Human 3D multicellular microtissues: An upgraded model for the in vitro mechanistic investigation of inflammation-associated drug toxicity.

Inflammation is one of the factors that may increase the sensitivity of hepatic cells to acetaminophen (APAP) induced toxicity. To investigate the mechanisms, we exposed 3-dimensional (3D) Human Liver Microtissues, a co-culture of primary human hepatocytes (PHH) and Kupffer cells (KCs), to 0, 0.5 (low), 5 (median) and 10 mM (high dose) APAP for 24 h, with/without lipopolysaccharide (LPS). Microarray-technology was used to evaluate the transcriptome changes. In the presence of LPS, the median-dose of APAP is sufficient to inhibit the expression of respiratory chain- and antioxidant-related genes, suggesting the involvement of reactive oxygen species (ROS) and oxidative stress. Furthermore, the median- and high-dose of APAP inhibited the expression of Fc fragment receptor (FcγR)-coding genes, regardless of the presence of LPS. The toll-like receptor 4 (TLR4) expression, however, was continuously elevated after the LPS/APAP co-exposures, which may result in reduced KC-phagocytosis and unbalanced cytokine patterns. Compared to the treatment with LPS only, LPS/APAP co-exposures induced the production of interleukin (IL)-8, a pro-inflammatory cytokine, but suppressed the secretion of IL-6, a cytokine regulating hepatic regeneration, along with the increase in APAP dosages. In addition to the disrupted mitochondrial functions, the presence of LPS exacerbated APAP toxicity. These findings suggest that 3D Microtissues are a suitable model for the mechanistic exploration of inflammation-associated drug toxicity.

Groin Pain and Muscular Imbalance of Quadriceps and Hamstrings in an Elite Soccer Player - A Case Study.

Soccer and football players are exposed to a high risk of groin pain. In some cases, the pubic symphysis is the origin of the problems.This article presents a case report of a young elite soccer player who, over a period of two years, suffered from pain in the groin and symphysis area. The right leg was the kicking leg. Imaging techniques did not reveal pathological findings. Sports hernia, osteomyelitis, enthesopathy, adductor tendonitis, and muscle sprains, as well as rheumatic or urogenital disorders were excluded.A 3 D posture analysis was performed to examine the statics of the body and pelvis. The maximum isometric strength of the left and right leg adductors and abductors, as well as the knee flexors and extensors were measured.We found a muscular imbalance resulting from the type of sport the athlete engaged in with an unfavourable ratio between the right knee extensor and flexor muscles. Comparing sides, an imbalance was also identified between the right and left knee extensor. This imbalance resulted in a one-sided forward tilt of the right hemi-pelvis. This pelvic torsion may lead to an increase in shear forces in the pubic symphysis, which we suspected to be the reason for the recurring problems.After three months of specific training exercises, the pelvic position was harmonised and the muscular imbalances were significantly reduced. Even 6 months after completion of the specific training exercises, the player remained without complaints despite his unvaried soccer training intensity.Causal treatment of functional pain in the groin or symphysis area should take into account the ipsilateral and contralateral strength ratios of the knee extensors and flexors as well as the three-dimensional position of the pelvis.

[Injury of the Obturator Internus Muscle--a Rare Differential Diagnosis in a Soccer Player]. / Verletzung des M. obturatorius internus--eine seltene Differenzialdiagnose beim Fußballspieler.

BACKGROUND: Lesions/irritations of the obturator internus muscle (OIM) are rare, several differential diagnoses are possible. PATIENT: This paper describes the case of an OIM injury in a professional football player. RESULTS: On clinical examination, painful internal rotation of the hip joint was an indication for a lesion/irritation of the OIM. MRI was the procedure of choice for imaging. Movement analysis served to detect a functional malposition. CONCLUSION: A short recovery time requires functional treatment as well as the use of orthopaedic aids to correct possible deformities.

[Acute and overuse injuries in soccer - what about the evidence level?]. / Verletzungen und Schäden im Fußball - Wie hoch ist die Evidenz?

