Pluripotency of a founding field: rebranding developmental biology.

The field of developmental biology has declined in prominence in recent decades, with off-shoots from the field becoming more fashionable and highly funded. This has created inequity in discovery and opportunity, partly due to the perception that the field is antiquated or not cutting edge. A 'think tank' of scientists from multiple developmental biology-related disciplines came together to define specific challenges in the field that may have inhibited innovation, and to provide tangible solutions to some of the issues facing developmental biology. The community suggestions include a call to the community to help 'rebrand' the field, alongside proposals for additional funding apparatuses, frameworks for interdisciplinary innovative collaborations, pedagogical access, improved science communication, increased diversity and inclusion, and equity of resources to provide maximal impact to the community.

Lineage tracing meets single-cell omics: opportunities and challenges.

A fundamental goal of developmental and stem cell biology is to map the developmental history (ontogeny) of differentiated cell types. Recent advances in high-throughput single-cell sequencing technologies have enabled the construction of comprehensive transcriptional atlases of adult tissues and of developing embryos from measurements of up to millions of individual cells. Parallel advances in sequencing-based lineage-tracing methods now facilitate the mapping of clonal relationships onto these landscapes and enable detailed comparisons between molecular and mitotic histories. Here we review recent progress and challenges, as well as the opportunities that emerge when these two complementary representations of cellular history are synthesized into integrated models of cell differentiation.

The emergence of transcriptional identity in somatosensory neurons.

More than twelve morphologically and physiologically distinct subtypes of primary somatosensory neuron report salient features of our internal and external environments1-4. It is unclear how specialized gene expression programs emerge during development to endow these subtypes with their unique properties. To assess the developmental progression of transcriptional maturation of each subtype of principal somatosensory neuron, we generated a transcriptomic atlas of cells traversing the primary somatosensory neuron lineage in mice. Here we show that somatosensory neurogenesis gives rise to neurons in a transcriptionally unspecialized state, characterized by co-expression of transcription factors that become restricted to select subtypes as development proceeds. Single-cell transcriptomic analyses of sensory neurons from mutant mice lacking transcription factors suggest that these broad-to-restricted transcription factors coordinate subtype-specific gene expression programs in subtypes in which their expression is maintained. We also show that neuronal targets are involved in this process; disruption of the prototypic target-derived neurotrophic factor NGF leads to aberrant subtype-restricted patterns of transcription factor expression. Our findings support a model in which cues that emanate from intermediate and final target fields promote neuronal diversification in part by transitioning cells from a transcriptionally unspecialized state to transcriptionally distinct subtypes by modulating the selection of subtype-restricted transcription factors.

In vitro characterization of the human segmentation clock.

The segmental organization of the vertebral column is established early in embryogenesis, when pairs of somites are rhythmically produced by the presomitic mesoderm (PSM). The tempo of somite formation is controlled by a molecular oscillator known as the segmentation clock1,2. Although this oscillator has been well-characterized in model organisms1,2, whether a similar oscillator exists in humans remains unknown. Genetic analyses of patients with severe spine segmentation defects have implicated several human orthologues of cyclic genes that are associated with the mouse segmentation clock, suggesting that this oscillator might be conserved in humans3. Here we show that human PSM cells derived in vitro-as well as those of the mouse4-recapitulate the oscillations of the segmentation clock. Human PSM cells oscillate with a period two times longer than that of mouse cells (5 h versus 2.5 h), but are similarly regulated by FGF, WNT, Notch and YAP signalling5. Single-cell RNA sequencing reveals that mouse and human PSM cells in vitro follow a developmental trajectory similar to that of mouse PSM in vivo. Furthermore, we demonstrate that FGF signalling controls the phase and period of oscillations, expanding the role of this pathway beyond its classical interpretation in 'clock and wavefront' models1. Our work identifying the human segmentation clock represents an important milestone in understanding human developmental biology.

