndrome) causes developmental delay in girls, while in boys, loss of the only allele of these genes leads to epileptic encephalopathy. The mechanism for these disorders remains unknown. CASK-linked cerebellar hypoplasia is presumed to result from defects in Tbr1-reelin-mediated neuronal migration. METHOD: Here we report clinical and histopathological analyses of a deceased 2-month-old boy with a CASK-null mutation. We next generated a mouse line where CASK is completely deleted (hemizygous and homozygous) from postmigratory neurons in the cerebellum. RESULT: The CASK-null human brain was smaller in size but exhibited normal lamination without defective neuronal differentiation, migration or axonal guidance. The hypoplastic cerebellum instead displayed astrogliosis and microgliosis, which are markers for neuronal loss. We therefore hypothesise that CASK loss-induced cerebellar hypoplasia is the result of early neurodegeneration. Data from the murine model confirmed that in CASK loss, a small cerebellum results from postdevelopmental degeneration of cerebellar granule neurons. Furthermore, at least in the cerebellum, functional loss from CASK deletion is secondary to degeneration of granule cells and not due to an acute molecular functional loss of CASK. Intriguingly, female mice with heterozygous deletion of CASK in the cerebellum do not display neurodegeneration. CONCLUSION: We suggest that X-linked neurodevelopmental disorders like CASK mutation and Rett syndrome are pathologically neurodegenerative; random X-chromosome inactivation in heterozygous mutant girls, however, results in 50% of cells expressing the functional gene, resulting in a non-progressive pathology, whereas complete loss of the only allele in boys leads to unconstrained degeneration and encephalopathy.

Retinal inputs signal astrocytes to recruit interneurons into visual thalamus.

Inhibitory interneurons comprise a fraction of the total neurons in the visual thalamus but are essential for sharpening receptive field properties and improving contrast-gain of retinogeniculate transmission. During early development, these interneurons undergo long-range migration from germinal zones, a process regulated by the innervation of the visual thalamus by retinal ganglion cells. Here, using transcriptomic approaches, we identified a motogenic cue, fibroblast growth factor 15 (FGF15), whose expression in the visual thalamus is regulated by retinal input. Targeted deletion of functional FGF15 in mice led to a reduction in thalamic GABAergic interneurons similar to that observed in the absence of retinal input. This loss may be attributed, at least in part, to misrouting of interneurons into nonvisual thalamic nuclei. Unexpectedly, expression analysis revealed that FGF15 is generated by thalamic astrocytes and not retino-recipient neurons. Thus, these data show that retinal inputs signal through astrocytes to direct the long-range recruitment of interneurons into the visual thalamus.

Anatomic Anterior Cruciate Ligament Reconstruction.

Anterior cruciate ligament reconstruction (ACLR) techniques have substantially evolved over the past several decades, driven by evidence that nonanatomic techniques increase the risk for instability, loss of motion, surgical failure, and posttraumatic osteoarthritis. Early techniques used transtibial femoral tunnel drilling, although improved understanding of the anatomy and biomechanics has led to independent femoral tunnel. Anatomic ACLR requires careful consideration of the native ACL dimensions and orientation. Although there is significant variation between patients, understanding of anatomic patterns allows for reliable identification of the ACL footprints and appropriate tunnel positioning, particularly in chronic injuries where the remanent ACL stump is degraded or absent. The femoral tunnel should be placed low and posterior on the lateral femoral condyle using the lateral intercondylar and bifurcate ridges as landmarks. The center of the tibial footprint can be determined by referencing the medial tibial spine and posterior border of anterior horn of lateral meniscus. Measurement of the dimensions of the native ACL and intercondylar notch is also critical for determining graft size and minimizing the risk of impingement, with a goal of reconstructing 50% to 80% of the tibial footprint area. Clinical outcome studies have demonstrated superior anteroposterior and rotatory knee stability with low surgical revision rates (reported between 3% and 5%). By adhering to the principles of anatomic ACLR, surgeons can produce an appropriately sized and located graft for the individual patient, thereby best restoring native knee kinematics and maximizing function. The aim of this infographic is to highlight essential features of anatomic ACLR techniques, which a focus on the native anatomy and surgical planning to achieve an anatomic ACLR.

Increased Failure Rates After Arthroscopic Bankart Repair After Second Dislocation Compared to Primary Dislocation With Comparable Clinical Outcomes.

