Are diabetes and its medications risk factors for the development of COVID-19? Data from a population-based study in Sicily

Background and aimsDiabetes mellitus (DM) has been associated with higher incidence of severe cases of COVID-19 in hospitalized patients, but it is unknown whether DM is a risk factor for the overall COVID-19 incidence. The aim of present study was to investigate whether there is an association of DM with COVID-19 prevalence and case fatality, and between different DM medications and risk for COVID-19 infection and death.Methods and resultsretrospective observational study on all SARS-CoV-2 positive (SARS-CoV-2⁺) cases and deaths in Sicily up to 2020, May 14th. No difference in COVID-19 prevalence was found between people with and without DM (RR 0.92 [0.79–1.09]). Case fatality was significantly higher in SARS-CoV-2⁺ with DM (RR 4.5 [3.55–5.71]). No diabetes medication was associated with differences in risk for SARS-Cov2 infection.Conclusionsin Sicily, DM was not a risk factor for COVID-19 infection, whereas it was associated with a higher case fatality.     

Effect on survival of the development of late-onset non-infectious pulmonary complications after stem cell transplantation

We evaluated the incidence, risk factors, and clinical outcome of late-onset non-infectious pulmonary complications (LONIPC) in 599 patients who underwent hematopoietic allogeneic stem cell transplantation (HSCT). The 2-year cumulative incidence of LONIPC was 10% among the 438 patients surviving more than 3 months after HSCT. Transplants from an unrelated donor and occurrence of extensive chronic graft-versus-host disease were the variables significantly associated with the development of LONIPC. The 5-year overall survival was significantly worse among patients with LONIPC than among those without (34% vs 65%, p=0.009). Causes of death were respiratory failure and infections. The relapse rate was similar in the two groups.     

Optimum inhomogeneity of local lattice distortions in La2CuO4+y

Electronic functionalities in materials from silicon to transition metal oxides are, to a large extent, controlled by defects and their relative arrangement. Outstanding examples are the oxides of copper, where defect order is correlated with their high superconducting transition temperatures. The oxygen defect order can be highly inhomogeneous, even in optimal superconducting samples, which raises the question of the nature of the sample regions where the order does not exist but which nonetheless form the “glue” binding the ordered regions together. Here we use scanning X-ray microdiffraction (with a beam 300 nm in diameter) to show that for La₂CuO_4+y, the glue regions contain incommensurate modulated local lattice distortions, whose spatial extent is most pronounced for the best superconducting samples. For an underdoped single crystal with mobile oxygen interstitials in the spacer La₂O_2+y layers intercalated between the CuO₂ layers, the incommensurate modulated local lattice distortions form droplets anticorrelated with the ordered oxygen interstitials, and whose spatial extent is most pronounced for the best superconducting samples. In this simplest of high temperature superconductors, there are therefore not one, but two networks of ordered defects which can be tuned to achieve optimal superconductivity. For a given stoichiometry, the highest transition temperature is obtained when both the ordered oxygen and lattice defects form fractal patterns, as opposed to appearing in isolated spots. We speculate that the relationship between material complexity and superconducting transition temperature T_c is actually underpinned by a fundamental relation between T_c and the distribution of ordered defect networks supported by the materials.     

Muscle synergy patterns as physiological markers of motor cortical damage

The experimental findings herein reported are aimed at gaining a perspective on the complex neural events that follow lesions of the motor cortical areas. Cortical damage, whether by trauma or stroke, interferes with the flow of descending signals to the modular interneuronal structures of the spinal cord. These spinal modules subserve normal motor behaviors by activating groups of muscles as individual units (muscle synergies). Damage to the motor cortical areas disrupts the orchestration of the modules, resulting in abnormal movements. To gain insights into this complex process, we recorded myoelectric signals from multiple upper-limb muscles in subjects with cortical lesions. We used a factorization algorithm to identify the muscle synergies. Our factorization analysis revealed, in a quantitative way, three distinct patterns of muscle coordination-including preservation, merging, and fractionation of muscle synergies-that reflect the multiple neural responses that occur after cortical damage. These patterns varied as a function of both the severity of functional impairment and the temporal distance from stroke onset. We think these muscle-synergy patterns can be used as physiological markers of the status of any patient with stroke or trauma, thereby guiding the development of different rehabilitation approaches, as well as future physiological experiments for a further understanding of postinjury mechanisms of motor control and recovery.     

