Gait kinematics and knee stability 10-years following posterior-stabilised total knee arthroplasty comparable to healthy adults >55.

PURPOSE: The purpose of this study was to compare the long-term objective biomechanical and functional parameters of a high-flexion total knee arthroplasty (TKA) design against healthy older adults to determine whether knee biomechanics are comparable in both populations. METHODS: One cohort of patients with a primary TKA, and a cohort of healthy adults over 55 years old with no musculoskeletal deficits or arthritis participated. Bilateral knee range of motion (RoM) was assessed with a goniometer, and gait patterns were analysed with a three-dimensional-motion capture system. An arthrometer quantified the anterior-posterior laxity of each knee. Statistical analyses were performed in SPSS software (α = 0.05). RESULTS: Twenty-three knees were replaced in 20 patients. At 9.8 ± 3.1 years postoperatively, patients' knees had a statistically significantly poorer RoM than healthy controls' knees (n = 23) due to limited flexion; p < 0.0001. Patients also failed to achieve the same degree of knee flexion as controls during downhill gait. No kinematic differences were observed during mid-flexion in level nor downhill gait; a state that has been associated with instability (p = 0.614; not significant [n.s]). There were no differences between groups in knee laxity (n.s). CONCLUSION: Patients in this study had similar gait patterns to healthy older adults during mid-flexion and were no more likely than the healthy controls to exhibit anterior-posterior translation of the knee > 7 mm; a known risk factor of instability. However, the knee flexion range was poorer. This likely led to bilateral pathological knee flexion patterns during downhill gait. LEVEL OF EVIDENCE: Level III.

The orphan receptor GPR88 controls impulsivity and is a risk factor for Attention-Deficit/Hyperactivity Disorder.

The neural orphan G protein coupled receptor GPR88 is predominant in the striatum and cortex of both rodents and humans, and considered a potential target for brain disorders. Previous studies have shown multiple behavioral phenotypes in Gpr88 knockout mice, and human genetic studies have reported association with psychosis. Here we tested the possibility that GPR88 contributes to Attention Deficit Hyperactivity Disorder (ADHD). In the mouse, we tested Gpr88 knockout mice in three behavioral paradigms, best translatable between rodents and humans, and found higher motor impulsivity and reduced attention together with the reported hyperactivity. Atomoxetine, a typical ADHD drug, reduced impulsivity in mutant mice. Conditional Gpr88 knockout mice in either D1R-type or D2R-type medium spiny neurons revealed distinct implications of the two receptor populations in waiting and stopping impulsivity. Thus, animal data demonstrate that deficient GPR88 activity causally promotes ADHD-like behaviors, and identify circuit mechanisms underlying GPR88-regulated impulsivity. In humans, we performed a family-based genetic study including 567 nuclear families with DSM-IV diagnosis of ADHD. There was a minor association for SNP rs2036212 with diagnosis, treatment response and cognition. A stronger association was found for SNP rs2809817 upon patient stratification, suggesting that the T allele is a risk factor when prenatal stress is involved. Human data therefore identify GPR88 variants associated with the disease, and highlight a potential role of life trajectories to modulate GPR88 function. Overall, animal and human data concur to suggest that GPR88 signaling should be considered a key factor for diagnostic and treatment of ADHD.

Mu opioid receptors in GABAergic neurons of the forebrain promote alcohol reward and drinking.

Mu opioid receptors (MORs) are widely distributed throughout brain reward circuits and their role in drug and social reward is well established. Substantial evidence has implicated MOR and the endogenous opioid system in alcohol reward, but circuit mechanisms of MOR-mediated alcohol reward and intake behavior remain elusive, and have not been investigated by genetic approaches. We recently created conditional knockout (KO) mice targeting the Oprm1 gene in GABAergic forebrain neurons. These mice (Dlx-MOR KO) show a major MOR deletion in the striatum, whereas receptors in midbrain (including the Ventral Tegmental Area or VTA) and hindbrain are intact. Here, we compared alcohol-drinking behavior and rewarding effects in total (MOR KO) and conditional KO mice. Concordant with our previous work, MOR KO mice drank less alcohol in continuous and intermittent two-bottle choice protocols. Remarkably, Dlx-MOR KO mice showed reduced drinking similar to MOR KO mice, demonstrating that MOR in the forebrain is responsible for the observed phenotype. Further, alcohol-induced conditioned place preference was detected in control but not MOR KO mice, indicating that MOR is essential for alcohol reward and again, Dlx-MOR KO recapitulated the MOR KO phenotype. Taste preference and blood alcohol levels were otherwise unchanged in mutant lines. Together, our data demonstrate that MOR expressed in forebrain GABAergic neurons is essential for alcohol reward-driven behaviors, including drinking and place conditioning. Challenging the prevailing VTA-centric hypothesis, this study reveals another mechanism of MOR-mediated alcohol reward and consumption, which does not necessarily require local VTA MORs but rather engages striatal MOR-dependent mechanisms.

