Clinical outcome is significantly better with spheroid-based autologous chondrocyte implantation manufactured with more stringent cell culture criteria.

Objective: Spherox (CO.DON AG) is an autologous chondrocyte implantation (ACI) product, consisting of spheroids of human autologous matrix-associated chondrocytes. The tendency of primary chondrocytes to dedifferentiate during cultivation and the high biologic variability caused by the autologous nature of the starting material makes it challenging to design a manufacturing process that performs consistently and delivers products that meet their intended function and the high quality criteria for cell-based ATMPs. The current study was submitted during the European authorization procedure, and addresses the requirement to justify the operational ranges of the manufacturing process using clinical data. Methods: In order to define the operational ranges, statistical correlation analyses were conducted between process parameters and clinical improvement data of 120 patients from Phase II and III treated with ACI (KOOS score, 1 year follow-up). Results: This approach identified cell culture time as a critical process parameter that negatively correlates with the product's efficacy. Subsequent analyses of the Phase III patients that were treated with chondrocyte spheroids that have been manufactured with shorter monolayer and spheroid cultivation times showed a higher average clinical improvement as well as a higher responder rate compared to the total group. In addition, retrospective analyses demonstrated superiority for the treatment with short-cultivated chondrocyte spheroids over micro-fracture treatment. Conclusion: These findings underscore the need to use clinical data to optimize the manufacturing process for autologous cell-based therapies. We expect that restricting the cultivation times during manufacturing minimizes the production of suboptimal batches, thus ensuring an efficacious product.

Findings and Management of the Rare Caput Flexum Deformity of the Hip: A Case Report.

CASE: A 10-year-old girl presented after possible occult hip trauma, with shortening of the leg being the initial clinical symptom, followed by motion-dependent pain. She had limited external rotation in extension with anterior apprehension. Radiographically, the deformity was an anterior tilt of the epiphysis with coxa vara. Surgery included surgical dislocation using a retinacular flap for the anterior open wedge femoral neck osteotomy for extension and posterior translation, with an excellent 4.5-year clinical outcome. CONCLUSIONS: Caput flexum is a rare deformity with localized premature closure of the anterior growth plate of the hip. To avoid secondary impingement, an osteotomy was successfully placed close to the deformity.

[Treatment of Osteochondral Lesions in the Ankle: A Guideline from the Group "Clinical Tissue Regeneration" of the German Society of Orthopaedics and Traumatology (DGOU)]. / Behandlung osteochondraler Läsionen des Sprunggelenks: Empfehlungen der Arbeitsgemeinschaft Klinische Geweberegeneration der DGOU.

Background: Osteochondral lesions (OCL) of the ankle are a common cause of ankle pain. Although the precise pathophysiology has not been fully elucidated, it can be assumed that a variety of factors are responsible, mainly including traumatic events such as ankle sprains. Advances in arthroscopy and imaging techniques, in particular magnetic resonance imaging (MRI), have improved the possibilities for the diagnosis of OCLs of the ankle. Moreover, these technologies aim at developing new classification systems and modern treatment strategies. Material and Methods: This article is a review of the literature. Recommendations of the group "Clinical Tissue Regeneration" of the German Society of Orthopaedics and Traumatology (DGOU) for the treatment of OCLs of the ankle are presented. The review gives a concise overview on the results of clinical studies and discusses advantages and disadvantages of different treatment strategies. Results: Non-operative treatment shows good results for selected indications in children and adolescents, especially in early stages of osteochondritis dissecans (OCD). However, surgical treatment is usually indicated in OCLs in adolescents and adults, depending on the size and location of the lesion. Various arthroscopic and open procedures are frequently employed, including reattachment of the fragment, local debridement of the lesion with fragment removal and curettage of the lesion, bone marrow-stimulation by microfracture or microdrilling (antegrade or retrograde), and autologous matrix-induced chondrogenesis (AMIC®) - with or without reconstruction of a subchondral bone defect or cyst by autologous cancellous bone grafting. Isolated subchondral cysts with an intact cartilage surface can be treated by retrograde drilling and possibly additional retrograde bone grafting. For larger defects or as salvage procedure, osteochondral cylinder transplantation (OATS® or Mosaicplasty®) or matrix-induced autologous chondrocyte transplantation (MACT) are recommended. Transplantation of so-called (osteochondral) mega grafts, such as autologous bone grafts or allografts, are used for very large osteochondral defects that cannot be reconstructed otherwise. Implantation of the so-called "small metal implants" - such as HemiCAP Talus® - is reserved for selected cases after failed primary reconstruction. Corrective osteotomies are indicated in accompanying axial malalignments. Conclusions: There are several different treatment strategies for OCLs, but clinical studies are rare and evidence is limited. Therefore, interventional studies, e.g. randomised controlled trials (RCTs), but also observational studies, e.g. based on data of the Cartilage Registry of the German Society of Orthopaedics and Traumatology (www.knorpelregister-dgou.de), are needed and are recommended by the authors.

