Individual and overlapping roles of BH3-only proteins Bim and Bad in apoptosis of lymphocytes and platelets and in suppression of thymic lymphoma development.

BH3-only proteins, such as Bim and Bad, contribute to tissue homeostasis by initiating apoptosis in a cell type- and stimulus-specific manner. Loss of Bim provokes lymphocyte accumulation in vivo and renders lymphocytes more resistant to diverse apoptotic stimuli and Bad has been implicated in the apoptosis of haematopoietic cells upon cytokine deprivation. To investigate whether their biological roles in apoptosis overlap, we generated mice lacking both Bim and Bad and compared their haematopoietic phenotype with that of the single-knockout and wild-type (wt) animals. Unexpectedly, bad(-/-) mice had excess platelets due to prolonged platelet life-span. The bim(-/-)bad(-/-) mice were anatomically normal and fertile. Their haematopoietic phenotype resembled that of bim(-/-) mice but lymphocytes were slightly more elevated in their lymph nodes. Although resting B and T lymphocytes from bim(-/-)bad(-/-) and bim(-/-) animals displayed similar resistance to diverse apoptotic stimuli, mitogen activated bim(-/-)bad(-/-) B cells were more refractory to cytokine deprivation. Moreover, combined loss of Bim and Bad-enhanced survival of thymocytes after DNA damage and accelerated development of γ-irradiation-induced thymic lymphoma. Unexpectedly, their cooperation in the thymus depended upon thymocyte-stromal interaction. Collectively, these results show that Bim and Bad can cooperate in the apoptosis of thymocytes and activated B lymphocytes and in the suppression of thymic lymphoma development.

Medium to long-term results after reconstruction of bone defects at the knee with tumor endoprostheses.

BACKGROUND AND OBJECTIVES: Limb salvage and reconstruction with tumor endoprostheses is considered as therapeutic standard in the treatment of bone defects at the knee. Few studies report long-term results so far. METHODS: Seventy-seven patients who had a cementless or cemented MUTARS endoprosthesis implanted were followed-up for a mean period of 46 months (3-128 months). The defects were due to primary tumor lesions in 69 cases or metastases in 8 cases. The distal femur (n = 49) or the proximal tibia (n = 28) was reconstructed predominantly with cementless implants (femur: 69%, tibia: 92%). The resection of the tumor was intraarticular in 46 and extraarticular in 31 patients. RESULTS: After 10 years probability of limb salvage was 92% with a recurrence rate of 3%. Complications were frequent with a revision rate of 58% and lead to a cumulative probability of survival of the initially implanted prosthesis of 57% after 5 years. Locking mechanism failure (n = 15) and aseptic loosening (n = 13) were the most frequent failure modes. CONCLUSIONS: Regardless of achieving a low recurrence rate and satisfactory functional results, we found a high complication rate after implantation of a megaprosthesis. This was particularly evident for extraarticular resections and cemented fixation, which should be avoided when possible.

Replacement of the proximal humerus with MUTARS tumor endoprostheses.

BACKGROUND AND OBJECTIVES: The aim of this study was to analyze our results using a modular endoprosthetic replacement system (MUTARS) for bone tumors of the proximal humerus. METHODS: Thirty-nine patients were treated with a MUTARS endoprosthesis of the proximal humerus. Mean follow-up duration was 38 months (3-138 months). Most operations were necessitated by metastasis (n=30); surgery for a primary tumor (n=9) was less frequent. The Enneking score was recorded and the active ranges of motion for shoulder flexion, abduction, and external rotation. Complete refixation of the rotator cuff was possible in 23 cases. Radiographs of the affected shoulders were obtained in two planes. RESULTS: Patient survival was 77% at 2 years and 45% at 11.5 years after surgery. The survival rate of the limb was 90% at 11.5 years. The mean Enneking score was 19 points (range 7-27 points). The mean shoulder flexion was 34 degrees (range 0-90 degrees ), abduction 33 degrees (range 0-90 degrees ), and external rotation 12 degrees (range 10-50 degrees ). Patients with a complete rotator cuff repair showed a significant better range of motion compared to patients with a partial or no repair (p<0.015). No signs of implant loosening were observed on postoperative radiographs. Seven complications occurred, five of them leading to implant revision. At 11.5 years after surgery, the survival rate for the whole cohort without complications was 72%, without revision of the implant 70%. CONCLUSIONS: Replacement of the proximal humerus with MUTARS endoprosthesis is a viable treatment option for bone tumors with satisfying results.

Expression of autoimmune regulator gene (AIRE) and T regulatory cells in human thymomas.

