The combined administration of LNC-encapsulated retinoic acid and calcitriol stimulates oligodendrocyte progenitor cell differentiation in vitro and in vivo after intranasal administration.

Intranasal administration is an efficient strategy for bypassing the BBB, favoring drug accumulation in the brain, and improving its efficiency. Lipid nanocapsules (LNC) are suitable nanocarriers for the delivery of lipophilic drugs via this route and can be used to encapsulate lipophilic molecules such as retinoic acid (RA) and calcitriol (Cal). As the hallmarks of multiple sclerosis (MS) are neuroinflammation and oligodendrocyte loss, our hypothesis was that by combining two molecules known for their pro-differentiating properties, encapsulated in LNC, and delivered by intranasal administration, we would stimulate oligodendrocyte progenitor cells (OPC) differentiation into oligodendrocytes and provide a new pro-remyelinating therapy. LNC loaded with RA (LNC-RA) and Cal (LNC-Cal) were stable for at least 8 weeks. The combination of RA and Cal was more efficient than the molecules alone, encapsulated or not, on OPC differentiation in vitro and decreased microglia cell activation in a dose-dependent manner. After the combined intranasal administration of LNC-RA and LNC-Cal in a mouse cuprizone model of demyelination, increased MBP staining was observed in the corpus callosum. In conclusion, intranasal delivery of lipophilic drugs encapsulated in LNC is a promising strategy for myelinating therapies.

The human dental apical papilla promotes spinal cord repair through a paracrine mechanism.

Traumatic spinal cord injury is an overwhelming condition that strongly and suddenly impacts the patient's life and her/his entourage. There are currently no predictable treatments to repair the spinal cord, while many strategies are proposed and evaluated by researchers throughout the world. One of the most promising avenues is the transplantation of stem cells, although its therapeutic efficiency is limited by several factors, among which cell survival at the lesion site. In our previous study, we showed that the implantation of a human dental apical papilla, residence of stem cells of the apical papilla (SCAP), supported functional recovery in a rat model of spinal cord hemisection. In this study, we employed protein multiplex, immunohistochemistry, cytokine arrays, RT- qPCR, and RNAseq technology to decipher the mechanism by which the dental papilla promotes repair of the injured spinal cord. We found that the apical papilla reduced inflammation at the lesion site, had a neuroprotective effect on motoneurons, and increased the apoptosis of activated macrophages/ microglia. This therapeutic effect is likely driven by the secretome of the implanted papilla since it is known to secrete an entourage of immunomodulatory or pro-angiogenic factors. Therefore, we hypothesize that the secreted molecules were mainly produced by SCAP, and that by anchoring and protecting them, the human papilla provides a protective niche ensuring that SCAP could exert their therapeutic actions. Therapeutic abilities of the papilla were demonstrated in the scope of spinal cord injury but could very well be beneficial to other types of tissue.

Total knee arthroplasty in valgus knee deformity: is it still a challenge in 2021?

Total knee arthroplasty in valgus knee deformities continues to be a challenge for a surgeon. Approximately 10% of patients who undergo total knee arthroplasty have a valgus deformity. While performing total knee arthroplasty in a severe valgus knee, one should aware with the technical aspects of surgical exposure, bone cuts of the distal femur and proximal tibia, medial and lateral ligament balancing, flexion and extension gap balancing, creating an appropriate tibiofemoral joint line, balancing the patellofemoral joint, preserving peroneal nerve function, and selection of the implant regarding constraint. Restoration of neutral mechanical axis and correct ligament balance are important factors for stability and longevity of the prosthesis and for good functional outcome. Thus, our review aims to provide step by step comprehensive knowledge about different surgical techniques for the correction of severe valgus deformity in total knee arthroplasty.

Two different posterior-stabilized mobile-bearing TKA designs: navigator evaluation of intraoperative kinematic differences.

