Erythropoietin as candidate for supportive treatment of severe COVID-19

In light of the present therapeutic situation in COVID-19, any measure to improve course and outcome of seriously affected individuals is of utmost importance. We recap here evidence that supports the use of human recombinant erythropoietin (EPO) for ameliorating course and outcome of seriously ill COVID-19 patients. This brief expert review grounds on available subject-relevant literature searched until May 14, 2020, including Medline, Google Scholar, and preprint servers. We delineate in brief sections, each introduced by a summary of respective COVID-19 references, how EPO may target a number of the gravest sequelae of these patients. EPO is expected to: (1) improve respiration at several levels including lung, brainstem, spinal cord and respiratory muscles; (2) counteract overshooting inflammation caused by cytokine storm/ inflammasome; (3) act neuroprotective and neuroregenerative in brain and peripheral nervous system. Based on this accumulating experimental and clinical evidence, we finally provide the research design for a double-blind placebo-controlled randomized clinical trial including severely affected patients, which is planned to start shortly

The neurobiological characterization of distinct cognitive subtypes in early-phase schizophrenia-spectrum disorders

INTRODUCTION: Cognitive deficits are present in some, but not all patients with schizophrenia-spectrum disorders (SSD). We and others have demonstrated three cognitive clusters: cognitively intact patients, patients with deficits in a few domains and those with global cognitive deficits. This study aimed to identify cognitive subtypes of early-phase SSD with matched controls as a reference group, and evaluated cognitive subgroups regarding clinical and brain volumetric measures. METHODS: Eighty-six early-phase SSD patients were included. Hierarchical cluster analysis was conducted using global performance on the Brief Assessment of Cognition in Schizophrenia (BACS). Cognitive subgroups were subsequently related to clinical and brain volumetric measures (cortical, subcortical and cortical thickness) using ANCOVA. RESULTS: Three distinct cognitive clusters emerged: relative to controls we found one cluster of patients with preserved cognition (n = 25), one moderately impaired cluster (n = 38) and one severely impaired cluster (n = 23). Cognitive subgroups were characterized by differences in volume of the left postcentral gyrus, left middle caudal frontal gyrus and left insula, while differences in cortical thickness were predominantly found in fronto-parietal regions. No differences were demonstrated in subcortical brain volume. DISCUSSION: Current results replicate the existence of three distinct cognitive subgroups including one relatively large group with preserved cognitive function. Cognitive subgroups were characterized by differences in cortical regional brain volume and cortical thickness, suggesting associations with cortical, but not subcortical development and cognitive functioning such as attention, executive functions and speed of processing

The importance of initial-final state correlations for the formation of fragments in heavy ion collisions

Using quantum molecular dynamics simulations, we investigate the formation of fragments in symmetric reactions between beam energies of E=30AMeV and 600AMeV. After a comparison with existing data we investigate some observables relevant to tackle equilibration: dsigma/dErat, the double differential cross section dsigma/pt.dpz.dpt,... Apart maybe from very energetic E>400AMeV and very central reactions, none of our simulations gives evidence that the system passes through a state of equilibrium. Later, we address the production mechanisms and find that, whatever the energy, nucleons finally entrained in a fragment exhibit strong initial-final state correlations, in coordinate as well as in momentum space. At high energy those correlations resemble the ones obtained in the participant-spectator model. At low energy the correlations are equally strong, but more complicated; they are a consequence of the Pauli blocking of the nucleon-nucleon collisions, the geometry, and the excitation energy. Studying a second set of time-dependent variables (radii, densities,...), we investigate in details how those correlations survive the reaction especially in central reactions where the nucleons have to pass through the whole system. It appears that some fragments are made of nucleons which were initially correlated, whereas others are formed by nucleons scattered during the reaction into the vicinity of a group of previously correlated nucleons.Comment: 45 pages text + 20 postscript figures Accepted for publication in Physical Review

Antibodies to the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) in cerebellar ataxia

