Meniscal allograft transplantation in the paediatric population: early referral is justified.

PURPOSE: The need for meniscal allograft transplantation (MAT) in children is rare, and as a result, there is a paucity of evidence detailing survivorship and clinical outcome. MAT has been shown to significantly reduce pain and improve function in the adult population. The aim of this study was to document the outcomes of a single surgeon case series of MAT in the paediatric population. METHODS: Analysis of a prospective meniscal allograft transplantation (MAT) group database of 280 patients was performed. Twenty-three patients met the inclusion criteria-undergoing MAT aged 18 years or younger. RESULTS: Fourteen were female and nine were male with median age of 17 (range 8-18). Thirteen (57%) were right knee and nineteen (83%) were lateral. Additional procedures included high tibial osteotomy, anterior cruciate ligament reconstruction, and microfracture procedures. The median follow-up was 3.8 years (range of 0.2 to 7.8 years). There have been no cases of graft failure. All patients demonstrated improvement in all the modalities of the KOOS outcome scores. At 5 years, the Lysholm score had improved from 57.9 to 87.6 (SD 12.1), Tegner activity score had improved from 2 to 5 (range 4-7) and IKDC score had improved from 40.6 to 78.6 (SD 15.8). Four patients required secondary surgical intervention. No patients developed a superficial or deep infection. CONCLUSION: Meniscal allograft transplantation in children is founded on the successful results of MAT in the adult population. We have demonstrated in this series that MAT can improve function and reduce pain in the paediatric population, and is, therefore, a viable treatment option for the management of the symptomatic paediatric meniscal-deficient knee. Early referral should be considered in the patients with post-meniscectomy syndrome, pain on weight bearing with a history of previous menisectomy. LEVEL OF EVIDENCE: IV.

Allograft tendons are a safe and effective option for revision ACL reconstruction: a clinical review.

Revision anterior cruciate ligament reconstruction remains a challenge, especially optimising outcome for patients with a compromised knee where previous autogenous tissue has been used for reconstruction. Allograft tissue has become a recognized choice of graft for revision surgery but questions remain over the risks and benefits of such an option. Allograft tendons are a safe and effective option for revision ACL reconstruction with no higher risk of infection and equivalent failure rates compared to autografts provided that the tissue is not irradiated, or any irradiation is minimal. Best scenarios for use of allografts include revision surgery where further use of autografts could lead to high donor site morbidity, complex instability situations where additional structures may need reconstruction, and in those with clinical and radiologic signs of autologous tendon degeneration. A surgeon needs to be able to select the best option for the challenging knee facing revision ACL reconstruction, and in the light of current data, allograft tissue can be considered a suitable option to this purpose.Level of evidence IV.

Anatomic ACL reconstruction: the normal central tibial footprint position and a standardised technique for measuring tibial tunnel location on 3D CT.

PURPOSE: The aim of this study was to define the normal ACL central tibial footprint position and describe a standardised technique of measuring tibial tunnel location on 3D CT for anatomic single-bundle ACL reconstruction. METHODS: The central position of the ACL tibial attachment site was determined on 76 MRI scans of young individuals. The central footprint position was referenced in the anterior-posterior (A-P) and medial-lateral (M-L) planes on a grid system over the widest portion of the proximal tibia. 3D CT images of 26 young individuals had a simulated tibial tunnel centred within the bony landmarks of the ACL footprint, and the same grid system was applied over the widest portion of the proximal tibia. The MRI central footprint position was compared to the 3D CT central footprint position to validate the technique and results. RESULTS: The median age of the 76 MRI subjects was 24 years, with 32 females and 44 males. The ACL central footprint position was at 39 (±3 %) and 48 (±2 %), in the A-P and M-L planes, respectively. There was no significant difference in this position between sexes. The median age of the 26 CT subjects was 25.5 years, with 10 females and 16 males. The central position of the bony ACL footprint was at 38 (±2 %) and 48 (±2 %), in the A-P and M-L planes, respectively. The MRI and CT central footprint positions were not significantly different in relation to the medial position, but were different in relation to the anterior position (A-P 39 % vs. 38 %, p = 0.01). The absolute difference between the central MRI and CT reference positions was 0.45 mm. CONCLUSIONS: The ACL's normal central tibial footprint reference position has been defined, and the technique of measuring tibial tunnel location with a standardised grid system is described. This study will assist surgeons in evaluating tibial tunnel position in anatomic single-bundle ACL reconstruction. LEVEL OF EVIDENCE: III.

