Helios Klinikum Krefeld

Circulating innate lymphoid cells (cILCs) comprise a complex mixture of subsets with effector functions and progenitor potential toward mature ILCs and natural killer (NK) cells. Here, we dissected cord blood (CB) cILC complexity using single-cell RNA sequencing (RNA-seq) combined with developmental and functional analyses. cILC1s comprise six different subsets, with four showing different maturation degrees and two resembling NK cell progenitors. Despite previously described transcriptional similarity to T cells, the developmental potential of cILC1s was restricted to NK cells using an artificial thymic organoid (ATO) model. cILC2s could be divided into four main subsets: CD161+, CD117+, activated cILC2s, and cytotoxic cILC2s. Finally, a CD161+CD28+CD117low ILC3 subset was identified that secreted IFNγ upon co-stimulation with a CD28 superagonist, suggesting an alternative activation stimulus for cILC3s. Altogether, this in-depth analysis provides a detailed picture of cILC diversity in immunologically naive CB and constitutes a versatile resource for further exploration of their translational potential.

Acknowledgements We thank all the local investigators and assistant personnel for their great effort. Furthermore, we thank all the POTTER-AF collaborators.

Self-assembled monolayers of alkane thiolate and alkane selenolate have been proven to inhibit atmospheric corrosion, but upon prolonged exposure to the important constituents of indoor atmosphere, namely humidified air with formic acid, the protective layer eventually breaks, but the exact reason is not yet clear. In this paper, we report on an XPS study of co-adsorbed formic acid and hexane selenol on a Cu surface. Adsorption of hexane selenol at room temperature breaks the Se-C bond, leaving a monolayer of Se on the surface, whereas adsorption at 140 K leaves a layer of selenolate. Formic acid exposure to the selenolate-Cu surface leads to adsorbed formate on unprotected areas and absorption of formic acid within the alkane chain network. During heating, the formic acid desorbs and the Se-C bond breaks, but formic acid does not accelerate the Se-C scission, which occurs just below room temperature both with and without formic acid. Thus, formic acid alone does not affect the Se-C bond, but its presence may create disorder and open up the alkane carpet for other species. Selenol removes formate and oxide from the surface at room temperature. The Se-C bond breaks and the alkane chain reacts with surface oxygen to form carbon oxides and volatile hydrocarbons.

How to explain post-exertional malaise (PEM)Post-acute infection syndromes (PAIS), including long COVID, post-VAC syndrome, and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), represent a growing and often misunderstood challenge. Despite persistent, debilitating symptoms such as fatigue and "brain fog," their exact pathophysiological mechanisms remain largely unclear.This hypothesis posits that chronically elevated endogenous production of carbon monoxide (CO), primarily through the enzyme heme oxygenase-1 (HO-1), is a previously underappreciated cause of these syndromes. Due to the extremely high affinity of CO for hemoglobin (Hb), this leads to "invisible hypoxia" at the cellular level, which remains undetected by standard diagnostics.This is partly because pulse oximetry incorrectly interprets COhb as oxygen (O2) and, due to the resulting disturbed Bohr effect, blood gas analyses will continue to show a normal ratio between O2 and carbon dioxide (CO2) and also interpret CO as O2. Special COHb diagnostics are only used in cases of acute suspected poisoning, which is not usually the case with PAIS.The resulting delayed accumulation of carboxyhemoglobin (COHb) and the resulting cell dysfunction, in conjunction with the long half-life of CO (4-6 hours in room air), offer a plausible explanation for post-exertional malaise (PEM), a key symptom of ME/CFS. In addition, oxidative stress, impaired nutrient uptake, the particular vulnerability of the child's brain, and many other conditions could be explained by this mechanism.The hypothesis is supported by existing research on mitochondrial dysfunction and oxygen utilization disorders in PAIS patients. Given the diagnostic difficulties and complexity of these syndromes, this work underscores the urgent need for interdisciplinary research to validate the role of endogenous CO in order to develop more accurate diagnostic and effective therapeutic approaches for those affected.

Zusammenfassung Im Rahmen eines internationalen Konsensusverfahrens haben die drei führenden Fachgesellschaften für kutane Lymphome – die International Society for Cutaneous Lymphomas (ISCL), die European Organisation for Research and Treatment of Cancer (EORTC) und das United States Cutaneous Lymphoma Consortium (USCLC) – zwei Leitlinien speziell für die Diagnostik und Therapie von Mycosis fungoides (MF) im Kindes- und Jugendalter entwickelt. Beide Empfehlungen wurden nach den Standards der EQUATOR Network-Richtlinien für Leitlinienentwicklung erstellt und basieren auf einem strukturierten, mehrstufigen Delphi-Prozess mit internationaler Expertenbeteiligung. Die erste Leitlinie befasst sich mit der altersgerechten Stadieneinteilung. Die zweite Leitlinie widmet sich der Therapie von MF im Kindes- und Jugendalter. Auch hier wurde ein modifizierter Delphi-Prozess mit zwei Feedbackrunden und einem abschließenden Konsensmeeting durchgeführt. Die Empfehlungen konzentrieren sich auf die Behandlung im Frühstadium und berücksichtigen sowohl krankheitsspezifische Faktoren – wie das Vorliegen der follikulotropen Variante – als auch patientenspezifische Aspekte, insbesondere im Hinblick auf altersbedingte Sicherheitsbedenken. Die therapeutischen Empfehlungen basieren auf etablierten Verfahren aus der Erwachsenenmedizin, wurden jedoch hinsichtlich Dosierung, Anwendungsdauer und Nebenwirkungsprofil an die Bedürfnisse junger Patientinnen und Patienten angepasst. Beide Leitlinien stellen einen wichtigen Schritt zur Standardisierung und altersgerechten Anpassung der Versorgung von Kindern und Jugendlichen mit MF dar und bieten erstmals strukturierte, konsensbasierte Empfehlungen für diese seltene Patientengruppe.