Autologous chondrocyte implantation (ACI) for cartilage defects of the knee: A guideline by the working group "Clinical Tissue Regeneration" of the German Society of Orthopaedics and Trauma (DGOU).

BACKGROUND: Autologous chondrocyte implantation (ACI) is an established and well-accepted procedure for the treatment of localised full-thickness cartilage defects of the knee. METHODS: The present review of the working group "Clinical Tissue Regeneration" of the German Society of Orthopaedics and Trauma (DGOU) describes the biology and function of healthy articular cartilage, the present state of knowledge concerning therapeutic consequences of primary cartilage lesions and the suitable indication for ACI. RESULTS: Based on best available scientific evidence, an indication for ACI is given for symptomatic cartilage defects starting from defect sizes of more than three to four square centimetres; in the case of young and active sports patients at 2.5cm(2), while advanced degenerative joint disease needs to be considered as the most important contraindication. CONCLUSION: The present review gives a concise overview on important scientific background and the results of clinical studies and discusses the advantages and disadvantages of ACI. LEVEL OF EVIDENCE: Non-systematic Review.

[The German Cartilage Registry (KnorpelRegister DGOU) for evaluation of surgical treatment for cartilage defects: experience after six months including first demographic data]. / Das KnorpelRegister DGOU zur Erfassung von Behandlungsergebnissen nach Knorpeloperationen: Erfahrungen nach 6 Monaten und erste epidemiologische Daten.

The German Cartilage Registry (KnorpelRegister DGOU) has been introduced in October 2013 and aims on the evaluation of patients who underwent cartilage repair for symptomatic cartilage defects. It represents a nation-wide cohort study which has been introduced by the working group "Tissue Regeneration" of the Germany Society of Orthopaedic Surgery and Traumatology and is technically based upon a web-based remote data entry (RDE) system. The present article describes first experiences with the registry including patient and treatment characteristics. Between October 2013 and April 2014, a total of 230 patients who had undergone surgical cartilage repair for symptomatic full-thickness cartilage defects of the knee has been included in the German Cartilage Registry from 23 cartilage repair centres. Mean age was 37.11 years (SD 13.61) and mean defect size was 3.68 cm(2) (SD 0.23). Since the introduction of the KnorpelRegister DGOU the total number of registered patients has increased steadily up to the most recent figure of 72 patients within one month. Patients were treated mainly according to the recommended therapies. The highest percentage in therapy is represented by the bone marrow stimulation techniques (55.02 %) as well as by the autologous chondrocyte transplantation (34.92 %). Unlike the patient collective in the majority of prospective randomised controlled trials, the patient population within the registry shows a high proportion of patients with accompanying pathologies, with an age of more than 50 years at the time of treatment and with unfavourably assessed accompanying pathologies such as an affection of the opposite cartilage surface or a previously resected meniscus. In summary, the technical platform and forms of documentation of the KnorpelRegister DGOU have proved to be very promising within the first six months. Unlike data from other clinical trials, the previous analysis of the patients' data and therapies reflects successfully the actual medical care situation of patients with cartilage defects of the knee joint. This analysis also provides new information on subgroups of patients that have not yet been recorded in the scientific literature. This will be part of the first analysis of clinical treatment data. An expansion of the KnorpelRegister DGOU to patients with cartilage defects of the ankle and hip joints is already decided upon and initialised.

Feasibility of arthroscopic 3-dimensional, purely autologous chondrocyte transplantation for chondral defects of the hip: a case series.