Sport and early osteoarthritis: the role of sport in aetiology, progression and treatment of knee osteoarthritis.

Sports activities are considered favourable for general health; nevertheless, a possible influence of sports practice on the development of early osteoarthritis (OA) is a cause for concern. A higher incidence of OA in knees and ankles of former high-impact sports players than in those of the normal population has been shown and it is still debatable whether the cause is either to be recognized generically in the higher number of injuries or in a joint overload. The possibility to address knee OA in its early phases may be strictly connected to the modification of specific extrinsic or intrinsic factors, related to the patient in order to save the joint from further disease progression; these include sport practice, equipment and load. Non-surgical therapies such as continuative muscles reinforce and training play a strong role in the care of athletes with early OA, particularly if professional. There is an overall agreement on the need of an early restoring of a proper meniscal, ligament and cartilage integrity in order to protect the knee and resume sports safely, whereas alignment is a point still strongly debatable especially for professional athletes. Remaining questions still to be answered are the risks of different sports in relation to one another, although an actual protective effect of low-impact sports, such as walking, swimming or cycling, has been recognized on the appearance or worsening of OA, the effect of continuing or ceasing to practice a sport on the natural history of early OA, and even following appropriate treatment is still unknown.

Outcome of meniscal allograft transplantation related to articular cartilage status: advanced chondral damage should not be a contraindication.

PURPOSE: Advanced chondral damage (bare bone) at presentation is considered a contraindication to meniscal allograft transplantation (MAT), yet there are few other options for young patients where arthroplasty is not appropriate. This study hypothesis is that MAT in patients with advanced chondral damage can obtain good clinical outcomes, equivalent to patients with minimal chondral damage. METHOD: A prospective longitudinal study of 99 consecutive patients who underwent MAT between May 2005 and Feb 2013, with a minimum of 1-year follow-up. Patients were categorised into two groups: 60 in Group A (Good) up to ICRS Chondral grade 3b involving <1 cm(2) and 39 in Group B (Bare) ICRS grade 3b involving >1 cm(2) or worse. Outcomes were assessed by PROMS (KOOS, IKDC, Lysholm, Tegner Activity Scale), with an endpoint of meniscal allograft failure. RESULTS: Mean follow-up was 2.9 years (range 1.1-9.1, SD 1.23), with a similar male to female and lateral to medial ratios between the groups (n.s). The age of Group B was significantly older than Group A (35 vs 29 years, p = 0.002). The status of the articular cartilage at the time of transplant was directly related to the number of years since index meniscectomy [(A) Mean 6.9 years, SD 6.3; (B) 11.9 years, SD 7.4; p = 0.001]. Pre-operatively, patients in Group B had significantly worse pain and functional outcome scores (KOOS p = 0.022, Lysholm p = 0.025, IKDC pain subset p = 0.035). The mean increase PROMs was significant in both groups at 1 year (KOOS p < 0.05, IKDC p < 0.001, Lysholm p < 0.001), and the pain and functional scores were no longer significantly different between groups (n.s.). The outcome measures continued to improve in both groups at 2 and 3 years, with slightly greater improvement in Group A. Failure of the meniscal allograft occurred in 9 patients (A:1, B:8) at a mean time of 1.1 years (SD 0.55). Kaplan-Meier survival at 2 years was 97.9% (A) and 78% (B) (p = 0.002). Logistic regression analysis demonstrated a relationship between survival and chondral grade (p = 0.001) and number of concomitant procedures (p < 0.001). CONCLUSION: Patients with advanced chondral damage should not be excluded from MAT. Though there is a higher initial failure rate, these patients obtain a similar therapeutic benefit to the traditional, ideal patient group. LEVEL OF EVIDENCE: III.

