Altered placental macrophage numbers and subsets in pregnancies complicated with intrahepatic cholestasis of pregnancy (ICP) compared to healthy pregnancies.

INTRODUCTION: Intrahepatic cholestasis of pregnancy (ICP) can result in adverse outcomes for both mother and fetus. Inflammatory (M1 subset) or anti-inflammatory (M2 subset) macrophage polarisation is associated with various complications of pregnancy. However, the influence of ICP on macrophage numbers and polarisation remains unknown. This study analyses macrophage density and distribution in placentas of patients with ICP compared to controls. Clinical parameters were correlated to macrophage distribution and ursodeoxycholic acid use (UDCA). METHODS: This study included routinely collected placental tissue samples of 42 women diagnosed with ICP and of 50 control pregnancies. Immunohistochemical staining was performed on placental tissue using CD68 antibody as a pan-macrophage marker, CD206 antibody as an M2 and HLA-DR antibody as an M1 macrophage marker. Macrophage density (cells/mm2) and distribution (CD206+/CD68+ or CD206+/CD68+HLA-DR+) in both decidua (maternal tissue) and villous parenchyma (fetal tissue) were compared between groups. Macrophage density and distribution were correlated to clinical parameters for ICP patients. RESULTS: The density of CD68+ macrophages differed significantly between groups in villous parenchyma. In both decidua and villous parenchyma, CD206+/CD68+ ratio was significantly lower in ICP patients compared to controls (p = 0.003 and p=<0.001, respectively). No difference was found based on UDCA use or in CD68+HLA-DR+ cell density. Significant correlations were found between macrophage density and peak serum bile acids and liver enzymes. DISCUSSION: In ICP patients, an immune shift was observed in both decidual and villous tissue, indicated by a lower CD206+/CD68+ ratio. ICP seems to affect placental tissue, however more research is required to understand its consequences.

Evaluation of single domain antibodies as nuclear tracers for imaging of the immune checkpoint receptor human lymphocyte activation gene-3 in cancer.

Recent advancements in the field of immune-oncology have led to a significant increase in life expectancy of patients with diverse forms of cancer, such as hematologic malignancies, melanoma and lung cancer. Unfortunately, these encouraging results are not observed in the majority of patients, who remain unresponsive and/or encounter adverse events. Currently, researchers are collecting more insight into the cellular and molecular mechanisms that underlie these variable responses. As an example, the human lymphocyte activation gene-3 (huLAG-3), an inhibitory immune checkpoint receptor, is increasingly studied as a therapeutic target in immune-oncology. Noninvasive molecular imaging of the immune checkpoint programmed death protein-1 (PD-1) or its ligand PD-L1 has shown its value as a strategy to guide and monitor PD-1/PD-L1-targeted immune checkpoint therapy. Yet, radiotracers that allow dynamic, whole body imaging of huLAG-3 expression are not yet described. We here developed single-domain antibodies (sdAbs) that bind huLAG-3 and showed that these sdAbs can image huLAG-3 in tumors, therefore representing promising tools for further development into clinically applicable radiotracers.

Using a TRAPS upstream transmission detector to verify multileaf collimator positions during dynamic radiotherapy delivery.

With the advancement of high-precision radiotherapy and the increasing use of higher intensity beams, the risk to the patient increases should the radiotherapy machine malfunction. Hence more accurate treatment verification is required. In this paper we provide a solution for real-time monitoring of X-ray beams from radiotherapy linear accelerators using monolithic active pixel sensors. We show that leaf errors can be detected with high precision in static fields and IMRT step and shoot, and accurate leaf tracking is possible in Volumetric Modulated Arc Therapy. The prototype MAPS detector meets the criteria of 1% attenuation acceptable for clinical use.

Building an oncology community of practice to improve cancer care.

