A non-randomized controlled clinical trial on autologous chondrocyte implantation (ACI) in cartilage defects of the medial femoral condyle with or without high tibial osteotomy in patients with varus deformity of less than 5°

Purpose

High tibial osteotomy (HTO) is a recommended concomitant surgery when treating cartilage lesions of the medial femoral condyle (MFC). Varus deformities of 5° and more were considered an indication for HTO in patients with cartilage defects. This study compares clinical outcome in patients with ACI and concomitant varus deformity of <5° with or without additional HTO.

Methods

43 patients with isolated cartilage defect of the MFC and varus deformity between 1° and 5° (mean age 39.14 ± 8.35 years; mean varus deformity 2.84 ± 1.19°) were included (follow-up 71.88 ± 23.99 months). Group A (n = 19) was treated with ACI and additional HTO; group B (n = 24) received ACI only. Survival rate in terms of absence of the need of reintervention was defined as main outcome parameter. In the subgroup without reintervention, functional outcome (KOOS and WOMAC) was evaluated.

Results

Overall rate of reintervention was 12 (27.9 %). Survival was significantly higher in group A (group A 89.5 %, group B 58.33 %; p = 0.023). Although a trend for better clinical outcome was observed for group A in the subgroup without reintervention, this observation lacked statistical significance (KOOS_symptoms group A 73.23, group B 59.64; p = 0.274).

Conclusion

While there is general consensus for treating varus deformities of >5° in patients with cartilage lesions of the medial femoral condyle, HTO also leads to a reduced rate of reinterventions and longer survival rates in patients with varus deformities of <5°.     

Interleukin-7 levels in synovial fluid increase with age and MMP-1 levels decrease with progression of osteoarthritis

Background and purpose

Little is known about biochemical mediators that correlate with the initiation and progression of knee osteoarthritis (OA). We therefore valuated the roles of cytokines and metalloenzymes in knee OA in relation to OA grading, age, and BMI.

Patients and methods

A multiplex ELISA-based immunoassay (Luminex technology) was used to measure biochemical mediators in the synovial fluid (SF) of 82 patients undergoing knee surgery. All patients were classified according to age, BMI, and OA grade. 24 patients had no signs of OA (knee reconstruction surgeries). The mediators that were tested for included interleukins (IL-1Ra, IL-6, IL-7, and IL-18), chemokines (CCL2 (MCP-1), CCL3 (MIP-1a), and CXCL8 (IL-8)), growth factors (HGF and VEGF), and matrix metalloproteinases (MMP-1, MMP-2, MMP-9, and MMP-13).

Results

There was a correlation between IL-7 levels in SF and age (p < 0.01). The 11 highest IL-7 levels were seen in patients who were aged between 59 and 72 but had different OA grades. In contrast, all patients who had severe OA in all 3 knee compartments (pan-OA) had only low or medium IL-7 levels. There was a negative correlation between MMP-1 levels in synovial fluid and grade of OA (p < 0.001). Correlation studies between pairs of mediators revealed two groups of mediators that are important in OA progression, dominated by MCP-1 and IL-1Ra.

Interpretation

IL-7 levels in SF are elevated in elderly people suffering from OA of different grades, but they are depressed in patients with severe 3-compartment OA, possibly due to widely impaired chondrocytes embedded in the affected cartilage tissue. The observed decrease in MMP-1 levels in SF, which is dependent on the severity of OA, may be caused by deterioration of superficial cartilage layers during progression of OA.

List of abbreviations

BMI

body mass index

CCL

chemokine (C-C motif) ligand

CXCL

chemokine (C-X-C motif) ligand

HGF

hepatocyte growth factor

ICRS

International Cartilage Repair Society

IL

interleukin

IL-1Ra

IL-1 receptor antagonist

MCP

monocyte chemoattractant protein

MIP

macrophage inflammatory protein

MMP

matrix metalloproteinase

OA

osteoarthritis

SF

synovial fluid

VEGF

vascular endothelial growth factor

Progression of knee OA is often driven by biomechanical forces (Englund 2010), whereas the etiology of OA in other joints is less affected by mechanical stress. Biochemical mediators such as cytokines, growth factors, and matrix metalloproteinases—acting individually or in networks—profoundly influence cellular responses in joint tissues, modifying both catabolic and anabolic activities involved in the pathogenesis of OA (Goldring and Goldring 2007). Ageing is the most prominent risk factor for OA, and chondrocyte senescence and aging-related changes in the matrix, such as articular surface fibrillation and proteoglycan changes, are most likely to contribute to joint ageing (Martin and Buckwalter 2002, Shane Anderson and Loeser 2010). However, despite intensive research efforts, little is known about biochemical factors whose levels may correlate with the severity of knee OA (Belo et al. 2007). Also, age-related changes in cytokine production in body fluids have not been investigated completely (Gardner and Murasko 2002).Biochemical mediators found in synovial fluid (SF) that affect the cellular functions of tissues of the knee joint include interleukins (ILs), chemokines, growth factors, and matrix metalloproteinases (MMPs). Interleukins, both pro- and anti-inflammatory, have a pivotal role in arthritic diseases and are potential targets of OA therapy. Chemokines, which are small, chemoattractant cytokines, have key roles in the accumulation of inflammatory cells at the site of inflammation. Growth factors produced by chondrocytes and subchondral bone regulate the growth of blood vessels in the joint. Some recent studies have supported the notion that inhibition of abnormal angiogenesis will provide effective therapeutic strategies for treatment of OA (Ashraf and Walsh 2008). MMPs and pro-inflammatory cytokines are involved in a collagen II-dependent feed-forward mechanism of matrix degradation in human articular cartilage (Klatt et al. 2009).To improve our understanding of the molecular and cellular processes involved in joint ageing and in the initiation and progression of OA, we wanted to determine the levels of biochemical mediators that correlate with the severity of knee OA or patient age.     

