Recovery of the medial gastrocnemius muscle after calcaneus fracture differs between contractile and elastic components.

BACKGROUND: Calcaneal fractures result in severe functional impairments and walking restrictions. Postoperative evaluation mainly focusses on the restoration of calcaneal anatomy while ankle plantar flexor insufficiency remains largely neglected. This study aims to investigate biomechanical and morphologic adaptions of elastic and contractile components of the gastrocnemius medialis after unilateral calcaneal fracture. METHODS: 20 Patients (BMI: 27.6 ± 3.1 kgm-2, Age: 50 ± 12 years) were measured using gait analysis and portable ultrasound over a follow-up of three, six and twelve months after surgery. Data comparison was performed using 20 matched healthy controls (BMI: 26.2 ± 2.9 kgm-2, Age: 48 ± 11 years). Static and dynamic behavior of the gastrocnemius muscle tendon unit, muscle fascicle and the serial-elastic element as well ankle joint kinematics and kinetics were analyzed. FINDINGS: Within patients, a significant (p < 0.05) increase in fascicle length (by 67%) during single support and a decrease of serial elastic element shortening (by 20%) during push off was found between three and twelve months follow-up comparisons. Patients showed differences for fascicle lengthening and pennation angle increase during single support after three and six months compared to healthy controls. A smaller shortening of the serial-elastic element (by 29%) and muscle-tendon unit (by 16%) persisted even for the twelve month comparisons. INTERPRETATION: Patients with calcaneal fracture showed an incomplete restoration of the medial gastrocnemius dynamic morphological behavior. While muscle fascicle contraction almost recovered, the serial elastic component still showed restrictions regarding its shortening behavior. Limited foot mobility and plantarflexor strength as well as lowered responsiveness of elastic tissues to mechanical loading are regarded as key mechanisms.

Gait characteristics and functional outcomes during early follow-up are comparable in patients with calcaneal fractures treated by either the sinus tarsi or the extended lateral approach.

BACKGROUND: To overcome the substantial functional loss after calcaneal fractures (CF), surgical treatment currently consists of two strategies, namely the commonly used extended lateral approach (ELA) and the less invasive sinus tarsi approach (STA). Despite the comparable anatomical restoration, the biomechanical and functional outcome of these strategies during early rehabilitation has not yet been investigated. RESEARCH QUESTION: To evaluate changes in gait characteristics and functional development in patients with CF treated by either STA or ELA. METHODS: A total of 56 patients with unilateral CF were included in this retrospective study. 26 patients were treated by ELA while 30 patients underwent surgery through the STA. Functional and biomechanical measurements were performed at follow-up periods of three and six months. Foot and ankle kinetics and kinematics were extracted using instrumented gait analysis with a multi segment foot model. Physical and mental components of the Short Form 36 (SF-36) and total scoring of the AOFAS hindfoot scale were used for functional evaluation. Statistical analysis was performed using Mann Whitney and Student's t-test. Effect sizes of group differences were calculated using Cohen's d. RESULTS: Comparisons between ELA and STA showed no significant difference regarding the biomechanical and functional outcome. Within-group comparisons showed significant (p < 0.05) improvements from three to six month follow-up. Ankle joint and hindfoot kinematics showed increased mobility during walking of up to 34% and 26%, respectively. Maximum ankle joint moment also improved by up to 34% while vertical ground reaction force increased by 8%. Functional outcome only revealed significant changes in the physical component of SF-36. SIGNIFICANCE: ELA and STA treatments revealed comparable functional improvements in patients with unilateral intraarticular calcaneal fractures during early rehabilitation. The less invasive STA provides adequate restoration of dynamic foot function and could serve as a viable alternative to the commonly used ELA.

Inhibition of lymphocyte function associated antigen 1 by LFA878 induces apoptosis in multiple myeloma cells and is associated with downregulation of the focal adhesion kinase/phosphatidylinositol 3 kinase/Akt pathway.