We report on a serum autoantibody associated with cerebellar ataxia. Immunohistochemical studies of sera from four patients referred for autoantibody testing revealed binding of high-titer (up to 1:5,000) IgG antibodies, mainly IgG1, to the molecular layer, Purkinje cell layer, and white matter on mouse, rat, porcine, and monkey cerebellum sections. The antibody bound to PC somata, dendrites, and axons, resulting in a binding pattern similar to that reported for anti-Ca/anti-ARHGAP26, but did not react with recombinant ARHGAP26. Extensive control studies were performed to rule out a broad panel of previously described paraneoplastic and non-paraneoplastic anti-neural autoantibodies. The characteristic binding pattern as well as double staining experiments suggested inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) as the target antigen. Verification of the antigen included specific neutralization of the tissue reaction following preadsorption with ITPR1 (but not ARHGAP26) and a dot-blot assay with purified ITPR1 protein. By contrast, anti-ARHGAP26-positive sera did not bind to ITPR1. In a parallel approach, a combination of histoimmunoprecipitation and mass spectrometry also identified ITPR1 as the target antigen. Finally, a recombinant cell-based immunofluorescence assay using HEK293 cells expressing ITPR1 and ARHGAP26, respectively, confirmed the identification of ITPR1. Mutations of ITPR1 have previously been implicated in spinocerebellar ataxia with and without cognitive decline. Our findings suggest a role of autoimmunity against ITPR1 in the pathogenesis of autoimmune cerebellitis and extend the panel of diagnostic markers for this disease

Efficacy of different types of cognitive enhancers for patients with schizophrenia. A meta-analysis

Cognitive impairment is a core feature of schizophrenia, which is predictive for functional outcomes and is, therefore, a treatment target in itself. Yet, literature on efficacy of different pharmaco-therapeutic options is inconsistent. This quantitative review provides an overview of studies that investigated potential cognitive enhancers in schizophrenia. We included pharmacological agents, which target different neurotransmitter systems and evaluated their efficacy on overall cognitive functioning and seven separate cognitive domains. In total, 93 studies with 5630 patients were included. Cognitive enhancers, when combined across all different neurotransmitter systems, which act on a large number of different mechanisms, showed a significant (yet small) positive effect size of 0.10 (k = 51, p = 0.023; 95% CI = 0.01 to 0.18) on overall cognition. Cognitive enhancers were not superior to placebo for separate cognitive domains. When analyzing each neurotransmitter system separately, agents acting predominantly on the glutamatergic system showed a small significant effect on overall cognition (k = 29, Hedges’ g = 0.19, p = 0.01), as well as on working memory (k = 20, Hedges’ g = 0.13, p = 0.04). A sub-analysis of cholinesterase inhibitors (ChEI) showed a small effect on working memory (k = 6, Hedges’ g = 0.26, p = 0.03). Other sub-analyses were positively nonsignificant, which may partly be due to the low number of studies we could include per neurotransmitter system. Overall, this meta-analysis showed few favorable effects of cognitive enhancers for patients with schizophrenia, partly due to lack of power. There is a lack of studies involving agents acting on other than glutamatergic and cholinergic systems, especially of those targeting the dopaminergic system

Recent Advances in Imprinting Disorders.

Imprinting disorders (ImpDis) are a group of currently 12 congenital diseases with common underlying (epi)genetic etiologies and overlapping clinical features affecting growth, development and metabolism. In the last years it has emerged that ImpDis are characterized by the same types of mutations and epimutations, i.e. uniparental disomies, copy number variations, epimutations, and point mutations. Each ImpDis is associated with a specific imprinted locus, but the same imprinted region can be involved in different ImpDis. Additionally, even the same aberrant methylation patterns are observed in different phenotypes. As some ImpDis share clinical features, clinical diagnosis is difficult in some cases. The advances in molecular and clinical diagnosis of ImpDis help to circumvent these issues, and they are accompanied by an increasing understanding of the pathomechanism behind them. As these mechanisms have important roles for the etiology of other common conditions, the results in ImpDis research have a wider effect beyond the borders of ImpDis. For patients and their families, the growing knowledge contributes to a more directed genetic counseling of the families and personalized therapeutic approaches.COST (BM1208), Bundesministerium für Bildung und Forschung (Network ‘Imprinting Diseases’, 01GM1513B), German Ministry of research and education (01GM1513B)This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/cge.1282

Amino acid variation in HLA class II proteins is a major determinant of humoral response to common viruses

The magnitude of the human antibody response to viral antigens is highly variable. To explore the human genetic contribution to this variability, we performed genome-wide association studies of the immunoglobulin G response to 14 pathogenic viruses in 2,363 immunocompetent adults. Significant associations were observed in the major histocompatibility complex region on chromosome 6 for influenza A virus, Epstein-Barr virus, JC polyomavirus, and Merkel cell polyomavirus. Using local imputation and fine mapping, we identified specific amino acid residues in human leucocyte antigen (HLA) class II proteins as the most probable causal variants underlying these association signals. Common HLA-DRβ1 haplotypes showed virus-specific patterns of humoral-response regulation. We observed an overlap between variants affecting the humoral response to influenza A and EBV and variants previously associated with autoimmune diseases related to these viruses. The results of this study emphasize the central and pathogen-specific role of HLA class II variation in the modulation of humoral immune response to viral antigens in humans