PURPOSE: The purpose of this study was to compare rates of recurrent dislocation and postsurgical outcomes in patients undergoing arthroscopic Bankart repair for anterior shoulder instability immediately after a first-time traumatic anterior dislocation versus patients who sustained a second dislocation event after initial nonoperative management. METHODS: A retrospective chart review was performed of patients undergoing primary arthroscopic stabilization for anterior shoulder instability without concomitant procedures and minimum 2-year clinical follow-up. Primary outcome was documentation of a recurrent shoulder dislocation. Secondary clinical outcomes included range of motion, Visual Analog Scale (VAS), American Shoulder and Elbow Surgeons Shoulder Score (ASES), and Shoulder Activity Scale (SAS). RESULTS: Seventy-seven patients (mean age 21.3 years ± 7.3 years) met inclusion criteria. Sixty-three shoulders underwent surgical stabilization after a single shoulder dislocation, and 14 underwent surgery after 2 dislocations. Average follow-up was 35.9 months. The rate of recurrent dislocation was significantly higher in the 2-dislocation group compared to single dislocations (42.8% vs 14.2%, P = .03). No significant difference was present in range of motion, VAS, ASES, and SAS scores. The minimal clinically important difference (MCID) was 1.4 for VAS and 1.8 for SAS scores. The MCID was met or exceeded in the primary dislocation group in 31/38 (81.6%) patients for VAS, 23/31 (74.1%) for ASES, and 24/31 for SES (77.4%) scores. For the second dislocation cohort, MCID was met or exceeded in 7/9 (77.8%) for VAS, 4/7 (57.1%) for ASES, and 5/7 for SES (71.4%) scores. CONCLUSION: Immediate arthroscopic surgical stabilization after a first-time anterior shoulder dislocation significantly decreases the risk of recurrent dislocation in comparison to those who undergo surgery after 2 dislocation events, with comparable clinical outcome scores. These findings suggest that patients who return to activities after a primary anterior shoulder dislocation and sustain just 1 additional dislocation event are at increased risk of a failing arthroscopic repair. STUDY DESIGN: Retrospective comparative study; Level of evidence, 3.

Knotted and knotless double row transosseous equivalent repair techniques for arthroscopic rotator cuff repair demonstrate comparable post-operative outcomes.

PURPOSE: To compare failure rates and outcomes after transosseous equivalent (TOE) double row (DR) knotted suture bridge versus knotless suture tape bridge repair techniques for rotator cuff tears. METHODS: A consecutive series of 272 shoulders in 256 patients who underwent arthroscopic, double row, TOE repair for full-thickness tears of the supraspinatus tendon were reviewed. Eighty-four shoulders were repaired using knotted suture bridge (KSB) technique, and 188 shoulders were repaired using all knotless suture tape bridge (KTB) technique. Revision procedures and concomitant subscapularis tendon repairs were excluded from analysis. The minimum follow-up was 12 months. Primary outcome was failure of surgical repair, defined as either confirmed retear on MRI and/or need for revision surgery. Secondary clinical outcome measures were assessed including range of motion, strength, visual analog scale (VAS), operative time, subjective shoulder value (SSV), Patient-Reported Outcomes Measurement Information System (PROMIS) mental and physical health, American Shoulder and Elbow Surgeons Shoulder Score (ASES), Brophy shoulder activity scores, and need for manipulation under anesthesia (MUA). RESULTS: A total of 127 shoulders (38 KSB and 89 KTB) met inclusion criteria for the study. No significant difference in demographic variables were present between the groups at baseline. Supraspinatus tear size and average follow-up time did not differ significantly between groups. Failure rates were similar between the KSB and KTB repairs (13.1 vs 7.9%, n.s.). There was no significant difference in functional outcomes including strength, range of motion in forward flexion and external rotation, as well as patient reported outcomes including VAS, SSV, PROMIS, ASES, and Brophy scores between the groups. There was also no difference in post-operative stiffness requiring MUA. CONCLUSION: Both KSB and KTB repair techniques demonstrate low retear rates with excellent functional outcomes when compared to pre-operative examination. Both KSB and KTB techniques are viable options for achieving a successful rotator cuff repair. LEVEL OF EVIDENCE: Level III.