No increase in adverse events with lateral extra-articular tenodesis augmentation of anterior cruciate ligament reconstruction - Results from the stability randomized trial.

OBJECTIVES: Results from the Stability Study suggest that adding a lateral extra-articular tenodesis (LET) to a hamstring tendon autograft reduces the rate of anterior cruciate ligament reconstruction (ACLR) failure in high-risk patients. The purpose of this study is to report adverse events over the 2-year follow-up period and compare groups (ACLR alone vs. ACLR + LET). METHODS: Stability is a randomized clinical trial comparing hamstring tendon ACLR with and without LET. Patients aged 14-25 years with an ACL deficient knee were included. Patients were followed and adverse events documented (type, actions taken, resolution) with visits at 3, 6, 12, and 24 months postoperatively. Adverse events were categorized as none, minor medical, minor surgical, contralateral ACL rupture, or graft rupture. Patient reported outcome measures (PROMs) collected at each visit included the Knee Injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee Score (IKDC), and ACL Quality of Life Questionnaire (ACL-QOL). RESULTS: In total, 618 patients were randomized (mean age 18.9 years, 302 (49%) male). Forty-five patients (7%) suffered graft rupture; 34 (11%) in the ACLR group compared to 11 (4%) in the ACLR + LET group (RRR = 0.67, 95% CI 0.36 to 0.83, p < 0.001). There were no differences in effusion or infection rates between groups. The ACLR + LET group experienced an increased number of hardware removals (10 vs. 4). Overall, the rate of minor medical events (11%), minor surgical events (7%), and ipsilateral or contralateral ACL tears (10%) were low considering the high-risk patient profile. Increasing severity of adverse events was associated with lower PROMs at 24 months post-operative. Patients in the ACLR + LET group reported greater degree of pain at 3 months only. There were no clinically significant differences in range of motion between groups. CONCLUSIONS: The addition of LET to hamstring tendon autograft ACLR in young patients at high risk of re-injury resulted in a statistically significant reduction in graft rupture. While the addition of LET may increase rates of hardware irritation, there was no significant increase in overall rates of minor medical adverse events, minor surgical events, or overall re-operation rates. The concerns regarding complications associated with a LET did not materialize in this study. LEVEL OF EVIDENCE: Level I.

Effect of high-impact aerobics and strength training on BMD in young women aged 20-35 years.

To evaluate the effects of a 12-month exercise intervention using either high-impact step aerobic exercise or moderate-intensity strength training on areal bone mineral density (aBMD) we studied 51 untrained women, aged 20-35 years, for this study. Whole body and heel and wrist aBMD were measured by dual-energy X-ray absorptiometry (DXA, Hologic or PIXI Lunar). Subjects were randomly assigned to: impact-loaded step aerobic exercise (SA, n=15), moderate-intensity lower body strength training (ST, n=16) or non-exercise control (CON, n=20). Data analysis only included those who completed 95% of each training routine and attended at least 80% of all sessions. Group differences in aBMD, leg press strength and urinary cross-link deoxypridinoline (µDPD) were analysed using analysis of variance. After a 12-month intervention, the SA elicited an increase in aBMD of the heel (4.4%, p<0.05) and leg press strength (15%, p<0.05), relative to baseline. Meanwhile, the ST showed an increase in leg press strength (48%, p<0.05) with no significant increase in aBMD at any measured site. Similar and unchanged µDPD was observed in all 3 groups at baseline, 6 and 12 months. In conclusion, a 12-month high-impact step aerobic exercise resulted in a significant increase in the heel aBMD in untrained young women, who complied with the exercise regimen. A moderate intensity strength training intervention of similar duration had no effect on aBMD although leg strength increased significantly.

Mesoporous silicas impregnated with cobalt and nickel oxide nanoparticles and the growth of carbon nanotubes there from.