The effects of knee meniscectomy on the development of osteoarthritis in the patellofemoral joint 40 years following meniscectomy.

Most knee osteoarthritis and meniscectomy studies focus on osteoarthritis in the tibiofemoral joint and ignore the patellofemoral joint. This study aims to assess the long-term effects of total meniscectomy on the patellofemoral joint. To our knowledge, this is the only study of osteoarthritis in the patellofemoral joint following meniscectomy that extends to a 40-year follow-up period. Twenty-two patients with osteoarthritis were evaluated at a mean of 40 years post-meniscectomy using standardised weight-bearing radiographs of the operated and non-operated knees. Patellofemoral joint osteoarthritis was diagnosed by the presence of osteophytes and joint space narrowing to less than 5 mm. Kellgren and Lawrence scores were calculated from the radiographs. Patellofemoral joint osteoarthritis and tibiofemoral joint osteoarthritis were correlated with International Knee Documentation Committee scores and range of movement measurements. A significant difference was observed between the operated and non-operated knees in terms of patellofemoral joint osteophyte formation. There was a significant difference in tibiofemoral joint Kellgren and Lawrence scores, International Knee Documentation Committee scores and range of movement measurements between knees with lateral facet patellofemoral joint space of < 5 mm and > 5 mm. This study shows an association between open total meniscectomy and patellofemoral joint osteoarthritis at 40 years following surgery. There was also an association between patellofemoral joint space narrowing in the lateral facet and tibiofemoral joint osteoarthritis. Possible causes include altered biomechanical loading patterns following meniscectomy as well as global processes within the knee.

Medium-term (5-year) comparison of the functional outcomes of combined anterior cruciate ligament and posterolateral corner reconstruction compared with isolated anterior cruciate ligament reconstruction.

PURPOSE: To present a 5-year comparison of the functional outcomes of combined anterior cruciate ligament (ACL) and posterolateral corner (PLC) reconstruction with those of isolated ACL reconstruction. METHODS: All patients were reviewed clinically and completed knee function questionnaires prospectively, by use of the International Knee Documentation Committee (IKDC) 2000, Knee Injury and Osteoarthritis Outcome Score (KOOS), and Lysholm scoring systems, preoperatively and at 1, 2, and 5 years postoperatively. Patients who underwent combined ACL-PLC reconstruction were identified and reviewed. These patients had intact lateral collateral ligaments. A comparison group was created from a group of patients who underwent isolated ACL reconstruction. The ACL group was selected to have the same profile with regard to age, sex, and meniscal procedure. RESULTS: There were 25 patients in the ACL-PLC group and 100 in the ACL group. All patients underwent restoration of their PLC function as shown on dial testing. The preoperative values for all KOOS measures and the Lysholm score were significantly lower in the ACL-PLC group than in the ACL group (P < .001). The IKDC score was not significantly different. All knee scores showed a significant improvement in both groups postoperatively at 1, 2, and 5 years (P < .001). At 5 years, the KOOS symptoms subscore (P < .001), KOOS pain subscore (P < .001), KOOS sports subscore (P < .001), KOOS quality-of-life subscore (P < .05), KOOS activities-of-daily living subscore (P < .001), aggregate score for all KOOS parameters (P < .001), and Lysholm score (P < .001) were significantly lower in the ACL-PLC group than in the ACL group. At 5 years, the IKDC scores were not significantly different. All patients in the ACL-PLC group resumed preinjury employment, and 23 of 25 had resumed sports. CONCLUSIONS: Combined ACL-PLC injuries have greater morbidity than isolated ACL injuries. However, return to work and sporting activity is possible in most cases after combined ACL-PLC reconstruction. The KOOS for sport outcomes suggests that sports were resumed at lower functional levels. LEVEL OF EVIDENCE: Level III, case-control study.