Reverse shoulder arthroplasty with preservation of the rotator cuff for primary glenohumeral osteoarthritis has similar outcomes to anatomic total shoulder arthroplasty and reverse shoulder arthroplasty for cuff arthropathy.

INTRODUCTION: Indications for reverse total shoulder arthroplasty (RSA) have expanded to include individuals with intact rotator cuffs such as patients with severe glenoid deformity or with concern of future rotator cuff insufficiency. The purpose of this study was to compare outcomes of RSA with an intact rotator cuff to RSA for cuff arthropathy and anatomic total shoulder arthroplasty (TSA). We hypothesized that outcomes of RSA with an intact rotator cuff would be comparable to RSA for cuff arthropathy and TSA but with diminished range of motion (ROM) compared with TSA. MATERIALS AND METHODS: Patients at one institution who underwent RSA and TSA between 2015 and 2020 with minimum 12-month follow-up were identified. RSA with preservation of the rotator cuff (+rcRSA) was compared to RSA for cuff arthropathy (-rcRSA) and anatomic TSA (TSA). Demographics and glenoid version/inclination were obtained. Pre- and postoperative ROM; patient-reported outcomes including visual analog scale (VAS), Subjective Shoulder Value (SSV), and American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) scores; and complications were obtained. RESULTS: Twenty-four patients underwent +rcRSA, 69 underwent -rcRSA, and 93 underwent TSA. There were more women in the +rcRSA cohort (75.8%) than in the -rcRSA (37.7%, P = .001) and TSA (37.6%, P = .001) cohorts. Mean age of the +rcRSA cohort (71.1) was greater than that of TSA (66.0, P = .021) but similar to that of -rcRSA (72.4, P = .237). Glenoid retroversion was greater in +rcRSA (18.2°) compared with -rcRSA (10.5°, P = .011) but was similar to TSA (14.7°; P = .244). Postoperatively, there were no differences in VAS or ASES between +rcRSA vs. -rcRSA and +rcRSA vs. TSA. SSV was lower in +rcRSA (83.9) compared with -rcRSA (91.8, P = .021), but was similar to TSA (90.5, P = .073). Similar ROM was achieved in forward flexion, external rotation, and internal rotation at final follow-up between +rcRSA and -rcRSA, but TSA had greater external rotation (44° vs. 38°, P = .041) and internal rotation (6.5° vs. 5.0°, P = .001) compared with +rcRSA. There were no differences in complication rates. DISCUSSION: At short-term follow-up, preservation of the rotator cuff in RSA demonstrated similarly excellent outcomes and low complication rates compared with RSA with a deficient rotator cuff and TSA, except for slightly lower internal and external rotation compared with TSA. Although multiple factors deserve consideration when choosing between RSA and TSA, RSA with preservation of the posterosuperior cuff is a viable treatment option for glenohumeral osteoarthritis, particularly in patients with severe glenoid deformity or those at risk for future rotator cuff insufficiency.

Remplissage reduces recurrent instability in high-risk patients with on-track Hill-Sachs lesions.

BACKGROUND: The purpose of this study was to compare recurrent instability rates between patients with on-track Hill-Sachs lesions who underwent arthroscopic labral repair (ALR) alone and those who underwent ALR with remplissage (ALR-R). Our hypothesis was that ALR-R would decrease the rate of recurrent instability, especially among patients at high risk of recurrent instability after ALR, such as contact athletes with near-track Hill-Sachs lesions. METHODS: We performed a multicenter, retrospective analysis of patients aged 14-50 years with on-track Hill-Sachs lesions who underwent ALR-R or ALR without remplissage between January 2014 and December 2019 with minimum 2-year follow-up. The exclusion criteria included prior ipsilateral shoulder surgery, >15% glenoid bone loss (GBL), off-track Hill-Sachs lesion, concomitant shoulder procedure, and connective tissue disorder. Age, sex, follow-up, and contact sports participation were recorded. GBL, Hills-Sachs interval (HSI), glenoid track, and distance to dislocation (DTD) were determined from preoperative magnetic resonance imaging scans. Affected-shoulder range of motion, Western Ontario Shoulder Instability Index scores, Subjective Shoulder Value scores, and recurrent dislocation and/or revision surgery status were also collected. A subgroup analysis was performed on "high-risk" patients (defined as participants in contact sports with DTD <10 mm) from each cohort. RESULTS: The ALR-R cohort included 56 patients, and the ALR cohort included 127. ALR-R patients had greater GBL (P = .004) and a greater HSI (P < .001). In the ALR-R cohort, only 1 patient (1.8%) had a recurrent dislocation and there were no revision operations. In comparison, in the ALR cohort, 14 patients (11.0%) had recurrent dislocations (P = .040) and 8 (6.3%) underwent revision operations (P = .11). Univariate analysis showed that remplissage protected against recurrent dislocation (P = .040) whereas younger age (P = .004), contact sports participation (P = .001), and increased GBL (P = .048) were associated with recurrent dislocation. Multivariate analysis showed that HSI (P = .001) and contact sports participation (P = .002) predicted recurrent dislocation. Among high-risk patients, only 1 patient (4.2%) in the ALR-R group had a recurrent instability event vs. 6 (66.7%) in the ALR group (P < .001). The high-risk ALR-R subgroup also had significantly better final Western Ontario Shoulder Instability Index (P = .008) and Subjective Shoulder Value (P = .001) scores than the high-risk ALR subgroup. CONCLUSIONS: Anterior shoulder instability patients with on-track Hill-Sachs lesions have lower recurrent dislocation rates after ALR plus remplissage when compared with ALR alone. This is especially true for high-risk patients, such as contact athletes with a DTD <10 mm.