Metal oxide-based nanoparticles of cobalt or nickel were deposited inside the pores and on the surface of hexagonal mesoporous silicas by a direct synthesis technique using Pluronic P85 and P123 surfactants as structure directing agents with the appropriate metal phthalocyanine as a metal precursor. Metal loadings were between 0.4-3.2 wt.%. XPS studies showed that the initial form of the metal oxide nanoparticles were [CoO] and [NiO] respectively. Samples of these materials formed from the P85 surfactant and 3.0 wt.% were used to grow carbon nanotubes (CNTs) from acetylene feedstock in a catalytic chemical vapour deposition (CCVD) reactor at 800 degrees C. CNT growth appeared to be random and the CNTs had diameters ranging from < 10 to > 90 nm. Treatment of the metal impregnated silicas with nitric acid produced materials which, under the same CNT growth conditions, afforded more uniform CNTs with diameters between 5-15 nm. No significant loss in mesophase ordering was seen in the TEM, PXRD or nitrogen physisorption analysis of the acid washed samples. CNTs grown with cobalt impregnated silicas formed with the P123 surfactant had diameters in the range 15-25 nm. Raman spectroscopy of the CNT products showed the nanotubes were highly graphitised and of good quality.

A pilot randomized trial of meniscal allograft transplantation versus personalized physiotherapy for patients with a symptomatic meniscal deficient knee compartment.

AIMS: Meniscal allograft transplantation is undertaken to improve pain and function in patients with a symptomatic meniscal deficient knee compartment. While case series have shown improvements in patient reported outcome measures (PROMs), its efficacy has not been rigorously evaluated. This study aimed to compare PROMs in patients having meniscal transplantation with those having personalized physiotherapy at 12 months. PATIENTS AND METHODS: A single-centre assessor-blinded, comprehensive cohort study, incorporating a pilot randomized controlled trial (RCT) was performed on patients with a symptomatic compartment of the knee in which a (sub)total meniscectomy had previously been performed. They were randomized to be treated either with a meniscal allograft transplantation or personalized physiotherapy, and stratified for malalignment of the limb. They entered the preference groups if they were not willing to be randomized. The Knee injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC) score and Lysholm score and complications were collected at baseline and at four, eight and 12 months following the interventions. RESULTS: A total of 36 patients entered the study; 21 were randomized and 15 chose their treatments. Their mean age was 28 years (range 17 to 46). The outcomes were similar in the randomized and preference groups, allowing pooling of data. At 12 months, the KOOS4 composite score (mean difference 12, p = 0.03) and KOOS subscales of pain (mean difference 15, p = 0.02) and activities of daily living (mean difference 18, p = 0.005) were significantly superior in the meniscal transplantation group. Other PROMs also favoured this group without reaching statistical significance. There were five complications in the meniscal transplantation and one in the physiotherapy groups. CONCLUSION: This is the first study to compare meniscal allograft transplantation to non-operative treatment. The results provide the best quality evidence to date of the symptomatic benefits of meniscal allograft transplantation in the short term, but a multicentre RCT is required to investigate this question further. Cite this article: Bone Joint J 2018;100-B:56-63.

Osteonecrosis of the medial tibial plateau: a case report.

Medial tibial plateau osteonecrosis is a disease that lacks distinguishing signs and symptoms, especially in the early stage, and requires clinicians to exercise a high degree of suspicion to prevent disease progression. We present a case of spontaneous osteonecrosis of the medial tibial plateau in a 59-year-old woman. Within 5 months of the onset of symptoms, the entire medial tibial plateau collapsed down into the metaphyseal region, causing severe varus deformity, instability, and inability to walk without crutches and a hinged knee brace. Initial symptoms of medial joint line pain and generalised swelling of the knee were attributed to early degenerative changes. Subsequent radiographs were misinterpreted as simple medial compartment arthritis. Due to severe bone loss and significant lateral collateral ligament attenuation, a total joint arthroplasty was required, using a stemmed tibial component with medial metal block and bone graft augmentation. The speed of bone collapse and the extension into the metaphysis, requiring complex joint arthroplasty, makes this case unique.

Adult native knee extensor mechanism ruptures.