INTRODUCTION: The purpose of this retrospective study was to describe technical aspects of arthroscopic, purely autologous chondrocyte transplantation of the hip and to report short-term data of the postoperative outcome in a consecutive series of patients. MATERIALS AND METHODS: We retrospectively analyzed six patients with a full-thickness chondral defect of the hip joint. The defect was treated with an arthroscopically applicable 3-dimensional purely autologous chondrocyte transplant product (chondrosphere(®); co.don(®) AG, Berlin, Germany) in a two-step surgical procedure. Patient-administered scores were assessed at baseline (day before transplantation) and at 6 weeks, 3, 6 and 12 months. RESULTS: Six out of six initially included patients (five males, one female) with a median age of 32.5 years and an average defect size of 3.5 cm(2) were available for follow-up after a mean of 11.2 months. Five acetabular and one femoral defect were treated. An overall statistically significant improvement was observed for all assessment scores (NHS, mHHS and SF 36). CONCLUSION: In this study, we displayed the feasibility and technical aspects of arthroscopic matrix-associated, purely autologous chondrocyte transplantation as a treatment option for full-thickness cartilage defects of the hip. The patient-administered assessment scores demonstrated an increase in activity level and quality of life after a 1-year follow-up. LEVEL OF EVIDENCE: Level IV, retrospective study.

[Autologous chondrocyte implantation (ACI) for cartilage defects of the knee: a guideline by the working group "Tissue Regeneration" of the German Society of Orthopaedic Surgery and Traumatology (DGOU)]. / Stellenwert der autologen Chondrozytentransplantation (ACT) in der Behandlung von Knorpelschäden des Kniegelenks - Empfehlungen der AG Klinische Geweberegeneration der DGOU.

Autologous chondrocyte transplantation/implantation (ACT/ACI) is an established and recognised procedure for the treatment of localised full-thickness cartilage defects of the knee. The present review of the working group "Clinical Tissue Regeneration" of the German Society of Orthopaedics and Traumatology (DGOU) describes the biology and function of healthy articular cartilage, the present state of knowledge concerning potential consequences of primary cartilage lesions and the suitable indication for ACI. Based on current evidence, an indication for ACI is given for symptomatic cartilage defects starting from defect sizes of more than 3-4 cm2; in the case of young and active sports patients at 2.5 cm2. Advanced degenerative joint disease is the single most important contraindication. The review gives a concise overview on important scientific background, the results of clinical studies and discusses advantages and disadvantages of ACI.

Assessment of the diagnostic value of dual-energy CT and MRI in the detection of iatrogenically induced injuries of anterior cruciate ligament in a porcine model.

INTRODUCTION: Magnetic resonance imaging (MRI) is the standard of reference for the non-invasive evaluation of ligament injuries of the knee. The development of dual-energy CT (DE-CT) made it possible to differentiate between tissues of different density by two simultaneous CT measurements with different tube voltages. This approach enables DE-CT to discriminate ligament structures without intra-articular contrast media injection. The aims of this study were on the one hand to determine the delineation of the anterior cruciate ligament (ACL) and on the other hand to assess the diagnostic value of DE-CT and MRI in the detection of iatrogenically induced injury of the ACL in a porcine knee joint model. MATERIALS AND METHODS: Twenty porcine hind legs, which were placed in a preformed cast in order to achieve a standardized position, were scanned using DE-CT. Thereafter, a 1.5-T MRI using a standard protocol was performed. The imaging procedures were repeated with the same parameters after inducing defined lesions (total or partial incision) on the ACL arthroscopically. After post-processing, two radiologists and two orthopedic surgeons first analyzed the delineation of the ACL and then, using a consensus approach, the iatrogenically induced lesions. The result of the arthrotomy was defined as the standard of reference. RESULTS: The ACL could be visualized both on DE-CT and MRI in 100% of the cases. As for the MRI, the sensitivity and specificity of detecting the cruciate ligament lesion respectively compared with the defined arthrotomy was 66.7% and 78.6% for intact cruciate ligaments, 100% and 75% in the case of a complete lesion, 33.3% and 78.6% for lesions of the anteromedial bundle, and 0% and 100% for lesions of the posterolateral bundle. In comparison, DE-CT demonstrated a sensitivity and specificity of 66.7% and 71.4% in the case of intact cruciate ligaments, 75% and 68.8% in the case of completely discontinued ACLs, 0% and 92.9% in the case of lesions of the anteromedial bundle, and 25% and 87.5% in the case of lesions of the posterolateral bundle. CONCLUSIONS: The present ex vivo experiment shows that both study modalities (DE-CT and MRI) are equal with regard to the delineation of the ACL, while MRI achieved higher sensitivity and specificity regarding iatrogenically induced complete ACL lesions. DE-CT could be a possible alternative to MRI for certain indications in the diagnosis of a knee ligament injury.

