Implementation of Outpatient Parenteral Antimicrobial Therapy (OPAT) in Patients with Complicated Periprosthetic Joint Infections. / Etablierung der ambulanten intravenösen Antibiotikatherapie (APAT) bei Patienten mit komplizierten Periimplantatinfektionen.

Periprosthetic joint infections (PJI) are a serious complication of arthroplasty with high morbidity. With growing bacterial resistance and limited disposability of oral antibiotics with sufficient bioavailability, the need for intravenous antibiotic application is raising. This causes long-term hospital stays and rising costs. In the course of transferring procedures into an outpatient setting as well as coping with pressures on hospital capacity, outpatient parenteral antimicrobial therapy (OPAT) can build a bridge for the treatment of such infections.In a single centre analysis, 47 cases treated with OPAT were studied in relation to pathogen, antimicrobial resistance, indication for OPAT and follow up. Furthermore, the patients received an anonymised questionnaire with 4 clusters of interest in terms of internal quality assessment on the success and evaluation of this therapeutic procedure. Special attention was paid to the descriptive analysis of patients with periprosthetic joint infections (n = 30).Between May 2021 and October 2022 out of 47 patients with OPAT, 30 cases with periprosthetic joint infections were identified. For infected hip- and knee arthroplasties, a remarkable spectrum of pathogens was found. In hip infections highly resistant strains of Staphylococcus epidermidis and Enterococci were detected. In knee infections, the pathogens were more susceptible, but however highly virulent Staphylococcus aureus and Streptococci. Difficult to treat, mixed infections were found in both locations. The indication for OPAT was based in half of the cases on the high level of antimicrobial resistance, with availability of only parenteral applicable antibiotics. Further indications were mixed infections and difficult to treat pathogens, with flucloxacillin therapy as well as OPAT as the last therapeutic option. The questionnaire showed 96% patient satisfaction in terms of organisation and acceptance of this kind of therapy. Complications or unexpected outpatient/ hospital treatments were very rare in connection with OPAT. Two thirds of patients reported completion of the treatment. In the clinical follow up (average of 5.7 months), 96.6% of cases were declared free of infection. In one patient the infection persisted.OPAT is a safe and reliable therapeutic option for outpatients to continue parenteral antimicrobial treatment in joint infections. Due to increasing pressure on hospitals in terms of costs and capacity, this therapy offers an alternative to inpatient treatment. The indication for OPAT should be set individually, risk adjusted and not generalised for all patients. The outpatient sector needs financial and structural support for comprehensive roll-out of this treatment in Germany. A further focus should be on the prevention of periprosthetic joint infections. With the knowledge of the expected pathogens and the surgical resources, the standards should be adapted. The choice of the antibiotic should be specified and the intervals of application be shortened, according to the surgical course, in order to yield high levels of agent concentration in the surgical area. Further investigations are required to test the superiority of OPAT versus the oral administration of antibiotics in long-term observations as well as to define the necessary duration of OPAT.

The health-related quality of life of sarcoma patients treated with neoadjuvant versus adjuvant radiotherapy - Results of a multi-center observational study.

AIM: The sequence of radiotherapy and resection in patients with soft tissue sarcomas is usually discussed on an individual basis. Better understanding of potential differences of health-related quality of life (QoL) between patients undergoing adjuvant (ART) versus neoadjuvant radiotherapy (NART) is therefore helpful for clinical decision making. METHODS: Adult sarcoma patients from 39 hospitals completed the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30). Differences in global QoL, physical functioning, role functioning, fatigue, pain, and insomnia between ART versus NART were investigated with multivariate regression, adjusting for age, gender, chemotherapy, grading, stage, tumor location, recurrence/distant metastasis, sarcoma type, time since last treatment, and treatment status using validated thresholds. RESULTS: A total of 1110 patients participated. Of them, 340 had received radiotherapy (NART: n = 95, 28%; ART: n = 245, 72%). Global QoL was 59.3 on average after NART and 60.5 after ART (Badj = 1.0, p = 0.74). Physical functioning was 65.9 compared to 70.5 (Badj = 4.2; p = 0.16), role function 48.8 vs. 56.7 (Badj = 7.0, p = 0.08), fatigue 47.5 vs. 45.4 (Badj = -1.2; p = 0.71), pain 40.2 vs. 34.1 (Badj = -6.8; p = 0.08), and insomnia 33.7 vs. 41.6 (Badj = 5.5, p = 0.16). Among patients with NART, clinically relevant QoL impairments were less frequent 2 years after treatment compared to < 2 years thereafter (n = 6 vs. n = 4 on average). CONCLUSION: There is little evidence for QoL differences in most domains and overall QoL between the two irradiation groups. However, patients after NART might experience worse role functioning and pain but fewer problems with insomnia compared to patients after ART.