In 2023, the VAS international working group on Buerger's Disease (BD) recommended two diagnostic criteria based on a prior Delphi study: "definitive" and "suspected". The "definitive" criteria are history of smoking, typical angiography, and typical histopathological features. All three features are mandatory to confirm a "definitive" diagnosis of BD. The conundrum is-what features should be considered typical of BD angiography? According to this review, segmental occlusion of infrapopliteal arteries, corkscrew collaterals that appear to continue the occluded arterial segment (Martorell's sign) or bypass the segmental occlusion, absence of atherosclerotic plaque or aneurysm could differentiate BD from ASO. Hence, for "typical" BD angiography, these manifestations should certainly be considered. However, data for differentiating angiography patterns of BD from the small- and medium-sized vasculitis including Behcet's disease, scleroderma, hepatitis associated vasculitis, and anti-phospholipid syndrome are limited. Further studies for investigating the angiography pattern in BD patients in early and late presentation of BD, particularly in the patients with long-term follow up, are highly recommended.

PURPOSE Low-dose radiation demonstrates efficacy in treating primary cutaneous T-cell lymphomas. This study evaluated the safety and efficacy of low-dose total skin electron beam therapy (TSEBT) regimens in patients with mycosis fungoides (MF). MATERIALS AND METHODS Patients with stage IB to IIB MF received low-dose TSEBT. The primary end point assessed was the overall response rate (ORR). The secondary end points included time to next treatment (TTNT), progression-free survival (PFS), and toxicity. Exploratory patient-reported outcome measures and potential soluble biomarkers were investigated. RESULTS In a study of 118 patients, 38 were in stage IB to IIA and 80 were in stage IIB according to International Society for Cutaneous Lymphomas /European Organisation for Research and Treatment of Cancer (EORTC) TNM classification. Patients had received a median of four previous treatments and were treated with either 12 Gy in eight fractions (65 patients) or 8 Gy in two fractions (53 patients). The ORR was 92% at 3 months. After a median follow-up of 45 months (95% CI, 36 to 54), the median TTNT was 16 months (95% CI, 8 to 24) and the median PFS was 11 months (95% CI, 8 to 14). There was no significant difference in outcome between the radiation regimens. Only 17% reported grade 2 toxicities, and the rate of grade 3 or higher toxicity was 4%. There were no significant differences in toxicity based on radiation dose or fractionation. Participants reported meaningful improvements, including reduced itching and skin disease burden, along with better scores on Skindex-29 and EORTC core quality of life questionnaire assessments. The study identified several prognostic factors and potential biomarkers in a multivariate analysis. CONCLUSION Low-dose TSEBT delivered with 8 Gy or 12 Gy provides significant clinical benefits and shows minimal toxicity. In a multivariate analysis, we identified several prognostic factors and potential biomarkers which could support patient selection.

Pathogenic variants in GABAA receptor subunit genes (GABR*) are important contributors to rare and common genetic epilepsies. Here, we present a comprehensive analysis of variants in GABRB1, which encodes the GABAA receptor β1 subunit, by revealing their functional implications, establishing genotype-phenotype correlations and evaluating treatment response. Clinical information on individuals carrying a GABRB1 variant was obtained through an international collaboration and literature review. Our cohort included 19 individuals (7 males, 12 females) from 15 families harbouring 13 different GABRB1 variants (11 missense, 1 indel, 1 stop). Functional analysis was performed using two-electrode voltage-clamp recordings in Xenopus laevis oocytes. For all 11 missense variants, α1β1γ2 GABAA receptors with a single mutant β1 subunit were used. Four missense variants were selected for further functional analysis using α5β1γ2 GABAA receptors with two mutant β1 subunits. Gain-of-function (GoF) effects, characterized by increased GABA-sensitivity, were observed for eight missense variants. Loss-of-function (LoF) effects were observed for one variant and no functional effects for two variants. Clinically, GoF variants were only observed in individuals with severe early-onset disease, including profound intellectual disability, hypotonia and early mortality. Additionally, cortical visual impairment, dysmorphisms and cortical atrophy were exclusive to this cohort. By integrating previously reported clinical data for variants in other GABR* genes, we validated that these features were associated with GoF variants more broadly. The only LoF variant was identified in a nuclear family with the relatively milder syndrome of genetic epilepsy with febrile seizures plus. Seizures were therapy-resistant in all individuals with GoF variants and a single individual with a LoF variant. The GABAergic anti-seizure medication (ASM) vigabatrin caused life-threatening side-effects in two individuals with GoF variants, while the sodium-channel blocker (SCB) lamotrigine exacerbated seizures in a single individual carrying a LoF variant. By integrating data from literature on all GABR* variants, we observed a potential dichotomy in treatment responses: GABAergic and broad-spectrum ASMs, such as valproate and levetiracetam, were more effective for individuals with LoF variants in GABR* genes, while SCBs showed greater benefit for GoF variants. Additionally, there is an increased risk of adverse effects of SCBs in LoF and vigabatrin in GoF variants. Our results highlight the importance of functional characterization of variants and clinical predictors in guiding treatment strategies for individuals with GABRB1 and other GABR* variants, although larger prospective studies are needed to confirm these observations.