Expression of the autoimmune regulator gene (AIRE) and the presence of CD25(+)/forkhead box p3 (FoxP3)(+) T regulatory (T(reg)) cells were investigated in histologically normal adult thymi and in thymomas using immunohistochemistry and quantitative real-time polymerase chain reaction (PCR). In the normal thymus staining for AIRE was detected in the nucleus of some epithelial-like cells located in the medulla; in thymomas AIRE-positive cells were extremely rare and could be detected only in the areas of medullary differentiation of two B1 type, organoid thymomas. RNA was extracted from 36 cases of thymoma and 21 non-neoplastic thymi obtained from 11 myasthenic (MG(+)) and 10 non-myasthenic (MG(-)) patients. It was found that AIRE is 8.5-fold more expressed in non-neoplastic thymi than in thymomas (P = 0.01), and that the amount of AIRE transcripts present in the thymoma tissue are not influenced by the association with MG, nor by the histological type. A possible involvement of AIRE in the development of MG was suggested by the observation that medullary thymic epithelial cells isolated from AIRE-deficient mice contain low levels of RNA transcripts for CHRNA 1, a gene coding for acetylcholine receptor. Expression of human CHRNA 1 RNA was investigated in 34 human thymomas obtained from 20 MG(-) patients and 14 MG(+) patients. No significant difference was found in the two groups (thymoma MG(+), CHRNA1 = 0.013 +/- 0.03; thymoma MG-, CHRNA1 = 0.01 +/- 0.03). In normal and hyperplastic thymi CD25(+)/Foxp3(+) cells were located mainly in the medulla, and their number was not influenced by the presence of MG. Foxp3(+) and CD25(+) cells were significantly less numerous in thymomas. A quantitative estimate of T(reg) cells revealed that the levels of Foxp3 RNA detected in non-neoplastic thymi were significantly higher (P = 0.02) than those observed in 31 cases of thymomas. Our findings indicate that the tissue microenvironment of thymomas is defective in the expression of relevant functions that exert a crucial role in the negative selection of autoreactive lymphocytes.

[Predictive factors of perioperative morbidity in revision total hip arthroplasty]. / Prädiktoren der perioperativen Morbidität in der Revisionshüftendoprothetik.

AIM: The awareness and prevention of perioperative morbidity are essential in revision total hip arthroplasty [THA]. Therefore, it was the purpose of this study to assess the rate of perioperative complications following revision THA in order to evaluate the impact of patient- and procedure-related variables. METHODS: 169 consecutive patients with a mean age of 71.7 years suffering from aseptic loosening of their THA were included in this retrospective study. Multivariate logistic regression models with estimation of the odds ratio [OR] and 95% confidence interval [CI] served to analyze the influence of operation duration, gender, revision status, ASA classification, and type of fixation of the primary implant on the perioperative morbidity. RESULTS: 68.6% of the cases were primary revisions, and 31.4% secondary or multiple revisions. 49.7% of the operations involved exchange of the complete implant whereas 39.1% comprised exchange of the cup and 11.2% exchange of the stem only. Mean operation duration was 130 minutes [min] (range: 40-260 min), and mean intraoperative blood loss was 2.6 L (0.5 to 12 L). The rate of intraoperative complications was 10.1 % with a 6.5 % fracture rate. Postoperatively the complication rate was 25.4% with an 8.3% rate of luxations. 11.8% of the patients had revision within the first three weeks after surgery. Regression models showed the significant impact of revision status (primary vs. secondary or multiple: OR 2.90, 95% CI 1.42-5.92) and operation duration (per min starting from the mean operation time: OR 1.01, 95% CI 1.00-1.02) on the resulting complication rate. Analysis of the perioperative complication rate following primary revisions revealed a significant difference (p = 0.03) between patients with cemented (15/36, 41.7%) and non-cemented (8/45, 17.8%) implants. CONCLUSIONS: Revision status with a three-fold increase in patients with multiple revisions as well as operation duration with a 1 % increase per min starting from the mean operation time significantly influence the perioperative morbidity. Patients with a first revision, furthermore, seem to be at greater risk for an adverse event perioperatively if their implant is fully cemented. These findings should be taken into account prior to initiating surgery.

[Outcome assessment in total knee arthroplasty: is the clinical measurement of range of motion a reliable measurable outcome variable?]. / Outcome-Messung in der Knieendoprothetik: Ist die klinische Bestimmung der Gelenkbeweglichkeit eine zuverlässig messbare Ergebnisgrösse?