PURPOSE: The purpose of this study was to compare two types of posterior-stabilized (PS) mobile-bearing (MB) total knee arthroplasties (TKAs). The hypothesis was that no major differences were going to be found among the two TKA designs. METHODS: Two cohorts of patients who were divided according to implant design (Cohort A, new design gradually reducing radius PS MB TKA; Cohort B, traditional dual-radius PS MB TKA) were analyzed by means of intraoperative navigation. All operations were guided by a non-image-based navigation system that recorded relative femoral and tibial positions in native and implanted knees during the following kinematic tests: passive range of motion (PROM), varus-valgus stress test at 0° and 30° (VV0, VV30) and anterior/posterior drawer test at 90° of flexion (AP90). RESULTS: There were no significative differences in kinematic tests between the two implants. Cohort A, however, showed a different post-implant trend for VV0 and VV30 that were lower than the pre-implant ones, as expected, while for Cohort B, the trend is opposite. However, the gradually reducing radius prosthesis (Cohort A) showed a trend of improving stability (29% compared to the preoperative status) in mid-flexion (VV30) which the traditional dual-radius design (Cohort B) would not. Moreover, we found no differences among postoperative results of the two TKA designs. CONCLUSION: Despite design variations, no difference has been found among the prostheses in terms of PROM, rotations and translations. Both design kinematics did not show paradoxical external rotations, but an increase in femoral translation in mid-flexion without affecting the functioning of the prosthesis. LEVEL OF EVIDENCE: II.

Anterior cruciate ligament revision with Achilles tendon allograft in young athletes.

BACKGROUND: Return to sport after revision ACL reconstruction is a controversial topic, several studies reported the results of different techniques and graft in sportsman, presenting an incredibly wide range of return to the same pre-injury activity level, from 0% to 100%. The purpose of this study was to evaluate the clinical outcomes and return to sport rate in young athletes after non anatomic double-bundle revision ACL reconstruction with Achilles allograft. HYPOTHESIS: The present revision technique was effective in terms of stability, return to sport and functional outcomes. MATERIAL AND METHODS: All the athletes undergone Revision ACL reconstruction with non-irradiated Achilles tendon allograft with a non-anatomical double-bundle technique were included in the study. A split Achilles tendon allograft was used to reproduce the anteromedial (AM) bundle using the over-the-top position, while the posterolateral (PL) bundle was reconstructed through a femoral tunnel located in the anatomical PL footprint. Sport activity, knee function with Lysholm score, knee laxity and re-injury or re-operations were evaluated. RESULTS: Twenty-six athletes (23 males, three females) with a mean age of 23.4±3.6 years were evaluated at a mean follow-up of 6.0±1.6 years. Overall 69% of patients returned to sport both at elite (44%) or county level (56%) after a mean 6.7±1.5 (3-9 range) months. The mean Lysholm score showed a significant improvement from 64.4±8.1 at pre-operative status to 83.8±11.3 at final follow-up (P<.0001). Seven patients (30%) were rated as excellent, nine (39%) as good, five (22%) as fair and 2 (9%) as poor. Three patients (12%) experienced a further graft rupture after a mean 2.6 years, (3.5 months-48 months range) and two had >5mm side-to-side difference at KT-1000. Therefore, the overall survival rate at mean six years follow-up was 81%. CONCLUSION: The ACL revision with a double-bundle technique using Achilles tendon allograft was successful in 81% of athletes at six years mean follow-up. TYPE OF STUDY AND LEVEL OF EVIDENCE: Retrospective case series, level IV.

Does the type of graft affect the outcome of revision anterior cruciate ligament reconstruction? a meta-analysis of 32 studies.