Bone Block Augmentation of the Posterior Glenoid for Recurrent Posterior Shoulder Instability Is Associated With High Rates of Clinical Failure: A Systematic Review.

PURPOSE: To determine whether posterior glenoid bone block augmentation performed for the treatment of recurrent posterior shoulder instability succeeds in restoring stability and is associated with rates of complications or clinical failures comparable to other glenoid bone augmentation procedures. METHODS: A comprehensive search of PubMed, MEDLINE, and EMBASE databases was performed. Level of evidence studies I to IV pertaining to posterior bone block augmentation reporting on outcomes or complications were included. The search was carried out in accordance with the Preferred Reported Items for Systematic Reviews and Meta-analyses guidelines. RESULTS: Screening of titles, abstracts, and manuscripts with application of inclusion and exclusion criteria yielded 17 full-text articles reporting on 269 shoulders undergoing bone block augmentation. Surgical technique varied between studies with regard to graft type (iliac crest, 13 studies; scapular spine, 2; acromion, 1; distal tibia allograft, 1), graft positioning (medial to 1.5 cm lateral to glenoid surface, equatorial to subequatorial), and open versus arthroscopic technique (open, 10 studies; arthroscopic, 4; both, 3). Four of the 8 studies with pre- and postoperative patient-reported outcomes (PROs) showed significant improvements in these outcomes at final follow-up. The postoperative outcomes ranged from 60 to 90 for Rowe scores (n = 7 studies) and 79 to 90 for Walch-Duplay scores (n = 7 studies). Complications were commonly encountered, with high rates of recurrent instability (0% to 73%) and revision procedures (0% to 67%) across different studies. CONCLUSION: Posterior bone block augmentation for recurrent posterior shoulder instability does not reliably yield substantial improvements in PROs, and complications are frequently observed. The substantial heterogeneity across studies and the small number of patients precludes any substantive judgements as to the superiority of one surgical technique over another. LEVEL OF EVIDENCE: IV, systematic review of level III and IV studies.

Low posterior tibial slope is associated with increased risk of PCL graft failure.

PURPOSE: To evaluate the effect of posterior tibial slope (PTS) on patient-reported outcomes (PROs) and posterior cruciate ligament (PCL) graft failure after PCL reconstruction. METHODS: Patients undergoing PCL reconstruction with a minimum 2-year follow-up were included in this retrospective cohort study. A chart review was performed to collect patient-, injury-, and surgery-related data. Medial PTS was measured on preoperative lateral radiographs. Validated PROs, including the International Knee Documentation Committee Subjective Knee Form, Knee injury and Osteoarthritis Outcome Score, Lysholm Score, Tegner Activity Scale, and Visual Analogue Scale for pain, were collected at final follow-up. A correlation analysis was conducted to assess the relationship between PTS and PROs. A logistic regression model was performed to evaluate if PTS could predict PCL graft failure. RESULTS: Overall, 79 patients with a mean age of 28.6 ± 11.7 years and a mean follow-up of 5.7 ± 3.3 years were included. After a median time from injury of 4.0 months, isolated and combined PCL reconstruction was performed in 22 (28%) and 57 (72%) patients, respectively. There were no statistically significant differences in PROs and PTS between patients undergoing isolated and combined PCL reconstruction (non-significant [n.s.]). There were no significant correlations between PTS and PROs (n.s.). In total, 14 (18%) patients experienced PCL graft failure after a median time of 17.5 months following PCL reconstruction. Patients with PCL graft failure were found to have statistically significantly lower PTS than patients without graft failure (7.0 ± 2.3° vs. 9.2 ± 3.3°, p < 0.05), while no differences were found in PROs (n.s.). PTS was shown to be a significant predictor of PCL graft failure, with a 1.3-fold increase in the odds of graft failure for each one-degree reduction in PTS (p < 0.05). CONCLUSIONS: This study showed that PTS does not affect PROs after PCL reconstruction, but that PTS represents a surgically modifiable predictor of PCL graft failure. LEVEL OF EVIDENCE: III.