Chromium and cobalt intoxication mimicking mitochondriopathy.

A 53-year old male with a history of progressive visual impairment, hearing loss, peripheral neuropathy, poorly controlled diabetes mellitus, cardiomyopathy, and weight loss was referred to the rare disease center due to the suspicion of mitochondrial cytopathy. In line with mitochondrial dysfunction, lactate in CSF was increased. Genetic testing by whole-exome sequencing and mitochondrial DNA did not reveal a likely cause. The case remained unsolved until he developed pain in his right hip, where he had received total hip arthroplasty 12 years earlier. An orthopedic evaluation revealed substantial shrinkage of the head of the hip prosthesis. Due to metal-on-metal wear, debris chromium and cobalt levels in serum were massively increased and significantly improved with multisystemic impairment after exchanging the defective implant.

Establishment and Characterization of a Sclerosing Spindle Cell Rhabdomyosarcoma Cell Line with a Complex Genomic Profile.

Sclerosing spindle cell rhabdomyosarcoma (SSRMS) is a rare rhabdomyosarcomas (RMS) subtype. Especially cases bearing a myogenic differentiation 1 (MYOD1) mutation are characterized by a high recurrence and metastasis rate, often leading to a fatal outcome. SSRMS cell lines are valuable in vitro models for studying disease mechanisms and for the preclinical evaluation of new therapeutic approaches. In this study, a cell line established from a primary SSRMS tumor of a 24-year-old female after multimodal chemotherapeutic pretreatment has been characterized in detail, including immunohistochemistry, growth characteristics, cytogenetic analysis, mutation analysis, evaluation of stem cell marker expression, differentiation potential, and tumorigenicity in mice. The cell line which was designated SRH exhibited a complex genomic profile, including several translocations and deletions. Array-comparative genomic hybridization (CGH) revealed an overall predominating loss of gene loci. The mesenchymal tumor origin was underlined by the expression of mesenchymal markers and potential to undergo adipogenic and osteogenic differentiation. Despite myogenic marker expression, terminal myogenic differentiation was inhibited, which might be elicited by the MYOD1 hotspot mutation. In vivo tumorigenicity could be confirmed after subcutaneous injection into NOD/SCID/γcnull mice. Summarized, the SRH cell line is the first adult SSRMS cell line available for preclinical research on this rare RMS subtype.

Modulating endothelial adhesion and migration impacts stem cell therapies efficacy.

BACKGROUND: Limited knowledge of stem cell therapies` mechanisms of action hampers their sustainable implementation into the clinic. Specifically, the interactions of transplanted stem cells with the host vasculature and its implications for their therapeutic efficacy are not elucidated. We tested whether adhesion receptors and chemokine receptors on stem cells can be functionally modulated, and consequently if such modulation may substantially affect therapeutically relevant stem cell interactions with the host endothelium. METHODS: We investigated the effects of cationic molecule polyethylenimine (PEI) treatment with or without nanoparticles on the functions of adhesion receptors and chemokine receptors of human bone marrow-derived Mesenchymal Stem Cells (MSC). Analyses included MSC functions in vitro, as well as homing and therapeutic efficacy in rodent models of central nervous system´s pathologies in vivo. FINDINGS: PEI treatment did not affect viability, immunomodulation or differentiation potential of MSC, but increased the CCR4 expression and functionally blocked their adhesion receptors, thus decreasing their adhesion capacity in vitro. Intravenously applied in a rat model of brain injury, the homing rate of PEI-MSC in the brain was highly increased with decreased numbers of adherent PEI-MSC in the lung vasculature. Moreover, in comparison to untreated MSC, PEI-MSC featured increased tumour directed migration in a mouse glioblastoma model, and superior therapeutic efficacy in a murine model of stroke. INTERPRETATION: Balanced stem cell adhesion and migration in different parts of the vasculature and tissues together with the local microenvironment impacts their therapeutic efficacy. FUNDING: Robert Bosch Stiftung, IZEPHA grant, EU grant 7 FP Health.