AIMS: Our aim was to perform a meta-analysis of the outcomes of revision anterior cruciate ligament (ACL) reconstruction, comparing the use of different types of graft. MATERIALS AND METHODS: A search was performed of Medline and Pubmed using the terms "Anterior Cruciate Ligament" and "ACL" combined with "revision", "re-operation" and "failure". Only studies that reported the outcome at a minimum follow-up of two years were included. Two authors reviewed the papers, and outcomes were subdivided into autograft and allograft. Autograft was subdivided into hamstring (HS) and bone-patellar tendon-bone (BPTB). Subjective and objective outcome measures were analysed and odds ratios with confidence intervals were calculated. RESULTS: A total of 32 studies met the inclusion criteria. Five studies used HS autografts, eight reported using BPTB autografts, two used quadriceps tendon autografts and eight used various types. Seven studies reported using allografts, while the two remaining used both BPTB autografts and allografts. Overall, 1192 patients with a mean age of 28.7 years (22.5 to 39) and a mean follow-up of 5.4 years (2.0 to 9.6) were treated with autografts, while 269 patients with a mean age of 28.4 years (25 to 34.6) and a mean follow-up of 4.0 years (2.3 to 6.0) were treated with allografts. Regarding allografts, irradiation with 2.5 mrad was used in two studies while the graft was not irradiated in the seven remaining studies. Reconstructions following the use of autografts had better outcomes than those using allograft with respect to laxity, measured by KT-1000/2000 (MEDmetric Corporation) and the rates of complications and re-operations. Those following the use of allografts had better mean Lysholm and Tegner activity scores compared with autografts. If irradiated allografts were excluded from the analysis, outcomes no longer differed between the use of autografts and allografts. Comparing the types of autograft, all outcomes were similar except for HS grafts which had better International Knee Documentation Committee scores compared with BPTB grafts. CONCLUSION: Autografts had better outcomes than allografts in revision ACL reconstruction, with lower post-operative laxity and rates of complications and re-operations. However, after excluding irradiated allografts, outcomes were similar between autografts and allografts. Overall, the choice of graft at revision ACL reconstruction should be on an individual basis considering, for instance, the preferred technique of the surgeon, whether a combined reconstruction is required, the type of graft that was previously used, whether the tunnels are enlarged and the availability of allograft. Cite this article: Bone Joint J 2017;99-B:714-23.

Total knee replacement: intraoperative and postoperative kinematic assessment.

BACKGROUND AND AIM: The main goals of the total knee arthroplasty (TKA) is to reduce the perceived pain and  restore knee mobility and function in case of osteoarthritic knees joints. Literature shows how the three major causes of TKA failures are related to wear, loosening and instability and this is due to a problem of imbalance and malalignment. Intraoperative and postoperative kinematics analysis could be of benefit for improving surgery outcome. The aim of the present paper is to give an overview of the two set-up with the highest accuracy for intraoperative and postoperative TKA kinematics evaluation, currently in use at Istituto Ortopedico Rizzoli. Introperative and Postoperative Evaluation: For intraoperative evaluation it has been presented a navigation system with a specifically developed software, while for the postoperative it has been presented the roentgen stereophotogrammetric analysis (RSA). The navigation system consists in a laptop connected with an optoelectronic localizer (Polaris, Northern Digital Inc, Canada).  Two reference arrays with passive optical markers and a marked probe are used to localize the knee joint in the 3D space and track the joint kinematics. The RSA is a radiographic technique used in orthopaedic field for measuring micromotion at bone/prosthesis interface or for joint kinematics evaluation. The RSA uses two X-ray sources synchronized with two digital flat-panels. CONCLUSIONS: The present paper shows that using the navigation system allows the surgeon to easily perform kinematic and alignment evaluation during TKA surgery while the RSA allows a quantitative evaluation of the joint kinematics during the recovery time.

Pharmacodynamics of ceftazidime/avibactam against extracellular and intracellular forms of Pseudomonas aeruginosa.

Objectives: When tested in broth, avibactam reverses ceftazidime resistance in many Pseudomonas aeruginosa that express ESBLs. We examined whether similar reversal is observed against intracellular forms of P. aeruginosa . Methods: Strains: reference strains; two engineered strains with basal non-inducible expression of AmpC and their isogenic mutants with stably derepressed AmpC; and clinical isolates with complete, partial or no resistance to reversion with avibactam. Pharmacodynamic model: 24 h concentration-response to ceftazidime [0.01-200 mg/L alone or with avibactam (4 mg/L)] of bacteria in broth or bacteria phagocytosed by THP-1 monocytes, with calculation of ceftazidime relative potency ( C s : concentration yielding a static effect) and maximal relative effect [ E max : cfu decrease at infinitely large antibiotic concentrations (efficacy in the model)] using the Hill equation. Cellular content of avibactam: quantification by LC-MS/MS. Results: For both extracellular and intracellular bacteria, ceftazidime C s was always close to its MIC. For ceftazidime-resistant strains, avibactam addition shifted ceftazidime C s to values close to the MIC of the combination in broth. E max was systematically below the detection limit (-5 log 10 ) for extracellular bacteria, but limited to -1.3 log 10 for intracellular bacteria (except for two isolates) with no effect of avibactam. The cellular concentration of avibactam reflected extracellular concentration and was not influenced by ceftazidime (0-160 mg/L). Conclusions: The potential for avibactam to inhibit ß-lactamases does not differ for extracellular and intracellular forms of P. aeruginosa , denoting an unhindered access to its target in both situations. The loss of maximal relative efficacy of ceftazidime against intracellular P. aeruginosa was unrelated to resistance via avibactam-inhibitable ß-lactamases.