PITX2 as a Sensitive and Specific Marker of Midgut Neuroendocrine Tumors: Results from a Cohort of 1157 Primary Neuroendocrine Neoplasms.

As neuroendocrine tumors (NETs) often present as metastatic lesions, immunohistochemical assignment to a site of origin is one of the most important tasks in their pathologic assessment. Because a fraction of NETs eludes the typical expression profiles of their primary localization, additional sensitive and specific markers are required to improve diagnostic certainty. We investigated the expression of the transcription factor Pituitary Homeobox 2 (PITX2) in a large-scale cohort of 909 NET and 248 neuroendocrine carcinomas (NEC) according to the immunoreactive score (IRS) and correlated PITX2 expression groups with general tumor groups and primary localization. PITX2 expression (all expression groups) was highly sensitive (98.1%) for midgut-derived NET, but not perfectly specific, as non-midgut NET (especially pulmonary/duodenal) were quite frequently weak or moderately positive. The specificity rose to 99.5% for a midgut origin of NET if only a strong PITX2 expression was considered, which was found in only 0.5% (one pancreatic/one pulmonary) of non-midgut NET. In metastases of midgut-derived NET, PITX2 was expressed in all cases (87.5% strong, 12.5% moderate), whereas CDX2 was negative or only weakly expressed in 31.3% of the metastases. In NEC, a fraction of cases (14%) showed a weak or moderate PITX2 expression, which was not associated with a specific tumor localization. Our study independently validates PITX2 as a very sensitive and specific immunohistochemical marker of midgut-derived NET in a very large collective of neuroendocrine neoplasms. Therefore, our data argue toward implementation into diagnostic panels applied for NET as a firstline midgut marker.

Return to sports and short-term follow-up of 101 cases of medial patellofemoral ligament reconstruction using gracilis tendon autograft in children and adolescents.

INTRODUCTION: An acute patellofemoral dislocation is the most common acute knee injury in children. Recent studies suggest up to 40% of immature patients may develop recurrent instability. MPFL reconstruction has become a mainstay for the treatment of patellofemoral instability. Aim of the recent study is to show our experiences of MPFL reconstruction in patellar instability in immature patients using a gracilis autograft in respect to return to sport, growth plate disorders and short-term results. MATERIALS AND METHODS: A total of 101 patients (50 females, 51 males) were included in this retrospective study. Mean age at time of operation was 14.8 ± 1.6 years. Primary outcome measures included patient satisfaction, Kujala score, recurrent instability, return to normal activity, return to sports, clinical leg axis and complications. Mann-Whitney U test was used for statistical analysis and alpha was set at p < 0.05 to declare significance. RESULTS: At a mean follow-up of 32.0 ± 12.1 months 90/101 patients could be followed-up. 84% of all patients were satisfied or very satisfied with the result at latest follow-up. 86.6% of all patients were able to return to sports, 2.3% had a relevant deviation of the clinical leg axis, but symmetrical. In sum complication rate was 2.9%. Redislocation rate was 0.9% (1/101). Kujala Score improved significantly from 47.1 preoperatively to 85.3 postoperatively (p < 0.01). CONCLUSION: Anatomic MPFL reconstruction using gracilis tendon allograft tissue is a safe procedure in children and adolescents with low risk of recurrent instability.

Internal fixation of radiation-induced fragility fractures of the pelvis: a case series.

