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International audience; Microglia and peripheral macrophages have both been implicated in amyotrophic lateral sclerosis (ALS), although their respective roles have yet to be determined. We now show that macrophages along peripheral motor neuron axons in mouse models and patients with ALS react to neurodegeneration. In ALS mice, peripheral myeloid cell infiltration into the spinal cord was limited and depended on disease duration. Targeted gene modulation of the reactive oxygen species pathway in peripheral myeloid cells of ALS mice, using cell replacement, reduced both peripheral macrophage and microglial activation, delayed symptoms and increased survival. Transcriptomics revealed that sciatic nerve macrophages and microglia reacted differently to neurodegeneration, with abrupt temporal changes in macrophages and progressive, unidirectional activation in microglia. Modifying peripheral macrophages suppressed proinflammatory microglial responses, with a shift toward neuronal support. Thus, modifying macrophages at the periphery has the capacity to influence disease progression and may be of therapeutic value for ALS.

Senescent cells accumulate in aging tissues, and their elimination can favor healthy aging1-4. Therefore, therapeutic interventions targeting cellular senescence may be promising strategies for delaying or reversing a vast range of age-related diseases5. As cells of the immune system are responsible for senescent cell elimination6-11, a possible anti-aging and pro-healthspan treatment is the specific activation of the immune system to induce senescent cell clearance. However, whether this elimination is limited by an immune checkpoint leading to tolerance of senescence cells is currently unknown. Here, we show that cellular senescence, elicited by various stressors other than oncogenic activation, triggers immune escape toward natural killer (NK) cells, which may thus limit the use of anti-senescence immunotherapies. Moreover, using mass spectrometry, we reveal that senescent cells reshuffle their glycosphingosine composition, toward a marked increase in the ganglioside content, including the appearance of disialylated ganglioside GD3. This senescence associated GD3 overexpression results from transcriptional upregulation of the gene encoding the enzyme ST8SIA1, which is responsible for GD3 synthesis. The high level of GD3 leads to a strong immunosuppressive signal affecting NK cell-mediated immunosurveillance. In a mouse model of lung fibrosis, senescent cell-dependent NK cell immunosuppression is blunted by in vivo administration of anti-GD3 monoclonal antibodies leading to a clear anti-fibrotic effect. These results demonstrate that GD3 upregulation in senescent cells drives a switch from immune clearance toward immune tolerance of senescent cells. Therefore, we propose that GD3 level acts as a senescence-associated immune checkpoint (SIC) that regulates NK cell functions toward senescent cells. Thus, targeting GD3 with specific antibodies may be a promising strategy for the development of effective anti-senescence immunotherapies.

It is unknown how providing prospective living donors with information about APOL1, including the benefits and drawbacks of testing, influences their desire for testing. In this study, we surveyed 102 participants with self-reported African ancestry and positive family history of kidney disease, recruited from our nephrology waiting room. We assessed views on APOL1 testing before and after presentation of a set of potential benefits and drawbacks of testing and quantified the self-reported level of influence individual benefits and drawbacks had on participants’ desire for testing in the proposed context of living donation. The majority of participants (92%) were aware of organ donation and more than half (56%) had considered living donation. And though we found no significant change in response following presentation of the potential benefits and the drawbacks of APOL1 testing by study end significance, across all participants, “becoming aware of the potential risk of kidney disease among your immediate family” was the benefit with the highest mean influence (3.3±1.4), while the drawback with the highest mean influence (2.9±1.5) was “some transplant centers may not allow you to donate to a loved one”. This study provides insights into the priorities of prospective living donors and suggests concern for how the information affects family members may strongly influence desires for testing. It also highlights the need for greater community engagement to gain a deeper understanding of the priorities that influence decision making on APOL1 testing.

International audience; A high number of biologically active and low-calcemic secosteroidal ligands of the vitamin D receptor (VDR) have been developed, some of which are already used clinically although with limited success in the treatment of hyperproliferative diseases because the required pharmaceutical dosages induce toxicity. We describe here the in silico design, synthesis, structural analysis and biological evaluation of two novel active lithocholic acid derivatives hydroxylated at the side chain as highly potent inhibitors of atopic dermatitis-relevant keratinocyte inflammation of potential therapeutic interest.

The bioethics literature has paid little attention to matters of informed reproductive decision-making among women of childbearing age who have chronic kidney disease (CKD), including women who are on dialysis or women who have had a kidney transplant. Women with CKD receive inconsistent and, sometimes, inadequate reproductive counseling, particularly with respect to information about pursuing pregnancy. We identify four factors that might contribute to inadequate and inconsistent reproductive counseling. We argue that women with CKD should receive comprehensive reproductive counseling, including information about the possibility of pursuing pregnancy, and that more rigorous research on pregnancy in women with CKD, including women on dialysis or who have received a kidney transplant, is warranted to improve informed reproductive decision making in this population.

We report the case of a 23-year-old man with nodal EMH (extramedullary hematopoiesis) occurring during treatment for a stage IIA "gray-zone" lymphoma. Although it is often related to myeloproliferative bone marrow disease, benign etiologies such as lenograstim treatment after chemotherapy can also induce EMH and be responsible for false-positive F-FDG PET/CT examinations. In this respect, GLUT overexpression in hematopoietic lineages and macrophages of the inflammatory environment are responsible for increased F-FDG uptake. Histopathologic confirmation of new hypermetabolic lesions on follow-up PET/CT may be required when the new lesions do not conform with the treatment responses in the preexisting lesions.