Biologically active γ-lactams: synthesis and natural sources.

The γ-lactam moiety is present in a large number of natural and non-natural biologically active compounds. The range of biological activities covered by these compounds is very broad. Functionalized γ-lactams are thus of high interest and have great potential in medicinal chemistry. This review provides a description of the title compounds by focusing on their synthesis, natural sources and biological activities.

Current use of navigation system in ACL surgery: a historical review.

PURPOSE: The present review aims to analyse the available literature regarding the use of navigation systems in ACL reconstructive surgery underling the evolution during the years. METHODS: A research of indexed scientific papers was performed on PubMed and Cochrane Library database. The research was performed in December 2015 with no publication year restriction. Only English-written papers and related to the terms ACL, NAVIGATION, CAOS and CAS were considered. Two reviewers independently selected only those manuscripts that presented at least the application of navigation system for ACL reconstructive surgery. RESULTS: One hundred and forty-six of 394 articles were finally selected. In this analysis, it was possible to review the main uses of navigation system in ACL surgery including tunnel positioning for primary and revision surgery and kinematic assessment of knee laxity before and after different surgical procedures. In the early years, until 2006, navigation system was mainly used to improve tunnel positioning, but since the last decade, this tool has been principally used for kinematics evaluation. Increased accuracy of tunnel placement was observed using navigation surgery, especially, regarding femoral, 42 of 146 articles used navigation to guide tunnel positioning. During the following years, 82 of 146 articles have used navigation system to evaluate intraoperative knee kinematic. In particular, the importance of controlling rotatory laxity to achieve better surgical outcomes has been underlined. CONLUSIONS: Several applications have been described and despite the contribution of navigation systems, its potential uses and theoretical advantages, there are still controversies about its clinical benefit. The present papers summarize the most relevant studies that have used navigation system in ACL reconstruction. In particular, the analysis identified four main applications of the navigation systems during ACL reconstructive surgery have been identified: (1) technical assistance for tunnel placement; (2) improvement in knowledge of the kinematic behaviour of ACL and other structures; (3) comparison of effectiveness of different surgical techniques in controlling laxities; (4) navigation system performance to improve the outcomes of ACL reconstruction and cost-effectiveness. LEVEL OF EVIDENCE: IV.

Technical variables of ACL surgical reconstruction: effect on post-operative static laxity and clinical implication.

PURPOSE: The hypothesis was that an alteration of different surgical variables of ACL reconstruction would produce significant changes in post-operative static laxity of knee joint. METHODS: Joint laxity was acquired by a surgical navigation system for 17 patients just after graft fixation during single-bundle reconstruction with extra-articular lateral tenodesis. The analysed laxity parameters were: internal/external rotation at 30° (IE30) and 90° (IE90) of flexion, varus/valgus rotation at 0° (VV0) and 30° (VV30) of flexion and anterior/posterior displacement at 30° (AP30) and 90° (AP90) of flexion. As surgical variables, the angles between the tibial tunnel and the three planes were defined as well as the lengths of the tunnel and the relationship between native footprints and tunnels. The same analysis was performed for the femoral side. All surgical variables were combined in a multivariate analysis to assess for predictive factors between them and post-operative laxities values. To quantify the performance of each multivariate model, the correlation ratio (η 2) and the corresponding P value (*P < 0.050) have been evaluated. RESULTS: Multivariate analysis underlined statistically significant models for the estimation of: AP30 (η 2 = 0.987; P = 0.014), IE30 (η 2 = 0.995; P = 0.005), IE90 (η 2 = 0.568; P = 0.010), VV0 (η 2 = 0.932; P = 0.003). The parameters that greatly affected the identified models were the orientation of the tibial tunnel with respect to the three anatomical planes. The estimation of AP30, IE30 and IE90 got lower value as the orientation of the tibial tunnel with respect to transverse plane decreases. Considering the orientation to sagittal ([Formula: see text]) and coronal ([Formula: see text]) plane, we found that their reduction provoked a decrease in the estimation of AP30, IE30 and IE90 (except [Formula: see text] that did not appear in the estimation of AP30). The estimation of VV0 got an increase of [Formula: see text], and [Formula: see text] which led to a laxity reduction. CONCLUSION: The main finding of the present in vivo study was the possibility to determine significant effects on post-operative static laxity level of different surgical variables of ACL reconstruction. In particular, the present study defined the conditions that minimize the different aspects of post-operative laxity at time-zero after surgery.

