Ethics experts and fetal patients: a proposal for modesty

Background Ethics consultation is recognized as an opportunity to share responsibility for difficult decisions in prenatal medicine, where moral intuitions are often unable to lead to a settled decision. It remains unclear, however, if the general standards of ethics consultation are applicable to the very particular setting of pregnancy. Main text We sought to analyze the special nature of disagreements, conflicts and value uncertainties in prenatal medicine as well as the ways in which an ethics consultation service (ECS) could possibly respond to them and illustrated our results with a case example. Ethics facilitation and conflict mediation, currently, have no broadly consented normative framework encompassing prenatal diagnosis and therapy as well as reproductive choice to draw on. Even so, they can still be helpful instruments for ethically challenging decision-making in prenatal medicine provided two additional rules are respected: For the time being, ECSs should (a) refrain from issuing content-heavy recommendations in prenatal medicine and (b) should not initiate conflict mediations that would involve the pregnant woman or couple as a conflict party. Conclusion It seems to be vital that ethics consultants as well as health care professionals acknowledge the current limitations and pitfalls of ethics consultation in prenatal medicine and together engage in the advancement of standards for this particularly complex setting

Multidisciplinary Ophthalmic Imaging In Vivo Imaging of a New Indocyanine Green Micelle Formulation in an Animal Model of Laser-Induced Choroidal Neovascularization

METHODS. The ICG was formulated with the nonionic solubilizer and emulsifying agent Kolliphor HS 15 to create ICG/HS 15 to improve the chemical stability and fluorescence efficacy. In vivo imaging was performed in rats that had undergone laser photocoagulation. Retinal uptake and fluorescence intensity of ICG and ICG/HS 15 were compared following intravenous injection of 3 dosages (0.05, 0.1, and 0.15 mg/kg body weight) at 7, 14, and 21 days following laser treatment. Postmortem analysis included histology with frozen sections and flat mounts. RESULTS. Immediately following injection of ICG or ICG/HS 15, a strong fluorescence was visible in the retinal vasculature and at the site of laser lesions. Pixel intensity was higher for ICG/HS 15 compared to conventional ICG at 8 minutes after injection for all different injection days and dosages. Over time, a continuous decrease of the fluorescent signal was observed for up to 60 minutes to baseline level. Flow cytometry data showed an increased uptake of micellar dye of macrophages and endothelial cells. Histology revealed an accumulation of the micellar dye within the laser lesion. CONCLUSIONS. Micelle formulated ICG can be visualized in the retinal vasculature and laserinduced CNV in vivo and ex vivo. Micellar ICG/HS 15 showed in vivo stronger signal intensity when compared to ICG for all tested dosages. Following further investigations, ICG/HS 15 may be evaluated in patients with retinal and choroidal diseases for more refined diagnosis

Das Verbot der pränatalen Diagnostik spätmanifestierender Erkrankungen im deutschen Gendiagnostikgesetz - eine Diskussion medizinischer und rechtlicher Aspekte und deren Implikation für die medizinethische Diskussion

Zusammenfassung: Am 1. Februar 2010 ist das Gendiagnostikgesetz (GenDG) in Kraft getreten. Die Debatte um einige Regelungsbereiche, wie beispielsweise das Neugeborenenscreening, reißt nicht ab. Ein Aspekt des Gesetzes ist im Rahmen der Debatte um die Präimplantationsdiagnostik (PID) in Deutschland unter neuen Vorzeichen zu diskutieren: Das - international bislang einzigartige - Verbot der pränatalen Diagnostik so genannter spätmanifestierender Erkrankungen, die erst nach der Vollendung des 18. Lebensjahres ausbrechen. In diesem Beitrag möchten wir Hinweise zur differenzierten Diskussion dieser in §15(2) GenDG bestimmten Verbotsnorm liefern. Obgleich Argumente, insbesondere das Recht auf Nichtwissen des geborenen Kindes, für ein solches Verbot sprechen, kommen wir aufgrund der medizinischen Sachlage und nach einer Analyse der Pro- und Kontraargumente aus ethischer und rechtlicher Sicht zu dem Schluss, dass ein generelles Verbot der pränatalen Diagnostik spätmanifestierender Erkrankungen im Sinne der Zielsetzung womöglich insuffizient ist sowie in der Begründung Inkonsistenzen zum bereits bestehenden Regelwerk aufweist, und lenken daher den Blick auf unter Umständen bessere Alternativen

Infection of ferrets with wild type-based recombinant canine distemper virus overwhelms the immune system and causes fatal systemic disease