A prospective study to assess the outcomes of revision anterior cruciate ligament reconstruction.

PURPOSE: Continuously increasing numbers of primary anterior cruciate ligament (ACL) reconstructions invites a parallel increase in graft failures and need for revision ACL reconstruction surgery. High failure rates has previously stigmatised the revision surgery. We performed this study using multiple outcome measures together with clinical examination to offer a full assessment of the outcomes of this procedure. METHODS: Twenty patients, with mean age of 29.4 years (17-50 years), were included in this study prior to their revision ACL reconstruction surgery. All patients were followed prospectively collecting the Knee injury and Osteoarthritis Outcome (KOOS), International Knee Documentation Committee (IKDC) and Tegner-Lysholm scores pre- and post-operatively together with clinical assessment of the antero-posterior knee laxity. RESULTS: After a mean follow up interval of 30 months (16-60 months) significant post-operative improvement of IKDC, Tegner-Lysholm scores and knee antero-posterior laxity together with the Symptoms, Activities of Daily Living (ADL) and Quality of Life (QOL) components of the KOOS score was noticed (P < 0.05). However, there was no similar improvement in pain and sports components of the KOOS score (P > 0.05). There was no difference in the outcomes of different graft types. CONCLUSION: Good outcomes of revision ACL reconstruction surgery are achievable. The use of different graft types did not affect the outcome of the procedure. Most of the patients opted to less aggressive sports participation after the revision procedure.

Immune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumor-promoting function.

Histone H3-mutant gliomas are deadly brain tumors characterized by a dysregulated epigenome and stalled differentiation. In contrast to the extensive datasets available on tumor cells, limited information exists on their tumor microenvironment (TME), particularly the immune infiltrate. Here, we characterize the immune TME of H3.3K27M and G34R/V-mutant gliomas, and multiple H3.3K27M mouse models, using transcriptomic, proteomic and spatial single-cell approaches. Resolution of immune lineages indicates high infiltration of H3-mutant gliomas with diverse myeloid populations, high-level expression of immune checkpoint markers, and scarce lymphoid cells, findings uniformly reproduced in all H3.3K27M mouse models tested. We show these myeloid populations communicate with H3-mutant cells, mediating immunosuppression and sustaining tumor formation and maintenance. Dual inhibition of myeloid cells and immune checkpoint pathways show significant therapeutic benefits in pre-clinical syngeneic mouse models. Our findings provide a valuable characterization of the TME of oncohistone-mutant gliomas, and insight into the means for modulating the myeloid infiltrate for the benefit of patients.

Functional outcome of primary hamstring anterior cruciate ligament reconstruction in patients with different body mass index classes.

PURPOSE: We compared functional outcomes after primary hamstring-graft anterior cruciate ligament (ACL) reconstruction in patients with different body mass index (BMI) classes. METHODS: Functional outcomes after ACL reconstruction were measured using the Knee Injury and Osteoarthritis Outcome Score (KOOS) and the Lysholm score. The procedures were carried out by a single surgeon between 2001 and 2009 in 2 groups of patients with different BMI classes: a normal-BMI group (BMI 18.5 to 24.9) and a high-BMI group (BMI ≥ 25), with a minimum of 2 years' follow-up. Rolimeter readings for ligament laxity as well as complications between the 2 groups were also analyzed. RESULTS: A total of 92 patients were reviewed, with the normal-BMI group consisting of 49 patients, whereas there were 43 patients in the high-BMI group. There were no significant differences between the groups in any of the preoperative and postoperative scores or ligament laxity. Both groups showed comparable clinically significant improvement in their postoperative scores compared with their preoperative scores. Patients in the high-BMI group had a slightly increased postoperative complication rate when compared with the normal-BMI group. CONCLUSIONS: Primary hamstring ACL reconstruction is an effective treatment option in patients irrespective of preoperative BMI. High BMI does not adversely affect functional outcomes as measured by the KOOS and Lysholm scores up to and at 2 years postoperatively, and these patients benefit in a manner comparable to that of patients with normal BMI. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

A systematic review of outcomes of high tibial osteotomy for the valgus knee.