Failed Arthroscopic Repair of a Large Reverse Hill-Sachs Lesion Using Bone Allograft and Cannulated Screws: A Case Report

Anterior impression fractures of the humeral head (reverse Hill-Sachs lesions) are typical concomitant bony injuries of posterior shoulder dislocations. When more than 20% of the humeral articulating surface is affected, surgical treatment is required, typically necessitating open surgery. Recently, cases of successful arthroscopic treatment of small reverse Hill-Sachs lesions involving less than 30% of the articulating surface have been reported. This article presents a case of a large reverse Hill-Sachs lesion affecting over 40% of the articulating surface that was treated arthroscopically by retrograde elevation, bone allografting, and cannulated screw insertion. The postoperative radiographic images showed a successful reduction of the impacted articulating surface of the humeral head. However, at 6 months' follow-up, the patient presented with pain and symptoms of a frozen shoulder. Cross-sectional imaging showed necrosis, partial absorption, and loss of reduction of the formerly elevated segment requiring humeral head replacement. This case report shows that even though the arthroscopic retrograde elevation of large reverse Hill-Sachs lesions is technically achievable, the outcome can be unsatisfactory because of the limitations in biologic healing response associated with large lesions of the humeral articulating surface.     

A Coupled Approach for Fluid Dynamic Problems Using the PDE Framework Peano

We couple different flow models, i.e. a finite element solver for the Navier-Stokes equations and a Lattice Boltzmann automaton, using the framework Peano as a common base. The new coupling strategy between the meso- and macroscopic solver is presented and validated in a 2D channel flow scenario. The results are in good agreement with theory and results obtained in similar works by Latt et al. In addition, the test scenarios show an improved stability of the coupled method compared to pure Lattice Boltzmann simulations.     

Role of iron deficiency and anemia in cardio-renal syndromes

Chronic heart failure is a common disorder associated with unacceptably high mortality rates. Chronic renal disease and anemia are two important comorbidities that significantly influence morbidity and mortality in patients with chronic heart failure (CHF). Progress in CHF again may cause worsening of kidney function and anemia. To describe this vicious cycle, the term cardio-renal anemia syndrome has been suggested. Iron deficiency is part of the pathophysiology of anemia in both CHF and chronic kidney disease, which makes it an interesting target for treatment of anemia in cardio-renal anemia syndrome. Recently, studies have highlighted the potential clinical benefits of treating iron deficiency in patients with CHF, even if these patients are nonanemic. This article summarizes studies investigating the influence of iron deficiency with or without anemia in chronic kidney disease and CHF and gives an overview of preparations of intravenous iron currently available.     

Podocyte EphB4 signaling helps recovery from glomerular injury

Eph receptor tyrosine kinases and their ligands (ephrins) have a pivotal role in the homeostasis of many adult organs and are widely expressed in the kidney. Glomerular diseases beginning with mesangiolysis can recover, with podocytes having a critical role in this healing process. We studied here the role of Eph signaling in glomerular disease recovery following mesangiolytic Thy1.1 nephritis in rats. EphB4 and ephrinBs were expressed in healthy glomerular podocytes and were upregulated during Thy1.1 nephritis, with EphB4 strongly phosphorylated around day 9. Treatment with NPV-BHG712, an inhibitor of EphB4 phosphorylation, did not cause glomerular changes in control animals. Nephritic animals treated with vehicle did not have morphological evidence of podocyte injury or loss; however, application of this inhibitor to nephritic rats induced glomerular microaneurysms, podocyte damage, and loss. Prolonged NPV-BHG712 treatment resulted in increased albuminuria and dysregulated mesangial recovery. Additionally, NPV-BHG712 inhibited capillary repair by intussusceptive angiogenesis (an alternative to sprouting angiogenesis), indicating a previously unrecognized role of podocytes in regulating intussusceptive vessel splitting. Thus, our results identify EphB4 signaling as a pathway allowing podocytes to survive transient capillary collapse during glomerular disease.     