Background: Communities of practice (cops) have been shown to be effective models for achieving quality outcomes in health care. Objective: Here, we describe the application of the cop model to the Canadian oncology context. Methods: We established an oncology cop at our urban community hospital and its networks. Goals were to decrease barriers to access, foster collaboration, and improve knowledge of guidelines in cancer care. We hosted 6 in-person multidisciplinary meetings, focusing on screening, diagnosis, and management of common solid tumours. Health care providers affiliated with our hospital were invited to attend and to complete post-meeting surveys. Likert scales assessed whether cop goals were realized. Results: Meetings attracted a mean of 57 attendees (range: 48-65 attendees), with a mean of 84% completing the surveys and consenting to the analysis. Attendees included family physicians (mean: 41%), specialist physicians (mean: 24%), nurses (mean: 10%), and allied health care providers (mean: 22%). Repeat attendance increased during the series, with 85% of attendees at the final meeting having attended 1 or more prior meetings. Across the series, most participants agreed or strongly agreed that the cop reduced barriers (mean: 76.0% ± 7.9%) and improved access to cancer care services (mean: 82.4% ± 8.1%) and subject matter experts (mean: 91.7% ± 4.2%); fostered teamwork (mean: 84.5% ± 6.8%) and a culture of collaboration (mean: 94.8% ± 4.2%); improved knowledge of cancer care services (mean: 93.3% ± 4.8%), standards of practice (mean: 92.3% ± 3.1%), and quality indicators (mean: 77.5% ± 6.3%); and improved cancer-related practice (mean: 88.8% ± 4.6%) and satisfaction in caring for cancer patients (mean: 82.9% ± 6.8%). Participant feedback carried a potential for bias. Conclusions: We demonstrated the feasibility of oncology cops and found that participants perceived their value in reducing barriers to access, fostering collaboration, and improving knowledge of guidelines in cancer care.

Oncology communities of practice: insights from a qualitative analysis.

Background: A community of practice (cop) is formally defined as a group of people who share a concern or a passion for something they do and who learn how to do it better as they interact regularly. Communities of practice represent a promising approach for improving cancer care outcomes. However, little research is available to guide the development of oncology cops. In 2015, our urban community hospital launched an oncology cop, with the goals of decreasing barriers to access, fostering collaboration, and improving practitioner knowledge of guidelines and services in cancer care. Here, we share insights from a qualitative analysis of feedback from participants in our cop. The objective of the project was to identify participant perspectives about preferred cop features, with a view to improving the quality of our community hospital's oncology cop. Methods: After 5 in-person meetings of our oncology cop, participants were surveyed about what the cop should start, stop, and continue doing. Qualitative methods were used to analyze the feedback. Results: The survey collected 250 comments from 117 unique cop participants, including family physicians, specialist physicians, nurses, and allied health care practitioners. Analysis identified participant perspectives about the key features of the cop and avenues for improvement across four themes: supporting knowledge exchange, identifying and addressing practice gaps, enhancing interprofessional collaboration, and fostering a culture of partnership. Conclusions: Based on the results, we identified several considerations that could be helpful in improving our cop. Our findings might help guide the development of oncology cops at other institutions.

Expression of Phosphate Transporters during Dental Mineralization.

The importance of phosphate (Pi) as an essential component of hydroxyapatite crystals suggests a key role for membrane proteins controlling Pi uptake during mineralization in the tooth. To clarify the involvement of the currently known Pi transporters (Slc17a1, Slc34a1, Slc34a2, Slc34a3, Slc20a1, Slc20a2, and Xpr1) during tooth development and mineralization, we determined their spatiotemporal expression in murine tooth germs from embryonic day 14.5 to postnatal day 15 and in human dental samples from Nolla stages 6 to 9. Using real-time polymerase chain reaction, in situ hybridization, immunohistochemistry, and X-gal staining, we showed that the expression of Slc17a1, Slc34a1, and Slc34a3 in tooth germs from C57BL/6 mice were very low. In contrast, Slc34a2, Slc20a1, Slc20a2, and Xpr1 were highly expressed, mostly during the postnatal stages. The expression of Slc20a2 was 2- to 10-fold higher than the other transporters. Comparable results were obtained in human tooth germs. In mice, Slc34a2 and Slc20a1 were predominantly expressed in ameloblasts but not odontoblasts, while Slc20a2 was detected neither in ameloblasts nor in odontoblasts. Rather, Slc20a2 was highly expressed in the stratum intermedium and the subodontoblastic cell layer. Although Slc20a2 knockout mice did not show enamel defects, mutant mice showed a disrupted dentin mineralization, displaying unmerged calcospherites at the mineralization front. This latter phenotypical finding raises the possibility that Slc20a2 may play an indirect role in regulating the extracellular Pi availability for mineralizing cells rather than a direct role in mediating Pi transport through mineralizing plasma cell membranes. By documenting the spatiotemporal expression of Pi transporters in the tooth, our data support the possibility that the currently known Pi transporters may be dispensable for the initiation of dental mineralization and may rather be involved later during the tooth mineralization scheme.