Breakup Density in Spectator Fragmentation

Proton-proton correlations and correlations of protons, deuterons and tritons with alpha particles from spectator decays following 197Au + 197Au collisions at 1000 MeV per nucleon have been measured with two highly efficient detector hodoscopes. The constructed correlation functions, interpreted within the approximation of a simultaneous volume decay, indicate a moderate expansion and low breakup densities, similar to assumptions made in statistical multifragmentation models. PACS numbers: 25.70.Pq, 21.65.+f, 25.70.Mn, 25.75.GzComment: 11 pages, LaTeX with 3 included figures; Also available from http://www-kp3.gsi.de/www/kp3/aladin_publications.htm

Addressing the 'hypoxia paradox' in severe COVID-19: literature review and report of four cases treated with erythropoietin analogues

Since fall 2019, SARS-CoV-2 spread world-wide, causing a major pandemic with estimated ~ 220 million subjects affected as of September 2021. Severe COVID-19 is associated with multiple organ failure, particularly of lung and kidney, but also grave neuropsychiatric manifestations. Overall mortality reaches > 2%. Vaccine development has thrived in thus far unreached dimensions and will be one prerequisite to terminate the pandemic. Despite intensive research, however, few treatment options for modifying COVID-19 course/outcome have emerged since the pandemic outbreak. Additionally, the substantial threat of serious downstream sequelae, called 'long COVID' and 'neuroCOVID', becomes increasingly evident. Main body of the abstract Among candidates that were suggested but did not yet receive appropriate funding for clinical trials is recombinant human erythropoietin. Based on accumulating experimental and clinical evidence, erythropoietin is expected to (1) improve respiration/organ function, (2) counteract overshooting inflammation, (3) act sustainably neuroprotective/neuroregenerative. Recent counterintuitive findings of decreased serum erythropoietin levels in severe COVID-19 not only support a relative deficiency of erythropoietin in this condition, which can be therapeutically addressed, but also made us coin the term 'hypoxia paradox'. As we review here, this paradox is likely due to uncoupling of physiological hypoxia signaling circuits, mediated by detrimental gene products of SARS-CoV-2 or unfavorable host responses, including microRNAs or dysfunctional mitochondria. Substitution of erythropoietin might overcome this 'hypoxia paradox' caused by deranged signaling and improve survival/functional status of COVID-19 patients and their long-term outcome. As supporting hints, embedded in this review, we present 4 male patients with severe COVID-19 and unfavorable prognosis, including predicted high lethality, who all profoundly improved upon treatment which included erythropoietin analogues. Short conclusion Substitution of EPO may among other beneficial EPO effects in severe COVID-19 circumvent downstream consequences of the 'hypoxia paradox'. A double-blind, placebo-controlled, randomized clinical trial for proof-of-concept is warranted

Breakup Conditions of Projectile Spectators from Dynamical Observables

Momenta and masses of heavy projectile fragments (Z >= 8), produced in collisions of 197Au with C, Al, Cu and Pb targets at E/A = 600 MeV, were determined with the ALADIN magnetic spectrometer at SIS. An analysis of kinematic correlations between the two and three heaviest projectile fragments in their rest frame was performed. The sensitivity of these correlations to the conditions at breakup was verified within the schematic SOS-model. The data were compared to calculations with statistical multifragmentation models and to classical three-body calculations. Classical trajectory calculations reproduce the dynamical observables. The deduced breakup parameters, however, differ considerably from those assumed in the statistical multifragmentation models which describe the charge correlations. If, on the other hand, the analysis of kinematic and charge correlations is performed for events with two and three heavy fragments produced by statistical multifragmentation codes, a good agreement with the data is found with the exception that the fluctuation widths of the intrinsic fragment energies are significantly underestimated. A new version of the multifragmentation code MCFRAG was therefore used to investigate the potential role of angular momentum at the breakup stage. If a mean angular momentum of 0.75$\hbar$/nucleon is added to the system, the energy fluctuations can be reproduced, but at the same time the charge partitions are modified and deviate from the data. PACS numbers: 25.70.Mn, 25.70.Pq, 25.75.Ld, 25.75.-qComment: 38 pages, RevTeX with 21 included figures; Also available from http://www-kp3.gsi.de/www/kp3/aladin_publications.htm