Introduction: Tests exist for ApoL1 genetic variants to determine whether a potential donor’s kidneys are at increased risk of kidney failure. Variants of the ApoL1 gene associated with increased risk are primarily found in people with West African ancestry. Given uncertainty about clinical implications of ApoL1 test results for living kidney donors and recipients and the lack of uniform guidelines for ApoL1 testing, transplant centers across the United States vary in ApoL1 testing practices. Research Questions: (1) What approach do transplant centers take to determine whether prospective donors are of West African ancestry? (2)How do transplant centers engage potential donors during the ApoL1 testing process? (3) What do transplant centers identify as concerns and barriers to ApoL1 testing? and (4) What actions do transplant centers take when a potential donor has 2 ApoL1 risk variants? Design: We explored the current practices of transplant centers by surveying nephrologists and transplant surgeons at transplant centers evaluating the majority of black living donors in the United States. Results: About half of these transplant centers offered ApoL1 testing. Of those who offered ApoL1 testing, only half involved the donor in decision-making about donation when the donor has 2 risk variants. Discussion: Unaddressed differences in the priorities of transplant centers and black living donors may stigmatize black donors and undermine trust in the health-care and organ donation systems. Variation in transplant center testing practices points to the critical need for further research and community engagement to inform the development of guidelines for ApoL1 testing.

Introduction Much of the higher risk for end-stage kidney disease (ESKD) in African American individuals relates to ancestry-specific variation in the apolipoprotein L1 gene (APOL1). Relative to kidneys from European American deceased-donors, kidneys from African American deceased-donors have shorter allograft survival and African American living-kidney donors more often develop ESKD. The National Institutes of Health (NIH)–sponsored APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) is prospectively assessing kidney allograft survival from donors with recent African ancestry based on donor and recipient APOL1 genotypes. Methods APOLLO will evaluate outcomes from 2614 deceased kidney donor-recipient pairs, as well as additional living-kidney donor-recipient pairs and unpaired deceased-donor kidneys. Results The United Network for Organ Sharing (UNOS), Association of Organ Procurement Organizations, American Society of Transplantation, American Society for Histocompatibility and Immunogenetics, and nearly all U.S. kidney transplant programs, organ procurement organizations (OPOs), and histocompatibility laboratories are participating in this observational study. APOLLO employs a central institutional review board (cIRB) and maintains voluntary partnerships with OPOs and histocompatibility laboratories. A Community Advisory Council composed of African American individuals with a personal or family history of kidney disease has advised the NIH Project Office and Steering Committee since inception. UNOS is providing data for outcome analyses. Conclusion This article describes unique aspects of the protocol, design, and performance of APOLLO. Results will guide use of APOL1 genotypic data to improve the assessment of quality in deceased-donor kidneys and could increase numbers of transplanted kidneys, reduce rates of discard, and improve the safety of living-kidney donation., Graphical abstract

The presence of 2 apolipoprotein L1 gene (APOL1) risk variants is associated with increased risk for chronic kidney disease and end-stage kidney disease. Inferior allograft outcomes following transplantation with kidneys from donors with 2 risk variants have also been reported. These data, coupled with anecdotal case reports and a recent cohort study of living donors, raise important questions about the potential increased kidney disease risk for living donors with APOL1 risk variants and the need for testing as part of the standard living donor evaluation process. We identify a series of questions that are central to the development of clinical policy regarding APOL1 testing of potential living kidney donors given the current uncertainty over the clinical implications of having 2 risk variants. We explore the ethical challenges that arise when determining when and to whom APOL1 testing should be offered, what potential donors should be told about APOL1 testing, how test results should be used to determine suitability for donation, if and when recipients should have access to results, and how clinical policy regarding APOL1 testing should be established.

Background This paper describes the use of real-time magnetic resonance imaging to simultaneously obtain magnetic resonance imaging (MRI) videos in both a sagittal and coronal plane during the performance of a musical exercise in five advanced trombone players. Methods Dual-slice recordings were implemented in a frame-interleaved manner with 20 ms acquisitions per frame to achieve two interleaved videos at a rate of 25 frames per second. A customized MATLAB toolkit was used for the extraction of line profiles from MRI videos to quantify tongue movements associated with exercise performance from both perspectives. Results Across all subjects, the analyses revealed precise coupling of vertical movements of the dorsal tongue surface (DTS), viewed from a sagittal perspective, with reduction in the vertical and horizontal dimensions of the air channel formed between the DTS and the hard palate, viewed from a coronal perspective. The cross-correlation between these movements was very strong (mean R=0.967). Conclusions These results demonstrate the unique utility of this dual-slice technology in describing the coordination of complex tongue movements occurring in two planes (i.e., three directions) simultaneously, lending a deeper understanding of lingual motor control during trombone performance.

Introduction Conflicting evidence exists regarding the definitive management of destructive colon injuries. Although diversion with an end ostomy can theoretically decrease initial complications, it mandates a more extensive reversal procedure. Conversely, anastomosis with proximal loop ostomy diversion, while simplifying the reversal, increases the number of suture lines and potential initial morbidity. Thus, the purpose of this study was to evaluate the impact of diversion technique on morbidity and mortality in patients with destructive colon injuries. Methods Consecutive patients with destructive colon injuries managed with diversion from 1996 to 2016 were stratified by demographics, severity of shock and injury, operative management, and timing of reversal. Outcomes, including ostomy complications (obstruction, ischemia, readmission) and reversal complications (obstruction, abscess, suture line failure, fascial dehiscence), were compared between patients managed with a loop versus end colostomy. Patients with rectal injuries and who died within 24 hours were excluded. Results A total of 115 patients were identified: 80 with end colostomy and 35 with loop ostomy. Ostomy complications occurred in 22 patients (19%), and 11 patients (10%) suffered reversal complications. There was no difference in ostomy-related (2.9% vs. 3.8%, p = 0.99) mortality. For patients without a planned ventral hernia (PVH), there was no difference in ostomy complications between patients managed with a loop versus end colostomy (12% vs. 18%, p = 0.72). However, patients managed with a loop ostomy had a shorter reversal operative time (95 vs. 245 minutes, p = 0.002) and reversal length of stay (6 vs. 10, p = 0.03) with fewer reversal complications (0% vs. 36%, p = 0.02). For patients with a PVH, there was no difference in outcomes between patients managed with a loop versus end colostomy. Conclusion For patients without PVH, anastomosis with proximal loop ostomy reduced reversal-related complications, operative time, LOS, and hospital charges without compromising initial morbidity. Therefore, loop ostomy should be the preferred method of diversion, if required, following destructive colon injury. Level of evidence Therapeutic, level IV.