Complications of robotic-assisted laparoscopic surgery distant from the surgical site.

With the ever-increasing popularity of robotic-assisted laparoscopic surgery over the past decades, the literature reporting complications distant from the surgical site involving the use of this technology has also grown. The goal of this non-systematic review is to summarise these reports with a systems-based presentation of these complications. The most commonly observed complications were related to the peripheral nervous system and the most devastating occurring in cardiac and ophthalmic systems. There were no reports of patient complications directly related to the robot itself. While several of the reported complications are not unique to robotic surgery, they are included to maintain awareness of their possibility. The limitation of surgical time, judicious fluid administration, and constant vigilance of patient positioning are all recommended as possible preventative measures.

[Treatment of fibromyalgia syndrome with gamma-hydroxybutyrate : A randomized controlled study]. / Die Behandlung des Fibromyalgiesyndroms mit Gamma-Hydroxybuttersäure : Eine randomisierte, kontrollierte Studie.

BACKGROUND: The etiology of fibromyalgia syndrome is not yet fully understood. Current hypotheses suggest a potential role of gamma-hydroxybutyrate (GHB) in influencing endocrinological abnormalities in patients with fibromyalgia. OBJECTIVE: The aim of the study was to investigate whether low dose GHB as a growth-hormone releasing substance reduces pain intensity and improves depressive mood, physical impairment and sleep quality in outpatients with fibromyalgia. Additionally, adverse events were recorded. MATERIAL AND METHODS: The pilot study was conducted in the outpatient clinic for pain at the clinic for anesthesiology and surgical intensive care of the Charité Universitätsmedizin Berlin. In the study 25 female patients with fibromyalgia according to the criteria of the American College of Rheumatology were randomized into 2 groups. Over 15 weeks patients of the intervention group received 25 mg/kg body weight oral GHB before going to bed and were compared with a placebo control group. In addition, all patients participated in operant behavioral pain treatment in a group setting. Dependent variables were pain intensity, depressive mood, physical impairment and quality of sleep. RESULTS: There were no group differences in the course of pain intensity (p = 0.61), depressive mood (p = 0.16), physical impairment (p = 0.25) and quality of sleep (p = 0.44); however, all symptoms improved across the groups from pretherapy to posttherapy. Low dose GHB did not increase growth hormone blood concentrations. The number of adverse events that were reported more than two times was similar in both groups. DISCUSSION: Administration of low dose GHB did not yield clinical improvements in female outpatients with fibromyalgia. General improvement in the course of treatment may have resulted from operant behavioral pain therapy. Future studies on GHB should control hypothetical risk factors for identification of non-responders.

Radiation endurance in Al2O3 nanoceramics.

The lack of suitable materials solutions stands as a major challenge for the development of advanced nuclear systems. Most issues are related to the simultaneous action of high temperatures, corrosive environments and radiation damage. Oxide nanoceramics are a promising class of materials which may benefit from the radiation tolerance of nanomaterials and the chemical compatibility of ceramics with many highly corrosive environments. Here, using thin films as a model system, we provide new insights into the radiation tolerance of oxide nanoceramics exposed to increasing damage levels at 600 °C -namely 20, 40 and 150 displacements per atom. Specifically, we investigate the evolution of the structural features, the mechanical properties, and the response to impact loading of Al2O3 thin films. Initially, the thin films contain a homogeneous dispersion of nanocrystals in an amorphous matrix. Irradiation induces crystallization of the amorphous phase, followed by grain growth. Crystallization brings along an enhancement of hardness, while grain growth induces softening according to the Hall-Petch effect. During grain growth, the excess mechanical energy is dissipated by twinning. The main energy dissipation mechanisms available upon impact loading are lattice plasticity and localized amorphization. These mechanisms are available in the irradiated material, but not in the as-deposited films.

Selective arterial Embolisation of Aneurysmal Bone Cysts of the Sacrum: a promising Alternative to Surgery.