Extensor mechanism rupture is a serious event requiring prompt diagnosis and treatment. Patella fractures are reportedly six times more frequent than soft tissue injuries such as quadriceps or patella tendon ruptures. Classically quadriceps and patella tendon ruptures are seen more in males, with those over 40 predominantly suffering from quadriceps tendon ruptures, often associated with an underlying condition, whereas patella tendon ruptures are mostly associated with sport injuries and are commonly seen in the under 40s. Almost all types of extensor mechanism ruptures benefit from early management which typically involves surgery. Diagnosis can be deemed easy to make by demonstrating inability to actively extend the knee, this however can be easily overlooked and missed in a busy emergency department leading to a late diagnosis and necessitating more complex surgery. Earlier surgical intervention and rehabilitation tend to produce improved outcomes.

Meniscal allograft transplantation: rationale for treatment.

The anatomy and microstructure of the menisci allow the effective distribution of load across the knee. Meniscectomy alters the biomechanical environment and is a potent risk factor for osteoarthritis. Despite a trend towards meniscus-preserving surgery, many tears are irreparable, and many repairs fail. Meniscal allograft transplantation has principally been carried out for pain in patients who have had a meniscectomy. Numerous case series have reported a significant improvement in patient-reported outcomes after surgery, but randomised controlled trials have not been undertaken. It is scientifically plausible that meniscal allograft transplantation is protective of cartilage, but this has not been established clinically to date.

Meniscal Transplantation and its Effect on Osteoarthritis Risk: an abridged protocol for the MeTEOR study: a comprehensive cohort study incorporating a pilot randomised controlled trial.

OBJECTIVES: Subtotal or total meniscectomy in the medial or lateral compartment of the knee results in a high risk of future osteoarthritis. Meniscal allograft transplantation has been performed for over thirty years with the scientifically plausible hypothesis that it functions in a similar way to a native meniscus. It is thought that a meniscal allograft transplant has a chondroprotective effect, reducing symptoms and the long-term risk of osteoarthritis. However, this hypothesis has never been tested in a high-quality study on human participants. This study aims to address this shortfall by performing a pilot randomised controlled trial within the context of a comprehensive cohort study design. METHODS: Patients will be randomised to receive either meniscal transplant or a non-operative, personalised knee therapy program. MRIs will be performed every four months for one year. The primary endpoint is the mean change in cartilage volume in the weight-bearing area of the knee at one year post intervention. Secondary outcome measures include the mean change in cartilage thickness, T2 maps, patient-reported outcome measures, health economics assessment and complications. RESULTS: This study is expected to report its findings in 2016. Cite this article: Bone Joint Res 2015;4:93-8.

Constitutive activation of muscarinic receptors by the G-protein Gq.

In the absence of ligands, G-protein coupled receptors interconvert between active and inactive conformations. These conformations are stabilized by agonists and antagonists, respectively. Like agonists, G-proteins are thought to preferentially associate with receptors in the active conformation and should therefore be able to promote their formation in the absence of agonist. We show that over-expression of Gq induces constitutive activation of compatible muscarinic receptors and that this activity is blocked by muscarinic antagonists. Gq also increases the potency and efficacy of agonists. These results indicate that regulation of G-protein levels has a profound impact on receptor control of cellular physiology, even in the absence of agonist ligands.

Constitutive activation of chimeric m2/m5 muscarinic receptors and delineation of G-protein coupling selectivity domains.

To derive structure/function relationships for muscarinic receptor/G-protein coupling, the m2 and m5 muscarinic receptors and a series of m2/m5 chimeras were tested for agonist binding and functional responses in a cellular proliferation/transformation assay. m5, which mediates stimulation of phosphatidylinositol turnover, displayed robust activity in the proliferation assay, whereas m2, which mediates inhibition of adenylyl cyclase, was inactive in the proliferation assay. Chimeras that contained m2 sequences in the i2 or i3 loops had impaired activity or were inactive, respectively. Chimeras that contained m2 segments reaching from the N-terminus to TM2, or from TM6 to the C-terminus, had enhanced activity relative to m5, and a chimera with both of these elements was constitutively activated.

The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine.