Paracrine Role for Somatostatin Interneurons in the Assembly of Perisomatic Inhibitory Synapses.

GABAergic interneurons represent a heterogenous group of cell types in neocortex that can be clustered based on developmental origin, morphology, physiology, and connectivity. Two abundant populations of cortical GABAergic interneurons include the low-threshold, somatostatin (SST)-expressing cells and the fast-spiking, parvalbumin (PV)-expressing cells. While SST+ and PV+ interneurons are both early born and migrate into the developing neocortex at similar times, SST+ cells are incorporated into functional circuits prior to PV+ cells. During this early period of neural development, SST+ cells play critical roles in the assembly and maturation of other cortical circuits; however, the mechanisms underlying this process remain poorly understood. Here, using both sexes of conditional mutant mice, we discovered that SST+ interneuron-derived Collagen XIX, a synaptogenic extracellular matrix protein, is required for the formation of GABAergic, perisomatic synapses by PV+ cells. These results, therefore, identify a paracrine mechanism by which early-born SST+ cells orchestrate inhibitory circuit formation in the developing neocortex.SIGNIFICANCE STATEMENT Inhibitory interneurons in the cerebral cortex represent a heterogenous group of cells that generate the inhibitory neurotransmitter GABA. One such interneuron type is the low-threshold, somatostatin (SST)-expressing cell, which is one of the first types of interneurons to migrate into the cerebral cortex and become incorporated into functional circuits. In addition, to contributing important roles in controlling the flow of information in the adult cerebral cortex, SST+ cells play important roles in the development of other neural circuits in the developing brain. Here, we identified an extracellular matrix protein that is released by these early-born SST+ neurons to orchestrate inhibitory circuit formation in the developing cerebral cortex.

Diverse GABAergic neurons organize into subtype-specific sublaminae in the ventral lateral geniculate nucleus.

In the visual system, retinal axons convey visual information from the outside world to dozens of distinct retinorecipient brain regions and organize that information at several levels, including either at the level of retinal afferents, cytoarchitecture of intrinsic retinorecipient neurons, or a combination of the two. Two major retinorecipient nuclei which are densely innervated by retinal axons are the dorsal lateral geniculate nucleus, which is important for classical image-forming vision, and ventral LGN (vLGN), which is associated with non-image-forming vision. The neurochemistry, cytoarchitecture, and retinothalamic connectivity in vLGN remain unresolved, raising fundamental questions of how it receives and processes visual information. To shed light on these important questions, used in situ hybridization, immunohistochemistry, and genetic reporter lines to identify and characterize novel neuronal cell types in mouse vLGN. Not only were a high percentage of these cells GABAergic, we discovered transcriptomically distinct GABAergic cell types reside in the two major laminae of vLGN, the retinorecipient, external vLGN (vLGNe) and the non-retinorecipient, internal vLGN (vLGNi). Furthermore, within vLGNe, we identified transcriptionally distinct subtypes of GABAergic cells that are distributed into four adjacent sublaminae. Using trans-synaptic viral tracing and in vitro electrophysiology, we found cells in each these vLGNe sublaminae receive monosynaptic inputs from retina. These results not only identify novel subtypes of GABAergic cells in vLGN, they suggest the subtype-specific laminar distribution of retinorecipient cells in vLGNe may be important for receiving, processing, and transmitting light-derived signals in parallel channels of the subcortical visual system.