Effects of a synovial fluid substitute on early recovery after arthroscopic subacromial decompression of the shoulder.

PURPOSE: The purpose of this pilot study was to determine whether the use of a synovial fluid substitute (Viscoseal) after arthroscopic subacromial decompression (ASD) of the shoulder was safe (primary outcome) and effective in reducing the postsurgical pain on the day of surgery and the time from surgery to discharge (secondary outcomes), compared with patients undergoing standard ASD alone. METHODS: Forty-six patients with primary isolated shoulder subacromial impingement were randomly assigned to either undergo SAD alone (control group: n = 21) or to receive 10 ml Viscoseal into the subacromial space at the end of the procedure (treatment group: n = 25). RESULTS: No adverse events were reported in either group. All clinical scores improved significantly in each group from preoperative to 12-week follow-up (p < 0.01). The Viscoseal group experienced significantly (p = 0.001) less severe pain 4 h after the surgery {mean 54.0 ± 43.1, median 50 [interquartile range (IQR) 0-100]} and shorter time from surgery to discharge [mean 5.2 ± 1.4, median 5 (IQR 4-6)] than the control group [mean 102.4 ± 40.2, median 100 (IQR 50-150) and mean 11.0 ± 5.3, median 12 (IQR 6-16), respectively]. The Viscoseal group also required less analgesia postoperatively than the control group in the first 8 h: 24% of the Viscoseal required no analgesia, while all patients in the control group required analgesia; 24% of the control group required opiates compared with 4% in the Viscoseal group. CONCLUSION: Viscoseal was safe and well tolerated after shoulder arthroscopy. It provided excellent pain relief and a faster discharge time after ASD of the shoulder. The use of Viscoseal should be investigated in larger randomized controlled trials and for other shoulder arthroscopy procedures. LEVEL OF EVIDENCE: Level II, Pilot Prospective Comparative Study.

Return to sport after anterior cruciate ligament reconstruction in professional soccer players.

BACKGROUND: To investigate time to return to sport and rate of professional sport activity in a homogenous group of competitive soccer players 4 years after anterior cruciate ligament (ACL) reconstruction and rehabilitation. METHODS: Twenty-one male professional soccer players (mean age 22.9±5.4 years) underwent non-anatomical double-bundle autologous hamstring ACL reconstruction and followed the same rehabilitative protocol. Clinical evaluation was performed preoperatively and at 3, 6 and 12-month follow-up. Data regarding return to train and official match, sport activity, complications and revision surgeries were collected at 4-year follow-up. RESULTS: Laxity test (KT-2000) and total KOOS mean score resulted in a significant improvement from the preoperative status to the 12-month follow-up (p<0.0001). The KOOS mean value showed a significant progressive improvement from the preoperative status to 6-month follow-up (p=0.0010) as well, while values collected at 6 and 12-month follow-up were comparable (p=0.2349). Returned to official matches 186±53 days after surgery. After 12 months, 95% came back to the same activity level performed before injury. Four years after ACL reconstruction, 15 patients (71%) were still playing competitive soccer. One patient (5%) underwent ACL failure and subsequent revision. CONCLUSIONS: The ACL reconstruction with the presented technique followed by patient-tailored rehabilitation, allowed 95% and 62% professional male soccer players to return to the same sport activity 1 year and 4 years after surgery respectively. However, 71% were still able to play competitive soccer at final follow-up. Clinical scores were restored after 6 months. LEVEL OF EVIDENCE: IV, case series.

The adductor tubercle as an important landmark to determine the joint line level in total knee arthroplasty: from radiographs to surgical theatre.