Purpose There is a limited understanding of factors that influence the efficacy of topical glaucoma medication. Our study is a long-term, case-control analysis of how systemic antihypertensive (anti-HTN) medications influence the change in IOP after initiating prostaglandin (PG) drop therapy. Materials and methods A retrospective chart review of 3,781 patients was performed on patients with a diagnosis of glaucoma suspect that progressed to primary open-angle glaucoma (POAG) by ICD-9 codes over a 10-year period. Inclusion criteria consisted of the following: 1) progression from preglaucoma to glaucoma diagnosis in a time span of ≥6 months; 2) two visual fields recorded between these dates; 3) initial average IOP of both eyes of ≥21 mmHg; and 4) initiation of topical PG therapy alone. IOP (in mmHg) was measured at initiation of PG drops and at next visit. Results One hundred eleven patients were qualified for analysis. Patients not on anti-HTN agents had an average IOP decrease of 6.38±0.56 mmHg. Comparatively, patients on anti-HTN agents had an average IOP decrease of 6.66±0.48 mmHg (P=0.61). In addition, there was no statistical difference between IOP decrease between patients on single vs multiple systemic anti-HTN agents (P=0.85). There were eight nonresponders to PGs on no anti-HTN medications and 12 nonresponders on anti-HTN medication (P=0.55). Conclusion Systemic anti-HTN medication use did not significantly impact IOP reduction after topical PG initiation for POAG. Additionally, nonresponse to PG therapy was not correlated to systemic anti-HTN use.

The hypercalcemic effects of the hormone 1α,25-dihydroxyvitamin D3 (calcitriol) and most of known vitamin D metabolites and analogs call for the development of non secosteroidal vitamin D receptor (VDR) ligands as new selective and noncalcemic agonists for treatment of hyperproliferative diseases. We report on the in silico design and stereoselective synthesis of six lithocholic acid derivatives as well as on the calcemic activity of a potent LCA derivative and its crystallographic structure in complex with zVDR LBD. The low calcemic activity of this compound in comparison with the native hormone makes it of potential therapeutic value. Structure-function relationships provide the basis for the development of even more potent and selective lithocholic acid-based VDR ligands.

International audience; X-ray-induced photodynamic therapy is based on the energy transfer from a nanoscintillator to a photosensitizer molecule, whose activation leads to singlet oxygen and radical species generation, triggering cancer cells to cell death. Herein, we synthesized ultra-small nanoparticle chelated with Terbium (Tb) as a nanoscintillator and 5-(4-carboxyphenyl succinimide ester)-10,15,20-triphenyl porphyrin (P1) as a photosensitizer (AGuIX@Tb-P1). The synthesis was based on the AGuIX@ platform design. AGuIX@Tb-P1 was characterised for its photo-physical and physico-chemical properties. The effect of the nanoparticles was studied using human glioblastoma U-251 MG cells and was compared to treatment with AGuIX@ nanoparticles doped with Gadolinium (Gd) and P1 (AguIX@Gd-P1). We demonstrated that the AGuIX@Tb-P1 design was consistent with X-ray photon energy transfer from Terbium to P1. Both nanoparticles had similar dark cytotoxicity and they were absorbed in a similar rate within the cells. Pre-treated cells exposure to X-rays was related to reactive species production. Using clonogenic assays, establishment of survival curves allowed discrimination of the impact of radiation treatment from X-ray-induced photodynamic effect. We showed that cell growth arrest was increased (35%-increase) when cells were treated with AGuIX@Tb-P1 compared to the nanoparticle doped with Gd

BackgroundCovid-19 affects mainly the respiratory tract but extra-pulmonary manifestations have been reported including neurologic disorders. Stroke is uncommonly reported in hospitalized patients with Covid-19. To assess the real burden of stroke during Covid-19 we performed a single-center review of stroke among patients with laboratory-confirmed Covid-19.MethodsWe retrospectively searched Colmar Hospital’s database for all the patients with laboratory confirmed Covid-19 who had a stroke between March 3 and April 21, 2020. Results We report seven cases (mean age 73 years) of ischemic stroke among 674 patients hospitalized for laboratory-confirmed coronavirus disease 2019 (Covid-19). Three patients experienced a stroke during hospitalization, and four patients were tested positive 24 h after their admission for stroke. Patients with stroke experienced a predominance of cardioembolic mechanisms, high levels of inflammatory markers, and procoagulative states. ConclusionIschemic stroke is a serious threat in patients with Covid-19, mainly due to an embolic mechanism and cardiologists and neurologists must collaborate in management and prevention of stroke during the Covid-19 pandemic

Background and Objective: Sustained-release dexamethasone intravitreal implant is an effective treatment for macular edema secondary to retinal vein occlusion (RVO) but ocular hypertension is a side effect. This study evaluated whether the addition of a single combination IOP-lowering medication will reliably control intraocular pressure (IOP) for those patients. Study Design/Patients and Methods: Retrospective chart review of 62 patients that underwent multiple injections of combination anti-VEGF and sustained-release dexamethasone intravitreal implant for macular edema secondary to RVO. IOP spikes were treated with brimonidine 0.2% - timolol 0.5%. IRB approval was obtained. Results: The average elevated IOP requiring treatment was 28.6 mmHg. The average IOP after adding brimonidine 0.2% - timolol 0.5% was 16.7 mmHg. 100 percent of treatment cycles had an IOP< 30 mmHg after starting treatment. Conclusions: Using one combination IOP-lowering drop can reliably control the ocular hypertension that occurs secondary to combination therapy for macular edema in RVO.

