Durch interne Emitter verursachte strahleninduzierte Nephropathie: Dosis-Effektbeziehungen, Prophylaxe und Therapie im präklinischen Modell der Radiopeptidtherapie neuroendokriner Tumoren

Die metabolische Endoradiotherapie mit radioaktiv markiertem DTPA-D-Glu1-Minigastrin ist eine neue Form der Radionuklidtherapie die zur Behandlung maligner Erkrankungen, wie dem medullären Schilddrüsenkarzinom und dem kleinzelligen Bronchialkarzinom eingesetzt werden kann. Versuche mit Minigastrin haben gezeigt, dass es in der Diagnostik möglich ist, die Lokalisation von Metastasen in einem früheren Stadium zu diagnostizieren als es bisher mit anderen konventionellen Mitteln möglich ist. Um jedoch das Tumorgewebe zu schädigen, sind hohe Aktivitäten nötig. Das dosislimitierende Organ ist hierbei die Niere, da sie neben dem Tumor auch größere Mengen des radioaktiven Peptids aufnimmt und einlagert. Eine Reduktion der Nierentoxizität würde einerseits die Hauptnebenwirkung und die damit verbundenen Folgeerscheinungen minimieren, die von einer leichten Proteinurie bis zu einer terminalen Niereninsuffizienz reichen können. In der Reduktion der Strahlennephrotoxizität spielt die Prävention eine größere Rolle als die Begrenzung des entstandenen Schadens. Daher beginnt die Therapie mit der Wahl geeigneter Peptide und Emitter. Das Ausmaß der Strahlennephropathie kann durch die Wahl geeigneter Emitter deutlich reduziert werden. Auger/Konversionselektronen-Emitter (z. B. 111In) haben sich dabei als besonders vielversprechende Strahlungsquellen herausgestellt, weil sie aufgrund ihres hohen linearen Energietransfers nur eine sehr begrenzte Reichweite bei einer gleichzeitig hohen Ionisationsdichte besitzen. Dies hat zur Folge, dass fast ausnahmslos nur die Zellen geschädigt werden, die das Peptid internalisieren. Neben dem Tumor wären das in erster Linie die Tubuluszellen der Niere, die jedoch das Potential zur Regeneration besitzen. Die weitaus radiosensibleren Strukturen, wie Gefäße und Glomeruli, erhalten so nur eine weitaus geringere Strahlendosis. Als zusätzlicher Schutz können Antioxidantien kurz vor der Bestrahlung gegeben werden. Amifostin hat sich dabei als sehr potentes Mittel herausgestellt. Neben Amifostin ist Selenit eine weitere Substanz, die das Ausmaß der Strahlen-nephropathie reduzieren kann. Da beide Substanzen über verschiedene Mechanismen zu einer Verminderung der Radiotoxizität führen, kann die Wirkung des Amifostins auch durch eine zusätzliche Gabe von Selenit additiv gesteigert werden. Die Vitamine A, C und E haben sich nicht als außerordentlich wirksam herausgestellt und sollten nicht allein in der Prävention eingesetzt werden. Des weiteren scheint ein erhöhter Blutdruck die Ausbildung eines Nierenschadens zu fördern und sollte daher auf physiologische Werte eingestellt werden. In dieser Studie konnte kein blutdrucksenkendes Mittel die Progressivität der Strahlen-nephropathie verringern, ferner verschlechterten die ACE-Hemmer sogar die Prognose. Auch die alleinige prophylaktische Gabe von Antihypertensiva stellt nach dieser Untersuchung keinen geeigneten Weg zur Verbesserung der Prognose dar. Eine Einstellung des Blutdrucks ist bei erhöhten Werten jedoch nötig. Obwohl kein Antihypertensivum deutlich besser geeignet zu sein scheint, sollten die ß-Adrenozeptor-Antagonisten besonders berücksichtig werden, da sie neben dem antihypertensiven Effekt noch die Reninsekretion unterdrücken können und zusätzlich antioxidative Eigenschaften besitzen

Joint Multi-Echo/Respiratory Motion-Resolved Compressed Sensing Reconstruction of Free-Breathing Non-Cartesian Abdominal MRI