PURPOSE: The sacrum is a rare but unfavourable location for Aneurysmal Bone Cysts (ABCs), surgical procedures aiming to achieve local tumour control can be mutilating. Aim of this study was to evaluate whether selective arterial embolisation (AE) of ABC of the sacrum is an effective treatment and might be an alternative to surgical treatment options. MATERIALS AND METHODS: Between 2007 and 2011 six patients (mean age 13.7 years, range 8 - 18 years) with an ABC of the sacrum were treated by AE. Follow-up was performed by MRI-scans as well as clinical examination (mean 36.5 months, range 14 - 56 months). RESULTS: No treatment related complications have been observed. AE resulted in devascularisation of ABC and led to local tumour control in all patients. A partial consolidation was noticed in three patients. Pain relief was achieved in five of six patients, neurological deficits dissolved. In two patients more than one embolization was necessary. In one of these patients due to exacerbation of pain a surgical decompression was performed. CONCLUSION: AE of sacral ABCs can serve as an effective and safe treatment option. Thus it might be an alternative to potentially harmful surgical procedures. In case of ongoing tumour growth or pain recurrence AE can be repeated. In case of treatment failure surgical interventions are still possible. KEY POINTS: • transarterial embolisation enables local tumour control in sacral ABCs. • transarterial embolisation of sacral ABCs is a safe procedure. • in case of tumour progression repetitive embolisations are possible and effective.

Epidermal tight junctions in health and disease.

The skin, the largest organ of the body, is an essential barrier that under homeostatic conditions efficiently protects and/or minimizes damage from both environmental (e.g. microorganisms, physical trauma, ultraviolet radiation) and endogenous (e.g., cancers, inflammation) factors. This formidable barrier function resides mainly in the epidermis, a dynamic, highly-stratified epithelium. The epidermis has 2 major barrier structures: stratum corneum, the outmost layer and tight junctions, intercellular junctions that seal adjacent keratinocytes in the stratum granulosum, found below the stratum corneum. In recent years there have been significant advances in our understanding of tight junction function, composition and regulation. Herein we review what is known about tight junctions in healthy skin and keratinocyte culture systems and highlight the dynamic crosstalk observed between tight junctions and the cutaneous immune system. Finally we discuss the preliminary observations suggesting that tight junction function or protein expression may be relevant for the pathogenesis of a number of common cutaneous inflammatory and neoplastic conditions.

Anti-phospholipase A2 receptor antibodies in recurrent membranous nephropathy.

About 70% of patients with primary membranous nephropathy (MN) have circulating anti-phospholipase A2 receptor (PLA2R) antibodies that correlate with disease activity, but their predictive value in post-transplant (Tx) recurrent MN is uncertain. We evaluated 26 patients, 18 with recurrent MN and 8 without recurrence, with serial post-Tx serum samples and renal biopsies to determine if patients with pre-Tx anti-PLA2R are at increased risk of recurrence as compared to seronegative patients and to determine if post-Tx changes in anti-PLA2R correspond to the clinical course. In the recurrent group, 10/17 patients had anti-PLA2R at the time of Tx versus 2/7 patients in the nonrecurrent group. The positive predictive value of pre-Tx anti-PLA2R for recurrence was 83%, while the negative predictive value was 42%. Persistence or reappearance of post-Tx anti-PLA2R was associated with increasing proteinuria and resistant disease in 6/18 cases; little or no proteinuria occurred in cases with pre-Tx anti-PLA2R and biopsy evidence of recurrence in which the antibodies resolved with standard immunosuppression. Some cases with positive pre-Tx anti-PLA2R were seronegative at the time of recurrence. In conclusion, patients with positive pre-Tx anti-PLA2R should be monitored closely for recurrent MN. Persistence or reappearance of antibody post-Tx may indicate a more resistant disease.

Integrated care pathways for airway diseases (AIRWAYS-ICPs).

The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will add value to existing public health knowledge by: 1) proposing a common framework of care pathways for chronic respiratory diseases, which will facilitate comparability and trans-national initiatives; 2) informing cost-effective policy development, strengthening in particular those on smoking and environmental exposure; 3) aiding risk stratification in chronic disease patients, using a common strategy; 4) having a significant impact on the health of citizens in the short term (reduction of morbidity, improvement of education in children and of work in adults) and in the long-term (healthy ageing); 5) proposing a common simulation tool to assist physicians; and 6) ultimately reducing the healthcare burden (emergency visits, avoidable hospitalisations, disability and costs) while improving quality of life. In the longer term, the incidence of disease may be reduced by innovative prevention strategies. AIRWAYSICPs was initiated by Area 5 of the Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing. All stakeholders are involved (health and social care, patients, and policy makers).

[Imaging diagnostics of bone sarcomas]. / Bildgebende Diagnostik der Knochensarkome.

