Sex-specific Difference of Hippocampal Synaptic Plasticity in Response to Sex Neurosteroids.

Numerous studies provide increasing evidence, which supports the ideas that every cell in the brain of males may differ from those in females due to differences in sex chromosome complement as well as in response to hormonal effects. In this study, we address the question as to whether actions of neurosteroids, thus steroids, which are synthesized and function within the brain, contribute to sex-specific hippocampal synaptic plasticity. We have previously shown that predominantly in the female hippocampus, does inhibition of the conversion of testosterone to estradiol affect synaptic transmission. In this study, we show that testosterone and its metabolite dihydrotestosterone are essential for hippocampal synaptic transmission specifically in males. This also holds true for the density of mushroom spines and of spine synapses. We obtained similar sex-dependent results using primary hippocampal cultures of male and female animals. Since these cultures originated from perinatal animals, our findings argue for sex-dependent differentiation of hippocampal neurons regarding their responsiveness to sex neurosteroids up to birth, which persist during adulthood. Hence, our in vitro findings may point to a developmental effect either directly induced by sex chromosomes or indirectly by fetal testosterone secretion during the perinatal critical period, when developmental sexual priming takes place.

Glenoid concavity has a higher impact on shoulder stability than the size of a bony defect.

PURPOSE: Surgical treatment of shoulder instability caused by anterior glenoid bone loss is based on a critical threshold of the defect size. Recent studies indicate that the glenoid concavity is essential for glenohumeral stability. However, biomechanical proof of this principle is lacking. The aim of this study was to evaluate whether glenoid concavity allows a more precise assessment of glenohumeral stability than the defect size alone. METHODS: The stability ratio (SR) is a biomechanical estimate of glenohumeral stability. It is defined as the maximum dislocating force the joint can resist related to a medial compression force. This ratio was determined for 17 human cadaveric glenoids in a robotic test setup depending on osteochondral concavity and anterior defect size. Bony defects were created gradually, and a 3D measuring arm was used for morphometric measurements. The influence of defect size and concavity on the SR was examined using linear models. In addition, the morphometrical-based bony shoulder stability ratio (BSSR) was evaluated to prove its suitability for estimation of glenohumeral stability independent of defect size. RESULTS: Glenoid concavity is a significant predictor for the SR, while the defect size provides minor informative value. The linear model featured a high goodness of fit with a determination coefficient of R2 = 0.98, indicating that 98% of the SR is predictable by concavity and defect size. The low mean squared error (MSE) of 4.2% proved a precise estimation of the SR. Defect size as an exclusive predictor in the linear model reduced R2 to 0.9 and increased the MSE to 25.7%. Furthermore, the loss of SR with increasing defect size was shown to be significantly dependent on the initial concavity. The BSSR as a single predictor for glenohumeral stability led to highest precision with MSE = 3.4%. CONCLUSION: Glenoid concavity is a crucial factor for the SR. Independent of the defect size, the computable BSSR is a precise biomechanical estimate of the measured SR. The inclusion of glenoid concavity has the potential to influence clinical decision-making for an improved and personalised treatment of glenohumeral instability with anterior glenoid bone loss.

Human interleukin-10 delivered intrathecally by self-complementary adeno-associated virus 8 induces xenogeneic transgene immunity without clinical neurotoxicity in swine.

INTRODUCTION: Intrathecal interleukin (IL)-10 delivered by plasmid or viral gene vectors has been proposed for clinical testing because it is effective for chronic pain in rodents, is a potential therapeutic for various human diseases, and was found to be nontoxic in dogs, when the human IL-10 ortholog was tested. However, recent studies in swine testing porcine IL-10 demonstrated fatal neurotoxicity. The present study aimed to deliver vector-encoded human IL-10 in swine, measure expression of the transgene in cerebrospinal fluid and monitor animals for signs of neurotoxicity. RESULTS: Human IL-10 levels peaked 2 weeks after vector administration followed by a rapid decline that occurred concomitant with the emergence of anti-human IL-10 antibodies in the cerebrospinal fluid and serum. Animals remained neurologically healthy throughout the study period. CONCLUSIONS: The findings of the present study suggest that swine are not idiosyncratically sensitive to intrathecal IL-10 because, recapitulating previous reports in dogs, they suffered no clinical neurotoxicity from the human ortholog. These results strongly infer that toxicity of intrathecal IL-10 in large animal models was previously overlooked because of a species mismatch between transgene and host. The present study further suggests that swine were protected from interleukin-10 by a humoral immune response against the xenogeneic cytokine. Future safety studies of IL-10 or related therapeutics may require syngeneic large animal models.

Fatal Meningitis in Swine after Intrathecal Administration of Adeno-associated Virus Expressing Syngeneic Interleukin-10.