Longtime Outcome After Intraosseous Application of Autologous Mesenchymal Stromal Cells in Pediatric Patients and Young Adults with Avascular Necrosis After Steroid or Chemotherapy.

Avascular necrosis (AVN) is a severe complication of immunosuppressant therapy or chemotherapy. A beneficial AVN therapy with core decompression (CD) and intraosseous infusion of mesenchymal stromal cells (MSCs) has been described in adult patients, but there are only few data on MSC applications in pediatric and young adult patients (PYAP). Between 2006 and 2015, 14 AVN lesions of 10 PYAP (6 females) with a median age of 16.9 years (range 8.5-25.8 years) received CD and intraosseous application of autologous MSCs. Data of these patients were analyzed regarding efficacy, safety, and feasibility of this procedure as AVN therapy and compared with a control group of 13 AVN lesions of 11 PYAP (5 females) with a median age of 17.9 years (range 13.5-27.5 years) who received CD only. During the follow-up analysis [MSC group: median 3.1 (1.6-5.8) years after CD; CD group: median 2.0 (1.5-8.5) years after CD], relative lesion sizes (as assessed by magnetic resonance imaging) compared with the initial lesion volume, were significantly lower (P < 0.05) in the MSC group (volume reduction to a median of 18.5%) when compared with the CD group (58.0%). One lesion in the MSC group comprised a complete remission. Size progression was not observed in either group. Clinical improvement (pain, mobility) was not significantly different between the two groups. None of the patients experienced treatment-related adverse effects. CD and additional MSC application was regarded safe, effective, feasible, and superior in reducing the lesion size when compared with CD only. Prospective, randomized clinical trials are needed to further evaluate these findings.

[Predictability of Postoperative Pain and Satisfaction. How Precise Are We and What Is the Role of Professional Experience?] / Die ärztliche Vorhersagepräzision eines OP-Erfolgs. Wie genau sind wir und welche Rolle spielt Berufserfahrung?

Background The indication for surgery is justified by an expected improvement for the patient. To evaluate the probability and extent of individual postoperative patient benefit, the surgeon needs to elaborate numerous parameters of potential relevance for the outcome beyond his key competence, that is the technical dimension of the operation. Despite the highest medical standards, individual postoperative satisfaction with surgery is highly variable, even in cases with a technically good result. The aim of the present study was to investigate the individual predictability of postoperative pain and satisfaction in patients with elective musculoskeletal surgery. Moreover, it was analysed whether the quality of the prediction of the outcome depends on professional experience and if a better prediction can be obtained in such a highly standardised procedure as primary total arthroplasty. Patients/Material and Methods In our hospital on the day before surgery, patients with their medical history are presented to the head of department and a short clinical examination is performed as well as a joint analysis of radiographic images. During this grand round, doctors gave a written preoperative estimation of both expected postoperative satisfaction and pain at 6 months after surgery on a scale from 0 - 10. At 6 months postoperatively, patients were asked to give their actual level for these two parameters. Preoperative estimations were obtained from both senior and resident physicians and compared with the values actually reported by the patient. Results A total of 194 physicians' predictions of 63 patients were analysed. Preoperative pain levels were reduced markedly by surgery from a median NRS of 6.25 to 2.5 (p < 0.001). Median prediction for postoperative pain was 2 (IQR 2), which is only slightly more optimistic than reported. On an individual level, the discrepancy between prediction and actual outcome was, however, considerable - with a median absolute difference of 2 (IQR 3) values on the scale. This means that only 50% of all predictions were close enough to the actual value to be at least in the correct half of the entire scale. When looking at prediction precision as a function of professional experience, no difference could be observed between senior and junior doctors (p = 0.738 for postoperative pain and p = 0.370 for satisfaction with surgery). Even in primary arthroplasty patients (n = 17), precision of outcome prediction for pain was no better that in the remaining collective (p = 0.634). With respect to postoperative satisfaction, precision of prediction was even worse (p = 0.042), as satisfaction was slightly underestimated by the physicians in the primary arthroplasty group, by a median of 1. Conclusion While general prediction showed almost perfect agreement with actual postoperative values, individual predictability showed highly variable results. Even in such a standardised collective as primary arthroplasty, this scattering of deviation was observed. Since professional experience did not lead to improved results, it can be speculated that, beside the technical dimension of surgery, other factors such as patient expectation are of crucial relevance for postoperative outcome. To further improve outcome and patient satisfaction with surgery we therefore recommend developing an individualised and realistic prognosis together with each patient, but bearing in mind own limits of outcome prediction.