Precision of Ci-navigated extension and flexion gap balancing in total knee arthroplasty and analysis of potential predictive variables.

INTRODUCTION: The aim of this study was to evaluate the accuracy of final limb alignment and flexion-extension and medial-lateral gap balancing in computer navigated total knee arthroplasty and to analyze various possible predictive variables that may affect the gaps in computer navigated knee arthroplasty. MATERIALS AND METHODS: The DePuy Ci system, a nonimage-based passive optical computer navigation system, was used in 225 patients with knee osteoarthritis to assist for the total knee arthroplasty. From the raw data the Ci-verified pre- and postoperative leg axis in extension, angle of tibia and femur resection, the flexion and extension angle, the medial and lateral extension and flexion gaps were extracted; and differences in gaps were calculated and subjected to statistical analysis. Leg alignment and implant position were determined only by the navigation system. Preoperative variables were evaluated for their impact on the final flexion/extension and medial/lateral gaps achieved. RESULTS: Though the preoperative femoro-tibial coronal alignment had a large variance, postoperatively 98.22% of the knee was found to be between -3° and +3° in the coronal limb alignment axis. The Ci-verified femoral and tibial cuts in the coronal plane showed a good accuracy. The sagittal alignment of the femoral cut ranged from 8.20° flexion to 3.20° of extension. Rectangular extension and flexion gaps were achieved with ≤3 mm of difference in gaps on medial and lateral sides in 98 and 93% of knees, respectively. Difference between extension and flexion gaps on the medial side was ≤3 mm in 83% and on the lateral side in 84% of the knees. Of all the possible predictive variables analyzed, Pearson correlation and multiple regression analysis showed significant correlation only between the medial-lateral gap difference in extension and the Ci-verified femoral cut, tibial cut and limb axis, all in the coronal plane. CONCLUSION: Computer-assisted navigated total knee replacement allows for accurate gap balancing that is not dependent on the various pre- and intraoperative factors mentioned, including age, sex, Range of motion preoperative deformity and grade of osteoarthritis. The Ci-calculated and verified tibial, and femoral cuts are the only possible factors affecting the extension gap.

[Acetabular revision surgery with the oblong revision cup : clinical and radiological results of 217 cases]. / Azetabuläre Revisionsoperationen mit der längsovalen Revisionspfanne : Klinische und radiologische Ergebnisse von 217 Fällen.

BACKGROUND: Deficiencies of the acetabular bone stock are an increasing and challenging problem in revision hip surgery. The LOR oblong revision cup is a valuable option in revision hip surgery. The purpose of this study was to assess outcomes with the LOR revision cup in hips with acetabular bone deficiency, analyze the complications, and identify predictors of survival rate. PATIENTS AND METHODS: From 1996 to 2002, 217 revision surgeries were performed with LOR cups. The mean patient age at operation was 67.5 years (range 29-87 years). The mean postoperative follow-up was 4 years (range 4-100 months). The patients were evaluated clinically and with the Harris hip score (HHS), UCLA score, and WOMAC index. A continuous radiographic assessment was done to detect heterotopic ossifications and radiolucencies or loosening on the basis of the Mayo hip score. Predictors of survival rate were estimated using Kaplan-Meier survivorship analysis. RESULTS: Twenty-four patients (7.4%) died during the study period. Seven patients (3.1%) had revisions because of aseptic loosening and two patients (0.9%) because of infection. Clinical assessment at follow-up showed a significantly improved mean HHS from 45 points preoperatively to 78 points postoperatively. At the most recent follow-up, patients with a body mass index below 30 or those classified as Charnley A had a significantly better HHS. Because of migration on the latest radiographs, revision was indicated in 4.8% of the cases. The survival rate of all LOR implants based on implant removal was 96% after 40 months and 87% after 80 months. Based on radiographic evidence of loosened implants, the survival rate was 94% after 40 months and 79% after 80 months. Patients with more than two revisions had reduced implant survivorship compared with those having one or two revisions. The factors "age at operation", "gender", "obesity", "ASA score", "Charnley score", and "activity according to the UCLA score" did not influence the survival rate. CONCLUSION: We recommend this component in revision surgery on the basis of satisfactory clinical and radiological results at a mean of 48 months of follow-up. We identified the number of revisions as a predictor of survival rate.