Long-term outcomes after arthroscopic transosseous-equivalent repair: clinical and magnetic resonance imaging results of rotator cuff tears at a minimum follow-up of 10 years.

PURPOSE: The objective of this study was to evaluate the long-term functional outcomes and structural integrity of medium to massive rotator cuff tears at 10-12 years of follow-up after arthroscopic transosseous-equivalent (TOE) repair. METHODS: This was a retrospective study of a consecutive series of patients who underwent primary arthroscopic TOE repair of medium- to massive-sized degenerative rotator cuff tears performed by a single surgeon between January 2007 and August 2009. Patients were examined at a minimum follow-up of 10 years, and magnetic resonance imaging (MRI) was performed to assess tendon integrity. The Constant score (CS), American Shoulder and Elbow Surgeons score, and pain level documented using a visual analog scale were compared between intact repairs and recurrent defects. Univariate analysis was performed to identify factors related to recurrent defects. RESULTS: A total of 102 patients met the inclusion criteria, and 79 shoulders in 76 patients (74.5% of eligible patients) with a mean age at surgery of 55 ± 8 years (range, 40-72 years) were available for clinical evaluation at a mean follow-up time of 10.9 years (range, 10-12 years). The mean anteroposterior tear size was 3.1 ± 1.1 cm, and there were 41 medium (52%), 26 large (33%), and 12 massive (15%) tears. MRI was performed in 72 shoulders in 69 patients (91% of available shoulders) and revealed that 13 shoulders had recurrent defects (Sugaya stages 4 and 5). During the follow-up period, 3 patients underwent revision surgery, and the overall recurrent defect rate was 21.3%. A clinically meaningful improvement was observed in all outcome measures at the final follow-up regardless of tendon integrity. Patients with intact repairs showed superior outcomes compared with those with recurrent defects; however, only the overall CS met the threshold for clinical relevance. A significant linear correlation was observed between the Sugaya classification and all outcome scores except the CS pain subscale; however, the strength of correlation was weak. The presence of diabetes (odds ratio [OR], 8.6; 95% confidence interval [CI], 2.25-33.2; P = .002), tear size (OR, 2.08; 95% CI, 1.16-3.46; P = .012), and tear retraction (OR, 4.07; 95% CI, 1.11-14.83; P = .033) were associated with recurrent defects in the univariate analysis. CONCLUSION: Arthroscopic TOE repair of rotator cuff tears provided improved clinical outcomes with a recurrent defect rate of 21.3% at 10-12 years after surgery. Future research focusing on tendon healing is needed as repair integrity on MRI correlates with clinical outcomes.

Toxoplasma infection induces microglia-neuron contact and the loss of perisomatic inhibitory synapses.

Infection and inflammation within the brain induces changes in neuronal connectivity and function. The intracellular protozoan parasite, Toxoplasma gondii, is one pathogen that infects the brain and can cause encephalitis and seizures. Persistent infection by this parasite is also associated with behavioral alterations and an increased risk for developing psychiatric illness, including schizophrenia. Current evidence from studies in humans and mouse models suggest that both seizures and schizophrenia result from a loss or dysfunction of inhibitory synapses. In line with this, we recently reported that persistent T. gondii infection alters the distribution of glutamic acid decarboxylase 67 (GAD67), an enzyme that catalyzes GABA synthesis in inhibitory synapses. These changes could reflect a redistribution of presynaptic machinery in inhibitory neurons or a loss of inhibitory nerve terminals. To directly assess the latter possibility, we employed serial block face scanning electron microscopy (SBFSEM) and quantified inhibitory perisomatic synapses in neocortex and hippocampus following parasitic infection. Not only did persistent infection lead to a significant loss of perisomatic synapses, it induced the ensheathment of neuronal somata by myeloid-derived cells. Immunohistochemical, genetic, and ultrastructural analyses revealed that these myeloid-derived cells included activated microglia. Finally, ultrastructural analysis identified myeloid-derived cells enveloping perisomatic nerve terminals, suggesting they may actively displace or phagocytose synaptic elements. Thus, these results suggest that activated microglia contribute to perisomatic inhibitory synapse loss following parasitic infection and offer a novel mechanism as to how persistent T. gondii infection may contribute to both seizures and psychiatric illness.

Associated Morbidity After the Percutaneous Release of the Medial Collateral Ligament for Knee Arthroscopy.