BACKGROUND: The optimal treatment for radiation-induced fragility fractures of the pelvis (RI-FFP) is not well evaluated due to the rarity of the condition. PURPOSE: The aim of this retrospective study was to assess the prevalence of RI-FFP, the radiological and clinical outcomes as well as the complications of patients treated with internal fixation. METHODS: A retrospective review of our database was performed to identify all surgically treated patients with RI-FFP. Surgical stabilization was recommended for patients with FFP type III and FFP type IV. Surgical stabilization was also recommended after 5-7 days for patients with FFP type II in case of unsuccessful conservative treatment. Demographic data, fracture patterns according to the FFP classification of Rommens and Hofmann, type of treatment and surgery-related complications including nonunion, hardware failure, fracture progression (secondary fracture) or infection were documented. RESULTS: Among 500 patients with FFP, the prevalence of patients with RI-FFP was 1% (5/500): 5 patients with a median age of 79 years (76-79). The median time interval from radiation to fracture was 18 months (18-24). All of them underwent internal fixation. Two patients experienced surgery-related complications, one due to hardware failure and one due to fracture progression. At median follow-up of 27 months, all fractures had healed. Patients reached a good level of mobility with a median Parker Mobility Score of 7 and suffered moderate pain with a median value of 2.5 on the numeric rating scale. CONCLUSION: RI-FFP remains a rare injury (1%). In our experience, patients, who underwent surgical treatment, obtained a high level of mobility and a moderate pain score after 2 years of follow-up. Internal fixation can be recommended in RI-FFP. Because bone healing may be impaired due to previous irradiation, highly stable constructs are required to avoid fracture progression or revision surgery. LEVEL OF EVIDENCE: III, retrospective study.

Combined Free Flaps for Optimal Orthoplastic Lower Limb Reconstruction: A Retrospective Series.

Background and Objectives: Open fracture of the lower limb can lead to substantial bone and soft tissue damage, resulting in a challenging reconstructive scenarios, especially in presence of bone or periosteal loss, with a relevant risk of non-union. This work analyzes outcomes of using a double approach for orthoplastic reconstruction, adopting the free medial condyle flap to solve the bone defects, associated to a second free flap for specific soft tissue coverage. Indications, outcomes and reconstructive rationales are discussed. Materials and Methods: A retrospective investigation was performed on patients who underwent complex two-flap microsurgical reconstruction from January 2018 to January 2022. Inclusion criteria in this study were the use of a free femoral condyle periostal/bone flap together with a second skin-only flap. Only distal third lower limb reconstructions were included in order to help equalize our findings. Out of the total number of patients, only patients with complete pre- and post-operative follow-up (minimum 6 months) data were included in the study. Results: Seven patients were included in the study, with a total of 14 free flaps. The average age was 49. Among comorbidities, four patients were smokers and none suffered from diabetes. Etiology of the defect was acute trauma in four cases and septic non-union in three cases. No major complications occurred, and all flaps healed uneventfully with complete bone union. Conclusions: Combining a bone periosteal FMC to a second skin free flap for tailored defect coverage allowed achievement of bone union in all patients, despite the lack of initial bone vascularization or chronic infection. FMC is confirmed to be a versatile flap for small-to-medium bone defects, especially considering its use as a periosteal-only flap, with minimal donor site morbidity. Choosing a second flap for coverage allows for a higher inset freedom and tailored reconstruction, finally enhancing orthoplastic success.

[Antiagregants, anticoagulants and proximal femur fracture]. / Antiagrégants, anticoagulants oraux directs et fracture du fémur proximal.

Hip fractures are common in the elderly, particularly due to an increased susceptibility to falls and greater bone frailty, especially in women. The consequences of such events are potentially serious. Early management (< 48 hours) significantly reduces the mortality and postoperative complications. Because of their comorbidities, older people are often on antiplatelet therapy, anticoagulant therapy, or both. However, there are no definitive recommendations for the perioperative management of antiplatelet and anticoagulant treatment in the early surgery of hip fractures. The purpose of this article is to review the management of these patients.