PURPOSE: The restoration of the normal joint line (JL) is important both in primary and revision total knee arthroplasty (TKA). However, the assessment of the femoro-tibial JL is still controversial. A strong correlation between femoral width (FW) and distance from adductor tubercle (AT) to JL was found on radiographs, with a ratio of 0.54. The hypothesis was that this ratio was applicable also in the surgical theatre by using measurements obtained intra-operatively with a caliper. METHODS: Femoral width, AT to JL distance and the RATIO between AT to JL distance and FW of 40 patients who underwent TKA were measured on radiograph and intra-operatively. Bland-Altman agreement tests with repeated measurements and linear regression analysis were used. The ratio was used to estimate the distance between JL and AT. RESULTS: The AT to JL distance/FW ratio calculated with linear regression resulted 0.54 for radiographic measurements and 0.53 for intra-operative measurements. There was no difference (0.009 ± 0.03) between the calculated ratios on radiographic and intra-operative measurements, and the correlation between intra-operative and radiographic measurements was 0.5 (p = 0.0016). CONCLUSIONS: This study shows that the validity of the radiographic method which uses an AT to JL distance/FW ratio to determine the level of the JL is confirmed also when using intra-operatively acquired measurements. Thus, this ratio represents a reliable tool to determine the JL level even in challenging prosthetic revision cases when the anatomical JL is missing. LEVEL OF EVIDENCE: Case series, Level IV.

Unicompartmental osteoarthritis: an integrated biomechanical and biological approach as alternative to metal resurfacing.

PURPOSE: Although traditionally not indicated for the treatment of osteoarthritis (OA), regenerative procedures are becoming a focus of increased interest due to their potential to provide pain relief and alter the progression of degenerative diseases. The purpose of this study was to assess whether a combined biomechanical and biological approach could offer good results in unicompartmental OA, thus delaying the need for unicompartmental arthroplasty in patients too young or refusing metal resurfacing. METHODS: Forty-three patients (mean age = 40.1 ± 11 years, 33 men and 10 women, mean BMI = 25 ± 3) affected by unicompartmental OA (Kellegren-Lawrence score = 3) in stable joints were enrolled and treated consecutively. Fifteen patients were treated with osteotomy and osteochondral biomimetic scaffold implant (3 of them also with meniscal substitution), 11 with osteotomy and meniscal scaffold implant, 9 with osteotomy and meniscal allograft implant, and 8 with both cartilage and meniscal reconstruction, depending on the specific joint compartment main requirements. Clinical evaluation was performed at 3-year (2-4) median follow-up using the following scoring systems: IKDC subjective and objective, VAS for pain, and Tegner scores. Failures, adverse events, and complications were also reported. RESULTS: The IKDC subjective score improved from 47.3 to 79.6 at the final evaluation (p < 0.0005), VAS improved from 6.1 to 2.3 (p < 0.0005), and also sport activity level evaluated with the Tegner score showed a significant improvement, from 2 (1-5) to 4 (3-10; p < 0.0005), even if without achieving the pre-injury level (6, p = 0.001). A further subanalysis confirmed the positive outcome obtained in all the treatment subgroups and showed a higher clinical improvement in patients under the age of 40 years (IKDC subjective 84.4 ± 13.2 vs 76.5 ± 17.3; p = 0.03). CONCLUSION: This integrated biological and biomechanical approach produced a marked improvement at short-medium follow-up in patients affected by unicompartmental OA. Even though a good outcome was achieved at all ages, patients under the age of 40 years presented a greater clinical and subjective improvement. Longer follow-up studies are needed to show results over time and confirm this approach as an effective alternative to unicompartmental implants.

Do pre-operative knee laxity values influence post-operative ones after anterior cruciate ligament reconstruction?

The objective of this study was to verify whether pre-reconstruction laxity condition effects post-reconstruction outcome. A total of 100 patients who underwent navigated Anterior Cruciate Ligament (ACL) reconstruction were included in the study and knee laxity analysed retrospectively. The knee was assessed in six different laxity tests before and after ACL reconstruction, namely antero-posterior (AP) and internal-external (IE) at 30° and 90°, and varus-valgus (VV) rotations at 0° and 30° of flexion. For each test, the least square (LS) fitting line based on pre-operative-to-post-operative laxity value was calculated. To what degree the post-operative laxity value is explainable by the corresponding pre-operative condition was evaluated by the LS line slope. Post-operatively, for each single patient, the grade of laxity decreased at any evaluated test. The strongest influence of pre-operative-to-post-operative laxity values was found during IE30 and IE90 tests. While AP30 and VV0 tests seem to be those in which the post-reconstruction laxity was barely affected by the pre-surgery condition. The analysis of the global laxity reduction confirms the previous results. Following this hypothesis, our study remarks on the importance of combined lesions to secondary restraints and the importance of fully understanding the residual laxity to optimize the surgical technique.