20S-hydroxyvitamin D3 [20S(OH)D3] is anti-inflammatory and not hypercalcemic, suggesting its potential as a lead compound. In this study, side chain modified 20S(OH)D3 analogs (4, 13, 23 and 33) together with their 1α-OH derivatives were synthesized and their metabolism and biological activities tested. 4, 13 and 23 are good substrates for CYP27B1, enabling enzymatic synthesis of their 1α-OH derivatives 5, 14 and 24. However, 33 could not be hydroxylated by CYP27B1 and acts as an inhibitor. All analogs were poorer substrates for CYP24A1 than calcitriol, indicating improved catabolic stability. While the parent analogs showed minimal VDR stimulating activity, their 1α-OH derivatives were potent VDR agonists. 4, 5, 14 and 24 significantly upregulated the expression of CYP24A1 at the mRNA level, consistent with their VDR activation abilities and indicating that 1α-hydroxylation is required to produce analogs with strong activity. These analogs have anti-inflammatory activities that are influenced by side chain composition and by 1α-hydroxylation. To understand their molecular interactions with the VDR, 20S(OH)D3, 4 and 33 were co-crystalized with the VDR ligand binding domain, which revealed subtle differences to the calcitriol-bound receptor. This study demonstrates the potential of the 20S(OH)D3 scaffold for the development of novel anti-inflammatory agents.

OBJECTIVE: Movements inside the oral cavity during lip trilling in horn-playing are poorly understood and controversial, particularly with respect to pedagogy. Developments in real-time magnetic resonance imaging (RT-MRI) allow representations of oral cavity movement during lip trill performance on a MRI-compatible horn to be recorded and quantified. METHODS: We present RT-MRI data on 11 highly skilled horn players obtained from serial images acquired at acquisition times of 33.3, 18.2, and 10.0 ms (i.e., at 30, 55 and 100 frames/sec) as they performed sixteenth note, whole-step trills between Eb4 and F4 (concert pitch) at two tempos, ~60 bpm and as fast as possible. RESULTS: For fast trilling (mean speed 178.3±24.7 bpm), 7 of 11 subjects exclusively utilized a tongue movement strategy, 3 used both a tongue and jaw strategy, and 1 exclusively used a jaw strategy. For trilling at ~60 bpm, all 11 subjects used a tongue movement strategy. CONCLUSIONS: We suggest using these movement strategies in teaching whole-step trills.

There is growing interest in offering vascularized composite allografts (VCAs) to children, particularly upper extremity and face transplants. This review identifies ethical issues that must be addressed as VCA programs consider including more children and adolescents. The primary ethical concern in pediatric VCA is that the potential benefits might not justify the risks. Other issues involve eligibility criteria, informed permission and assent, authorizing donations and procuring VCAs, donor and recipient privacy and confidentiality, oversight and evaluation of transplants, and cost-effectiveness and resource allocation. A final concern is the obligation to avoid unfairly denying children and adolescents access to research participation and the benefits of research findings. While some observers find the uncertainty and risk of harm too great to expand access to VCA in minors, others disagree. Ethical concerns, particularly those related to the risks relative to potential benefits, may be the primary barrier to pediatric VCA. Carefully developed guidance and policy can facilitate the ethical inclusion and exclusion of children and adolescents from VCA protocols.

OBJECTIVE: The functional role of the glottis in brass performance is poorly understood and controversial, particularly with respect to pedagogy. Technological limitations have prevented the non-invasive, systematic study of the glottis in the past, but developments in real-time magnetic resonance imaging (RT-MRI) allow representations of glottal movement during performance on a MRI-compatible horn to be recorded and quantified. METHODS: We present RT-MRI data obtained on 6 advanced-level horn players from serial images acquired at an acquisition time of 33.3 ms as they performed sustained note exercises on three notes (concert Eb2, Eb4, and Bb4) at each of three dynamics (pp, mf, and ff) and a staccato exercise. An advanced-level trumpet player was also studied performing a modification of the staccato exercise designed to minimize vertical movement of the larynx. Glottal movements and positions in the coronal plane were analyzed using a customized MATLAB toolkit. RESULTS: In sustained note playing, there is a significant influence of dynamic on the degree of glottal adduction/abduction. There is greater adduction with softer notes, and greater abduction with louder notes. In slow staccato playing, glottal closure accompanies the cessation of each note and persists until iteration of the next note in the sequence. CONCLUSIONS: We demonstrate that RT-MRI provides a suitable method to identify and quantify glottal movement during horn playing. We further show that there is a direct relationship between dynamic level and glottal adduction/abduction, and that the glottis is involved in performing notes during slow staccato playing.

This symposium includes 12 personal narratives from individuals who have faced a cancer diagnosis-either their own or their child's-where the disease itself, or their treatment, threatened future fertility. Three additional stories are available in the online supplement. Three commentaries on these narratives are written by an expert in oncofertility, a healthcare ethicist, and a pediatrician completing a fellowship in hematology/oncology. The observations and insights these authors share underscore the importance of addressing fertility loss and preservation early in the cancer journey. These contributions will help clinicians better understand the significance of fertility issues for children and younger adults diagnosed with cancer. They also can contribute to policy discussions about the role of health insurance in meeting the needs of cancer patients. Patients and families reading these stories and commentaries will appreciate learning from the experiences of others.

Recent advances in uterus transplantation (UTx) suggest it is on a trajectory toward becoming an accepted clinical practice to treat absolute uterine factor infertility (AUFI). Additional uses have been envisioned but not studied. UTx programs thus far have relied largely on ethical frameworks associated with clinical research, surgical innovation, organ transplantation, and assisted reproductive technologies, as reflected in the Revised Montreal Criteria and the Indianapolis Consensus. This article argues that it is time to develop integrated guidelines that incorporate existing evidence, acknowledge and address tensions among the ethical frameworks that have informed judgments of UTx for AUFI thus far, identify and address ethical questions on which existing frameworks are silent, and anticipate future ethical issues in UTx research.