Interleukin-10 (IL-10) delivered by intrathecal (i.t.) gene vectors is a candidate investigational new drug (IND) for several chronic neurological disorders such as neuropathic pain. We performed a preclinical safety study of IL-10. A syngeneic large animal model was used delivering porcine IL-10 (pIL-10) to the i.t. space in swine by adeno-associated virus serotype 8 (AAV8), a gene vector that was previously found to be nontoxic in the i.t. space. Unexpectedly, animals became ill, developing ataxia, seizures, and an inability to feed and drink, and required euthanasia. Necropsy demonstrated lymphocytic meningitis without evidence of infection in the presence of normal laboratory findings for body fluids and normal histopathology of peripheral organs. Results were replicated in a second animal cohort by a team of independent experimenters. An extensive infectious disease and neuropathology workup consisting of comprehensive testing of tissues and body fluids in a specialized research veterinary pathology environment did not identify a pathogen. These observations raise the concern that i.t. IL-10 therapy may not be benign, that previously used xenogeneic models testing the human homolog of IL-10 may not have been sensitive enough to detect toxicity, and that additional preclinical studies may be needed before clinical testing of IL-10 can be considered.

Preclinical toxicity evaluation of AAV for pain: evidence from human AAV studies and from the pharmacology of analgesic drugs.

Gene therapy with adeno-associated virus (AAV) has advanced in the last few years from promising results in animal models to >100 clinical trials (reported or under way). While vector availability was a substantial hurdle a decade ago, innovative new production methods now routinely match the scale of AAV doses required for clinical testing. These advances may become relevant to translational research in the chronic pain field. AAV for pain targeting the peripheral nervous system was proven to be efficacious in rodent models several years ago, but has not yet been tested in humans. The present review addresses the steps needed for translation of AAV for pain from the bench to the bedside focusing on pre-clinical toxicology. We break the potential toxicities into three conceptual categories of risk: First, risks related to the delivery procedure used to administer the vector. Second, risks related to AAV biology, i.e., effects of the vector itself that may occur independently of the transgene. Third, risks related to the effects of the therapeutic transgene. To identify potential toxicities, we consulted the existing evidence from AAV gene therapy for other nervous system disorders (animal toxicology and human studies) and from the clinical pharmacology of conventional analgesic drugs. Thereby, we identified required preclinical studies and charted a hypothetical path towards a future phase I/II clinical trial in the oncology-palliative care setting.

Biomechanical Analysis of Coracoid Stability After Coracoplasty: How Low Can You Go?

Background: Arthroscopic coracoplasty is a procedure for patients affected by subcoracoid impingement. To date, there is no consensus on how much of the coracoid can be resected with an arthroscopic burr without compromising its stability. Purpose: To determine the maximum amount of the coracoid that can be resected during arthroscopic coracoplasty without leading to coracoid fracture or avulsion of the conjoint tendon during simulated activities of daily living (ADLs). Study Design: Controlled laboratory study. Methods: A biomechanical cadaveric study was performed with 24 shoulders (15 male, 9 female; mean age, 81 ± 7.9 years). Specimens were randomized into 3 treatment groups: group A (native coracoid), group B (3-mm coracoplasty), and group C (5-mm coracoplasty). Coracoid anatomic measurements were documented before and after coracoplasty. The scapula was potted, and a traction force was applied through the conjoint tendon. The stiffness and load to failure (LTF) were determined for each specimen. Results: The mean coracoid thicknesses in groups A through C were 7.2, 7.7, and 7.8 mm, respectively, and the mean LTFs were 428 ± 127, 284 ± 77, and 159 ± 87 N, respectively. Compared with specimens in group A, a significantly lower LTF was seen in specimens in group B (P = .022) and group C (P < .001). Postoperatively, coracoids with a thickness ≥4 mm were able to withstand ADLs. Conclusion: While even a 3-mm coracoplasty caused significant weakening of the coracoid, the individual failure loads were higher than those of the predicted ADLs. A critical value of 4 mm of coracoid thickness should be preserved to ensure the stability of the coracoid process. Clinical Relevance: In correspondence with the findings of this study, careful preoperative planning should be used to measure the maximum reasonable amount of coracoplasty to be performed. A postoperative coracoid thickness of 4 mm should remain.

Biomechanical Value of a Protective Proximal Humeral Cerclage in Reverse Total Shoulder Arthroplasty.