Conservative treatment of spontaneous osteonecrosis of the knee in the early stage: pulsed electromagnetic fields therapy.

HYPOTHESIS: pulsed electromagnetic fields treatment might improve symptoms in the early stage of spontaneous osteonecrosis of the knee. METHODS: Twenty-eight patients (19M/9F, age 49.8±16.4 years) suffering from symptomatic (pain) Koshino stage I spontaneous osteonecrosis of the knee, confirmed by magnetic resonance imaging (MRI) were treated with local pulsed electromagnetic fields therapy (6 h daily for 90 days). Clinical evaluation: baseline, 6- and 24-month follow-up by VAS for pain, knee society score (KSS), Tegner and EQ-5D scales. MRI evaluation: baseline and 6-month follow-up, measuring bone marrow lesion's areas and grading these lesions by WORMS score. Failures: patients undergoing knee arthroplasty. RESULTS: Pain significantly reduced at 6 months (from 73.2±20.7 to 29.6±21.3, p<0.0001), which remained almost unchanged at final follow-up (27.0±25.1). KSS significantly increased in first 6 months (from 34.0±13.3 to 76.1±15.9, p<0.0001) and was slightly reduced at final follow-up (72.5±13.5, p=0.0044). Tegner median level increased from baseline to 6-month follow-up (1(1-1) and 3(3-4), respectively, p<0.0001) and remained stable. EQ-5D improved significantly throughout the 24 months (0.32±0.33, baseline; 0.74±0.23, 6-month follow-up (p<0.0001); 0.86±0.15, 24-month follow-up (p=0.0071)). MRI evaluation: significant reduction of total WORMS mean score (p<0.0001) and mean femoral bone marrow lesion's area (p<0.05). This area reduction was present in 85% and was correlated to WORMS grading both for femur, tibia and total joint (p<0.05). Four failures (14.3%) at 24-month follow-up. CONCLUSIONS: Pulsed electromagnetic fields stimulation significantly reduced knee pain and necrosis area in Koshino stage I spontaneous osteonecrosis of the knee already in the first 6 months, preserving 86% of knees from prosthetic surgery at 24-month follow-up. No correlation was found between MRI and clinical scores. LEVEL OF EVIDENCE: Level IV; case series.

Gut microbiota-derived propionate reduces cancer cell proliferation in the liver.

BACKGROUND: Metabolites released by the gut microbiota may influence host metabolism and immunity. We have tested the hypothesis that inulin-type fructans (ITF), by promoting microbial production of short-chain fatty acids (SCFA), influence cancer cell proliferation outside the gut. METHODS: Mice transplanted with Bcr-Abl-transfected BaF3 cells, received ITF in their drinking water. Gut microbiota was analysed by 16S rDNA polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE) and qPCR. Serum Short-chain fatty acids were quantified by UHPLC-MS. Cell proliferation was evaluated in vivo, by molecular biology and histology, and in vitro. RESULTS: Inulin-type fructans treatment reduces hepatic BaF3 cell infiltration, lessens inflammation and increases portal propionate concentration. In vitro, propionate reduces BaF3 cell growth through a cAMP level-dependent pathway. Furthermore, the activation of free fatty acid receptor 2 (FFA2), a Gi/Gq-protein-coupled receptor also known as GPR43 and that binds propionate, lessens the proliferation of BaF3 and other human cancer cell lines. CONCLUSION: We show for the first time that the fermentation of nutrients such as ITF into propionate can counteract malignant cell proliferation in the liver tissue. Our results support the interest of FFA2 activation as a new strategy for cancer therapeutics. This study highlights the importance of research focusing on gut microbes-host interactions for managing systemic and severe diseases such as leukaemia.