Combined application of arsenic trioxide and lithium chloride augments viability reduction and apoptosis induction in human rhabdomyosarcoma cell lines.

Rhabdomyosarcomas (RMS) are the most prevalent soft tissue sarcomas affecting children and adolescents. Despite intensive treatment consisting of multimodal chemotherapy and surgery RMS patients diagnosed with metastatic disease expect long term survival rates of only 20%. Often multidrug resistance arises upon initial response emphasizing the need for new therapeutic drugs to improve treatment efficiency. Previously, we demonstrated the efficacy of the FDA approved drug arsenic trioxide (ATO) specifically inhibiting viability and clonal growth as well as inducing cell death in human RMS cell lines of different subtypes. In this study, we combined low dose ATO with lithium chloride (LiCl), which is approved as mood stabilizer for the treatment of bipolar disorder, but also inhibits growth and survival of different cancer cell types in pre-clinical research. Indeed, we could show additive effects of LiCl and ATO on viability reduction, decrease of colony formation as well as cell death induction. In the course of this, LiCl induced inhibitory glycogen synthase kinase-3ß (GSK-3ß) serine 9 phosphorylation, whereas glioma associated oncogene family 1 (GLI1) protein expression was particularly reduced by combined ATO and LiCl treatment in RD and RH-30 cell lines, showing high rates of apoptotic cell death. These results imply that combination of ATO with LiCl or another drug targeting GSK-3 is a promising strategy to enforce the treatment efficiency in resistant and recurrent RMS.

Generation of induced pluripotent stem cells derived from a 77-year-old healthy woman as control for age related diseases.

Induced pluripotent stem cells (iPSCs) hold great promise to model diseases, where the disease affected cell type is difficult to access. A major obstacle for the development of disease models is the lack of well characterized control iPSCs from old people not affected by such a disease. Furthermore, gene-editing approaches often require iPSCs from healthy donors, where pathogenic mutations can be inserted if patient material is not available. Here, we report the generation of an iPSC line (16423 #6) from a 77-year-old woman, who did not display any disease symptoms at the time, when the skin biopsy was taken.

Arsenic trioxide potentiates the effectiveness of etoposide in Ewing sarcomas.

Ewing sarcomas (ES) are rare mesenchymal tumours, most commonly diagnosed in children and adolescents. Arsenic trioxide (ATO) has been shown to efficiently and selectively target leukaemic blasts as well as solid tumour cells. Since multidrug resistance often occurs in recurrent and metastatic ES, we tested potential additive effects of ATO in combination with the cytostatic drugs etoposide and doxorubicin. The Ewing sarcoma cell lines A673, RD-ES and SK-N-MC as well as mesenchymal stem cells (MSC) for control were treated with ATO, etoposide and doxorubicin in single and combined application. Viability and proliferation (MTS assay, colony formation, 3D spheroid culture) as well as cell death induction (western blot analysis, flow cytometry) were analysed. In the MTS viability assays ATO treatment significantly reduced the metabolic activity of all three ES cell lines (A673, RD-ES and SK-N-MC) examined. Moreover, all ES cell lines were sensitive to etoposide, whereas MSC remained unaffected by the drug concentrations used. With the exception of ATO in RD-ES cells, all drugs induced apoptosis in the ES cell lines, indicated by caspase-3 and PARP cleavage. Combination of the agents potentiated the reduction of viability as well as the inhibitory effect on clonal growth. In addition, cell death induction was obviously enhanced in RD-ES and SK-N-MC cells by a combination of ATO and etoposide compared to single application. Summarised, the combination of low dose, physiologically easily tolerable ATO with commonly used etoposide and doxorubicin concentrations efficiently and selectively suppressed viability and colony formation in ES cell lines, whereas a combination of ATO and etoposide was favourable for cell death induction. In addition to an increase of the effectiveness of the cytostatic drugs and prevention of potential drug resistance, this approach may also reduce toxicity effects, since the individual doses can be reduced.