Artificial organs: a new option for treating osteoarthritis.

Osteoarthritis is usually regarded as a localized disease whose optimal treatment is a therapy applied directly to the affected joint. Unfortunately, current local therapies such as repeated intraarticular injections or constant infusions are associated with a higher risk of infection. One way to overcome this would be to transfer substances made locally by cells within the joint. However, attempts using direct vector transfers or intraarticular injections of ex vivo modified cells could not achieve a sustained protein secretion over several months. Another method of delivering biological factors (i.e.growth hormones) intraarticularly is to transplant an artificial organ, capable of supporting the regeneration of natural cartilage, directly into the affected joint The main difficulty of having to produce bioactive factors over a long period of time is overcome by implanting a chamber-like system filled with either genetically modified cells or a drug-releasing matrix. This drug delivery system would be located at a peripheral site of the joint and could release substances directly into the joint cavity which would be transported via the synovial fluid and/or diffused to the chondrocytes or synoviocytes.

[Revision of unicompartmental knee arthroplasty]. / Revision unikondylärer Knieprothesen.

Despite the good midterm survivorship reported for unicondylar knee arthroplasty, an increase in revision surgery has to be expected due to increased replacement rates. The reasons for failure as well as distribution are different for unicondylar knee arthroplasty compared to total knee arthroplasty. The main reasons for revision are aseptic loosening and the progression of osteoarthritis. In most cases, unicondylar knee arthroplasty will be revised to total knee arthroplasty. To obtain good revision results, the cause of implant failure has to be analysed carefully. In the case of contained bone defects, the reconstruction can be supported with bone grafting. For those cases with uncontained defects, implants with augmentation and, in some cases, stem extensions are needed. The modularity of the revision implant should cover different intraoperative requirements.

[Predictors of tibial head transposition in the therapy of varus knee osteoarthritis]. / Prädiktoren der Tibiakopfumstellung in der Therapie der Varusgonarthrose.

PURPOSE: The aim of this study was to find predictors for the clinical outcome in patients who underwent a high tibial osteotomy (HTO). METHOD: Between 1984 and 1996 a high tibial valgus osteotomy was performed in 155 patients with genu varum. 133 HTO patients were available for follow-up at an average postoperative time of 9.3 +/- 3.0 years. The degree of osteoarthritis was evaluated by radiological (Kellgren) and arthroscopic scoring systems (Outerbridge). Survival time of HTO was estimated using Kaplan-Meier survivorship analysis. RESULTS: The survival rate of HTO was 95 % after 5 years and 77 % after 10 years. In the medial compartment of knee joints with a preoperative Outerbridge stage III/IV or Kellgren stage III/IV the survival rate of HTO was significantly lower when compared to stages 0/I/II (p < 0.05). Age, sex, tibial malalignment and severity of osteoarthritis in the lateral compartment had no influence on survival rates. The pre-postoperative comparison of radiologically visible signs of osteoarthritis showed mainly either no (46.5 %) or only small (50.5 %) progression. We found that patients who underwent a HTO had good and very good clinical outcomes. CONCLUSION: We identified severity of preoperative radiological osteoarthritis and intraoperative chondromalacia as predictors of survival rate.

[Obesity and arthritis]. / Ubergewicht und Arthrose.

An increasing prevalence and incidence of osteoarthritis especially in aging populations results in different socioeconomic problems. Recent studies have shown an association between osteoarthritis and overweight especially for knee and hip joints. The mechanisms responsible for the destruction of joints are still unknown, however. Obesity and overweight can lead to higher force transmission on joints at least in lower extremities, but mechanical factors hardly explain the association between overweight and hand osteoarthritis shown in different studies. There may be additional metabolic effects responsible for cartilage destruction, but distinct mechanisms have not been demonstrated up to now. They would, however, support preventive measures as well as therapeutic approaches.

Identification, quantification and isolation of mesenchymal progenitor cells from osteoarthritic synovium by fluorescence automated cell sorting.