Reverse shoulder arthroplasty (RSA) is a commonly performed salvage procedure for failed proximal humeral fracture fixation. The rate of intraoperative periprosthetic fractures is higher compared to primary RSA. The goal of this study was to investigate the biomechanical value of a protective cerclage during stem impaction in a revision surgery setting. Twenty-eight fresh-frozen human humeri were used to assess different configurations for steel wire and FiberTape cerclages. A custom-built biomechanical test setup simulated the mallet strikes during the stem impaction process with the Univers Revers prothesis stem. The mallet energy until the occurrence of a first crack was not different between groups. The total energy until progression of the fracture distally to the cerclage was significantly higher in the cerclage groups compared to the native humerus (9.5 J vs. 3.5 J, respectively; p = 0.0125). There was no difference between the steel wire and FiberTape groups (11.4 J vs. 8.6 J, respectively; p = 0.2695). All fractures were located at the concave side of the stem at the metaphyseal calcar region. This study demonstrates that a protective cerclage can successfully delay the occurrence of a fracture during stem impaction in reverse shoulder arthroplasty. A FiberTape cerclage is biomechanically equally efficient compared to a steel wire cerclage.

The Glenolabral Articular Disruption Lesion Is a Biomechanical Risk Factor for Recurrent Shoulder Instability.

PURPOSE: To investigate the biomechanical effect of a glenolabral articular disruption (GLAD) lesion on glenohumeral laxity. METHODS: Human cadaveric glenoids (n = 10) were excised of soft tissue, including the labrum to focus on the biomechanical effects of osteochondral surfaces. Glenohumeral dislocations were performed in a robotic test setup, while displacement forces and three-dimensional morphometric properties were measured. The stability ratio (SR), a biomechanical characteristic for glenohumeral stability, was used as an outcome parameter, as well as the path of least resistance, determined by a hybrid robot displacement. The impacts of chondral and bony defects were analyzed related to the intact glenoid. Statistical comparison of the defect states on SR and the path of least resistance was performed using repeated-measures ANOVA and Tukey's post hoc test for multiple comparisons (P < .05). The relationship between concavity depth and SR was approximated in a nonlinear regression. RESULTS: The initial SR of the intact glenoid (28.3 ± 7.8%) decreased significantly by 4.7 ± 3% in case of a chondral defect (P = .002). An additional loss of 3.2 ± 2.3% was provoked by a 20% bony defect (P = .004). The path of least resistance was deflected significantly more inferiorly by a GLAD lesion (2.9 ± 1.8°, P = .002) and even more by a bony defect (2.5 ± 2.9°, P = .002). The nonlinear regression with concavity depth as predictor for the SR resulted in a high correlation coefficient (r = .81). CONCLUSIONS: Chondral integrity is an important contributor to the SR. Chondral defects as present in GLAD lesions may cause increased laxity, influence the humeral track on the glenoid during dislocation, and represent a biomechanical risk factor for a recurrent instability. CLINICAL RELEVANCE: Cartilage deficiency corresponding to GLAD lesions may be a risk factor for impaired surgical outcomes.

Promising Mid-Term Outcomes after Humeral Head Preserving Surgery of Posterior Fracture Dislocations of the Proximal Humerus.

BACKGROUND: The aim of this study was to evaluate the clinical outcome after humeral head preserving surgical treatment of posterior fracture dislocations of the proximal humerus. METHODS: Patients with a posterior fracture dislocation of the proximal humerus that were operatively treated in two level-1 trauma centers within a timeframe of 8 years were identified. With a minimum follow-up of 2 years, patients with humeral head preserving surgical treatment were invited for examination. RESULTS: 19/24 fractures (79.2%; mean age 43 years) were examined with a mean follow-up of 4.1 ± 2.1 years. Of these, 12 fractures were categorized as posteriorly dislocated impression type fractures, and 7 fractures as posteriorly dislocated surgical neck fractures. Most impression type fractures were treated by open reduction, allo- or autograft impaction and screw fixation (n = 11), while most surgical neck fractures were treated with locked plating (n = 6). Patients with impression type fractures showed significantly better ASES scores (p = 0.041), Simple Shoulder Test scores (p = 0.003), Rowe scores (p = 0.013) and WOSI scores (p = 0.023), when compared to posteriorly dislocated surgical neck fractures. Range of motion was good to excellent for both groups with no significant difference. CONCLUSIONS: This mid-term follow-up study reports good to very good clinical results for humeral head preserving treatment.

Development and first biomechanical validation of a score to predict bone implant interface stability based on clinical qCT scans.