High-Resolution Microfluidic Single-Cell Transcriptional Profiling Reveals Clinically Relevant Subtypes among Human Stem Cell Populations Commonly Utilized in Cell-Based Therapies.

Stem cell therapies can promote neural repair and regeneration, yet controversy regarding optimal cell source and mechanism of action has slowed clinical translation, potentially due to undefined cellular heterogeneity. Single-cell resolution is needed to identify clinically relevant subpopulations with the highest therapeutic relevance. We combine single-cell microfluidic analysis with advanced computational modeling to study for the first time two common sources for cell-based therapies, human NSCs and MSCs. This methodology has the potential to logically inform cell source decisions for any clinical application.

Targeting hedgehog signalling by arsenic trioxide reduces cell growth and induces apoptosis in rhabdomyosarcoma.

Rhabdomyosarcomas (RMS) are soft tissue tumours treated with a combination of surgery and chemotherapy. However, mortality rates remain high in case of recurrences and metastatic disease due to drug resistance and failure to undergo apoptosis. Therefore, innovative approaches targeting specific signalling pathways are urgently needed. We analysed the impact of different hedgehog (Hh) pathway inhibitors on growth and survival of six RMS cell lines using MTS assay, colony formation assay, 3D spheroid cultures, flow cytometry and western blotting. Especially the glioma-associated oncogene family (GLI) inhibitor arsenic trioxide (ATO) effectively reduced viability as well as clonal growth and induced cell death in RMS cell lines of embryonal, alveolar and sclerosing, spindle cell subtype, whereas normal skeletal muscle cells were hardly compromised by ATO. Combination of ATO with itraconazole potentiated the reduction of colony formation and spheroid size. These results show that ATO is a promising substance for treatment of relapsed and refractory RMS by directly targeting GLI transcription factors. The combination with itraconazole or other chemotherapeutic drugs has the opportunity to enforce the treatment efficiency of resistant and recurrent RMS.

Quality of Life, Physical and Mental Status and Contentment of Patients with Localized Soft Tissue or Bone Sarcoma: A Questionnaire Analysis.

Extremity soft tissue and bone sarcomas represent a rare group of bone and connective tissue cancers. In literature, there is little information about psycho-emotional status and impact on quality of life after the diagnosis and treatment of this kind of tumors. The aim of this survey was to define the profile of the patients at risk and their need for psychooncological care. Our self-created questionnaire consists of 71 items related to the individual emotional, mental and physical situation after the diagnosis of soft tissue and bone sarcoma. Sixty-six patients, surgically treated at our department, were included. Only 37.5% of the patients considered themselves to be completely emotional stable. Psychooncological treatment was accepted mostly by female patients, by patients with higher education level and by married patients. Emotional stability and confidence in future were associated with a strong familiar background, with numerous consultations of psychooncological service and also to gender and physical condition. Current quality of life was strongly correlated to physical condition. Thanks to our questionnaire, we disclosed few risk factors for negative emotional outcome after therapy, such as higher age, social isolation, female gender and poor physical status.

Brake response time is significantly impaired after total knee arthroplasty: investigation of performing an emergency stop while driving a car.

