Parkinson’s disease (PD) is characterized by alpha-synuclein misfolding with subsequent intraneuronal amyloid formation and accumulation, low grade neuroinflammatory changes, and selective neurodegeneration. Available evidence suggests that the pathology usually begins in the gut and olfactory mucosa, spreading to the brain via the vagus and olfactory nerves, by a prion-like mechanism. A causal relationship has not been established, but gut dysbiosis is prevalent in PD and may lead to intestinal inflammation and barrier dysfunction. Additionally, epidemiological data indicate a link between inflammatory bowel diseases and PD. Calprotectin and zonulin are markers of intestinal inflammation and barrier permeability, respectively. We evaluated their serum and fecal levels in 22 patients with sporadic PD and 16 unmatched healthy controls. Mean calprotectin was higher in PD, both in serum (14.26 mcg/ml ± 4.50 vs. 5.94 mcg/ml ± 3.80, p = 0.0125) and stool (164.54 mcg/g ± 54.19 vs. 56.19 mcg/g ± 35.88, p = 0.0048). Mean zonulin was also higher in PD serum (26.69 ng/ml ± 3.55 vs. 19.43 ng/ml ± 2.56, p = 0.0046) and stool (100.19 ng/ml ± 28.25 vs. 37.3 ng/ml ± 13.26, p = 0.0012). Calprotectin was above the upper reference limit in 19 PD serums and 6 controls (OR = 10.56, 95% CI = 2.17–51.42, p = 0.0025) and in 20 PD stool samples and 4 controls (OR = 30, 95% CI = 4.75–189.30, p = 0.000045). Increased zonulin was found only in the stool samples of 8 PD patients. Despite the small sample size, our findings are robust, complementing and supporting other recently published results. The relation between serum and fecal calprotectin and zonulin levels and sporadic PD warrants further investigation in larger cohorts.

COVID-19 mRNA vaccines effectively reduce incidence of severe disease, hospitalisation and death. The biodistribution and pharmacokinetics of the mRNA-containing lipid nanoparticles (LNPs) in these vaccines are unknown in humans. In this study, we used qPCR to track circulating mRNA in blood at different time-points after BNT162b2 vaccination in a small cohort of healthy individuals. We found that vaccine-associated synthetic mRNA persists in systemic circulation for at least 2 weeks. Furthermore, we used transmission electron microscopy (TEM) to investigate SARS-CoV-2 spike protein expression in human leukemic cells and in primary mononuclear blood cells treated in vitro with the BNT162b2 vaccine. TEM revealed morphological changes suggestive of LNP uptake, but only a small fraction of K562 leukemic cells presented spike-like structures at the cell surface, suggesting reduced levels of expression for these specific phenotypes.

Mutant calreticulin (CALR) proteins resulting from a -1/+2 frameshifting mutation of the CALR exon 9 carry a novel C-terminal amino-acid sequence and drive the development of myeloproliferative neoplasms (MPNs). Mutant CALRs were shown to interact with and activate the thrombopoietin receptor (TpoR/MPL) in the same cell. We report that mutant CALR proteins are secreted and can be found in patient plasma at levels up to 160ng/mL, with a mean of 25.64ng/mL. Plasma mutant CALR is found in complex with soluble Transferrin Receptor 1 (sTFRC) that acts as a carrier protein and increases CALR mutant half-life. Recombinant mutant CALR proteins bound and activated the TpoR on cell lines and primary megakaryocytic progenitors from CALR-mutated patients where they drive Tpo-independent colony formation. Importantly, the CALR-sTFRC complex remains functional for TpoR activation. By bioluminescence resonance energy transfer assay, we show that mutant CALR proteins produced in one cell can specifically interact in trans with the TpoR on a target cell. Cells that carry both TpoR and mutant CALR are hypersensitive to exogenous CALR mutant proteins in comparison to cells that only carry TpoR, and respond to levels of CALR mutant proteins similar to those in patient plasma. This is consistent with CALR mutated cells exposing at the cell-surface TpoR carrying immature N-linked sugars. Thus, secreted mutant CALR proteins will act more specifically on the MPN clone. In conclusion, a chaperone, CALR, can turn into a rogue cytokine through somatic mutation of its encoding gene.

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Background: Non‐insulin dependent diabetes mellitus (NIDDM) represents an independent risk factor for cardiovascular diseases (CVD), being characterized by a continnous low‐grade inflammation and endothelial activation state. Plasma platelet ‐ activating factor ‐ acetylhydrolases (PAF‐AHs) are a subgroup of Ca2+ ‐independent phospholipase A2 family (also known as lipoprotein‐associated phospholipases A2) that hydrolyze and inactivate the lipid mediator platelet‐activating factor (PAF) and/or oxidized phospholipids. This enzyme is considered to play an important role in inflammatory diseases and atherosclerosis. The present study aims to investigate the relations between the levels of PAF‐AH activity and LDL‐cholesterol/HDL‐cholesterol (LDL‐ch/HDL‐ch) ratio in NIDDM patients as compared to controls. Methods: serum PAF‐AH activity was measured in 50 patients with dyslipidemia, in 50 NIDDM patients and in 50 controls (normal lipid and glucose levels). Total cholesterol, LDL‐ch, HDL‐ch, triglyceride and blood glucose were determined in all subjects. Results: All NIDDM patients display hiperlipidemia, with increased LDL‐ch and triglyceride levels. There is a significant correlation between LDL‐ch levels (especially LDL‐ch / HDL‐ch ratio) and PAF‐AH activity in dyslipidemic and NIDDM patients. Conclusion: Diabetic and dyslipidemic patients have an increased plasma PAF‐AH activity correlated with their LDL‐ch levels and mainly with LDL‐ch / HDL‐ch ratio. Plasma PAF‐AH high levels appear to be important as a risk marker for endothelial dysfunction in patients with NIDDM.

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The presence of hyaline cartilage has been previously documented in heart tissue of different vertebrates, ranging from birds to superior mammals. However, there is scarce published data regarding the appearance of focal deposits of hyaline‐like cartilage within the hearts of laboratory rats. Few mechanisms that could trigger the appearance of this type of cartilage in heart were hypothesized (e.g., mechanical stress, ageing). Using different microscopy techniques this report confirms the presence of hyaline cartilage and bone in Wistar rats, which underwent left anterior coronary artery ligation for experimental myocardial infarction. The presented (ultra)structural evidence of focal chondroid metaplasia in the papillary muscles and close to the insertion point in the ventricular mass of the infarcted heart suggests a structural adaptation of cardiac myocardium to the newly acquired kinetics of left ventricular wall, after experimental myocardial infarction. Specific cartilaginous matrix proteins are known to mediate cardiac extracellular matrix remodeling, and this study provides evidence of a complete transition to a cartilaginous pattern in postinfarcted heart, which may nonetheless constitute a supplemental risk factor of a further heart failure condition. Moreover, for heart focal chondrogenesis, we also presume the involvement of the cellular and molecular inflammatory milieu that dominates the first 24 hr border zone landscape of the experimental myocardial infarction lesion. Anat Rec, 302:947–953, 2019. © 2018 Wiley Periodicals, Inc.