BackgroundThe embouchure of trumpet players is of utmost importance for tone production and quality of playing. It requires skilled coordination of lips, facial muscles, tongue, oral cavity, larynx and breathing and has to be maintained by steady practice. In rare cases, embouchure dystonia (EmD), a highly task specific movement disorder, may cause deterioration of sound quality and reduced control of tongue and lip movements. In order to better understand the pathophysiology of this movement disorder, we use real-time MRI to analyse differences in tongue movements between healthy trumpet players and professional players with embouchure dystonia.MethodsReal-time MRI videos (with sound recording) were acquired at 55 frames per second, while 10 healthy subjects and 4 patients with EmD performed a defined set of exercises on an MRI-compatible trumpet inside a 3 Tesla MRI system. To allow for a comparison of tongue movements between players, temporal changes of MRI signal intensities were analysed along 7 standardized positions of the tongue using a customised MATLAB toolkit. Detailed results of movements within the oral cavity during performance of an ascending slurred 11-note harmonic series are presented.ResultsPlaying trumpet in the higher register requires a very precise and stable narrowing of the free oral cavity. For this purpose the anterior section of the tongue is used as a valve in order to speed up airflow in a controlled manner. Conversely, the posterior part of the tongue is much less involved in the regulation of air speed. The results further demonstrate that healthy trumpet players control movements of the tongue rather precisely and stable during a sustained tone, whereas trumpet players with EmD exhibit much higher variability in tongue movements.ConclusionControl of the anterior tongue in trumpet playing emerges as a critical feature for regulating air speed and, ultimately, achieving a high-quality performance. In EmD the observation of less coordinated tongue movements suggests the presence of compensatory patterns in an attempt to regulate (or correct) pitch. Increased variability of the anterior tongue could be an objective sign of dystonia that has to be examined in further studies and extended to other brass instruments and may be also a potential target for therapy options.

Background: In French Polynesia, thyroid cancer mortality and incidence is reported to be the highest in the world. Excessive levels of non-essential trace elements (nETE) in the body are associated with several types of cancer. Objective: The present study aims to provide quantitative information on food contamination by mercury (Hg), lead (Pb), arsenic (As) and cadmium (Cd) in French Polynesia and its potential correlation with measurements performed in fingernails of Polynesians, and then to investigate the potential association between these nETE and different thyroid cancer risks. Methods: The study population included 229 interviewed cases and 373 interviewed controls We performed a descriptive analysis of Polynesian food and examined the association between thyroid cancer risk and daily intake levels of nETE and with fingernail nETE levels. Results: Hg contamination was mainly present in sea products, Pb contamination was present in almost all samples, Cd was detectable in starchy food and As was detectable in all sea products. No patient exceeded dietary contamination WHO limits for Pb, 2 participants exceeded it for Hg and 3 individuals (0.5%) for cadmium. In fingernail clippings, the most detectable pollutant was Pb (553 participants), then Hg (543 participants) then Cd (only in 130 participants). Thyroid cancer risk was increased more than 4 times by Pb daily intake in patients with a history of cancer in first-degree relatives than in ones without (p for interaction =0.01), and 2 times more in women with more than 3 pregnancies than in those with none or less (p for interaction =0.005); it was also increased following As intake by more than 30% in patients with a history of cancer in first-degree relatives than in ones without (p for interaction =0.05). Conclusion: Locally produced foods are not a source of nETE exposure in French Polynesia. Dieatry nETE exposure and fingernail nETE concentration are not associated to differentiated thyroid cancer risk. No correlation found between nETE dietary exposure and fingernail nETE concentration.

International audience; Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with strong immunosuppressive activity that promote tumor growth. In this study, we describe a mechanism by which cancer cells control MDSCs in human cancers by upregulating TRF2, a protein required for telomere stability. Specifically, we showed that the TRF2 upregulation in cancer cells has extratelomeric roles in activating the expression of a network of genes involved in the biosynthesis of heparan sulfate proteoglycan, leading to profound changes in glycocalyx length and stiffness, as revealed by atomic force microscopy. This TRF2-dependent regulation facilitated the recruitment of MDSCs, their activation via the TLR2/MyD88/IL-6/STAT3 pathway leading to the inhibition of natural killer recruitment and cytotoxicity, and ultimately tumor progression and metastasis. The clinical relevance of these findings is supported by our analysis of cancer cohorts, which showed a correlation between high TRF2 expression and MDSC infiltration, which was inversely correlated with overall patient survival.

The language of ethics expertise has become particularly important in bioethics in light of efforts to establish the value of the clinical ethics consultation (CEC), to specify who is qualified to function as a clinical ethics consultant, and to characterize how one should evaluate whether or not a person is so qualified. Supporters and skeptics about the possibility of ethics expertise use the language of ethics expertise in ways that reflect competing views about what ethics expertise entails. We argue for clarity in understanding the nature of expertise and ethics expertise. To be an ethics expert, we argue, is to be an expert in knowing what ought to be done. Any attempt to articulate expertise with respect to knowing what ought to be done must include an account of ethics that specifies the nature of moral truth and the means by which we access this truth or a theoretical account of ethics such that expertise in another domain is linked to knowing or being better at judging what ought to be done and the standards by which this "knowing" or "being better at judging" is determined. We conclude with a discussion of the implications of our analysis for the literature on ethics expertise in CEC. We do think that there are clear domains in which a clinical ethics consultant might be expert but we are skeptical about the possibility that this includes ethics expertise. Clinical ethics consultants should not be referred to as ethics experts.

A growing number of U.S. stem cell clinics treat a variety of illnesses and injuries, yet few have conducted the necessary clinical research to ensure safety and efficacy. The authors highlight the importance of collaboration between scientists, regulators, patients and patient advocates in developing effective policies and practices for unproven stem cell-based intervention clinics.