AIM: The aim of this clinical study was to investigate the reliability of the clinical assessment (visual and goniometric) of the range of motion of the knee joint. METHOD: 30 patients were assessed concerning the range of motion of their knee joints by visual and goniometric measurements. Assessment was performed by three investigators. The obtained data were used to analyse the intra- and interobserver reliability. Statistical analysis was performed using the Spearman coefficient of correlation [r (s)]. RESULTS: Intraobserver agreement was consistent across observers regarding the visual and goniometric assessment of flexion (r (s) > 0.6), whereas reliability was uniformly low for both measurements regarding the assessment of extension (r (s) < 0.6). Interobserver agreement was consistent across all three goniometric and two out of three visual assessments regarding the measurement of flexion (r (s) > 0.6); the interobserver reproducibility of extension, however, was uniformly low both for the visual and goniometric measurements (r (s) < 0.6). CONCLUSION: Reliability of clinical assessment of range of motion should be taken critically into consideration whilst performing classical function-related scoring systems when measuring outcome after total joint arthroplasty, since these scoring systems are strongly based on a valid and reliable assessment of range of motion.

[Reliability of transcutaneous measurement of oxygen tension on the lower leg]. / Reliabilität der transkutanen Sauerstoffpartialdruckmessung an der unteren Extremität.

AIM: Measurement of transcutaneous oxygen tension is increasingly used to determine the appropriate level of amputation in patients with vascular disease. The purpose of the present study was to analyze the intra- and interrater reliability of transcutaneous oxygen [tcpO (2)] measurements in a homogeneous study group. METHOD: Five investigators assessed the transcutaneous oxygen tension of both lower legs of seven persons in a fixed setting. Assessment was repeated with the same examiners and the same examinees after 24 hours. TcpO (2) was measured at the posterior aspect of the lower leg twenty centimeters below the knee joint line. The TCM 400 Monitoring System (Radiometer Medical AIS, Bronshoj, Denmark) was used. Statistical analysis of the intra- and interrater reliability was performed with the Spearman coefficient of correlation. RESULTS: An overall mean of 56.2 +/- 10.6 mmHg was found. For the first examination, a mean of 55.3 +/- 10.6 mmHg was observed, whereas for the second examination it was 57.0 +/- 10.5 mmHg. Analysis of intrarater reliability showed a coefficient of correlation of r (s) = 0.56 (p < 0.0001). For interrater reliability, we found coefficients of correlation ranging from r (s) = 0.20 (p = 0.20) to r (s) = 0.69 (p = 0.0004). CONCLUSION: Analysis of transcutaneous oxygen tension measurements performed by different investigators in a fixed setting revealed a non- homogeneous intra- and interrater reliability, which should be taken into account prior to initiating therapy.

[Analysis of validity and reliability of three radiographic classification systems for preoperative assessment of bone stock loss in revision total hip arthroplasty]. / Gültigkeit und Reproduzierbarkeit radiologischer Klassifikationskriterien des knöchernen Substanzdefekts vor Revisionshüftendoprothetik.

AIM: It was the purpose of this prospective study to analyze validity and reliability of three different radiographic classification systems, which are used to assess bone stock loss prior to revision total hip arthroplasty. METHOD: Investigation was performed using the classification systems according to 1) Paprosky et al., 2) Hungerford et al., and 3) the German Society of Orthopaedics and Traumatology (DGOT). Twenty-eight consecutive patients with diagnosis of aseptic failure of total hip arthroplasty were enrolled in the study. Interrater agreement was analyzed by evaluating the classifications preoperatively by three investigators with different level of clinical experience using a blinded observer technique. Validity was analyzed by comparison of preoperative radiographic findings (n = 3) and an intraoperative control by visualization and palpation (n = 1). Spearman coefficient of correlation (r(s)) was used to establish levels of agreement among multiple ordinal variables. RESULTS: Interrater reliability testing using paired comparison between the three investigators revealed non-homogeneous coefficients of correlation (r(s): Paprosky femur: 0.45 - 0.67, acetabulum: 0.38 - 0.63; Hungerford: 0.46 - 0.66; DGOT femur: 0.38 - 0.59, acetabulum: 0.42 - 0.76). Paired analysis of correlation between preoperative and intraoperative findings again showed non-homogeneous coefficients of correlation (r(s): Paprosky femur: 0.59 - 0.68, acetabulum: 0.39 - 0.70; Hungerford: 0.39 - 0.74; DGOT femur: 0.44 - 0.60, acetabulum: 0.36 - 0.76). In general, defects were grossly underestimated preoperatively. The level of experience did not influence the validity of measurements. CONCLUSION: Our results indicate that these classifications do not provide valid and reliable assessment of femoral and acetabular bone stock loss prior to revision total hip arthroplasty.

Revision total hip arthroplasty: the influence of gender and age on the perioperative complication rate.