PURPOSE: Osteoarthritis is a prolific condition in an increasingly ageing and obese population. Research into treatments of this condition and their efficacy are vital. Outcomes of high tibial osteotomy (HTO) for the varus knee is widely reported. There is less evidence for HTO in the valgus knee. This systematic review aimed to compile all literature reporting the outcomes of HTO to correct the valgus knee, focusing on post-operative clinical outcomes. METHODS: Ovid MEDLINE, Embase and Web of Science were searched using key terms: Osteoarthritis [All Fields] AND High tibial osteotomy [All Fields] AND Lateral OR Valgus [All Fields]. Papers were screened for eligibility based on an inclusion and exclusion criteria. Full text screening was completed by two reviewers and data was extracted from the agreed included papers by one reviewer. Quality assessments of the papers were also conducted. PROSPERO ID: CRD42021239045. RESULTS: Across 17 papers reporting 517 knees, the average pre-operative femorotibial and hip-knee-ankle angles were corrected from 13.6 ± 7.0° and 4.9 ± 1.9° valgus to 2.8 ± 2.9° and 1.2 ± 1.7° varus. Studies show that the procedure is successful at offloading the lateral knee compartment and some evidence it can delay the need for a total knee replacement. However, its impact on overall quality of life remains poorly understood. CONCLUSIONS: High tibial osteotomy may be a viable treatment option for valgus knee deformities caused by lateral compartment osteoarthritis. Nevertheless, research into the procedure remains limited. Importantly, our understanding of the relationship between the achieved alignment and outcome remains largely unknown. LEVEL OF EVIDENCE: IV.

The BioPoly Partial Resurfacing Knee Implant Provides Beneficial Clinical Outcomes: A Concise Follow-up, at 5 Years, of a Previous Report.

Abstract: We previously conducted a single-arm, prospective study in which 31 patients (mean age [and standard deviation], 42.5 ± 11.3 years) with cartilage lesions were treated with use of the BioPoly Partial Resurfacing Knee Implant. Treatment outcomes were compared with those reported for the standard of care, microfracture. We found that the mean KOOS (Knee injury and Osteoarthritis Outcome Score) Quality of Life score at 5 years in the BioPoly cohort was noninferior to (p = 0.004), and indeed greater than (p = 0.021), that in the microfracture cohort. The BioPoly cohort demonstrated improvement in the mean scores for all KOOS domains at every postoperative time point (p < 0.025). The mean score for the visual analog scale (VAS) for pain significantly improved (p < 0.025) at all time points up to 4 years and trended toward significant improvement at 5 years (p = 0.027). This study indicated that the BioPoly implant was safe, provided significant improvement starting at 6 months and continuing to 5 years, and provided greater improvement than microfracture for some outcome measures. Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Chronic tianeptine induces tolerance in analgesia and hyperlocomotion via mu-opioid receptor activation in mice.

Introduction: Tianeptine is approved in some countries to treat depression and anxiety. In addition to its activity on serotonin and glutamate neurotransmission, tianeptine has been proven to be a mu-opioid receptor (MOR) agonist, but only a few preclinical studies have characterized the opioid-like behavioral effects of tianeptine. Methods: In this study, we tested tianeptine activity on G protein activation using the [S35] GTPγS binding assay in brain tissue from MOR+/+ and MOR-/- mice. Then, to determine whether tianeptine behavioral responses are MOR-dependent, we characterized the analgesic, locomotor, and rewarding responses of tianeptine in MOR+/+ and MOR-/- mice using tail immersion, hot plate, locomotor, and conditioned place preference tests. Results: Using the [S35] GTPγS binding assay, we found that tianeptine signaling is mediated by MOR in the brain with properties similar to those of DAMGO (a classic MOR agonist). Furthermore, we found that the MOR is necessary for tianeptine's analgesic (tail immersion and hot plate), locomotor, and rewarding (conditioned place preference) effects. Indeed, these behavioral effects could only be measured in MOR+/+ mice but not in MOR-/- mice. Additionally, chronic administration of tianeptine induced tolerance to its analgesic and hyperlocomotor effects. Discussion: These findings suggest that tianeptine's opioid-like effects require MOR and that chronic use could lead to tolerance.

A Compendium of Syngeneic, Transplantable Pediatric High-Grade Glioma Models Reveals Subtype-Specific Therapeutic Vulnerabilities.