Les fractures de la hanche sont fréquentes chez les personnes âgées, notamment en raison d'une prédisposition accrue aux chutes et d'une plus grande fragilité des os, principalement chez les femmes. Les conséquences de tels événements sont potentiellement graves. Une prise en charge précoce (< 48 heures) diminue de manière significative la mortalité et les complications postopératoires. En raison de leurs comorbidités, les personnes âgées sont souvent sous traitement antiagrégant, anticoagulant ou les deux. Or il n'existe pas de recommandations définitives quant à la gestion périopératoire des traitements antiagrégants et anticoagulants de la chirurgie urgente de la fracture du fémur. Le but de cet article est de faire le point sur la prise en charge de ces patients.

Is there a correlation between pelvic incidence and orientation of the acetabulum? An analysis based on a three-dimensional statistical model of the pelvic ring.

The pelvic ring is a complex anatomical structure building up the connection between the trunk and the legs. Whilst there is a broad discussion in the literature about the dynamic interaction between spine, pelvis and the hip joints, there is still little information about the relation and interaction of the constant pelvic parameters. Based on a three-dimensional (3D) statistical model consisting of 150 uninjured and bony healthy pelves (100 Europeans, 50 Japanese; 81 males, 69 females; average age 74.3 years ± 17.5 years) an evaluation of pelvic incidence (PI) and acetabular orientation in anteversion and inclination was performed and potential correlations of these intraindividual constant parameters were investigated. Pelvic incidence is defined as the angle between the perpendicular to the sacral plate at its midpoint and the line connecting this point to the middle axis of the femoral heads. Acetabular anteversion is defined as the angle between the perpendicular to the best-fit plane on the acetabular rim and the coronal plane measured in strict lateral view. Acetabular inclination is defined as the angle between the perpendicular to the best-fit plane on the acetabular rim and the sagittal plane in strict frontal view. Data were further analysed with regard to different subgroup's age, sex and ethnicity. A positive correlation between PI and acetabular anteversion could be demonstrated. Further, PI and also the acetabular parameters anteversion and inclination were found to be significantly higher in the European individuals than in the Asian. The results of the present study demonstrate a relation between the anatomical configuration of the constant pelvic parameters building up the connection points to the next proximal respectively caudal skeleton section. The findings might lead to more comprehensive treatment strategies in case of trauma or degenerative pathologies of the pelvis in the future.

A small set of conserved genes, including sp5 and Hox, are activated by Wnt signaling in the posterior of planarians and acoels.

Wnt signaling regulates primary body axis formation across the Metazoa, with high Wnt signaling specifying posterior identity. Whether a common Wnt-driven transcriptional program accomplishes this broad role is poorly understood. We identified genes acutely affected after Wnt signaling inhibition in the posterior of two regenerative species, the planarian Schmidtea mediterranea and the acoel Hofstenia miamia, which are separated by >550 million years of evolution. Wnt signaling was found to maintain positional information in muscle and regional gene expression in multiple differentiated cell types. sp5, Hox genes, and Wnt pathway components are down-regulated rapidly after ß-catenin RNAi in both species. Brachyury, a vertebrate Wnt target, also displays Wnt-dependent expression in Hofstenia. sp5 inhibits trunk gene expression in the tail of planarians and acoels, promoting separate tail-trunk body domains. A planarian posterior Hox gene, Post-2d, promotes normal tail regeneration. We propose that common regulation of a small gene set-Hox, sp5, and Brachyury-might underlie the widespread utilization of Wnt signaling in primary axis patterning across the Bilateria.