Canine distemper virus (CDV) causes systemic infection resulting in severe and often fatal disease in a large spectrum of animal host species. The virus is closely related to measles virus and targets myeloid, lymphoid, and epithelial cells, but CDV is more virulent and the infection spreads more rapidly within the infected host. Here, we aimed to study the pathogenesis of wild-type CDV infection by experimentally inoculating ferrets with recombinant CDV (rCDV) based on an isolate directly obtained from a naturally infected raccoon. The recombinant virus was engineered to express a fluorescent reporter protein, facilitating assessment of viral tropism and virulence. In ferrets, this wild type-based rCDV infected myeloid, lymphoid, and epithelial cells, and the infection resulted in systemic dissemination to multiple tissues and organs, especially those of the lymphatic system. High infection percentages in immune cells resulted in depletion of these cells both from circulation and from lymphoid tissues. The majority of CDV-infected ferrets reached their humane endpoints within 20 d and had to be euthanized. In that period, the virus also reached the central nervous system in several ferrets, but we did not observe the development of neurological complications during the study period of 23 d. Two out of 14 ferrets survived CDV infection and developed neutralizing antibodies. We show for the first time the pathogenesis of a non-adapted wild type-based rCDV in ferrets. IMPORTANCE Infection of ferrets with recombinant canine distemper virus (rCDV) expressing a fluorescent reporter protein has been used as proxy to understand measles pathogenesis and immune suppression in humans. CDV and measles virus use the same cellular receptors, but CDV is more virulent, and infection is often associated with neurological complications. rCDV strains in current use have complicated passage histories, which may have affected their pathogenesis. Here, we studied the pathogenesis of the first wild type-based rCDV in ferrets. We used macroscopic fluorescence to identify infected cells and tissues; multicolor flow cytometry to determine viral tropism in immune cells; and histopathology and immunohistochemistry to characterize infected cells and lesions in tissues. We conclude that CDV often overwhelmed the immune system, resulting in viral dissemination to multiple tissues in the absence of a detectable neutralizing antibody response. This virus is a promising tool to study the pathogenesis of morbillivirus infections.</p

Inoculation of raccoons with a wild-type-based recombinant canine distemper virus results in viremia, lymphopenia, fever, and widespread histological lesions

Raccoons are naturally susceptible to canine distemper virus (CDV) infection and can be a potential source of spill-over events. CDV is a highly contagious morbillivirus that infects multiple species of carnivores and omnivores, resulting in severe and often fatal disease. Here, we used a recombinant CDV (rCDV) based on a full-genome sequence detected in a naturally infected raccoon to perform pathogenesis studies in raccoons. Five raccoons were inoculated intratracheally with a recombinant virus engineered to express a fluorescentreporter protein, and extensive virological, serological, histological, and immunohistochemical assessments were performed at differenttime points post inoculation. rCDV-infected white blood cells were detected as early as 4 days post inoculation (dpi). Raccoon necropsies at 6 and 8 dpi revealed replication in the lymphoid tissues, preceding spread into peripheral tissues observed during necropsies at 21 dpi. Whereas lymphocytes, and to a lesser extent myeloid cells, were the main target cells of CDV at early time points, CDV additionally targeted epithelia at 21 dpi. At this later time point, CDV-infected cells were observed throughout the host. We observed lymphopenia and lymphocyte depletion from lymphoid tissues after CDV infection, in the absence of detectable CDV neutralizing antibodies and an impaired ability to clear CDV, indicating that the animals were severely immunosuppressed. The use of a wild-type-based recombinant virus in a natural host species infection study allowed systematic and sensitive assessment of antigen detection by immunohistochemistry, enabling further comparative pathology studies of CDV infection in differentspecies.</p

Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6

Background: The most common spinocerebellar ataxias (SCA)—SCA1, SCA2, SCA3, and SCA6—are caused by (CAG)n repeat expansion. While the number of repeats of the coding (CAG)n expansions is correlated with the age at onset, there are no appropriate models that include both affected and preclinical carriers allowing for the prediction of age at onset. Methods: We combined data from two major European cohorts of SCA1, SCA2, SCA3, and SCA6 mutation carriers: 1187 affected individuals from the EUROSCA registry and 123 preclinical individuals from the RISCA cohort. For each SCA genotype, a regression model was fitted using a log-normal distribution for age at onset with the repeat length of the alleles as covariates. From these models, we calculated expected age at onset from birth and conditionally that this age is greater than the current age. Results: For SCA2 and SCA3 genotypes, the expanded allele was a significant predictor of age at onset (−0.105±0.005 and −0.056±0.003) while for SCA1 and SCA6 genotypes both the size of the expanded and normal alleles were significant (expanded: −0.049±0.002 and −0.090±0.009, respectively; normal: +0.013±0.005 and −0.029±0.010, respectively). According to the model, we indicated the median values (90% critical region) and the expectancy (SD) of the predicted age at onset for each SCA genotype according to the CAG repeat size and current age. Conclusions: These estimations can be valuable in clinical and research. However, results need to be confirmed in other independent cohorts and in future longitudinal studies.This study was supported by grants EUROSCA/LSHM-CT-2004-503304 from the European Union, grant from the European Community's Seventh Framework Programme (FP7/2007-2013 n° 2012-305121 NEUROMICS), GeneMove/01 GM 0503 from the German Ministry of Education and Research, within the framework of the ERA-Net for Research Programmes on Rare Diseases, grant 3 PO5B 019 24 from the Polish Ministry of Scientific Research and Information Technology, and grant No 674N—RISCA/2010—2014 from Polish Ministry of Science and Higher Education. The research leading to these results has received funding from the programme ‘Investissements d'avenir’ ANR-10-IAIHU-06. BPvdW is supported by research grants from the Netherlands Brain Foundation, the Royal Dutch Society for Physical Therapy, BBMRI-NL, and the Radboud University Medical Centre. MB is supported by the grant OTKA K 103983. AF was supported by a grant from POR CREME 2007-20013. AB was supported by the grant EUROSCA/LSHM-CT-2004-503304 and by the grant NEUROMICS (7th framework programme) from the European Union. AB, AD and GS received funding from the VERUM Foundation. AD received support from ANR (French Research Agency) and Eranet for the Risca project, PG and AC work at University College London Hospitals/University College London which receives a proportion of its funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme. Paola Giunti receives funding from the EC (HEALTH-F2-2010-242193; FP7 Grant). DeNDRoN, Ataxia UK and NIHR, Department of Health