OBJECTIVE: Identification, quantification and isolation of subpopulations with characteristics of mesenchymal progenitor cells (MPC) from the synovial membrane (SM) from patients with osteoarthritis (OA). METHOD: Cells from the SM of patients with end stage OA who underwent total knee joint replacement were enzymatically isolated. One aliquot was directly analyzed by fluorescence automated cell sorting (FACS) using various combinations of surface markers of bone marrow MPC (CD9, CD44, CD54, CD90, and CD166). Remaining cells were cultivated on plastic, expanded over several passages, analyzed by FACS again and tested for their osteo- and chondrogenic potential. The differentiation was analyzed by immuno-/histochemistry and by RT-PCR for the expression of lineage related marker genes. RESULTS: Using FACS analysis we could show that the relative proportion of subpopulations expressing triplicate combinations of CD9, CD44, CD54, CD90 and CD166 in the SM from OA patients varies between 3 and 10%. Upon cultivation their relative amount markedly increased to values between 24 and 48%. Within the heterogeneous cell populations it was possible to induce osteogenic and chondrogenic differentiation. Initial sorting for CD9/CD90/CD166 triplicate positive cells proved that this subpopulation contains cells with multipotency for mesenchymal differentiation and thus characteristics of MPC. CONCLUSION: Our results show that SM from OA patients contains cells that express typical combinations of MPC surface markers and have the potency of osteogenic and chondrogenic differentiation. Their relative enrichment during in vitro cultivation and the possibility of cell sorting to get more homogenous populations offer interesting perspectives for possible future therapeutic applications.

Total condylar knee arthroplasty: a long-term followup.

Between July 1977 and December 1983, 80 patients underwent 120 arthroplasties using a total condylar knee prostheses. Forty-one patients (68 knees) died and 13 patients were lost to followup. Twenty-six patients with 34 total condylar replacements were available for clinical followup. During the followup, 10 knees in nine patients (8.3%) from the overall 80 patients (120 knees) underwent revision; three (four knees) for aseptic loosening, one for periprosthetic fracture, three for infection, and two patients underwent revision for pain. Three revisions (three patients) occurred in the group of 26 patients available for followup. The average age of this group of patients at followup was 78 years (range, 53-94 years). There were 10 men and 16 women. Considering the high mean age of the patients in the series and patients' overall health status, the clinical results were extremely good. Kaplan-Meier analysis showed a survivorship of 91% at 23 years followup, considering revision as an end point. Although there have been several changes in total knee replacement designs, materials, and implantation techniques, the long-term outcome of the original total condylar knee prosthesis is excellent.

Immunohistological analysis of cytokine expression in human osteoarthritic and healthy cartilage.

OBJECTIVE: To investigate osteoarthritic cartilage in comparison to normal cartilage in humans for the presence of the most relevant cytokines/growth factors known to be important for degradation and formation of new cartilage. METHODS: Cartilage from knee or hip joints was obtained from 10 patients with osteoarthritis (OA) and from 7 age matched control patients with intact cartilage. Additionally, normal cartilage from 2 young patients (12 and 17 years old) was obtained after knee traumas. Immunohistological staining of cartilage sections was performed using antibodies for the following cytokines/growth factors: tumor necrosis factor alpha (TNF-alpha), interleukin 1alpha (IL-1alpha), IL-1beta, interferon-gamma, IL-6, IL-4, IL-10, transforming growth factor beta1 (TGF-beta1), insulin-like growth factor I (IGF-I), IGF-II, platelet derived growth factor AA (PDGF-AA), and PDGF-BB. RESULTS: Immunohistochemical stainings were positive for all cytokines in OA cartilage, while only a faint or no staining was found in healthy cartilage. Activated chondrocytes expressing most of the cytokines were located in the middle and partly in the lower layer of cartilage, with the exception of IGF-I, which was expressed exclusively in the upper cartilage layer close to the surface. More chondrocytes stained positive for TNF-alpha than for IL-1, and expression of the degrading cytokine TNF-alpha was inversely correlated to the expression of the regulatory cytokines IL-4, IL-10, and TGF-beta. CONCLUSION: The most relevant cytokines known to be involved in cartilage metabolism are produced by chondrocytes themselves. They are upregulated in OA cartilage, suggesting that they serve some regulatory function and could be a target for future treatment.