Pediatric high-grade gliomas (pHGG) are lethal, incurable brain tumors frequently driven by clonal mutations in histone genes. They often harbor a range of additional genetic alterations that correlate with different ages, anatomic locations, and tumor subtypes. We developed models representing 16 pHGG subtypes driven by different combinations of alterations targeted to specific brain regions. Tumors developed with varying latencies and cell lines derived from these models engrafted in syngeneic, immunocompetent mice with high penetrance. Targeted drug screening revealed unexpected selective vulnerabilities-H3.3G34R/PDGFRAC235Y to FGFR inhibition, H3.3K27M/PDGFRAWT to PDGFRA inhibition, and H3.3K27M/PDGFRAWT and H3.3K27M/PPM1DΔC/PIK3CAE545K to combined inhibition of MEK and PIK3CA. Moreover, H3.3K27M tumors with PIK3CA, NF1, and FGFR1 mutations were more invasive and harbored distinct additional phenotypes, such as exophytic spread, cranial nerve invasion, and spinal dissemination. Collectively, these models reveal that different partner alterations produce distinct effects on pHGG cellular composition, latency, invasiveness, and treatment sensitivity. SIGNIFICANCE: Histone-mutant pediatric gliomas are a highly heterogeneous tumor entity. Different histone mutations correlate with different ages of onset, survival outcomes, brain regions, and partner alterations. We have developed models of histone-mutant gliomas that reflect this anatomic and genetic heterogeneity and provide evidence of subtype-specific biology and therapeutic targeting. See related commentary by Lubanszky and Hawkins, p. 1516. This article is highlighted in the In This Issue feature, p. 1501.

Knee registries: state of the art.

Sports injuries, trauma and the globally ageing and obese population require increasing levels of knee surgery. Shared decision making has replaced the paternalistic approach to patient management. Evidence-based medicine underpins surgical treatment strategies, from consenting an individual patient to national healthcare system design. The evolution of successful knee-related registries starting from specific arthroplasty registries has given rise to ligament reconstruction, osteotomy and cartilage surgery registries developing as platforms for surgical outcome data collection. Stakeholders include surgeons and their patients, researchers, healthcare systems, as well as the funding insurers and governments. Lately, implant manufacturers have also been mandated to perform postmarket surveillance with some hoping to base that on registry data. Aiming to assess the current status of knee-related registries, we performed a comprehensive literature and web search, which yielded 23 arthroplasty, 8 ligament, 4 osteotomy and 3 articular cartilage registries. Registries were evaluated for their scope, measured variables, impact and limitations. Registries have many advantages as they aim to increase awareness of outcomes; identify trends in practice over time, early failing implants, outlier surgeon or institution performance; and assist postmarketing surveillance. International collaborations have highlighted variations in practice. The limitations of registries are discussed in detail. Inconsistencies are found in collected data and measured variables. Potential measurement and selection biases are outlined. Without mandated data collection and with apparent issues such as unverified patient reporting of complications, registries are not designed to replace adverse event recording in place of a proper safety and efficacy study, as demanded by regulators. Registry 'big data' can provide evidence of associations of problems. However, registries cannot provide evidence of causation. Hence, without careful consideration of the data and its limitations, registry data are at risk of incorrectly drawn conclusions and the potential of misuse of the results. That must be guarded against. Looking at the future, registry operators benefit from a collective experience of running registries as they mature, allowing for improvements across specialties. Large-scale registries are not only of merit, improving with stakeholder acceptance, but also are critical in furthering our understanding of our patients' outcomes. In doing so, they are a critical element for our future scientific discourse.

Dysfunction of the posterior cruciate ligament in total knee arthroplasty.

PURPOSE: Total knee arthroplasty (TKA) is typically carried out either with retention (CR) of the posterior cruciate ligament (PCL) or with sacrifice of this ligament and implantation of a posterior stabilised (PS) prosthesis. This paper investigates a comparison of PCL function in knees treated for osteoarthritis with TKA where the PCL is preserved to those knees treated with TKA and posterior stabilisation. METHODS: One hundred and sixty-eight patients (232 knees) who had undergone TKA with either a PS or CR implant were included in the study. Clinical assessment included antero-posterior (AP) laxity and posterior sag assessment with an arthrometer. RESULTS: The mean AP laxity at 90° of flexion for CR TKAs was 6.5 mm (±3.1) and was the same [6.5 mm (±2.4)] as in the PS group. However, 56% of the PCL-preserved knees had a posterior sag of over 3 mm compared to 18% of the knees in the PS group. The American Knee Society Scores for either group showed that, although the mean function score was the same, the knee score was superior in the PS group (77 vs. 84). The range of motion was also superior in the PS group (111° vs. 105°). CONCLUSION: The use of the PS prosthesis for TKA provides a more predictable outcome with regard to posterior sag and a better maximum flexion than a CR implant.