Treatment Motivations and Expectations in Patients with Actinic Keratosis: A German-Wide Multicenter, Cross-Sectional Trial

Patient-centered motives and expectations of the treatment of actinic keratoses (AK) have received little attention until now. Hence, we aimed to profile and cluster treatment motivations and expectations among patients with AK in a nationwide multicenter, cross-sectional study including patients from 14 German skin cancer centers. Patients were asked to complete a self-administered questionnaire. Treatment motives and expectations towards AK management were measured on a visual analogue scale from 1–10. Specific patient profiles were investigated with subgroup and correlation analysis. Overall, 403 patients were included. The highest motivation values were obtained for the items “avoid transition to invasive squamous cell carcinoma” (mean ± standard deviation; 8.98 ± 1.46), “AK are considered precancerous lesions” (8.72 ± 1.34) and “treating physician recommends treatment” (8.10 ± 2.37; p < 0.0001). The highest expectation values were observed for the items “effective lesion clearance” (8.36 ± 1.99), “safety” (8.20 ± 2.03) and “treatment-related costs are covered by health insurance” (8.00 ± 2.41; p < 0.0001). Patients aged ≥77 years and those with ≥7 lesions were identified at high risk of not undergoing any treatment due to intrinsic and extrinsic motivation deficits. Heat mapping of correlation analysis revealed four clusters with distinct motivation and expectation profiles. This study provides a patient-based heuristic tool for a personalized treatment decision in patients with AK

Spinocerebellar ataxia type 14: refining clinicogenetic diagnosis in a rare adult‐onset disorder

Objectives: Genetic variant classification is a challenge in rare adult-onset disorders as in SCA-PRKCG (prior spinocerebellar ataxia type 14) with mostly private conventional mutations and nonspecific phenotype. We here propose a refined approach for clinicogenetic diagnosis by including protein modeling and provide for confirmed SCA-PRKCG a comprehensive phenotype description from a German multi-center cohort, including standardized 3D MR imaging. Methods: This cross-sectional study prospectively obtained neurological, neuropsychological, and brain imaging data in 33 PRKCG variant carriers. Protein modeling was added as a classification criterion in variants of uncertain significance (VUS). Results: Our sample included 25 cases confirmed as SCA-PRKCG (14 variants, thereof seven novel variants) and eight carriers of variants assigned as VUS (four variants) or benign/likely benign (two variants). Phenotype in SCA-PRKCG included slowly progressive ataxia (onset at 4-50 years), preceded in some by early-onset nonprogressive symptoms. Ataxia was often combined with action myoclonus, dystonia, or mild cognitive-affective disturbance. Inspection of brain MRI revealed nonprogressive cerebellar atrophy. As a novel finding, a previously not described T2 hyperintense dentate nucleus was seen in all SCA-PRKCG cases but in none of the controls. Interpretation: In this largest cohort to date, SCA-PRKCG was characterized as a slowly progressive cerebellar syndrome with some clinical and imaging features suggestive of a developmental disorder. The observed non-ataxia movement disorders and cognitive-affective disturbance may well be attributed to cerebellar pathology. Protein modeling emerged as a valuable diagnostic tool for variant classification and the newly described T2 hyperintense dentate sign could serve as a supportive diagnostic marker of SCA-PRKCG

Spinocerebellar Ataxia Types 1, 2, 3 and 6: the Clinical Spectrum of Ataxia and Morphometric Brainstem and Cerebellar Findings

n/