OBJECTIVE: The objective of this study was to investigate whether total knee arthroplasty (TKA) impairs the ability to perform an emergency stop. DESIGN: An automatic transmission brake simulator was developed to evaluate total brake response time. A prospective repeated-measures design was used. Forty patients (20 left/20 right) were measured 8 days and 6, 12, and 52 wks after surgery. RESULTS: Eight days postoperative total brake response time increased significantly by 30% in right TKA and insignificantly by 2% in left TKA. Brake force significantly decreased by 35% in right TKA and by 25% in left TKA during this period. Baseline values were reached at week 12 in right TKA; the impairment of outcome measures, however, was no longer significant at week 6 compared with preoperative values. Total brake response time and brake force in left TKA fell below baseline values at weeks 6 and 12. Brake force in left TKA was the only outcome measure significantly impaired 8 days postoperatively. CONCLUSION: This study highlights that categorical statements cannot be provided. This study's findings on automatic transmission driving suggest that right TKA patients may resume driving 6 wks postoperatively. Fitness to drive in left TKA is not fully recovered 8 days postoperatively. If testing is not available, patients should refrain from driving until they return from rehabilitation.

Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.

The genetic diagnosis in inherited optic neuropathies often remains challenging, and the emergence of complex neurological phenotypes that involve optic neuropathy is puzzling. Here we unravel two novel principles of genetic mechanisms in optic neuropathies: deep intronic OPA1 mutations, which explain the disease in several so far unsolved cases; and an intralocus OPA1 modifier, which explains the emergence of syndromic 'optic atrophy plus' phenotypes in several families. First, we unravelled a deep intronic mutation 364 base pairs 3' of exon 4b in OPA1 by in-depth investigation of a family with severe optic atrophy plus syndrome in which conventional OPA1 diagnostics including gene dosage analyses were normal. The mutation creates a new splice acceptor site resulting in aberrant OPA1 transcripts with retained intronic sequence and subsequent translational frameshift as shown by complementary DNA analysis. In patient fibroblasts we demonstrate nonsense mediated messenger RNA decay, reduced levels of OPA1 protein, and impairment of mitochondrial dynamics. Subsequent site-specific screening of >360 subjects with unexplained inherited optic neuropathy revealed three additional families carrying this deep intronic mutation and a base exchange four nucleotides upstream, respectively, thus confirming the clinical significance of this mutational mechanism. Second, in all severely affected patients of the index family, the deep intronic mutation occurred in compound heterozygous state with an exonic OPA1 missense variant (p.I382M; NM_015560.2). The variant alone did not cause a phenotype, even in homozygous state indicating that this long debated OPA1 variant is not pathogenic per se, but acts as a phenotypic modifier if it encounters in trans with an OPA1 mutation. Subsequent screening of whole exomes from >600 index patients identified a second family with severe optic atrophy plus syndrome due to compound heterozygous p.I382M, thus confirming this mechanism. In summary, we provide genetic and functional evidence that deep intronic mutations in OPA1 can cause optic atrophy and explain disease in a substantial share of families with unsolved inherited optic neuropathies. Moreover, we show that an OPA1 modifier variant explains the emergence of optic atrophy plus phenotypes if combined in trans with another OPA1 mutation. Both mutational mechanisms identified in this study-deep intronic mutations and intragenic modifiers-might represent more generalizable mechanisms that could be found also in a wide range of other neurodegenerative and optic neuropathy diseases.

Influence of left- and right-side total hip arthroplasty on the ability to perform an emergency stop while driving a car.

OBJECTIVE: To show the possible effect of left- and right-side total hip arthroplasty (THA) on the ability to perform an emergency stop when driving a car. DESIGN: Inception cohort. SETTING: A driving simulator using an actual car cabin, specifically developed for the experiment, was used for testing driving ability. PARTICIPANTS: Patients (N=40; 20 left-side THA/20 right-side THA) were tested preoperatively and in increments of 8 days and 6, 12, and 52 weeks after surgery. INTERVENTIONS: Left- and right-side THA. MAIN OUTCOME MEASURES: Reaction time, movement time, total brake response time (TBRT), and maximum brake force. RESULTS: Eight days postoperatively, measurements on driving performance indicated a slight worsening for all outcome parameters in patients after left-side THA and considerably more worsening in patients after right-side THA. For both patient groups, significant improvements in outcome measures were noted during the 1-year follow-up. Brake force declined significantly in patients with left-side THA (P=.012) and in patients after right-side THA (P<.001). A total of 35% of the patients with right-side THA and 15% with left-side THA could not meet the 600 ms TBRT threshold 6 weeks postoperatively. CONCLUSIONS: Most patients who underwent right-side THA reached their preoperative baseline 6 weeks after surgery. Most of the patients with left-side THA showed no TBRT limitations 8 days postoperatively. Because of the patients' highly individual rehabilitation course and considering the possible consequences of the premature resumption of driving a motor vehicle, individual examination and recommendation are necessary.