AIM: Over the last years, several studies on harmful events (h. e.) in soccer have been published. The aim was to develop a ranking of these studies according to their evidence, and to analyse the data with respect to the number of study participants, athletes' status, gender distribution, and genesis of harmful events in soccer. METHODS: Between 1976 and 2011, the data bases MEDLINE, EBMR, and SPOTLIT were scanned by the keywords/combinations: soccer, acute injuries, overuse injuries, training, and match. In doing so, 644 initially potential relevant articles were found. On the basis of the QUORUM standard, 78 potentially relevant articles were filtered out, and an EVIDENCE BASED LEVEL (EBL) was assigned. The results were rated according to importance and shown descriptively, because the heterogeneity of the study inhibited meta-analytical evaluation. RESULTS: 23 % of the publications could be assigned to EBL 2a - 2c, 27 % to EBL 3a and 3b, and 50 % to EBL 4 and 5. The studies comprised altogether 22 294 male and 2375 female athletes; 87 % of the male and 29 % of the female were professional athletes. 7 usable publications with a total of 8011 h. e. in men and 6 publications with 1055 h. e. in women dealt with contact/non-contact genesis of h. e.. 46 % male (72 % female) athletes suffered from h. e. caused by contact events, and 54 % male (28 % female) athletes suffered from h. e. caused by non-contact events. The distribution of acute and overuse injuries was analysed in 9969 h. e. in men (11 publications), and in 624 h. e. in women (5 publications). On average, the number of acute injuries (90 % male, 86 % female) was much higher than that of overuse injuries. The prevalence of h. e. with respect to training or match playing was analysed in 11 studies with 10 078 h. e. in men, and in 4 studies with 546 harmful events in women. 35 % of men's h. e. occurred during training and 65 % during matches, whereas 60 % of the women's h. e. occurred during training and 40 % during matches. CONCLUSION: The number of athletes included in the studies is quite low in relation to the number of active athletes. Studies of professional athletes are over-represented. Independent of gender, there are more acute injuries than overuse injuries, whereas the distribution of harmful events with respect to genesis and occurrence during training and match is gender-specific. The studies' evidence level is quite low in relation to the socio-economic significance of this kind of sport; the studies' evidence is higher for women.

Multi-cell type human liver microtissues for hepatotoxicity testing.

Current 2-dimensional hepatic model systems often fail to predict chemically induced hepatotoxicity due to the loss of a hepatocyte-specific phenotype in culture. For more predictive in vitro models, hepatocytes have to be maintained in a 3-dimensional environment that allows for polarization and cell-cell contacts. Preferably, the model will reflect an in vivo-like multi-cell type environment necessary for liver-like responses. Here, we report the characterization of a multi-cell type microtissue model, generated from primary human hepatocytes and liver-derived non-parenchymal cells. Liver microtissues were stable and functional for 5 weeks in culture enabling, for example, long-term toxicity testing of acetaminophen and diclofenac. In addition, Kupffer cells were responsive to inflammatory stimuli such as LPS demonstrating the possibility to detect inflammation-mediated toxicity as exemplified by the drug trovafloxacin. Herewith, we present a novel 3D liver model for routine testing in 96-well format capable of reducing the risk of unwanted toxic effects in the clinic.

[Inflammatory diseases of the spinal column and the myelon]. / Entzündliche Erkrankungen der Wirbelsäule und des Myelons.

Inflammatory diseases of the spine and the spinal cord (myelon) can be caused by a wide range of pathological conditions. Except for degenerative inflammatory diseases of the spine, infectious and autoimmune disorders are relatively rare. The latter can also be a significant source of pain and disability, especially if these hard to diagnose conditions go untreated. In cases of advanced disease some entities, such as spondylodiscitis or rheumatoid arthritis can cause severe neurological impairment especially by progressive intraspinal spread. Inflammation of the myelon cannot be depicted with conventional radiographs in general and by computed tomography only occasionally. In these cases magnetic resonance imaging is the method of choice to detect early abnormalities of the myelon and to provide detailed information for the differential diagnosis.

[Postoperative findings in the spinal column]. / Postoperative Befunde an der Wirbelsäule.

Postoperative imaging after spinal surgery is usually performed to document the correct positioning of implants or to rule out complications if patients still suffer from pain after surgery. Depending on the question various imaging modalities can be used all of which have benefits and limitations. Conventional X-ray is used for the documentation of the correct positioning of spinal implants, stability (olisthesis) and during follow-up to rule out fractures or instability of the implants, whereas soft tissue changes cannot be completely assessed. Besides these indications, imaging is usually performed because of ongoing symptoms (pain for the most part) of the patients. Soft tissue changes including persistent or recurrent herniated disc tissue, hematoma or infection can best be depicted using magnetic resonance imaging (MRI) which should be performed within the immediate postoperative period to be able to distinguish physiological development of scar tissue from inflammatory changes in the area of the surgical approach. Often imaging alone cannot differentiate between these and imaging can therefore only be considered as an adjunct. Computed tomography is the modality of choice for the evaluation of bony structures and an adjunct of new therapies such as image-guided application of cement for kyphoplasty or vertebroplasty.

