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.

Intrathecal (IT) gene transfer using adeno-associated virus (AAV) may be clinically promising as a treatment for chronic pain if it can produce sufficiently high levels of a transgene product in the cerebrospinal fluid (CSF). While this strategy was developed in rodents, no studies investigating CSF levels of an analgesic or anti-allodynic protein delivered by IT AAV have been performed in large animals. Interleukin-10 (IL-10) is an anti-allodynic cytokine, for which target therapeutic levels have been established in rats. The present study tested IT AAV8 encoding either human IL-10 (hIL-10) or enhanced green fluorescent protein (EGFP) in a dog model of IT drug delivery. AAV8/hIL-10 at a dose of 3.5×1012 genome copies induced high hIL-10 levels in the CSF, exceeding the target concentration previously found to be anti-allodynic in rodents by >1000-fold. AAV8/EGFP targeted the primary sensory and motor neurons and the meninges. hIL-10, a xenogeneic protein in dogs, induced anti-hIL-10 antibodies detectable in the dogs’ CSF and serum. The high hIL-10 levels demonstrate the efficacy of AAV for delivery of secreted transgenes into the IT space of large animals suggesting a strong case for further development towards clinical testing.

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.

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.