PURPOSE: To summarize available data on the morbidity associated with percutaneous release of the medial collateral ligament (MCL) of the knee during arthroscopy via a "pie-crusting" technique. METHODS: A search of the literature was performed using the MEDLINE and Web of Science databases to identify studies examining the morbidity of percutaneous MCL release during arthroscopy. Only English-language articles were included; technical articles and studies not focused on the use of this technique were omitted. Two independent reviewers performed the literature search, data extraction, and quality assessment. The outcomes analyzed included resultant knee instability, functional outcome scores, visual analog scale pain scores, and saphenous nerve or greater saphenous vein injury. RESULTS: Six studies met the eligibility criteria. The studies included a total of 234 knees undergoing MCL release, with a mean patient age of 41.1 years. This MCL release typically generated grade I MCL laxity, which usually diminished or resolved over time and did not require brace application. The functional outcome scores of patients undergoing MCL release did not differ from those of patients undergoing the same procedure without MCL release. Postoperative pain was not significantly different between patients who underwent MCL release and those who did not. There was a 0% incidence of injury to the saphenous nerve or greater saphenous vein with MCL release in the included studies. CONCLUSIONS: Percutaneous MCL release during knee arthroscopy is a method of increasing the medial tibiofemoral joint space without causing any significant short- or long-term complications including residual valgus instability, pain, loss of function, or damage to surrounding structures. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies.

Collagen XIII secures pre- and postsynaptic integrity of the neuromuscular synapse.

Both transmembrane and extracellular cues, one of which is collagen XIII, regulate the formation and function of the neuromuscular synapse, and their absence results in myasthenia. We show that the phenotypical changes in collagen XIII knock-out mice are milder than symptoms in human patients, but the Col13a1-/- mice recapitulate major muscle findings of congenital myasthenic syndrome type 19 and serve as a disease model. In the lack of collagen XIII neuromuscular synapses do not reach full size, alignment, complexity and function resulting in reduced muscle strength. Collagen XIII is particularly important for the preterminal integrity, and when absent, destabilization of the motor nerves results in muscle regeneration and in atrophy especially in the case of slow muscle fibers. Collagen XIII was found to affect synaptic integrity through binding the ColQ tail of acetylcholine esterase. Although collagen XIII is a muscle-bound transmembrane molecule, it also undergoes ectodomain shedding to become a synaptic basal lamina component. We investigated the two forms' roles by novel Col13a1tm/tm mice in which ectodomain shedding is impaired. While postsynaptic maturation, terminal branching and neurotransmission was exaggerated in the Col13a1tm/tm mice, the transmembrane form's presence sufficed to prevent defects in transsynaptic adhesion, Schwann cell invagination/retraction, vesicle accumulation and acetylcholine receptor clustering and acetylcholinesterase dispersion seen in the Col13a1-/- mice, pointing to the transmembrane form as the major conductor of collagen XIII effects. Altogether, collagen XIII secures postsynaptic, synaptic and presynaptic integrity, and it is required for gaining and maintaining normal size, complexity and functional capacity of the neuromuscular synapse.

Distribution and development of molecularly distinct perineuronal nets in visual thalamus.

Visual information is detected by the retina and transmitted into the brain by retinal ganglion cells. In rodents, the visual thalamus is a major recipient of retinal ganglion cells axons and is divided into three functionally distinct nuclei: the dorsal lateral geniculate nucleus (dLGN), ventral LGN (vLGN), and intergeniculate leaflet. Despite being densely innervated by retinal input, each nucleus in rodent visual thalamus possesses diverse molecular profiles which underpin their unique circuitry and cytoarchitecture. Here, we combined large-scale unbiased proteomic and transcriptomic analyses to elucidate the molecular expression profiles of the developing mouse dLGN and vLGN. We identified several extracellular matrix proteins as differentially expressed in these regions, particularly constituent molecules of perineuronal nets (PNNs). Remarkably, we discovered at least two types of molecularly distinct Aggrecan-rich PNN populations in vLGN, exhibiting non-overlapping spatial, temporal, and cell-type specific expression patterns. The mechanisms responsible for the formation of these two populations of PNNs also differ as the formation of Cat315+ PNNs (but not WFA+ PNNs) required input from the retina. This study is first to suggest that cell type- and molecularly specific supramolecular assemblies of extracellular matrix may play important roles in the circuitry associated with the subcortical visual system and in the processing of visual information. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. Cover Image for this issue: doi: 10.1111/jnc.14203.