PURPOSE OF THE STUDY: Aim of this study was to report the incidence of complications in a consecutive series of revision total hip arthroplasties (THA). Gender and age as a risk factor for the occurrence of perioperative complications in patients undergoing revision THA were analyzed specifically. MATERIAL: All consecutive revision THA (n = 169) for aseptic loosening, which were performed between 1998 and 2002 were evaluated. Our study population had a mean age of 71.7 years and consisted of 65.7% women and 34.3% men. Complete exchange of the primary implant was performed in 49.7% (84/169). The cup was replaced in 66 cases (39.1%) the stem only in 11.2% of patients (19/169). METHODS: Retrospective analysis was performed assessing the influence of gender and age on the complication rate by multiple regression models, estimating odds ratios (OR) and their 95% confidence intervals (CI). RESULTS: Comparable complication rates to those reported in the literature were found. Overall incidence of complications was 29.6% with a fracture rate of 6.5%, dislocation rate of 8.3%, nerve palsy rate of 4.7% and occurrence of thromboembolism in 1.8% of the reported cases. Mortality rate during the observed period was low (0.6%). We were not able to provide statistical evidence for the impact of gender and age on the complication rate. DISCUSSION: A comparable complication rate following revision THA to those reported in the literature was found in our study sample. Corresponding to other authors a higher risk of nerve palsy and thromboembolism among women was assessed. The observed correlation of fracture rates and female gender might be attributable to osteoporotic bone in postmenopausal women. Dislocation seemed to be more frequent in older patients, which has been described previously as well. Our low mortality rate in revision THA comparable to previous reports might be due to our short observation period. CONCLUSIONS: Revision THA is associated with a higher risk of complications than primary THA. A predictive value of gender and age in regard to the overall complication rate could not be confirmed which should be considered while deciding about the therapeutic strategy confronted with an aseptically loosened THA. To provide statistical evidence of a correlation between gender, fracture and nerve palsy as well as age and dislocation rates greater study populations are required.

[Revision total hip arthroplasty: analysis of the predictive value of a radiographic classification system for assessment of bone stock loss]. / Revisionshüftendoprothetik: Untersuchung des prädiktiven Werts einer radiologischen Defektklassifikation.

AIM: The aim of this study was to evaluate the predictive value of a radiographic classification system concerning implant and bone graft in revision total hip arthroplasty. This classification is used to assess bone stock loss prior to surgery, thus hypothetically enabling an adequate choice of the implant and bone graft required. METHOD: 33 consecutive patients with the diagnosis of aseptic failure of total hip arthroplasty were included in the study. The investigation was performed using the classification system according to Saleh et al. The predictive value was analyzed by comparing the radiographically based recommendation concerning implant and bone graft and the intraoperative procedure according to a blinded observer technique. The Spearman coefficient of correlation (r (s)) was used to establish levels of agreement among multiple ordinal variables. RESULTS: Analysis of correlation between preoperative radiological estimations and intraoperative conclusions concerning implant and bone graft revealed coefficients of correlation (r (s)) of 0.53 (p < 0.01) for the acetabular and of 0.63 (p < 0.01) for the femoral classification. CONCLUSION: Our results indicate that the Saleh classification does not provide sufficient information for preoperative assessment of the revision implant and bone graft required concerning the acetabular side, whereas planning of the operative procedure regarding the femoral implant seems to be possible. These ambivalent findings should be taken into account prior to revision total hip arthroplasty.

[Revision total hip arthroplasty: how do metaphyseal onset, diaphyseal fill and a three-point-stem-fixation influence the postoperative subsidence of a revision straight-stem?]. / Revisionshüftendoprothetik: Wie beeinflussen der metaphysäre Prothesenaufsitz, der diaphysäre Formschluss und der 3-Punkte-Schaftkontakt das postoperative Sinterungsverhalten eines zementfreien Revisionsgeradschaftes?

AIM: It was the purpose of this study to determine the postoperative subsidence of a cementless hip revision stem in regard to the degree of metaphyseal onset, diaphyseal fit and a three-point contact of the stem in the femur. METHODS: Data of 50 revision total hip replacements using a cementless revision straight stem (PFM-R) could be investigated. The degree of subsidence was measured on pelvic X-rays 6 and 12 months postoperatively. The degree of metaphyseal onset, diaphyseal fit and a three-point contact of the stem in the femur was determined on the immediate postoperative X-rays. RESULTS: The amount of subsidence was strongly related to the degree of metaphyseal onset. With minor onset (up to 25 % of the possible) stems subsided 9.4 (6 months), respectively, 13.2 millimeters (12 months) in average within the investigation periods. If there was a large degree of metaphyseal onset (more than 75 % of the possible) the average subsidence was only 1.6 (6 months) or 0.9 millimeters, respectively (12 months). Neither the amount of diaphyseal fit nor the presence of three-point contact of the stem in the femur influenced the subsidence significantly. Conclusion The amount of the postoperative subsidence of stems in cementless revision total hip arthroplasty is predominantly influenced by the degree of the metaphyseal onset of the prosthesis.