We propose a novel respiratory motion-resolved MR image reconstruction method that jointly treats multi-echo k-space raw data. Continuously acquired non-Cartesian multi-echo/multi-coil k-space data with free breathing are sorted/binned into the motion states from end-expiratory to end-inspiratory phases based on a respiratory motion signal. Temporal total variation applied to the motion state dimension of each echo is then coupled in the $\ell_2$ sense for joint reconstruction of the multiple echoes. Reconstructed source images of the proposed method are compared with conventional echo-by-echo motion-resolved reconstruction, and R2* of the proposed and echo-by-echo methods are compared with respect to a clinical reference. We demonstrate that inconsistency between echoes is successfully suppressed in the proposed joint reconstruction method, producing high-quality source images and R2* measurements compared to clinical reference

Territorial songs indicate male quality in the sac-winged bat Saccopteryx bilineata (Chiroptera, Emballonuridae)

Defense of territories in many animal species involves the advertisement of territory holder quality by acoustic signaling. In the sac-winged bat Saccopteryx bilineata, males engage in territorial countersinging when reoccupying their day-roost territories in the morning and in the evening before abandoning the roost for the night. Females roost mainly in male territories, and territory holders are reproductively more successful than nonterritorial males. In territorial songs of male S. bilineata, we distinguished 6 syllable types and parameterized their acoustic properties. The analysis of 11 microsatellite loci allowed assignments of juveniles to their parents. Males had a higher reproductive success both when they uttered more territorial songs per day and when their long buzz syllables had a lower end frequency of the fundamental harmonic. Long buzzes had a harsh quality due to a pulsation of the fundamental frequency at the syllable onset and also had the highest sound pressure level of all syllable types in most territorial songs. Territorial songs and especially long buzz syllables are thus likely to advertise territory holder quality and competitive abilit

Infrared molecular fingerprinting of blood-based liquid biopsies for the detection of cancer

Recent omics analyses of human biofluids provide opportunities to probe selected species of biomolecules for disease diagnostics. Fourier-transform infrared (FTIR) spectroscopy investigates the full repertoire of molecular species within a sample at once. Here, we present a multi-institutional study in which we analysed infrared fingerprints of plasma and serum samples from 1639 individuals with different solid tumours and carefully matched symptomatic and non-symptomatic reference individuals. Focusing on breast, bladder, prostate, and lung cancer, we find that infrared molecular fingerprinting is capable of detecting cancer: training a support vector machine algorithm allowed us to obtain binary classification performance in the range of 0.78-0.89 (area under the receiver operating characteristic curve [AUC]), with a clear correlation between AUC and tumour load. Intriguingly, we find that the spectral signatures differ between different cancer types. This study lays the foundation for high-throughput onco-IR-phenotyping of four common cancers, providing a cost-effective, complementary analytical tool for disease recognition

Clinically Actionable Hypercholesterolemia and Hypertriglyceridemia in Children with Nonalcoholic Fatty Liver Disease

OBJECTIVE: To determine the percentage of children with nonalcoholic fatty liver disease (NAFLD) in whom intervention for low-density lipoprotein cholesterol or triglycerides was indicated based on National Heart, Lung, and Blood Institute guidelines. STUDY DESIGN: This multicenter, longitudinal cohort study included children with NAFLD enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Nonalcoholic Steatohepatitis Clinical Research Network. Fasting lipid profiles were obtained at diagnosis. Standardized dietary recommendations were provided. After 1 year, lipid profiles were repeated and interpreted according to National Heart, Lung, and Blood Institute Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction. Main outcomes were meeting criteria for clinically actionable dyslipidemia at baseline, and either achieving lipid goal at follow-up or meeting criteria for ongoing intervention. RESULTS: There were 585 participants, with a mean age of 12.8 years. The prevalence of children warranting intervention for low-density lipoprotein cholesterol at baseline was 14%. After 1 year of recommended dietary changes, 51% achieved goal low-density lipoprotein cholesterol, 27% qualified for enhanced dietary and lifestyle modifications, and 22% met criteria for pharmacologic intervention. Elevated triglycerides were more prevalent, with 51% meeting criteria for intervention. At 1 year, 25% achieved goal triglycerides with diet and lifestyle changes, 38% met criteria for advanced dietary modifications, and 37% qualified for antihyperlipidemic medications. CONCLUSIONS: More than one-half of children with NAFLD met intervention thresholds for dyslipidemia. Based on the burden of clinically relevant dyslipidemia, lipid screening in children with NAFLD is warranted. Clinicians caring for children with NAFLD should be familiar with lipid management