BACKGROUND: Bone tumors and especially bone sarcomas are rare lesions of the skeletal system in comparison to the much more frequently occurring bone metastases. Despite the relative rarity they are important differential diagnoses of bone lesions. OBJECTIVE: The aim of this article is to give the reader an insight into the fundamentals of the primary imaging of bone sarcomas and to illustrate this with the help of two examples (e.g. osteosarcoma and chondrosarcoma). RESULTS: The foundation of the imaging of bone sarcomas is the radiograph in two planes. This method delivers important information on bone tumors. This information should be analyzed with the help of the Lodwick classification, the configuration of periosteal reactions and a possible reaction of the cortex. A possible tumor matrix and the localization within the skeleton or within long bones also provide important information for differential diagnostic delimitation. Magnetic resonance imaging (MRI) with specific adapted bone tumor sequences allows an exact local staging of a bone sarcoma. In addition to local imaging a compartmental MRI which illustrates the entire extent of tumor-bearing bone and the adjacent joints should be performed to rule out possible skip lesions. The most common distant metastases of osteosarcoma and chondrosarcoma occur in the lungs; therefore, a computed tomography (CT) of the chest is part of staging. Other imaging methods, such as CT of the tumor, positron emission tomography CT (PET-CT), bone scan and whole body MRI supplement the imaging depending on tumor type.

De novo membranous nephropathy in renal allograft associated with antibody-mediated rejection and review of the literature.

A 71-year-old woman with unknown renal failure etiology received living donor transplantation had normal graft function for many years. At 11 years from transplantation, she developed nephrotic syndrome. Allograft biopsy showed membranous nephropathy (MN) and C4d positivity in the peritubular capillaries, suggestive of antibody-mediated rejection. At the time of nephrosis onset, she had new donor-specific antibody positivity. The case is unusual in that the diagnosis of de novo MN is based on evidence that she had antibody-mediated rejection. De novo MN remains relatively uncommon; we have reviewed the literature on this diagnosis.

Ewing sarcoma dissemination and response to T-cell therapy in mice assessed by whole-body magnetic resonance imaging.

BACKGROUND: Novel treatment strategies in Ewing sarcoma include targeted cellular therapies. Preclinical in vivo models are needed that reflect their activity against systemic (micro)metastatic disease. METHODS: Whole-body magnetic resonance imaging (WB-MRI) was used to monitor the engraftment and dissemination of human Ewing sarcoma xenografts in mice. In this model, we evaluated the therapeutic efficacy of T cells redirected against the Ewing sarcoma-associated antigen GD2 by chimeric receptor engineering. RESULTS: Of 18 mice receiving intravenous injections of VH-64 Ewing sarcoma cells, all developed disseminated tumour growth detectable by WB-MRI. All mice had lung tumours, and the majority had additional manifestations in the bone, soft tissues, and/or kidney. Sequential scans revealed in vivo growth of tumours. Diffusion-weighted whole-body imaging with background signal suppression effectively visualised Ewing sarcoma growth in extrapulmonary sites. Animals receiving GD2-targeted T-cell therapy had lower numbers of pulmonary tumours than controls, and the median volume of soft tissue tumours at first detection was lower, with a tumour growth delay over time. CONCLUSION: Magnetic resonance imaging reliably visualises disseminated Ewing sarcoma growth in mice. GD2-retargeted T cells can noticeably delay tumour growth and reduce pulmonary Ewing sarcoma manifestations in this aggressive disease model.

Very early recurrence of anti-Phospholipase A2 receptor-positive membranous nephropathy after transplantation.

Membranous nephropathy is a common cause of adult nephrotic syndrome, with recent evidence suggesting that 70% of idiopathic disease is associated with anti-Phospholipase A(2) receptor autoantibodies. We describe a 63-year-old man with membranous nephropathy who underwent a kidney transplant and developed recurrent membranous nephropathy with fine granular co-localization of Phospholipase A(2) receptor and IgG evident on transplant biopsy on day 6 and elevated circulating levels of serum anti-Phospholipase A(2) receptor autoantibody that declined over time in conjunction with improvement in the serum creatinine and urinary protein. This is a very early case of Phospholipase A(2) receptor-associated recurrent membranous nephropathy with circulating anti-Phospholipase A(2) receptor autoantibody, which supports the emerging evidence that idiopathic membranous nephropathy is an autoimmune disease.