Mechanical behaviour of standardized, endoskeleton-including hip spacers implanted into composite femurs.

Two-stage reconstruction using an antibiotic loaded cement spacer is the preferred treatment method of late hip joint infections. Hip spacers maintain stability of the joint and length of the limb during treatment period. However, as the material strength of bone cement (PMMA) is limited, spacer fractures led to serious complications in the past. This study investigated the load capacity of custom made hip spacers, developed at the 'Klinik für Orthopädie und Orthopädische Chirurgie' (Universitätsklinikum des Saarlandes, Homburg/Saar, Germany), and implanted into composite femurs. In a quasi-static test, non-reinforced spacers tolerated hip joint loads of about 3000 N, whereas reinforced spacers with titanium-grade-two endoskeletons doubled this load up to 6000 N. Even for cyclic loading, endoskeleton-including hip spacers tolerated loads of >4500 N with 500,000 load cycles. Thus, an endoskeleton-including spacer should provide a mobile and functional joint through the treatment course. A generated FE-model was used to determine the fracture stresses and allows for further sensitivity analysis.

Treatment of proximal femur infections with antibiotic-loaded cement spacers.

In case of periprosthetic hip infections the implantation of antibiotic-loaded PMMA spacers is accepted for an adequate treatment option. Although their indication for the treatment of destructive, bacterial infections of the proximal femur would make sense, literature data are scarce. Hence, the aim of this study was to evaluate the efficacy of antibiotic-impregnated spacers in the treatment of proximal femur infections. In 10 consecutive patients (5 M/ 5 F, mean age 66 y.) with bacterial proximal femur infections, a femoral head/neck resection was prospectively performed with a subsequent implantation of an antibiotic-loaded spacer. The joint-specific outcome was evaluated by the Merle d'Aubigne and the Mayo hip score, the general outcome by SF-36. The time periods were divided into "infection situation", "between stages" and meanly 1 year "after prosthesis implantation". The spacers were meanly implanted over 90 [155-744] days. In all cases an infection eradication could be achieved. After infection eradication, a prosthesis implantation was performed in 8 cases. The general scores showed significant increases at each time period. With regard to the dimension "pain", both scores demonstrated a significant increase between "infection situation" and "between stages", but no significance between "between stages" and "after prosthesis implantation". Spacers could be indicated in the treatment of proximal femur infections. Besides an infection eradication, a pain reduction is also possible.

Development of a reinforced PMMA-based hip spacer adapted to patients' needs.

Two-stage reimplantation using an interval hip prosthesis (spacer) of antibiotic-impregnated bone cement has become a well-accepted method to eradicate infection and prevent limb shortening. However, custom made as well as prefabricated spacers share a weakness of limited strength and hence several fractures of spacers have been observed, even for partial weight bearing. The purpose of this study was therefore to improve the strength of the custom made spacer, used at the Orthopaedic Department of the Saarland University Hospital (Germany). As the material strength of bone cement is limited, several reinforced spacers with a metal core consisting of titanium grade two have been developed and investigated. Loading procedure was close to the ISO 7206/4, though small adaptation was made. An inserted rod of titanium grade two increased the collapse load up to 1000-1300 N, but considering a maximum expected load of about three times the body weight, still below the required value. A "full-stem" reinforced spacer, i.e. spacer with a titanium endoskeleton and a minimum of 2-3mm PMMA-coating in order to assure drug release, provides a mobile and functional joint through the treatment course. Those with 8mm thickness of titanium endoskeleton endured up to one million load cycles in a load range of 300-2300 N. To give further support for individual cases a meaningful S-N curve for this device was determined.

[Ski sport. Trend--pattern of injuries--prevention]. / Skisport. Aktuelle Entwicklung--Verletzungsmuster--Prävention.

Skiing is one of the most favoured winter sports, supported by the introduction of carving skis ten years ago. There's a close correlation between the design of the carving ski and a new skiing technique. Only a small number of persons is able to carve correctly. A special fitness program is necessary to be prepared adequately to the skills of carving. As proven by the latest injury statistics, the number of injuries has been declining over the last years. Due to the new skiing technique, injury patterns have changed. The most frequently affected injured region is still the knee joint. Prevention can be done by fitness training, watching instructional ski videos, and usage of well-fitting sports equipment. A new trend is the Telemark-technique, which shows different injury patterns than carving.

Inline skating injuries: medical and sociological aspects.