The contribution of stem cell therapy to skeletal muscle remodeling in heart failure

Background

The aim of our study was to investigate whether stem cell (SC) therapy with human amniotic fluid stem cells (hAFS, fetal stem cells) and rat adipose tissue stromal vascular fraction cells–GFP positive cells (rSVC-GFP) was able to produce favorable effects on skeletal muscle (SM) remodeling in a well-established rat model of right heart failure (RHF).

Methods

RHF was induced by monocrotaline (MCT) in Sprague–Dawley rats. Three weeks later, four millions of hAFS or rSVC-GFP cells were injected via tail vein. SM remodeling was assessed by Soleus muscle fiber cross sectional area (CSA), myocyte apoptosis, myosin heavy chain (MHC) composition, satellite cells pattern, and SC immunohistochemistry.

Results

hAFS and rSVC-GFP injection produced significant SC homing in Soleus (0.68 ± 1.0 and 0.67 ± 0.75% respectively), with a 50% differentiation toward smooth muscle and endothelial cells. Pro-inflammatory cytokines were down regulated to levels similar to those of controls.SC-treated (SCT) rats showed increased CSA (p < 0.004 vs MCT) similarly to controls with a reshift toward the slow MHC1 isoform. Apoptosis was significantly decreased (11.12. ± 8.8 cells/mm³ hAFS and 13.1 + 7.6 rSVC-GFP) (p < 0.001 vs MCT) and similar to controls (5.38 ± 3.0 cells/mm³).RHF rats showed a dramatic reduction of satellite cells(MCT 0.2 ± 0.06% Pax7 native vs controls 2.60 ± 2.46%, p < 0.001), while SCT induced a repopulation of both native and SC derived satellite cells (p < 0.005).

Conclusions

SC treatment led to SM remodeling with satellite cell repopulation, decreased atrophy and apoptosis. Modulation of the cytokine milieu might play a crucial pathophysiological role with a possible scenario for autologous transplantation of SC in pts with CHF myopathy.     

Phenotypic and functional heterogeneity of human NK cells developing after umbilical cord blood transplantation: a role for human cytomegalovirus?

Natural killer (NK) cells play a crucial role in early immunity after hematopoietic stem cell transplantation because they are the first lymphocyte subset recovering after the allograft. In this study, we analyzed the development of NK cells after intrabone umbilical cord blood (CB) transplantation in 18 adult patients with hematologic malignancies. Our data indicate that, also in this transplantation setting, NK cells are the first lymphoid population detectable in peripheral blood. However, different patterns of NK-cell development could be identified. Indeed, in a group of patients, a relevant fraction of NK cells expressed a mature phenotype characterized by the KIR(+)NKG2A(-) signature 3-6 months after transplantation. In other patients, most NK cells maintained an immature phenotype even after 12 months. A possible role for cytomegalovirus in the promotion of NK-cell development was suggested by the observation that a more rapid NK-cell maturation together with expansion of NKG2C(+) NK cells was confined to patients experiencing cytomegalovirus reactivation. In a fraction of these patients, an aberrant and hyporesponsive CD56(-)CD16(+)p75/AIRM1(-) NK-cell subset (mostly KIR(+)NKG2A(-)) reminiscent of that described in patients with viremic HIV was detected. Our data support the concept that cytomegalovirus infection may drive NK-cell development after umbilical CB transplantation.     

A novel mechanism of sustained platelet αIIbβ3 activation via PEAR1

Because single nucleotide polymorphisms (SNPs) in platelet endothelial aggregation receptor 1 (PEAR1) are associated with differential functional platelet responses in healthy subjects, we studied the function of PEAR1 in human platelets. During platelet aggregation by various agonists, the membrane expression of PEAR1 and its tyrosine phosphorylation increased. The recombinant PEAR1 EMI domain (GST-EMI) competitively reduced platelet adhesion to surface-coated PEAR1, diminished platelet aggregation, and eliminated PEAR1 phosphorylation. Polyclonal antibodies against the extracellular PEAR1 domain triggered PEAR1 phosphorylation in a src family kinase (SFK)-dependent manner. Such resulted in downstream signaling, culminating in extensive platelet degranulation and irreversible aggregation reactions interrupted by excess monovalent anti-GST-EMI F(ab) fragments. In resting platelets, the cytoplasmic tail of PEAR1 was found complexed to c-Src and Fyn, but on its phosphorylation, phospho-PEAR1 recruited p85 PI3K, resulting in persistent activation of PI3K and Akt. Thus, αIIbβ3 activation was amplified, hence stabilizing platelet aggregates, a signaling cascade fully interrupted by the SFK inhibitor PP1 and the PI3K inhibitor LY294002. This study is the first demonstration of a functional role for PEAR1 in platelet activation, underpinning the observed association between PEAR1 and platelet function in genome-wide association studies.     