Sufficient implant anchoring in osteoporotic bone is one major challenge in trauma and orthopedic surgery. In these cases, preoperative planning of osteosynthesis is becoming increasingly important. This study presents the development and first biomechanical validation of a bone-implant-anchorage score based on clinical routine quantitative computer tomography (qCT) scans. 10 pairs of fresh frozen femora (mean age 77.4 years) underwent clinical qCT scans after placing 3 referential screws (for matching with the second scan). Afterwards, three 4.5 mm cortical screws (DePuy Synthes, Zuchwil, Switzerland) were placed in each distal femur in the dia-metaphyseal transition followed by the second CT scan. The femur was segmented using thresholding and its outer shape was visualized as a surface model. A 3D model of the cortex screw in STL format was used to model the screw surface precisely. For each femur, the 3 cortex screw models were exactly positioned at the locations previously determined using the second CT scan. The BMD value was calculated at the center of each triangle as an interpolation from the measured values at the three vertices (triangle corners) in the CT. Scores are based on the sum of all the triangles' areas multiplied by their BMD values. Four different scores were calculated. A screw pull-out test was performed until loss of resistance. A quadratic model adequately describes the relation between all the scores and pull-out values. The square of the best score explains just fewer than 70% of the total variance of the pull-out values and the standardized residual which were approximately normally distributed. In addition, there was a significant correlation between this score and the peak pull-out force (p < 0.001). The coefficient of determination was 0.82. The presented score has the potential to improve preoperative planning by adding the mechanical to the anatomical dimension when planning screw placement.

Clinical Application and Outcomes of Upper Extremity Double Plating. / Klinische Anwendung und Ergebnisse der Doppelplattenosteosynthese an der oberen Extremität.

Dual plating in fractures of the upper extremity is well established for the distal humerus. The indication for the use of dual plating has been expanded over the last few years. While dual plating was originally frequently used in revisions of non-unions, it is nowadays also used in primary fixation of diverse complex fractures of the upper extremity. The high biomechanical fixation strength of dual plating is advantageous in regions with high bending and torsional stresses, such as the humeral shaft. An additional anterior plate provides high fixation strength and reduces the risk of loss of reduction in complex proximal humeral fractures and allows for direct fixation of lesser tuberosity fragments. Low-profile plates have been introduced for complex proximal ulna fractures. In dual plating the improved mechanical stability is combined with a reduced risk of implant related soft tissue irritations. The present article provides an overview of current indications for dual plating of upper extremity fractures and outlines technical aspects as well as advantages over conventional fixation techniques.

Biomechanics of Upper Extremity Double Plating. / Die Biomechanik der Doppelplattenosteosynthese an der oberen Extremität.

Double plating (DP) is an established treatment modality in traumatology. For certain indications, such as open reduction and internal fixation of bicondylar tibial plateau fractures and distal humeral fractures, DP is standard of care in the clinical routine. However, the principles of DP can be transferred to other anatomic regions and indications. In the past years, DP has been brought more and more into focus. For revision cases, such as the treatment of fracture non-unions, DP seems generally useful. In anatomical locations with high torsional stress and bending forces, but also in regions with traction forces by muscles and tendons DP provides multiplanar stability and therefore seems to have biomechanical advantages. Usually two smaller implants can replace one larger implant. Thus, the number of points of fixation can be increased, the stability can be improved and soft-tissue irritations by bulky implants can be minimized. Along with the established indication and application at the distal humerus, there is biomechanical evidence in the current literature for DP of clavicle fractures and humeral shaft fractures. Furthermore, DP provides mechanical advantages in the treatment of certain proximal humeral fractures and olecranon fractures. This review of the literature summarizes the published literature on biomechanics of upper extremity DP.

Isolated fractures of the greater tuberosity: When are they treated conservatively?: A baseline study.

BACKGROUND: This study analyzed the indications for conservative management of isolated greater tuberosity (GT) fractures. The rate of secondary interventions for failed conservative treatment was also assessed. METHODS: A retrospective data evaluation of isolated GT fractures was performed from the clinical database of two level-I trauma centers from January 2010 to June 2017. Conservatively treated GT fractures were identified and subdivided according to etiology, morphology, and amount of initial displacement. Secondary surgical interventions were recorded and subcategorized into fracture-associated interventions and interventions for associated soft tissue lesions. RESULTS: We identified 114 fractures. Nine cases were excluded because patients refused surgery or their comorbidities ruled it out. Only two of the remaining 105 patients had an initial displacement >3 mm. All other GT fractures (n = 103, 98%) were not displaced or only slightly displaced (0-3 mm). The fracture was associated with an anterior shoulder dislocation in 39 cases (37%); 17 patients (16.2%) underwent surgery after primary conservative treatment. Four of these 17 patients presented with a secondary displacement of the GT fragment. In all other cases (76.5%), an associated soft tissue lesion necessitated revision surgery. Young age, anterior shoulder dislocation, and concomitant injuries were risk factors for revision surgery after primary conservative treatment. CONCLUSION: Secondary interventions are required more frequently after shoulder dislocation. Surgery is most likely required for associated soft tissue lesions rather than for secondary displacements. Thus, detailed physical examination and magnetic resonance imaging should be used to screen for concomitant soft tissue injuries accompanying GT fractures to prevent revision surgeries.