Loss of MeCP2 in immature neurons leads to impaired network integration.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations or deletions in Methyl-CpG-binding Protein 2 (MeCP2), a brain-enriched transcriptional regulator. MeCP2 is highly expressed during neuronal maturation and its deficiency results in impaired dendritic morphogenesis and reduced dendritic spine numbers in developing neurons. However, whether MeCP2 deficiency impacts the integration of new neurons has not been directly assessed. In this study, we developed a modified rabies virus-mediated monosynaptic retrograde tracing method to interrogate presynaptic integration of MeCP2-deficient new neurons born in the adult hippocampus, a region with lifelong neurogenesis and plasticity. We found that selective deletion of MeCP2 in adult-born new neurons impaired their long-range connectivity to the cortex, whereas their connectivity within the local hippocampal circuits or with subcortical regions was not significantly affected. We further showed that knockdown of MeCP2 in primary hippocampal neurons also resulted in reduced network integration. Interestingly, (1-3) insulin-like growth factor-1 (IGF-1), a small peptide under clinical trial testing for RTT, rescued neuronal integration deficits of MeCP2-deficient neurons in vitro but not in vivo. In addition, (1-3) IGF-1 treatment corrected aberrant excitability and network synchrony of MeCP2-deficient hippocampal neurons. Our results indicate that MeCP2 is essential for immature neurons to establish appropriate network connectivity.

Asymmetry of the pelvic ring evaluated by CT-based 3D statistical modeling.

The human pelvis is a complex anatomical structure that consists of the innominate bones, sacrum and coccyx to form the pelvic ring. Even though considered to be a symmetric entity, asymmetry of the pelvic ring (APR) might occur to alter its anatomy, function, or biomechanics or to impact assessment and treatment of clinical cases. APR and its assessment is complicated by the intricate anatomy of the pelvic ring. There is only limited information and understanding about APR with no established evaluation methods existing. The objective of the present study was to adopt CT-based 3D statistical modeling and analysis to assess APR within the complex anatomy of the pelvic ring. We were interested to establish a better understanding of APR with knowledge and applications transferred to human anatomy, related research, and development subjects and to clinical settings. A series of 150 routine, clinical, pelvic CT protocols of European and Asian males and females (64 ± 15 (20-90) years old) were post-processed to compute gender- and ancestry-specific 3D statistical models of the pelvic ring. Evaluations comprised principal component analysis (PCA) that included size, shape, and asymmetry patterns and their variations to be assessed. Four different CT-based 3D statistical models of the entire pelvic ring were computed according to the gender and ancestry specific groups. PCA mainly displayed size and shape variations. Examination of additional PCA modes permitted six distinct asymmetry patterns to be identified. They were located at the sacrum, iliac crest, pelvic brim, pubic symphysis, inferior pubic ramus, and near to the acetabulum. Accordingly, the pelvic ring demonstrated not to be entirely symmetric. Assessment of its asymmetry proved to be a challenging task. Using CT-based 3D statistical modeling and PCA, we identified six distinct APRs that were located at different anatomical regions. These regions are more prone to APRs than other sites. Minor asymmetry patterns have to be distinguished from the distinct APRs. Side differences with regard to size, shape, and/or position require to be taken into account. APRs may be due different load mechanisms applied via spine or lower extremity or locally. There is a need for simpler and efficient, yet reliable methods to be routinely transferred to human anatomy, related research, and development subjects and to clinical settings.

A multicentre analytical comparison study of inter-reader and inter-assay agreement of four programmed death-ligand 1 immunohistochemistry assays for scoring in triple-negative breast cancer.

AIMS: Studies in various cancer types have demonstrated discordance between results from different programmed death-ligand 1 (PD-L1) assays. Here, we compare the reproducibility and analytical concordance of four clinically developed assays for assessing PD-L1-positivity in tumour-infiltrating immune cells in the tumour area (PD-L1-IC-positivity) in triple-negative breast cancer (TNBC). METHODS AND RESULTS: Primary TNBC resection specimens (n = 30) were selected based on their PD-L1-IC-positivity per VENTANA SP142 (<1%: 15 cases; 1-5%: seven cases; >5%: eight cases). Serial histological sections were stained for PD-L1 using VENTANA SP142, VENTANA SP263, DAKO 22C3 and DAKO 28-8. PD-L1-IC-positivity and tumour cell expression (≥1 versus <1%) were scored by trained readers from seven sites using online virtual microscopy. The adjusted mean of PD-L1-IC-positivity for SP263 (7.8%) was significantly higher than those for the other three assays (3.7-4.9%). Differences in adjusted means were statistically significant between SP263 and the other three assays (P < 0.0001) but not between the three remaining assays when excluding SP263 (P = 0.0961-0.6522). Intra-class correlation coefficients revealed moderate-to-strong inter-reader agreement for each assay (0.460-0.805) and poor-to-strong inter-assay agreement for each reader (0.298-0.678) on PD-L1-IC-positivity. CONCLUSIONS: In this first multicentre study of different PD-L1 assays in TNBC, we show that PD-L1-IC-positivity for SP142, 22C3 and 28-8 was reproducible and analytically concordant, indicating that these three assays may be analytically interchangeable. The relevance of the higher PD-L1-IC-positivity for SP263 should be further investigated.