Posterior root tear fixation of the lateral meniscus combined with arthroscopic ACL double-bundle reconstruction: technical note of a transosseous fixation using the tibial PL tunnel

According to our observation in ACL reconstruction, we find root tears of the posterior horn of the lateral meniscus as a common concomitant injury in ACL-deficient knees. This might be a consequence of initial trauma or of the increased anterior–posterior translation of the tibia and an overload impact on the posterior meniscus root in ACL-deficient knees. A tear of the posterior horn of the medial meniscus causes a 25% increase in peak pressure in the medial compartment compared with that found in the intact condition. The repair restores the peak contact pressure to normal (Allaire et al. in J Bone Joint Surg Am 90(9):1922–1931, [2008]). A tear of the posterior horn of the lateral meniscus might have similar consequences. We hypothesize the surgical anatomical reattachment of the root at the tibia helping to restore knee joint kinematics and helping to advance ACL-graft function. This article presents an arthroscopical technique to reattach the posterior meniscus root in combination with ACL double-bundle reconstruction. The procedure uses the tibial PL tunnel to fix the meniscus suture.     

Aromatase inhibitors as solely treatment in postmenopausal breast cancer patients

Several studies evaluating the clinical effectiveness of endocrine therapy alone in breast cancer patients aged 70 years or older reported comparable survival rates to conventional surgical therapy, although the incidence of local recurrences was higher. Primary endocrine therapy is therefore only recommended as an alternative approach in elderly woman with estrogen receptor positive tumors who are deemed inoperable or who refuse surgery. We report our experience with aromatase inhibitors as primary endocrine therapy for estrogen receptor positive breast cancer in postmenopausal woman who are impaired by other diseases, refuse surgery or are of old age. Fifty-six patients with fifty-seven ER+ operable breast cancers who refused surgery, were judged ineligible for surgery because of comorbidity, or were of old age were treated with endocrine therapy using aromatase inhibitors only. Digital mammography and high-end breast ultrasound were used to assess tumor sizes. The mean age of the patients was 74 years (range 52-102 years). All patients suffered from breast cancer. The mean follow-up interval was 40 months (range 5-92 months). Seven patients (12%) achieved complete clinical remission, 31 (57%) partial response giving an overall objective response rate of 69%. In addition, seven (12%) patients showed stable disease, giving a clinical benefit rate (complete remission + partial response + stable disease rate) of 81%. Eleven patients (19%) progressed after an initial partial response or stable disease. Only one patient (2%) progressed on endocrine therapy within the first months. Eventually, 22 (39%) patients underwent surgery after informed consent to achieve better local tumor control. Primary endocrine therapy with aromatase inhibitors may offer an effective and safe alternative to surgery giving a high local control rate in postmenopausal women who refuse surgery, who are judged ineligible for surgery, or are of old age.     

Comparison of 1.0 M gadobutrol and 0.5 M gadopentate dimeglumine-enhanced MRI in 471 patients with known or suspected renal lesions: results of a multicenter, single-blind, interindividual, randomized clinical phase III trial

The purpose of this phase III clinical trial was to compare two different extracellular contrast agents, 1.0 M gadobutrol and 0.5 M gadopentate dimeglumine, for magnetic resonance imaging (MRI) in patients with known or suspected focal renal lesions. Using a multicenter, single-blind, interindividual, randomized study design, both contrast agents were compared in a total of 471 patients regarding their diagnostic accuracy, sensitivity, and specificity to correctly classify focal lesions of the kidney. To test for noninferiority the diagnostic accuracy rates for both contrast agents were compared with CT results based on a blinded reading. The average diagnostic accuracy across the three blinded readers (‘average reader’) was 83.7% for gadobutrol and 87.3% for gadopentate dimeglumine. The increase in accuracy from precontrast to combined precontrast and postcontrast MRI was 8.0% for gadobutrol and 6.9% for gadopentate dimeglumine. Sensitivity of the average reader was 85.2% for gadobutrol and 88.7% for gadopentate dimeglumine. Specificity of the average reader was 82.1% for gadobutrol and 86.1% for gadopentate dimeglumine. In conclusion, this study documents evidence for the noninferiority of a single i.v. bolus injection of 1.0 M gadobutrol compared with 0.5 M gadopentate dimeglumine in the diagnostic assessment of renal lesions with CE-MRI.

MRI thermometry: Fast mapping of RF‐induced heating along conductive wires

Conductive implants are in most cases a strict contraindication for MRI examinations, as RF pulses applied during the MRI measurement can lead to severe heating of the surrounding tissue. Understanding and mapping of these heating effects is therefore crucial for determining the circumstances under which patient examinations are safe. The use of fluoroptic probes is the standard procedure for monitoring these heating effects. However, the observed temperature increase is highly dependent on the positioning of such a probe, as it can only determine the temperature locally. Temperature mapping with MRI after RF heating can be used, but cooling effects during imaging lead to a significant underestimation of the heating effect. In this work, an MRI thermometry method was combined with an MRI heating sequence, allowing for temperature mapping during RF heating. This technique may provide new opportunities for implant safety investigations. Magn Reson Med, 2008. © 2008 Wiley‐Liss, Inc.