The Relationships between Coronal Plane Alignments and Patient-Reported Outcomes Following High Tibial Osteotomy: A Systematic Review.

OBJECTIVE: This systematic review aimed to determine whether coronal angular corrections correlate with patient reported outcomes following valgus-producing high tibial osteotomy (HTO). DESIGN: Ovid MEDLINE, Embase, and Web of Science were systematically searched. Studies that reported hip-knee-ankle angles (HKA) or femorotibial angles (FTA), and the Oxford Knee Score (OKS), visual analogue scale (VAS) score, Knee Injury and Osteoarthritis Outcome Score (KOOS), or EQ-5D before and after valgus-producing HTO were eligible. Correlation analyses were performed where appropriate to investigate the relationships between variables. PROSPERO ID: CRD42019135467. RESULTS: This study included 39 articles including 50 cohorts. VAS was reported in 22 studies, OKS in 9, KOOS in 12 and EQ-5D in 2. The HKA angle was corrected from 7.1° ± 1.7° varus to 2.3° ± 1.7° valgus at final follow-up. The FTA changed from 3.0° ± 2.0° varus to 7.7° ± 1.3° valgus. Outcome scores improved with clinical and statistical significance postoperatively. Spearman correlations for nonparametric data revealed greater changes in knee alignment were moderately associated with larger improvements in VAS scores (r = 0.50). Furthermore, those who experienced greater changes in alignment showed larger improvements in the KOOS Activity and Quality of Life domains (r = 0.72 and r = 0.51, respectively). CONCLUSION: On average, patients did not achieve the "ideal correction" of 3° to 6° valgus postoperatively. Nevertheless, statistical and clinical improvements in patient-reported outcome measure scores were consistently reported. This suggests that the "ideal correction" may be more flexible than 3° to 6°.

The First Report of the International Cartilage Regeneration and Joint Preservation Society's Global Registry.

OBJECTIVE: The International Cartilage Regeneration and Joint Preservation Society's (ICRS's) global registry, aims to be the best source of information for patients and an unbiased resource of evidence-based medicine for scientists and clinicians working to help those unfortunate enough to suffer the pain and disability associated with articular cartilage lesions. This article constitutes the scientific summary of the reports' main findings. DESIGN: The article outlines the historical precedents in the development of orthopedic registries from the earliest tumor registries, then local arthroplasty databases that led ultimately to international collaborations between national arthroplasty and soft tissue registries. The ICRS global cartilage registry was designed from the outset as a GDPR (General Data Protection Regulation) compliant, multilingual, multinational cooperative system. It is a web-based user-friendly, live in 11 languages by end 2019, which can be accessed via https://cartilage.org/society/icrs-patient-registry/. Patients and clinicians enter data by smartphone, tablet, or computer on any knee cartilage regeneration and joint preservation treatment, including the use of focal arthroplasty. Knee Injury and Osteoarthritis Outcome Score and Kujala patient-reported outcome measures are collected preoperatively, 6 months, 12 months, and annually for ten years thereafter. EQ-5D data collection will allow cost-effectiveness analysis. Strengths, weaknesses, and future plans are discussed. RESULTS: Since inception the registry has 264 users across 50 countries. Major findings are presented and discussed, while the entire first ICRS global registry report is available at https://cartilage.org/society/icrs-patient-registry/registry-annual-reports/. Conclusion. A measure of the maturity of any registry is the publication of its findings in the peer reviewed literature. With the publication of its first report, the ICRS global registry has achieved that milestone.

Alkyladenine DNA glycosylase deficiency uncouples alkylation-induced strand break generation from PARP-1 activation and glycolysis inhibition.