Unmodified Clay Nanosheets at the Air-Water Interface.

Quasi-two-dimensional (2D) nanolayers, such as graphene oxide or clay layers, adhere to gas-liquid or liquid-liquid interfaces. Particularly, clays are of wide general interest in this context because of their extensive and crucial use as Pickering emulsion stabilizers, as well as for their ability to provide colloidosome capsules. So far, clays could only be localized at oil-water or air-saline-water interfaces in aggregated states, while our results now show that clay nanosheets without any modification can be located at air-deionized-water interfaces. The clay mineral used in the present work is synthetic fluorohectorite with a very high aspect ratio and superior quality in homogeneity and charge distribution compared to other clay minerals. This clay mineral is more suitable for achieving unmodified clay anchoring to fluid interfaces compared to other clay minerals used in previous works. In this context, we studied clay nanosheet organization at the air-water interface by combining different experimental methods: Langmuir-Blodgett trough studies, scanning electron microscopy (SEM) studies of film deposits, grazing-incidence X-ray off-specular scattering (GIXOS), and Brewster angle microscopy (BAM). Clay films formed at the air-water interface could be transferred to solid substrates by the Langmuir-Schaefer method. The BAM results indicate a dynamic equilibrium between clay sheets on the interface and in the subphase. Because of this dynamic equilibrium, the Langmuir monolayer surface pressure does not change significantly when pure clay sheets are spread on the liquid surface. However, also, GIXOS results confirm that there are clay nanosheets at the air-water interface. In addition, we find that clay sheets modified by a branched polymer are much more likely to be confined to the interface.

cbpManager: a web application to streamline the integration of clinical and genomic data in cBioPortal to support the Molecular Tumor Board.

BACKGROUND: Extensive sequencing of tumor tissues has greatly improved our understanding of cancer biology over the past years. The integration of genomic and clinical data is increasingly used to select personalized therapies in dedicated tumor boards (Molecular Tumor Boards) or to identify patients for basket studies. Genomic alterations and clinical information can be stored, integrated and visualized in the open-access resource cBioPortal for Cancer Genomics. cBioPortal can be run as a local instance enabling storage and analysis of patient data in single institutions, in the respect of data privacy. However, uploading clinical input data and genetic aberrations requires the elaboration of multiple data files and specific data formats, which makes it difficult to integrate this system into clinical practice. To solve this problem, we developed cbpManager. RESULTS: cbpManager is an R package providing a web-based interactive graphical user interface intended to facilitate the maintenance of mutations data and clinical data, including patient and sample information, as well as timeline data. cbpManager enables a large spectrum of researchers and physicians, regardless of their informatics skills to intuitively create data files ready for upload in cBioPortal for Cancer Genomics on a daily basis or in batch. Due to its modular structure based on R Shiny, further data formats such as copy number and fusion data can be covered in future versions. Further, we provide cbpManager as a containerized solution, enabling a straightforward large-scale deployment in clinical systems and secure access in combination with ShinyProxy. cbpManager is freely available via the Bioconductor project at https://bioconductor.org/packages/cbpManager/ under the AGPL-3 license. It is already used at six University Hospitals in Germany (Mainz, Gießen, Lübeck, Halle, Freiburg, and Marburg). CONCLUSION: In summary, our package cbpManager is currently a unique software solution in the workflow with cBioPortal for Cancer Genomics, to assist the user in the interactive generation and management of study files suited for the later upload in cBioPortal.