RATIONALE: Clozapine is a unique antipsychotic, with efficacy against positive symptoms in treatment-resistant schizophrenic patients, and the ability to improve cognition and treat the negative symptoms characteristic of this disease. Despite its unique clinical actions, no specific molecular mechanism responsible for these actions has yet been described. OBJECTIVES AND METHODS: To comprehensively profile a large library of neuropsychiatric drugs, including most antipsychotics, at human monoamine receptors using R-SAT, an in vitro functional assay. RESULTS: Profiling revealed that N-desmethylclozapine (NDMC), the principal metabolite of clozapine, but not clozapine itself, is a potent and efficacious muscarinic receptor agonist, a molecular property not shared by any other antipsychotic. To further explore the role of NDMC muscarinic receptor agonist properties in mediating the physiological actions of clozapine, systemically administered NDMC was found to stimulate the phosphorylation of mitogen-activated protein kinase (MAP kinase) in mouse CA1 hippocampal neurons, an effect that was blocked by scopolamine, confirming central M1 muscarinic receptor agonist activity in vivo. Lastly, an analysis of clozapine and NDMC serum levels in schizophrenic patients indicated that high NDMC/clozapine ratios better predicted improvement in cognitive functioning and quality of life than the levels of either compound alone. CONCLUSIONS: The muscarinic receptor agonist activities of NDMC are unique among antipsychotics, and provide a possible molecular basis for the superior clinical effects of clozapine pharmacotherapy.

Treatment of gonorrhea in pregnancy.

OBJECTIVE: To evaluate prospectively the 1989 Centers for Disease Control recommendations for treatment of gonorrhea in pregnancy. METHODS: Two hundred fifty-two women referred with probable endocervical gonorrhea had pre-treatment endocervical, rectal, and oral cultures for Neisseria gonorrhoeae and direct fluorescent antibody testing for Chlamydia trachomatis. They were assigned randomly to receive ceftriaxone 250 mg intramuscularly (IM), spectinomycin 2 g IM, or amoxicillin 3 g orally plus probenecid 1 g orally. Treatment was unblinded and in a 1:1:1 distribution. RESULTS: Two hundred forty-five women (97%) had endocervical infection, 68 (27%) had rectal infection, and 17 (7%) had pharyngeal infection. One hundred two of 252 women (40%) had concomitant endocervical C trachomatis. The overall efficacy was 235 of 252 subjects (93%) (95% confidence interval [CI] 90.1-96.4%). Ceftriaxone was effective in 80 of 84 cases (95%) (95% CI 90.6-99.9%), amoxicillin with probenecid was effective in 75 of 84 cases (89%) (95% CI 82.5-96%), and spectinomycin was effective in 80 of 84 cases (95%) (95% CI 90.6-99.9%). No significant difference was noted in overall efficacy or by site of infection. There was no increased incidence of congenital malformations in the offspring spring of any treatment group. CONCLUSIONS: Ceftriaxone and spectinomycin are safe and effective for the treatment of gonorrhea in pregnancy. Amoxicillin with probenecid has lower efficacy and is not recommended for treatment of gonococcal infection in pregnancy.

Constitutively active muscarinic receptors.

Mutations that increase constitutive activity and alter ligand binding have been used to investigate the structure and mechanism of activation of muscarinic receptors. These data are reviewed with reference to the recently published three-dimensional structure of rhodopsin. Residues in TM3 and TM6 where amino acid substitutions increased constitutive activity align with residues within the core of the receptor. A nucleus of these residues is located immediately below the predicted binding site of acetylcholine. The i2 loop where mutations also increase constitutive activity was found to loop away from the i3 loop, which has been found to modulate G-protein coupling specificity.

Exploring the potential for subtype-selective muscarinic agonists in glaucoma.

Pilocarpine has been used to lower intraocular pressure (IOP) in glaucoma patients for more than 100 years. Since the identification of five muscarinic receptor subtypes, there has been an interest in separating the IOP-lowering effects from the ocular side effects of pupil constriction and lens accommodation. However, all these actions seem to be mediated by the M3 receptor. A novel muscarinic receptor agonist, AGN 199170, that has no activity on the M3 subtype was compared to pilocarpine in a monkey glaucoma model. This compound lowered IOP suggesting that muscarinic agonists targeted at muscarinic receptors other than the M3 subtype may be able to selectively lower IOP.