OBJECTIVE: Embouchure dystonia (EmD) is a variant of focal task-specific dystonia in musicians characterized by the loss of control in facial and oral muscles while controlling airflow into the mouthpiece of a wind or brass instrument. We compared tongue position variability (TPV) during sustained notes between healthy, elite horn players and horn players affected by EmD. METHODS: Real-time MRI films at 33.3 ms resolution were obtained from 8 healthy elite and 5 EmD horn players as they performed on a non-ferromagnetic horn at each of three different dynamic levels: pianissimo, mezzo forte, and fortissimo. Nine profile lines (3 from anterior, 3 from middle, and 3 from posterior oral cavity regions) were overlaid on each image using a customized MATLAB toolkit, and the variability of the dorsal tongue edge position was examined at each dynamic from temporal intensity profiles produced by MATLAB. RESULTS: Despite trends for more pronounced TPV (larger standard deviations) in the elite musicians (p=0.062), 2-way repeated measures ANOVA revealed no significant differences between groups. However, dynamic level significantly influenced TPV for all subjects, combined (p=0.048) and different regions of the oral cavity showed differing TPV (p EmD, p

Objectives There are little data regarding the practice of electroconvulsive therapy (ECT) in correctional settings in the United States. A survey was conducted to study the current practice of ECT in US prisons. We hypothesize that ECT is underutilized in the correctional setting. We also review the ethical aspects of using ECT for the treatment of mental illness in the prison population. Methods A 12-question survey via a Survey Monkey link was emailed to chiefs of psychiatry, or the equivalent, of each state's department of corrections. We examined the frequency of Likert-type responses, tabulated individual comments for qualitative review, and grouped for comparison. Results Email contacts for chiefs of psychiatry, or the equivalent, for the department of corrections in 45 states (90%) were obtained and a survey link was sent. Thirty-one (68.9%) of 45 responded to the survey. Respondent estimates of the number of inmates with mental illness in 31 prison systems varied from less than 500 to more than 4500. Of these 31, 12 (38.7%) had more than 4500 inmates with mental illness. Four systems reported the use of ECT within the last 5 years. Of those, one reported use in the last 1 to 6 months, and 3 reported use in the last 2 to 5 years. Of these 4 prison systems, all felt that they had up to 10 patients who would benefit if ECT continued to be offered or became available in the future. None of these systems provided ECT within the prison. The inmates were referred to a local state psychiatric facility, a university hospital, or other institutions. The reasons for not using ECT as reported by the respondents are grouped under subheadings of stigma, ethical concerns, logistical concerns, and others. Conclusions Considering the high prevalence of mental illness in prisons, one might expect a high prevalence of ECT responsive mental illness and, hence, provision of ECT to some prisoners with mental illness. However, our survey suggests that the use of ECT in prisons in the United States is low. Stigma, ethical concerns, and logistical concerns were the main hindrances for providing ECT to prisoners with mental illness. Given that ECT is the standard of care in certain clinical scenarios, physicians are obligated to offer such treatment to inmates when necessary. It can be argued that failure of the prison to offer the standard of care is unethical and unconstitutional.

This paper describes the use of real-time MRI at 30 frames/s in studying motor function within the oropharyngeal cavity of a trumpet, horn, trombone, and tuba player. Using Image J and customized MB-Ruler Pro software, analyses of discrete 33.3 ms snapshots of motion extracted from real-time MRI films obtained during an ascending five note sequence performed on a plastic practice device (B.E.R.P.) revealed inter-instrument differences in oropharyngeal cavity size and tongue conformation when moving from lower to higher notes. Tuba and trombone show a progressive decrease in oropharyngeal area featuring an upward and forward displacement of the tongue. Trumpet showed progressive increases in oropharyngeal area, with the posterior compartment showing the largest change, while horn essentially showed no change. A novel dynamic quantitative analysis method is also described utilizing Matlab. This method employs user-specified line profiles, aligned to the direction of the movement of interest. It takes advantage of time-varying pixel luminescence to derive spatial and temporal gradients. These gradients make possible the acquisition of kinematic data to describe movement in terms of slower position changes (spatial gradient) as well as fast, articulatory movements (temporal gradient). Spatial gradient analysis for the trumpet player demonstrates a progressive raising of the tongue during the ascending five note exercise. Temporal gradient analysis of double-tonguing revealed similarities in range of motion, anti-phase behavior, and frequency across instruments with respect to movements of the tongue tip and back of tongue. The paper concludes by making recommendations for extending these methods to studying musician’s dystonia.

International audience; Optimal salvage chemotherapy regimen for patients with relapsed or refractory Hodgkin and non-Hodgkin lymphoma remains unclear but often based on platinum regimens. This retrospective study assesses in real life the toxicities profiles of patients with relapsed or refractory lymphoma treated with DHA (dexamethasone, high dose aracytine cytarabine) plus platinum salt (dexamethasone-High dose aracytine (cis)platin (DHAP), dexamethasone-High dose aracytine carboplatin (DHAC), or dexamethasone-High dose aracytine Oxaliplatin (DHAOX)), from February 2007 to May 2013 in 2 French hospitals. Toxicities were recorded from medical files and assessed according to the National Cancer Institute Common Toxicity Criteria version 3.0. Potential risk factors of renal insufficiency were tested by univariate analyses. A total of 276 patients were treated: 168 with DHAP (60.9%), 79 with DHAOX (28.6%), and 29 with DHAC (10.5%). Rituximab was associated in 80.1% of patients (n = 221). Renal failure was reported in 97 patients, mainly with cisplatin regimen (86.6%) leading to 8.9% grade III to IV renal failure (P = .001). Renal insufficiency was reversible in most patients but remained persistent in 24, with all of them being treated with DHAP except 1. Cisplatin-based regimen (50.0% versus 12.0%, P \\textless .05) and female (44.6% versus 29.7%, P \\textless .05) appeared to be at higher risks of renal failure. Platinum cumulative dose is a significant risk factor of nephrotoxicity. Hematologic toxicity was more frequent with carboplatin and cisplatin with at least 1 event (all toxicity grade) respectively in 79.3% and 71.4% of patients treated (P \\textless .005). Auditory toxicity was mainly reported with cisplatin (n = 19; 4 grade I-II and 15 grade III-IV). Oxaliplatin was implicated in 77.6% of neurotoxicity (n = 59), mainly moderate (grade I-II). In conclusion, DHAOX and DHAC regimens have more favorable toxicity profile than DHAP regimen. Their lack of renal toxicity makes them attractive regimens, which may be interesting for patients eligible for autologous stem cell transplantation. Nevertheless, these results have to be confirmed by the therapeutic efficacy of these 3 regimens