The Toll pathway underlies host sexual dimorphism in resistance to both Gram-negative and Gram-positive bacteria in mated Drosophila.

BACKGROUND: Host sexual dimorphism is being increasingly recognized to generate strong differences in the outcome of infectious disease, but the mechanisms underlying immunological differences between males and females remain poorly characterized. Here, we used Drosophila melanogaster to assess and dissect sexual dimorphism in the innate response to systemic bacterial infection. RESULTS: We demonstrated sexual dimorphism in susceptibility to infection by a broad spectrum of Gram-positive and Gram-negative bacteria. We found that both virgin and mated females are more susceptible than mated males to most, but not all, infections. We investigated in more detail the lower resistance of females to infection with Providencia rettgeri, a Gram-negative bacterium that naturally infects D. melanogaster. We found that females have a higher number of phagocytes than males and that ablation of hemocytes does not eliminate the dimorphism in resistance to P. rettgeri, so the observed dimorphism does not stem from differences in the cellular response. The Imd pathway is critical for the production of antimicrobial peptides in response to Gram-negative bacteria, but mutants for Imd signaling continued to exhibit dimorphism even though both sexes showed strongly reduced resistance. Instead, we found that the Toll pathway is responsible for the dimorphism in resistance. The Toll pathway is dimorphic in genome-wide constitutive gene expression and in induced response to infection. Toll signaling is dimorphic in both constitutive signaling and in induced activation in response to P. rettgeri infection. The dimorphism in pathway activation can be specifically attributed to Persephone-mediated immune stimulation, by which the Toll pathway is triggered in response to pathogen-derived virulence factors. We additionally found that, in absence of Toll signaling, males become more susceptible than females to the Gram-positive Enterococcus faecalis. This reversal in susceptibility between male and female Toll pathway mutants compared to wildtype hosts highlights the key role of the Toll pathway in D. melanogaster sexual dimorphism in resistance to infection. CONCLUSION: Altogether, our data demonstrate that Toll pathway activity differs between male and female D. melanogaster in response to bacterial infection, thus identifying innate immune signaling as a determinant of sexual immune dimorphism.

Inflammatory demyelination alters subcortical visual circuits.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory demyelinating disease classically associated with axonal damage and loss; more recently, however, synaptic changes have been recognized as additional contributing factors. An anatomical area commonly affected in MS is the visual pathway; yet, changes other than those associated with inflammatory demyelination of the optic nerve, i.e., optic neuritis, have not been described in detail. METHODS: Adult mice were subjected to a diet containing cuprizone to mimic certain aspects of inflammatory demyelination as seen in MS. Demyelination and inflammation were assessed by real-time polymerase chain reaction and immunohistochemistry. Synaptic changes associated with inflammatory demyelination in the dorsal lateral geniculate nucleus (dLGN) were determined by immunohistochemistry, Western blot analysis, and electrophysiological field potential recordings. RESULTS: In the cuprizone model, demyelination was observed in retinorecipient regions of the subcortical visual system, in particular the dLGN, where it was found accompanied by microglia activation and astrogliosis. In contrast, anterior parts of the pathway, i.e., the optic nerve and tract, appeared largely unaffected. Under the inflammatory demyelinating conditions, as seen in the dLGN of cuprizone-treated mice, there was an overall decrease in excitatory synaptic inputs from retinal ganglion cells. At the same time, the number of synaptic complexes arising from gamma-aminobutyric acid (GABA)-generating inhibitory neurons was found increased, as were the synapses that contain the N-methyl-D-aspartate receptor (NMDAR) subunit GluN2B and converge onto inhibitory neurons. These synaptic changes were functionally found associated with a shift toward an overall increase in network inhibition. CONCLUSIONS: Using the cuprizone model of inflammatory demyelination, our data reveal a novel form of synaptic (mal)adaption in the CNS that is characterized by a shift of the excitation/inhibition balance toward inhibitory network activity associated with an increase in GABAergic inhibitory synapses and a possible increase in excitatory input onto inhibitory interneurons. In addition, our data recognize the cuprizone model as a suitable tool in which to assess the effects of inflammatory demyelination on subcortical retinorecipient regions of the visual system, such as the dLGN, in the absence of overt optic neuritis.