CM-AVM syndrome in a neonate: case report and treatment with a novel flow reduction strategy

Mutations in the RASA-1 gene underlie several related disorders of vasculogenesis. Capillary malformation-arteriovenous malformation (CM-AVM) is one such entity and was recently encountered in a neonate who demonstrated its clinical and radiologic features. A single mutation in the RASA-1 gene was detected. A novel flow reduction strategy was employed to a large AVM affecting the patient’s upper limb. The imaging findings, surgical procedure and patient’s improved post-operative state are described

Increased Virulence of an Epidemic Strain of Mycobacterium massiliense in Mice

Chronic pulmonary disease and skin/soft tissue infections due to non-tuberculous mycobacteria (NTM) of the Mycobacterium chelonae-abscessus-massiliense group is an emerging health problem worldwide. Moreover, the cure rate for the infections this group causes is low despite aggressive treatment. Post-surgical outbreaks that reached epidemic proportions in Brazil recently were caused by M. massiliense isolates resistant to high-level disinfection with glutaraldehyde (GTA). Understanding the differences in the virulence and host immune responses induced by NTM differing in their sensitivity to disinfectants, and therefore their relative threat of causing outbreaks in hospitals, is an important issue.We compared the replication and survival inside macrophages of a GTA-susceptible reference Mycobacterium massiliense clinical isolate CIP 108297 and an epidemic strain from Brazil, CRM-0019, and characterized the immune responses of IFNγ knockout mice exposed to a high dose aerosol with these two isolates. CRM-0019 replicated more efficiently than CIP 108297 inside mouse bone marrow macrophages. Moreover, the animals infected with CRM-0019 showed a progressive lung infection characterized by a delayed influx of CD4+ and CD8+ T cells, culminating in extensive lung consolidation and demonstrated increased numbers of pulmonary CD4+ Foxp3+ regulatory T cells compared to those infected with the reference strain. Immunosuppressive activity of regulatory T cells may contribute to the progression and worsening of NTM disease by preventing the induction of specific protective immune responses.These results provide the first direct evidence of the increased virulence in macrophages and mice and pathogenicity in vivo of the Brazilian epidemic isolate and the first observation that NTM infections can be associated with variable levels of regulatory T cells which may impact on their virulence and ability to persist in the host

In Children with Nonalcoholic Fatty Liver Disease, Zone 1 Steatosis is Associated with Advanced Fibrosis

Background & Aims Focal zone 1 steatosis, although rare in adults with nonalcoholic fatty liver disease (NAFLD), does occur in children with NAFLD. We investigated whether focal zone 1 steatosis and focal zone 3 steatosis are distinct subphenotypes of pediatric NAFLD. We aimed to determine associations between the zonality of steatosis and demographic, clinical, and histologic features in children with NAFLD. Methods We performed a cross-sectional study of baseline data from 813 children (age <18 years; mean age, 12.8 ± 2.7 years). The subjects had biopsy-proven NAFLD and were enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network. Liver histology was reviewed using the Nonalcoholic Steatohepatitis Clinical Research Network scoring system. Results Zone 1 steatosis was present in 18% of children with NAFLD (n = 146) and zone 3 steatosis was present in 32% (n = 244). Children with zone 1 steatosis were significantly younger (10 vs 14 years; P < .001) and a significantly higher proportion had any fibrosis (81% vs 51%; P < .001) or advanced fibrosis (13% vs 5%; P < .001) compared with children with zone 3 steatosis. In contrast, children with zone 3 steatosis were significantly more likely to have steatohepatitis (30% vs 6% in children with zone 1 steatosis; P < .001). Conclusions Children with zone 1 or zone 3 distribution of steatosis have an important subphenotype of pediatric NAFLD. Children with zone 1 steatosis are more likely to have advanced fibrosis and children with zone 3 steatosis are more likely to have steatohepatitis. To achieve a comprehensive understanding of pediatric NAFLD, studies of pathophysiology, natural history, and response to treatment should account for the zonality of steatosis

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements