C-type natriuretic peptide plasma levels increase in patients with chronic heart failure as a function of clinical severity

BACKGROUND: [corrected] C-type natriuretic peptide (CNP), secreted by the endothelium and the heart, is structurally related to atrial and brain natriuretic peptides, but its clinical significance in chronic heart failure (CHF) is controversial. AIM: To investigate the role of CNP in CHF, plasma CNP levels were determined in a prospective series of 133 patients with CHF (age 64 +/- 1 years, left ventricular ejection fraction (EF), 31.5 +/- 0.7%, mean +/-S.E.M.) and in 21 age-matched healthy subjects. METHODS AND RESULTS: CNP was measured by a radioimmunoassay (sensitivity: 0.41+/-0.009 pg/tube) after a preliminary solid-phase extraction. Plasma level of CNP in healthy subjects was 2.7 +/- 0.2 pg/ml and significantly increased in CHF, as a function of clinical severity: 4.9 +/- 0.7 pg/ml in NYHA class I; 7.0 +/- 0.4 pg/ml in class II (p < 0.001 vs. controls); 9.6 +/- 0.7 pg/ml in class III (p < 0.001 vs. controls and class I and II), and 11.8 +/- 2.0 pg/ml in class IV (p < 0.001 vs. controls, class I and II; Fisher's test after ANOVA). A significant relation was also found between CNP plasma levels and EF (R = 0.40, p < 0.001). CONCLUSION: Plasma CNP elevation is related to clinical and functional disease severity. These findings suggest a pathophysiological role for this peptide that, for its vasorelaxing activity, could influence the endothelial vasomotor response in CHF.     

Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and α-granule deficiency

The gray platelet syndrome is a rare inherited bleeding disorder characterized by macrothrombocytopenia and deficiency of alpha (α)-granules in platelets. The genetic defect responsible for gray platelet syndrome was recently identified in biallelic mutations in the NBEAL2 gene. We studied 11 consecutive families with inherited macrothrombocytopenia of unknown origin and α-granule deficiency. All of them underwent NBEAL2 DNA sequencing and evaluation of the platelet phenotype, including a systematic assessment of the α-granule content by immunofluorescence analysis for α-granule secretory proteins. We identified 9 novel mutations hitting the two alleles of NBEAL2 in 4 probands. They included missense, nonsense and frameshift mutations, as well as nucleotide substitutions that altered the splicing mechanisms as determined at the RNA level. All the individuals with NBEAL2 biallelic mutations showed almost complete absence of platelet α-granules. Interestingly, the 13 individuals assumed to be asymptomatic because carriers of a mutated allele had platelet macrocytosis and significant reduction of the α-granule content. However, they were not thrombocytopenic. In the remaining 7 probands, we did not identify any NBEAL2 alterations, suggesting that other genetic defect(s) are responsible for their platelet phenotype. Of note, these patients were characterized by a lower severity of the α-granule deficiency than individuals with two NBEAL2 mutated alleles. Our data extend the spectrum of mutations responsible for gray platelet syndrome and demonstrate that macrothrombocytopenia with α-granule deficiency is a genetic heterogeneous trait. In terms of practical applications, the screening of NBEAL2 is worthwhile only in patients with macrothrombocytopenia and severe reduction of the α-granules. Finally, individuals carrying one NBEAL2 mutated allele have mild laboratory abnormalities, suggesting that even haploinsufficiency has an effect on platelet phenotype.     

A role for all-trans-retinoic acid in the early steps of lymphatic vasculature development

The molecular mechanisms that regulate the earliest steps of lymphatic vascular system development are unknown. To identify regulators of lymphatic competence and commitment, we used an in vitro vascular assay with mouse embryonic stem cell-derived embryoid bodies (EBs). We found that incubation with retinoic acid (RA) and, more potently, with RA in combination with cAMP, induced the expression of the lymphatic competence marker LYVE-1 in the vascular structures of the EBs. This effect was dependent on RA receptor (RAR)-α and protein kinase A signaling. RA-cAMP incubation also promoted the development of CD31+/LYVE-1+/Prox1+ cell clusters. In situ studies revealed that RAR-α is expressed by endothelial cells of the cardinal vein in ED 9.5-11.5 mouse embryos. Timed exposure of mouse and Xenopus embryos to excess of RA upregulated LYVE-1 and VEGFR-3 on embryonic veins and increased formation of Prox1-positive lymphatic progenitors. These findings indicate that RA signaling mediates the earliest steps of lymphatic vasculature development.     

Chagas disease reactivation in rheumatologic patients: association with immunosuppressive therapy and humoral response

Clinical Rheumatology - Evidence for Chagas disease reactivation (CDR) in rheumatologic patients under rheumatologic treatments (RTs) is scarce. To screen and follow-up patients with rheumatic...     

Age-related factors that affect B cell responses to vaccination in mice and humans

Aging significantly changes the ability to respond to vaccinations and infections. In this review, we summarize published results on age-related changes in response to infection with the influenza virus and on the factors known to increase influenza risk infection leading to organ failure and death. We also summarize how aging affects the response to the influenza vaccine with a special focus on B cells, which have been shown to be less responsive in the elderly. We show the cellular and molecular mechanisms contributing to the dysfunctional immune response of the elderly to the vaccine against influenza. These include a defective interaction of helper T cells (CD4+) with B cells in germinal centers, changes in the microenvironment, and the generation of immune cells with a senescence-associated phenotype. Finally, we discuss the effects of aging on metabolic pathways and we show how metabolic complications associated with aging lead to immune dysfunction.     

Biology and grading of pleomorphic xanthoastrocytoma—what have we learned about it?

Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytoma predominantly affecting children and young adults. We performed comprehensive genomic characterization on a cohort of 67 patients with histologically defined PXA (n = 53, 79%) or anaplastic PXA (A‐PXA, n = 14, 21%), including copy number analysis (ThermoFisher Oncoscan, n = 67), methylation profiling (Illumina EPIC array, n = 43) and targeted next generation sequencing (n = 32). The most frequent alterations were CDKN2A/B deletion (n = 63; 94%) and BRAF p.V600E (n = 51, 76.1%). In 7 BRAF p.V600 wild‐type cases, alternative driver alterations were identified involving BRAF, RAF1 and NF1. Downstream phosphorylation of ERK kinase was uniformly present. Additional pathogenic alterations were rare, with TERT, ATRX and TP53 mutations identified in a small number of tumors, predominantly A‐PXA. Methylation‐based classification of 46 cases utilizing a comprehensive reference tumor allowed assignment to the PXA methylation class in 40 cases. A minority grouped with the methylation classes of ganglioglioma or pilocytic astrocytoma (n = 2), anaplastic pilocytic astrocytoma (n = 2) or control tissues (n = 2). In 9 cases, tissue was available from matched primary and recurrent tumors, including 8 with anaplastic transformation. At recurrence, two tumors acquired TERT promoter mutations and the majority demonstrated additional non‐recurrent copy number alterations. Methylation class was preserved at recurrence. For 62 patients (92.5%), clinical follow‐up data were available (median follow‐up, 5.4 years). Overall survival was significantly different between PXA and A‐PXA (5‐year OS 80.8% vs. 47.6%; P = 0.0009) but not progression‐free survival (5‐year PFS 59.9% vs. 39.8%; P = 0.05). WHO grade remained a strong predictor of overall survival when limited to 38 cases defined as PXA by methylation‐based classification. Our data confirm the importance of WHO grading in histologically and epigenetically defined PXA. Methylation‐based classification may be helpful in cases with ambiguous morphology, but is largely confirmatory in PXA with well‐defined morphology.     

Mobile ECMO in COVID-19 patient: case report

Journal of Artificial Organs - At July 25, 2020, WHO had recorded more than 16.1 million confirmed COVID-19 cases, 1% of them developed critical illness. These patients can experience rapid...     

Molecular docking to Toxoplasma gondii thymidylate synthase-dihydrofolate reductase and efficacy of raltitrexed in infected mice

Parasitology Research - Toxoplasmosis is a zoonosis of worldwide distribution. Currently, two drugs, pyrimethamine and sulfadiazine, are used as a reference in the treatment of toxoplasmosis, but...     

Molecular typing and in vitro resistance of Cryptococcus neoformans clinical isolates obtained in Germany between 2011 and 2017

Cryptococcosis is a fungal infection of the central nervous system predominantly caused by Cryptococcus neoformans in immunocompromised patients. In several countries worldwide, up to 50% of isolates show in vitro resistance to clinically used antifungals including fluconazole. No prospective data on susceptibility to antifungal drugs are available for Germany. In this study, we characterised all C. neoformans isolates collected from individual patients’ samples at the German reference laboratory for cryptococcosis 2011 and 2017 (n = 133) by multi-locus sequence typing and phenotypic drug susceptibility testing. We identified serotype A/genotype VNI isolates belonging to clonal complexes previously described from Europe, Africa, Asia and South America as the most prevalent agents of cryptococcosis in Germany. Overall, we observed minimal inhibitory concentrations (MICs) above the epidemiological cut-offs (ECVs) in 1.6% of isolates regarding fluconazole and 2.3% of isolates regarding 5-flucytosine. Here, two C. neoformans var. grubii isolates displayed decreased drug susceptibility to fluconazole, one of them additionally to 5-flucytosine. We also found 5-flucytosine MICs above the ECV for two C. neoformans var. neoformans isolates. We identified a novel mutation in the ERG11 gene which might be associated with the elevated fluconazole MIC in one of the isolates. The clinical importance of the detected in vitro resistance is documented by patient histories showing relapsed infection or primary fatal disease. Of note, sertraline demonstrated antifungal activity comparable to previous reports. Systematic collection of susceptibility data in combination with molecular typing of C. neoformans is important to comprehensively assess the spread of isolates and to understand their drug resistance patterns.