Surgical debridement of infected pubic symphysitis supports optimal outcome.

INTRODUCTION: Infected pubic symphysitis (IPS) is a rare bacterial infection of the pubic symphysis that causes subpubic pain, disability and ultimately permanent immobility. Due to difficult diagnosis, patients present with long-standing complaints and consult several doctors. To date, no validated treatment protocol exists and most patients are treated conservatively with antibiotics. This study was aimed to assess the results after careful surgical debridement and pathogen-specific antibiotic treatment in IPS. MATERIALS AND METHODS: A chart review of eight patients with proven IPS was performed. Five of eight patients filled in a specific own-developed questionnaire and could be examined clinically and radiologically at a mean of 13 months (range: 6-30 months) postoperatively. RESULTS: There were six males and two females with an average age of 69 years (range: 55-80 years). The mean duration of symptoms before surgical treatment was 10.5 months (range: 1-30 months). There were no complications due to the surgical debridement. There was no recurrence of infection at the pubic symphysis during the follow-up period. The most common pathogen was Pseudomonas aeruginosa in three patients. Mean preoperative pain, measured on the visual analogue scale (VAS, range: 0-10) for the four analysed categories in the five follow-up patients was 7.2, 30 days postoperatively 2.7 and 13 months postoperatively 0.4. There was a steady increase in the quality of life (QoL) 30 days postoperatively and at the 13 months follow-up when compared to preoperative values. CONCLUSIONS: Surgical debridement is the keystone for treatment of IPS and should be combined with local and systemic antibiotic therapy.

Using immuno-PET imaging to monitor kinetics of T cell-mediated inflammation and treatment efficiency in a humanized mouse model for GvHD.

PURPOSE: Hematopoietic stem cell transplantation is the only curative treatment for several hematological malignancies and immune deficiency syndromes. Nevertheless, the development of graft-versus-host disease (GvHD) after transplantation is a severe complication with high morbidity and mortality. The aim of this study was to image human T cells during GvHD development and their migration into GvHD-related organs. By using a radiolabeled anti-human CD3 monoclonal antibody (mAb), we were able to visualize GvHD progression in a humanized mouse model. METHODS: Human peripheral blood mononuclear cells (PBMC) were transferred into immunodeficient mice (initially n = 11 mice/group) to induce GvHD. One group additionally received regulatory T cells (Treg) for prevention of GvHD. T cell migration was visualized by sequential small animal PET/MRI using 89Zr-labeled anti-human CD3 mAb. Flow cytometry and immunohistochemistry were used to measure T cell frequencies in relevant organs at different time points after engraftment. RESULTS: Using radiolabeled anti-CD3 mAb, we successfully visualized human T cells in inflamed organs of mice by 89Zr-anti-CD3-PET/MRI. Upon GvHD progression, we observed increased numbers of CD3+ T cells in the liver (22.9% on day 3; 94.2% on day 10) and the spleen (4.4% on day 3; 58.8% on day 10) which correlated with clinical symptoms. The liver showed distinct spot-like lesions representing a strong focal accumulation of T cells. Administration of Treg prior GvHD induction reduced T cell accumulation in the liver from 857 ± 177 CD3+ cells/mm2 to 261 ± 82 CD3+ cells/mm2 and thus prevented GvHD. CONCLUSION: 89Zr-labeled anti-human CD3 mAb can be used as a proof of concept to detect the exact spatio-temporal distribution of GvHD-mediating T cells. In the future, radiolabeled T cell-specific mAb could be employed as a predictive early biomarker during the course of GvHD maybe even before clinical signs of the disease become evident. Furthermore, monitoring T cell migration and proliferation might improve tailored GvHD therapy.