[End-stage renal disease after sarcoma therapy - case 3/2014]. / Terminales Nierenversagen nach Sarkomtherapie - Fall 3/2014.

HISTORY AND ADMISSION FINDINGS: A 67-year-old male patient developed progressive renal failure following successful treatment of a soft tissue sarcoma that comprised surgical resection after neoadjuvant radiochemotherapy with the application of doxorubicin (cumulative dose 180 mg/m²) and ifosfamide (cumulative dose 33 g/m²). INVESTIGATIONS: Plasma creatinine concentration was elevated to 4.5 mg/dl. Upon detection of glucosuria and α1-microglobulinuria renal biopsy was performed. DIAGNOSIS, TREATMENT AND COURSE: Histologic analysis revealed massively injured tubules that could be explained by a toxic effect of ifosfamide. Glomeruli were not affected and appeared normal. After two months of conservative therapy, the patient developed an uremic syndrome requiring hemodialysis. Ever since kidney function did not recover albeit preserved diuresis. CONCLUSIONS: Ifosfamide can cause end-stage renal disease by a tubulotoxic effect that may be the result of a selective intracellular uptake into the proximal tubule via the human organic cation transporter 2 (OCT2).

Osteoarthritis of the knee or hip significantly impairs driving ability (cross-sectional survey).

BACKGROUND: Advising patients about when they can drive after surgery is common practice after arthroplasty of the knee or hip. In the literature, the preoperative braking performance values of the patients are frequently taken as the "safe" landmark. We hypothesised that osteoarthritis (OA), the most frequent reason for arthroplasty, already compromises the ability to perform an emergency stop. We expected that both Reaction Time (RT) and Movement Time (MT) as components of the Total Brake Response Time (TBRT), would be prolonged in patients with OA of the knee or hip in comparison with healthy subjects. We also expected maximum pressure levels on the brake pedal to be reduced in such cases. METHODS: A real car cabin was equipped with pressure sensors on the accelerator and brake pedals to measure RT, MT, TBRT and maximum Brake Force (BF) under realistic spatial constraints. Patients with OA of the knee (right n = 18, left n = 15) or hip (right n = 20, left n = 19) were compared with a healthy control group (n = 21). RESULTS: All measured values for TBRT in the control group remained below 600 ms. OA of the right hip or knee significantly prolonged the braking performance (right hip: TBRT p = 0.025, right knee: TBRT p < 0.001), whereas OA of the left hip did not impair driving ability (TBRT p = 0.228). Intriguingly, OA of the left knee prolonged RT and MT to the same degree as OA on the contralateral side (RT p = 0.001, MT p < 0.001). CONCLUSIONS: This study demonstrates that depending on the localisation of OA, driving capability can be impaired; OA can significantly increase the total braking distance. To ensure safe traffic participation the safety margin for TBRT should be strictly set, under our experimental conditions, at around 600 ms. Moreover, therapeutic approaches to OA, such as physiotherapy, and patients receiving surgery of the left knee should take into account that left knee OA can also impair driving ability. CLINICAL TRIAL REGISTRATION NUMBER: Project number of the ethics committee of the University of Tübingen: 268/2009BO2; 267/2009BO2.

Antibacterial potency of V.A.C. GranuFoam Silver(®) Dressing.