INTRODUCTION: Inline skating is becoming more and more popular all over the world. This results in a rapid increase in sports injuries. The aim of our study was to analyse injury patterns and injury causes as well as the influence of the social status on possessing and using protective equipment. PATIENTS AND METHODS: We recorded and evaluated 76 accidents in our outpatient department by means of standardised questionnaires over a period of 18 months. We checked the direct circumstances of the accident, social situation and aspects of the family's social status. RESULTS: The average age of the injured person was 12.5 years. The most common injury localisations were the distal forearm (39.5 %) and the wrist (9.2 %), the most common types of injuries were fractures (51.9 %, especially upper extremity) and distortions (17.6 %). Most injuries happened in easy driving situations, like gliding, turning and braking. The injured children did not differ significantly from the general population. The willingness of children to wear special safety gear increased with the social status of their family. CONCLUSION: Learning the fundamental techniques can improve driving skills and reduce the number of injuries. Integration of skating lessons in physical education at school is desirable, especially regarding the injured person's age and would improve their willingness to wear protectors, independent of the social status.

[Cubital tunnel syndrome--simple nerve decompression or decompression with subcutaneous anterior transposition?]. / Sulcus-ulnaris-Syndrom: Einfache Dekompression oder subkutane Vorverlagerung?

The purpose of this prospective, randomised and controlled study was to evaluate which kind of operative technique for treatment of cubital tunnel syndrome is favourable: subcutaneous anterior transposition or nerve decompression without transposition. This study included 66 patients suffering from pain and/either neurological deficits with clinically and electrographically proven cubital tunnel syndrome. 32 patients underwent nerve decompression without transposition, whereas 34 underwent subcutaneous transposition of the nerve. Follow-up examinations evaluating pain, motor and sensory deficits as well as motor nerve conduction velocities were performed three, nine and 24 months postoperatively. Irrespectively of operative procedures (simple decompression vs. subcutaneous anterior transposition) there were no significant differences between the outcomes of the two groups at either postoperative follow-up examination (p > 0.05).

[Differential diagnosis of back pain]. / Differenzialdiagnose des Rückenschmerzes.

Back pain is one of the most frequent clinical pictures encountered in a physician's practice. It can pose a great burden on the individual and in addition have a multifactorial origin. It can be caused by intervertebral discs, vertebral joints, nerve roots, ligaments, sacroiliac joints, or a combination of the above. Back pain, as a symptom of a systemic disease, can also be a warning signal of grave disorders such as malignancies or in the event of aortic aneurysm. The well-considered choice of appropriate diagnostic procedures and suitable treatment requires a thorough knowledge of this multifactorial clinical picture.

[Postoperative syndrome after spine surgery]. / Postoperatives Syndrom nach Wirbelsäuleneingriffen.

Postoperative syndrome after spine surgery, i.e., symptoms or syndromes caused by complications or procedure-related consequences, is gaining more and more importance. Due to great improvements concerning imaging and operative techniques (microsurgery, instrumentation) the total number of spinal surgeries as well as their related complications are increasing. Procedure-related postoperative complications including neurological deficit syndromes can occur acutely or at a later date. Concerning imaging techniques for postoperative evaluation after spinal surgery there are several modalities available. Their indications depend on complex factors including initial pathology the surgery was performed for, kind of surgical technique (surgical approach, instrumentation), anatomy of the patient as well as the time between onset of symptoms and surgery. In cases of ambiguous findings, the combination of different imaging techniques can be instrumental.

[Spondylitis/spondylodiscitis]. / Spondylitis/Spondylodiszitis.

Spondylitis is an inflammation of the vertebral body. If the infection is manifested in the vertebral motor segment it is called spondylodiscitis, which can be divided into specific and nonspecific forms. It is clinically impressive that at the beginning of the disease, the patients who are quite often immunosuppressed suffer from localized, especially nocturnally exacerbated backache. The initial diagnostic work-up generally consists of clinical history, examination, laboratory tests, and (especially advanced) imaging findings. Although computed tomography still remains the most frequently used advanced imaging technique, magnetic resonance imaging is the golden standard for the diagnosis of spondylitis and spondylodiscitis.

[Indications for use of the V.A.C.-system in the orthopedic surgery]. / Indikationen zum Einsatz der Vakuum-Therapie in der septischen orthopädischen Chirurgie.