Multiple myeloma (MM) is still an incurable disease and adhesion of MM cells to bone marrow stromal cells is one of the hallmarks of the disease. Lymphocyte function associated antigen 1 (LFA-1) is an adhesion molecule that mediates lymphocyte adhesion, but its role in MM is only poorly understood. The aim of the presented study was to improve knowledge on LFA-1 and associated pathways in MM for the development of molecular targeted therapies. We demonstrate that LFA-1 is expressed in U266, RPMI-8226, OPM-2, and NCI-H929 MM cell lines and in primary cells of eight tested patients. The LFA-1 inhibitor LFA878 induces apoptosis in all four cell lines as revealed by annexin V staining and caspase 3 cleavage. Apoptosis is not hampered by adhesion to stromal cells. Additionally, the soluble ligand, intracellular adhesion molecule 1 (ICAM-1), which is increased in the serum of MM patients, does not protect from melphalan-induced apoptosis. Western blots demonstrate downregulation of FAK, PI3-K, and Akt upon LFA878 treatment. Additionally, sequential inhibition of the pathway by simultaneous application of Src family kinase or PI3-K inhibitors significantly increases LFA878 induced apoptosis. We conclude that LFA-1/FAK/PI3-K/Akt is a survival pathway in MM and that targeted inhibition may provide new therapeutic options.

Operative Management of Periarticular Medial Clavicle Fractures-Report of 10 Cases.

BACKGROUND:: The periarticular medial clavicle fracture is a rare injury and can be treated conservatively in the majority of cases. However, up to 8% of the patients develop symptomatic nonunion, and fracture dislocation correlates with the number of poor functional results. Operative treatment may be beneficial in these cases. Studies with large series of operated patients are still missing. METHODS:: We investigated 10 patients with operative treatment of periarticular medial clavicle fractures. Preoperative X-ray or computed tomography scan was obtained, and follow-up assessment was performed at determined intervals, including physical examination and X-ray evaluation of bone healing. Finally, functional assessment was carried out from September 2009 to July 2010 using the Disabilities of the Arm, Shoulder and Hand score. RESULTS:: All operated patients had displaced periarticular medial clavicle fractures. A direct surgical approach was performed, and denudation of the bone fragments was avoided. In 8 of 10 cases, we used locking plates, preferentially the T-locking plate. In 6 of 10 patients, three screws were placed in the medial fragment or the sternum. The arm was immobilized in a sling for 2 weeks to 3 weeks, followed by careful passive and increasing active motion exercises. In 9 of 10 operated patients, we observed fracture healing and good functional results. Two patients with paraplegia/tetraplegia were excluded from final assessment but demonstrated fracture healing. In one case, we observed early material loosening caused by misused locking system and wound infection. CONCLUSIONS:: Operative treatment can be considered for periarticular, dislocated medial-end clavicle fractures. Computed tomography scan can be useful for operative planning and is mostly performed in patients with multiple injuries. Locking plates, such as the T-locking plate or the pilon reconstruction plate, are preferred devices. For rigid fixation, at least three locking screws should be placed in the medial bone fragment. The plate can be removed 18 months after osteosynthesis.

Bendamustine induces G2 cell cycle arrest and apoptosis in myeloma cells: the role of ATM-Chk2-Cdc25A and ATM-p53-p21-pathways.

PURPOSE: Multiple myeloma is a fatal hematological disease caused by malignant transformation of plasma cells. Bendamustine has been proven to be a potent alternative to melphalan in phase 3 studies, yet its molecular mode of action is still poorly understood. METHODS: The four-myeloma cell lines NCI-H929, OPM-2, RPMI-8226, and U266 were cultured in vitro. Apoptosis was measured by flow cytometry after annexin V FITC and propidium iodide staining. Cell cycle distribution of cells was determined by DNA staining with propidium iodide. Intracellular levels of (phosphorylated) proteins were determined by western blot. RESULTS: We show that bendamustine induces apoptosis with an IC50 of 35-65 mug/ml and with cleavage of caspase 3. Incubation with 10-30 mug/ml results in G2 cell cycle arrest in all four-cell lines. The primary DNA-damage signaling kinases ATM and Chk2, but not ATR and Chk1, are activated. The Chk2 substrate Cdc25A phosphatase is degraded and Cdc2 is inhibited by inhibitory phosphorylation of Tyr15 accompanied by increased cyclin B levels. Additionally, p53 activation occurs as phosphorylation of Ser15, the phosphorylation site for ATM. p53 promotes Cdc2 inhibition by upregulation of p21. Targeting of p38 MAPK by the selective inhibitor SB202190 significantly increases bendamustine induced apoptosis. Additionally, SB202190 completely abrogates G2 cell cycle arrest. CONCLUSION: Bendamustine induces ATM-Chk2-Cdc2-mediated G2 arrest and p53 mediated apoptosis. Inhibition of p38 MAPK augments apoptosis and abrogates G2 arrest and can be considered as a new therapeutic strategy in combination with bendamustine.