DNA alkylation damage is repaired by base excision repair (BER) initiated by alkyladenine DNA glycosylase (AAG). Despite its role in DNA repair, AAG-initiated BER promotes cytotoxicity in a process dependent on poly (ADP-ribose) polymerase-1 (PARP-1); a NAD+-consuming enzyme activated by strand break intermediates of the AAG-initiated repair process. Importantly, PARP-1 activation has been previously linked to impaired glycolysis and mitochondrial dysfunction. However, whether alkylation affects cellular metabolism in the absence of AAG-mediated BER initiation is unclear. To address this question, we temporally profiled repair and metabolism in wild-type and Aag-/- cells treated with the alkylating agent methyl methanesulfonate (MMS). We show that, although Aag-/- cells display similar levels of alkylation-induced DNA breaks as wild type, PARP-1 activation is undetectable in AAG-deficient cells. Accordingly, Aag-/- cells are protected from MMS-induced NAD+ depletion and glycolysis inhibition. MMS-induced mitochondrial dysfunction, however, is AAG-independent. Furthermore, treatment with FK866, a selective inhibitor of the NAD+ salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT), synergizes with MMS to induce cytotoxicity and Aag-/- cells are resistant to this combination FK866 and MMS treatment. Thus, AAG plays an important role in the metabolic response to alkylation that could be exploited in the treatment of conditions associated with NAD+ dysregulation.

A comparison of Star Excursion Balance Test reach distances between ACL deficient patients and asymptomatic controls.

ACL injury has been associated with a decrease in proprioceptive performance and specifically postural control. Tests of postural control have been criticised for not being sufficiently challenging. The Star Excursion Balance Test (SEBT) has been proposed to offer sufficient challenge to be a sensitive test for detecting performance deficits related to pathology. The purpose of this study was to determine if decrements SEBT reach distance is associated with ACL deficiency (ACLD). Twenty five ACLD patients ACLD (17 male and 8 female, mean age 30 (SD 4.5) years) and twenty five matched controls were examined carrying out the SEBT. Factorial ANOVA showed the main effects of limb (p=0.006) and direction (p<0.001) and interaction of limb and direction (p=0.015) all had significant differences between the groups. Further analysis revealed significant differences between the control group and the ACLD limb for the limb movement directions of anterior (p=0.0032), lateral (p=0.005), posterior-medial (p=0.0024) and medial (p=0.001). There were also significant differences between the control limbs and uninjured limb of the patients for the directions of medial (p=0.001) and lateral (p=0.001). ACLD patients appear to have deficiencies in their dynamic postural control when compared to normal asymptomatic subjects. Interestingly, in the ACLD patients, their uninjured leg show deficits compared to the control in two of the four directions the ACLD leg was deficient, this may be indicative of a postural control deficit in these patients, which may have predisposed to the ACL injury and would warrant further study.

Oxycodone-Mediated Activation of the Mu Opioid Receptor Reduces Whole Brain Functional Connectivity in Mice.

Oxycodone is a potent medicinal opioid analgesic to treat pain. It is also addictive and a main cause for the current opioid crisis. At present, the impact of oxycodone on coordinated brain network activities, and contribution of the mu opioid receptor (MOR) to these effects, is unknown. We used pharmacological magnetic resonance imaging in mice to characterize MOR-mediated oxycodone effects on whole-brain functional connectivity (FC). Control (CTL) and MOR knockout (KO) animals were imaged under dexmedetomidine in a 7Tesla scanner. Acquisition was performed continuously before and after 2 mg/kg oxycodone administration (analgesic in CTL mice). Independent component analysis (data-driven) produced a correlation matrix, showing widespread oxycodone-induced reduction of FC across 71 components. Isocortex, nucleus accumbens (NAc), pontine reticular nucleus, and periacqueducal gray (PAG) components showed the highest number of significant changes. Seed-to-voxel FC analysis (hypothesis-driven) was then focused on PAG and NAc considered key pain and reward centers. The two seeds showed reduced FC with 8 and 22 Allen Brain Atlas-based regions, respectively, in CTL but not KO mice. Further seed-to-seed quantification showed highest FC modifications of both PAG and NAc seeds with hypothalamic and amygdalar areas, as well as between them, revealing the strongest impact across reward and aversion/pain centers of the brain. In conclusion, we demonstrate that oxycodone reduces brain communication in a MOR-dependent manner, and establish a preliminary whole-brain FC signature of oxycodone. This proof-of-principle study provides a unique platform and reference data set to test other MOR opioid agonists and perhaps discover new mechanisms and FC biomarkers predicting safer analgesics.