International audience; Bone marrow (BM)-derived mesenchymal stromal cells (MSCs) frequently display alterations in several hematologic disorders, such as acute lymphoid leukemia, acute myeloid leukemia (AML), and myelodysplastic syndromes. In acute leukemias, it is not clear whether MSC alterations contribute to the development of the malignant clone or whether they are simply the effect of tumor expansion on the microenvironment. We extensively investigated the characteristics of MSCs isolated from the BM of patients with de novo AML at diagnosis (L-MSCs) in terms of phenotype (gene and protein expression, apoptosis and senescence levels, DNA double-strand break formation) and functions (proliferation and clonogenic potentials, normal and leukemic hematopoiesis-supporting activity). We found that L-MSCs show reduced proliferation capacity and increased apoptosis levels compared with MSCs from healthy controls. Longer population doubling time in L-MSCs was not related to the AML characteristics at diagnosis (French-American-British type, cytogenetics, or tumor burden), but was related to patient age and independently associated with poorer patient outcome, as was cytogenetic prognostic feature. Analyzing, among others, the expression of 93 genes, we found that proliferative deficiency of L-MSCs was associated with a perivascular feature at the expense of the osteo-chondroblastic lineage with lower expression of several niche factors, such as KITLG, THPO, and ANGPT1 genes, the cell adhesion molecule VCAM1, and the developmental/embryonic genes, BMI1 and DICER1. L-MSC proliferative capacity was correlated positively with CXCL12, THPO, and ANGPT1 expression and negatively with JAG1 expression. Anyway, these changes did not affect their in vitro capacity to support normal hematopoiesis and to modify leukemic cell behavior (protection from apoptosis and quiescence induction). Our findings indicate that BM-derived MSCs from patients with newly diagnosed AML display phenotypic and functional alterations such as proliferative deficiency that could be attributed to tumor progression, but does not seem to play a special role in the leukemic process.

Background/Aims: An early evaluation with positron emission tomography (FDG-PET) has been demonstrated to be a valuable tool in the prediction of Hodgkin lymphoma's outcome. Herein we report a retrospective study on the outcome of Hodgkin lymphoma treated in accordance with interim FDG-PET results. Methods: 48 patients with de novo Hodgkin lymphoma were treated with 2 cycles of chemotherapy. According to the interim FDG-PET (PET2) evaluation, pre-established treatment was continued if PET2 was considered negative. Patients with a positive PET2 result underwent a salvage therapy. Progression-free survival (PFS) and overall survival (OS) were chosen as end points. Results: PET2 scan results were negative for 37 patients and positive for 11 patients. After salvage therapy, 7/11 patients were in complete remission and 4 patients had stable disease and were considered for third-line therapy. After a median follow-up of 5.2 years, 46 patients were still alive. The 4-year PFS were 84.5 and 45.4% for PET2-negative and PET2-positive patients, respectively (p = 0.007). In multivariate analysis, PET2 scan and extranodal disease remained relevant on PFS (p = 0.001 and 0.009, respectively). No difference was seen in OS. Conclusion: Our retrospective study suggests that salvage therapy for non-responder Hodgkin lymphoma using interim FDG-PET could improve the PFS of this group of patients.

The outcome of systemic and local therapies (e.g. chemotherapy, radiotherapy, surgery, focal ablation) for prostate cancer can be significantly improved by using tumor-specific adjuvants prior to treatment ("preconditioning"). We propose to use dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to monitor the in vivo response of a mouse model of prostate cancer treated with a vascular disruptive agent, TNF-α, delivered on a gold nanoparticle (NP-TNF). Six male nude mice bearing 4-5 week old LNCaP tumors were scanned at 9.4 T. DCE-MRI was performed two days before and 4-5 h after treatment with NP-TNF. An intraperitoneal (i.p.) bolus of gadolinium-DTPA (Gd) was administered and contrast enhancement was measured for 90 min. Concentration-time curves of Gd were calculated and the area under the Gd curve (AUGC) was determined pre- and post-treatment. NP-TNF treatment caused an increase in contrast uptake in tumors. Interestingly, the early concentration (10 min post Gd bolus i.p.) was similar in both untreated and treated conditions; however, 90 min after injection, [Gd] was 3.4 times higher than before treatment. AUGC doubled from (11 ± 6) [Gd] × min before treatment to (22 ± 9) [Gd] × min after treatment. An increase in signal enhancement was also observed in the muscle but to a lesser degree. We also evaluated the kinetics of intravenous Gd administration in mice bearing a jugular vein catheter to mimic the delivery method used in clinical trials. The overall treatment effects were independent of the delivery pathway of the contrast agent. In conclusion, we show that DCE-MRI is suitable to detect changes associated with a vascular disruptive agent in a mouse model of prostate cancer. The ability to characterize the effects of nanoparticle therapy in vivo with non-destructive methods is important, as such compounds, in combination with treatment strategies, are progressing towards clinical trials.