INTRODUCTION: V.A.C.(®) GranuFoam™ therapy is regularly used in the surgical therapy of infected wounds and soft tissue injuries. Silver nanoparticles can destroy bacterial cell walls and inhibit enzymes for cell replication. Silver dressings are therefore successfully used for many indications in wound therapy. In this study, we investigated the antimicrobial potency of ionic silver released from the silver-coated V.A.C.(®) GranuFoam™ during vacuum therapy. Silver dressing was exposed to agar plates populated with bacteria to measure silver release. MATERIALS AND METHODS: A total of 15 agar plates colonised with either Staphylococcus aureus populations or with Staphylococcus epidermidis, were loaded with V.A.C. GranuFoam Silver(®) Dressing polyurethane foam (KCI, San Antonio, Texas). Each of 13 pieces of silver-coated foam was applied to an agar plate. Two plates were loaded with conventional black foam without any coating. After connecting to a vacuum pump, the vacuum therapy of the 15 plates lasted 5 days. The zone of inhibition of bacterial growth around the foam was measured daily. Silver release was also determined as a function of time. RESULTS: At each time point, there was evidence of silver in the agar independent of bacterial colonisation. The S. aureus agar showed a consecutive increase in silver concentration from baseline upon 48 h after exposure to the negative pressure of V.A.C. therapy. An increasing mean silver level after 48, 72 and 96 h was measured under V.A.C. therapy with a peak value after 120 h. In contrast, the results from the S. epidermidis plates did not follow a linear pattern. At the beginning of vacuum therapy, we documented a rise in silver concentration. After 48-96h, the silver levels fluctuated. A maximum zone of inhibition in both bacterial colonised plates (S. aureus and S. epidermidis) was found 39 h after the start of the V.A.C. GranuFoam Silver(®) therapy. CONCLUSION: From our results, we confirmed the antimicrobial effect of the silver ions against S. aureus and S. epidermidis under continuous V.A.C. GranuFoam(®) Silver therapy with a negative pressure of 25 mmHg. Furthermore we could quantify the amounts of silver, which were released from the foam under negative pressure as a function of time.

Phenotype, donor age and gender affect function of human bone marrow-derived mesenchymal stromal cells.

BACKGROUND: Mesenchymal stromal cells (MSCs) are attractive for cell-based therapies ranging from regenerative medicine and tissue engineering to immunomodulation. However, clinical efficacy is variable and it is unclear how the phenotypes defining bone marrow (BM)-derived MSCs as well as donor characteristics affect their functional properties. METHODS: BM-MSCs were isolated from 53 (25 female, 28 male; age: 13 to 80 years) donors and analyzed by: (1) phenotype using flow cytometry and cell size measurement; (2) in vitro growth kinetics using population doubling time; (3) colony formation capacity and telomerase activity; and (4) function by in vitro differentiation capacity, suppression of T cell proliferation, cytokines and trophic factors secretion, and hormone and growth factor receptor expression. Additionally, expression of Oct4, Nanog, Prdm14 and SOX2 mRNA was compared to pluripotent stem cells. RESULTS: BM-MSCs from younger donors showed increased expression of MCAM, VCAM-1, ALCAM, PDGFRß, PDL-1, Thy1 and CD71, and led to lower IL-6 production when co-cultured with activated T cells. Female BM-MSCs showed increased expression of IFN-γR1 and IL-6ß, and were more potent in T cell proliferation suppression. High-clonogenic BM-MSCs were smaller, divided more rapidly and were more frequent in BM-MSC preparations from younger female donors. CD10, ß1integrin, HCAM, CD71, VCAM-1, IFN-γR1, MCAM, ALCAM, LNGFR and HLA ABC were correlated to BM-MSC preparations with high clonogenic potential and expression of IFN-γR1, MCAM and HLA ABC was associated with rapid growth of BM-MSCs. The mesodermal differentiation capacity of BM-MSCs was unaffected by donor age or gender but was affected by phenotype (CD10, IFN-γR1, GD2). BM-MSCs from female and male donors expressed androgen receptor and FGFR3, and secreted VEGF-A, HGF, LIF, Angiopoietin-1, basic fibroblast growth factor (bFGF) and NGFB. HGF secretion correlated negatively to the expression of CD71, CD140b and Galectin 1. The expression of Oct4, Nanog and Prdm14 mRNA in BM-MSCs was much lower compared to pluripotent stem cells and was not related to donor age or gender. Prdm14 mRNA expression correlated positively to the clonogenic potential of BM-MSCs. CONCLUSIONS: By identifying donor-related effects and assigning phenotypes of BM-MSC preparations to functional properties, we provide useful tools for assay development and production for clinical applications of BM-MSC preparations.