INTRODUCTION: The vacuum-assisted closure (V.A.C.)-therapy is accepted for an efficient option in the treatment of infected wounds with healing complications. However, reports on its use in the septic orthopedic surgery are seldom. Hence, the aim of this study is to demonstrate our experience with the V.A.C.-system in the treatment of orthopedic-related infections. PATIENTS-METHODS: Various musculoskeletal infections with prolonged wound healing (infections after Achilles tendon reconstruction, fibula osteosynthesis, dorsal spondylodesis, and total hip arthroplasty, skin necrosis after total knee arthroplasty and wound dehiscence after resection and irradiation of a liposarcoma) have been treated with the V.A.C.-device. After infection sanitation we performed skin graft transplantation in 3 cases for definitive wound closure, also assisted by the V.A.C.-therapy. RESULTS: An infection eradication with implant preservation, where necessary, could have been achieved in all cases. No complications were observed in the cases with the skin graft transplantations. No infection persistence or reinfection occurred at a mean follow-up of 36 months. DISCUSSION: The V.A.C.-therapy seems to be a valuable adjunct in the treatment of infected wounds in the orthopedic surgery, however, definitive conclusion should await the results of future clinical studies with large series.

[V.A.C.-therapy: a treatment option for wound healing complications after achilles tendon reconstruction]. / Die V.A.C.-Therapie als Behandlungsoption von Wundheilungsstörungen nach Achillessehnenrekonstruktion.

INTRODUCTION: The postoperative course after Achilles tendon reconstruction is associated with a high incidence rate of infections and wound healing complications, which can lead to protracted healing process and, hence, limit the clinical outcome. PATIENT-METHODS: A 66-year-old male was referred to our clinic with an Achilles tendon rupture. MRI confirmed the diagnosis, an augmented tenoplasty was performed for tendon reconstruction. 11 weeks after surgery the patient presented himself again with an open wound and local infection signs. RESULTS: The surgical treatment included debridement and jet lavage. The V.A.C.-device with the white polyvinyl sponge at an initial pressure of 200 mm Hg was used. A pathogen organism could not be identified. For infection eradication a broad spectrum systemic antibiosis (cefuroxime and gentamicin) was applied. On 3., 6. and 14. day the dressings were changed and the wound was revised under progredient closure. At beginning formation of granulation tissue the pressure was reduced to 150-100 mm Hg. At decreasing blood inflammation parameters and amelioration of the local wound condition the patient could check out after 3 weeks hospitalization. After further successful ambulant management by means of the V.A.C.-therapy a meshgraft transplantation was performed (enlargement factor 1.5; layer thickness 0.3 mm). The V.A.C.-device was applied again at a pressure of 150 mm Hg with a single dressing change after 5 days. At a follow-up of 31 months no further complications occurred. DISCUSSION: The V.A.C.-therapy seems to be a valuable tool in the treatment of wounds with a critical local vascularity. After successful wound preconditioning the healing process of skin grafts transplants can be also optimised by means of the V.A.C.-device.

Simple decompression or subcutaneous anterior transposition of the ulnar nerve for cubital tunnel syndrome.

The purpose of this prospective randomised study was to evaluate which operative technique for treatment of cubital tunnel syndrome is preferable: subcutaneous anterior transposition or nerve decompression without transposition. This study included 66 patients suffering from pain and/or neurological deficits with clinically and electromyographically proven cubital tunnel syndrome. Thirty-two patients underwent nerve decompression without transposition and 34 underwent subcutaneous transposition of the nerve. Follow-up examinations evaluating pain, motor and sensory deficits as well as motor nerve conduction velocities, were performed 3 and 9 months postoperatively. There were no significant differences between the outcomes of the two groups at either postoperative follow-up examination. We recommend simple decompression of the nerve in cases without deformity of the elbow, as this is the less invasive operative procedure.

[Spinal syndrome triggered by a lumbar spinal av malformation. A case report]. / Wirbelsäulensyndrom, ausgelöst durch eine lumbale spinale AV-Malformation. Ein Fallbericht.

We report the case of a 64-year-old male suffering from long-term claudicatio spinalis who underwent surgery in an orthopedic outpatient ward for posterior lumbar interbody fusion and bony decompression due to spinal stenosis. Postoperatively, the clinical symptoms, consisting of difficulties with walking and stocking-like dysesthesia of both lower extremities, did not improve. Due to persistent complaints, spinal MRI was performed which revealed myelomalacia and moreover was indicative of dural arteriovenous (AV) malformation at the L2-3 spinal level, which was verified as a type Ia AV fistula (according to Spetzler) by digital subtraction angiography (DSA). After microsurgical treatment of the AV fistula, clinical symptoms improved and control DSA could demonstrate complete disconnection of the fistula without any signs of recanalization. This case demonstrates that neurological deficits of patients suffering from degenerative spinal disorders can generally be considered as caused by more common spinal disease such as lumbar stenosis. Since vascular malformations may also cause neurological deficits and even mimic symptoms of spinal stenosis, it is important to consider these entities in diagnostic evaluation.