The upregulation of PPARgamma/RXRalpha transcriptional activity has emerged as a key event in luminal bladder tumors. It renders tumor cell growth PPARgamma-dependent and modulates the tumor microenvironment to favor escape from immuno-surveillance. The activation of the pathway has been linked to PPARG gains/amplifications resulting in PPARgamma overexpression and to recurrent activating point mutations of RXRalpha. Here, we report recurrent mutations of PPARgamma that also activate the PPARgamma/RXRalpha pathway, conferring PPARgamma-dependency and supporting a crucial role of PPARgamma in luminal bladder cancer. These mutations are found throughout the protein-including N-terminal, DNA-binding and ligand-binding domains-and most of them enhance protein activity. Structure-function studies of PPARgamma variants with mutations in the ligand-binding domain allow identifying structural elements that underpin their gain-of-function. Our study reveals genomic alterations of PPARG that lead to pro-tumorigenic PPARgamma/RXRalpha pathway activation in luminal bladder tumors and may open the way towards alternative options for treatment.

OBJECTIVE: Motor control of the muscles of the face, lips, and tongue of horn players has traditionally been described from externally observed phenomena. Developments in real-time, high-speed magnetic resonance imaging (MRI) extend the scope of study to include descriptive and quantitative information from within the mouth. We employed these developments to compare oral movement strategies between 12 elite horn players and 5 horn players with embouchure dystonia (ED). METHODS: Serial images with an acquisition time of 33.3 ms were obtained from each subject as they performed 6 exercises on an MRI-compatible horn: 1) a slurred ascending harmonic sequence, 2) a slurred descending harmonic sequence, 3–6) sustained high and low notes, each performed softly and loudly. Temporal changes in pixel luminescence along a series of lines positioned within the oral cavity were calculated using a customized MATLAB toolkit. This allowed the extraction of temporal line profiles for comparative analyses between elite and dystonic horn players. RESULTS: Differing motor strategies of controlling the tongue and jaw were observed during ascending and descending exercises. In ascending exercises, the elite players employed a strategy of elevation and anterior tongue displacement and elevation of the jaw, whereas dystonic players exhibited more variability in their responses. With descending exercises, both groups exhibited a lowering of the tongue and jaw, though this was more pronounced and consistent in the elite horn players. Sustained note exercises also elicited differences between groups. We suggest that elite strategies are more efficient and that the less-efficient patterns of dystonic players may exacerbate muscular tension with ED.

The nature, possibility, and implications of ethics expertise (or moral expertise) in general and of bioethics expertise in particular has been the focus of extensive debate for over thirty years. What is ethics expertise and what does it enable experts to do? Knowing what ethics expertise is can help answer another important question: What, if anything, makes a claim of expertise legitimate? In other words, how does someone earn the appellation "ethics expert?" There remains deep disagreement on whether ethics expertise is possible, and if so, what constitutes such expertise and what it entails and legitimates. Discussion of bioethics expertise has become particularly important given the growing presence of bioethicists in the clinical setting as well as efforts to professionalize bioethics through codes of ethics and certification (or quasi-certification) efforts. Unlike in the law or in engineering, where there may be a body of knowledge that professional organizations or others have articulated as important for education and training of experts, ethics expertise admits of no such body of knowledge or required experience. Nor is there an entity seen as having the authority to articulate the necessary scope of knowledge. Questions about whether there is such a body of knowledge for particular areas within bioethics have emerged and played a central role in professionalization efforts in recent years, especially in the area of clinical ethics.

Through many conversations with health professionals throughout the United States on such matters, I have come to a clear realization. Those who write and talk about the dream of global health equity can make people think, but can not make them care. It is only through direct involvement with the poor in the developing world (or here at home) that medical students and others in the medical profession at large will find reasons to care and, ultimately, find ways to change the health of the world’s most vulnerable—Edward O’Neil, Jr., MD (2006a, p. 848).

In order to evaluate psychiatric factors that potentially influence assessment of consent capacity, 195 IRB members read summaries of hypothetical medical (cancer vs. neuropathic pain) and psychiatric trials. They then rated research participants' capacity for consent (capable or not capable), autonomy, and decisional abilities, as well as the legal risk to the institution of the study. Levels of depression information varied across the medical disorders. Significantly fewer IRB members judged participants in the depression trial to possess adequate capacity for consent relative to 4 of 6 medical conditions; legal risk to the institution also was rated higher in the psychiatric study. While IRB members judged participants in depression trials to have less capacity for consent and to pose higher levels of institutional risk than medical trial participants, the addition of increasing information regarding depressive co-morbidities had little or no effect on judgments of medical studies. Implications are discussed relative to the apparent overprotection of participants in psychiatric trials and underprotection of those in medical trials.

Friedreich's ataxia (FRDA) and ataxia with oculomotor apraxia type 2 (AOA2) are the two most frequent forms of autosomal recessive cerebellar ataxias. However, brain metabolism in these disorders is poorly characterized and biomarkers of the disease progression are lacking. We aimed at assessing the neurochemical profile of the pons, the cerebellar hemisphere and the vermis in patients with FRDA and AOA2 to identify potential biomarkers of these diseases.Short-echo, single-voxel proton ((1)H) magnetic resonance spectroscopy data were acquired from 8 volunteers with FRDA, 9 volunteers with AOA2, and 38 control volunteers at 4T. Disease severity was assessed by the Friedreich's Ataxia Rating Scale (FARS).Neuronal loss/dysfunction was indicated in the cerebellar vermis and hemispheres in both diseases by lower total N-acetylaspartate levels than controls. The putative gliosis marker myo-inositol was higher than controls in the vermis and pons in AOA2 and in the vermis in FRDA. Total creatine, another potential gliosis marker, was higher in the cerebellar hemispheres in FRDA relative to controls. Higher glutamine in FRDA and lower glutamate in AOA2 than controls were observed in the vermis, indicating different mechanisms possibly leading to altered glutamatergic neurotransmission. In AOA2, total N-acetylaspartate levels in the cerebellum strongly correlated with the FARS score (p0.01).Distinct neurochemical patterns were observed in the two patient populations, warranting further studies with larger patient populations to determine if the alterations in metabolite levels observed here may be utilized to monitor disease progression and treatment.