Open reduction and internal fixation of acetabular fractures in patients of old age.

MATERIAL AND METHODS: There is an ongoing debate on which treatment for acetabular fractures in elderly patients is the most appropriate. This study was set up to identify the role of open reduction and internal fixation of acetabular fractures in persons of old age. We retrospectively reviewed the medical charts and radiological data of all patients older than 65 years, who suffered an isolated acetabular fracture and were admitted in our Department between 2010 and 2014 (5-year period). Complications, outcome and mortality were recorded. Of all surviving patients, quality of life (QoL), mobility and independence were graded with European Quality of Life 5 Dimensions 3 Level (EQ-5D-3L), European Quality of Life 5 Dimensions Visual Analogue Scale (EQ-5D-VAS), Numeric Rating Scale (NRS), Elderly Mobility Scale (EMS) and Tinetti Mobility Test (TMT). RESULTS: Seventy patients could be identified. There were 52 men (74%) and 18 women (26%) with a median age of 79.0 years (range: 65-104 years). Forty-six patients (66%) had been treated with open reduction and internal fixation (ORIF), 24 (34%) conservatively. There were negative predictive factors-subchondral impaction, damage to the femoral head and multiple fragments-in 54% of the operative group. With ORIF, an anatomical reduction could be achieved in 27 patients (59%), an acceptable in 18 (39%) and a poor in one (2%). At follow-up, 18 patients (26%) had died and 23 (33%) were not able to participate. The follow-up rate of the surviving operatively treated patients was 77%. Eleven of 46 operated patients (24%) needed a conversion to a total hip arthroplasty (THA). All patients undergoing conversion had imperfect reduction after surgery. No patient in the non-operative group underwent conversion to THA during follow-up. The median follow-up time of operatively treated patients without conversion (n = 17) was 30 months (range, 16-73 months), of patients with THA (n = 9) 30 months after conversion (range, 17-55 months). Quality of reduction correlated to QoL, mobility and independence in all recorded parameters. Patients with secondary THA had similar good outcomes as patients after ORIF without later conversion. Men had better outcome than women. CONCLUSION: ORIF of acetabular fractures in patients of old age results in excellent outcomes at short-term follow-up when anatomical reduction can be achieved. In case of negative predictive factors, ORIF cannot be regarded as a definitive solution, rather as the construction of a stable socket for secondary THA. The decision of therapy should be made dependent on pre-operative radiographic parameters.

Effects of a 12-week home exercise therapy program on pain and neuromuscular activity in patients with patellofemoral pain syndrome.

INTRODUCTION: The aim of this study is to evaluate the effects of a 12-week home exercise therapy program on pain, function and neuromuscular activity of the vastus medialis and vastus lateralis. MATERIALS AND METHODS: Fifty patients with patellofemoral pain syndrome were treated with a 12-week online home exercise program. The primary outcomes of pain and function were assessed at the 12-week follow-up using the Visual Analog Scale and Kujala Score, respectively. Secondary outcomes were the muscle onset time and the ratio of vastus medialis and vastus lateralis during different daily activities. RESULTS: After 12 weeks, patients showed significant (p < 0.05) improvements of 27 points on the Visual Analog Scale and 10 points on Kujala Score. Differences in pre-post comparison regarding both temporal and amplitude-related neurophysiological differences between the vastus medialis and lateralis were only found when the subjects were divided into groups of different electromyographic patterns. Then changes in the pre-post comparison were particularly evident in the patient group with a delayed vastus medialis onset and a lower activity of the vastus medialis compared to the VL. CONCLUSION: Pain and function improved significantly after a home exercise therapy program in patients with patellofemoral pain syndrome. In addition, patients with a delayed onset or reduced activity of the vastus medialis compared to the vastus lateralis experienced a reduction in this imbalance.