Beneficial effect of sulphate-bicarbonate-calcium water on gallstone risk and weight control

AIM: To investigate the effect of drinking sulphate-bicarbonate-calcium thermal water (TW) on risk factors for atherosclerosis and cholesterol gallstone disease.METHODS: Postmenopausal women with functional dyspepsia and/or constipation underwent a 12 d cycle of thermal (n = 20) or tap (n = 20) water controlled drinking. Gallbladder fasting volume at ultrasound, blood vitamin E, oxysterols (7-β-hydroxycholesterol and 7-ketocholesterol), bile acid (BA), triglycerides, total/low density lipoprotein and high density lipoprotein cholesterol were measured at baseline and at the end of the study. Food consumption, stool frequency and body weight were recorded daily.RESULTS: Blood lipids, oxysterols and vitamin E were not affected by either thermal or tap water consumption. Fasting gallbladder volume was significantly (P < 0.005) smaller at the end of the study than at baseline in the TW (15.7 ± 1.1 mL vs 20.1 ± 1.7 mL) but not in the tap water group (19.0 ± 1.4 mL vs 19.4 ± 1.5 mL). Total serum BA concentration was significantly (P < 0.05) higher at the end of the study than at baseline in the TW (5.83 ± 1.24 μmol vs 4.25 ± 1.00 μmol) but not in the tap water group (3.41 ± 0.46 μmol vs 2.91 ± 0.56 μmol). The increased BA concentration after TW consumption was mainly accounted for by glycochenodeoxycholic acid. The number of pasta (P < 0.001), meat (P < 0.001) and vegetable (P < 0.005) portions consumed during the study and of bowel movements per day (P < 0.05) were significantly higher in the TW than in the tap water group. Body weight did not change at the end of the study as compared to baseline in both groups.CONCLUSION: Sulphate-bicarbonate-calcium water consumption has a positive effect on lithogenic risk and intestinal transit and allows maintenance of a stable body weight despite a high food intake.     

Ca2+-dependent structural rearrangements within Na+-Ca2+ exchanger dimers

Cytoplasmic Ca(2+) is known to regulate Na(+)-Ca(2+) exchanger (NCX) activity by binding to two adjacent Ca(2+)-binding domains (CBD1 and CBD2) located in the large intracellular loop between transmembrane segments 5 and 6. We investigated Ca(2+)-dependent movements as changes in FRET between exchanger proteins tagged with CFP or YFP at position 266 within the large cytoplasmic loop. Data indicate that the exchanger assembles as a dimer in the plasma membrane. Addition of Ca(2+) decreases the distance between the cytoplasmic loops of NCX pairs. The Ca(2+)-dependent movements detected between paired NCXs were abolished by mutating the Ca(2+) coordination sites in CBD1 (D421A, E451A, and D500V), whereas disruption of the primary Ca(2+) coordination site in CBD2 (E516L) had no effect. Thus, the Ca(2+)-induced conformational changes of NCX dimers arise from the movement of CBD1. FRET studies of CBD1, CBD2, and CBD1-CBD2 peptides displayed Ca(2+)-dependent movements with different apparent affinities. CBD1-CBD2 showed a Ca(2+)-dependent phenotype mirroring full-length NCX but distinct from both CBD1 and CBD2.     

Membrane receptors for interleukin 2 on hematopoietic precursors in chronic myeloid leukemia

In this report we present data on the expression of IL2 receptors on chronic phase CML cells. Using an anti IL2 receptor monoclonal antibody (McAb aIL2r) in indirect immunofluorescence we found significant proportions (42.2% +/- 19.7 SD) of the CML cells (previously depleted of E rosetting T cells) to be IL2 receptor positive following incubation in suspension for 18 hours at 37 degrees C. Noninduced cells did not express IL2 receptors. After induction the aIL2r positive and negative cell subpopulations were sorted and analyzed separately for morphology, lineage specific cell surface markers, and clonogenic cell numbers. The IL2 receptor positive CML subpopulations mainly contained blast cells and monocytes and revealed reactivity with myeloid McAbs but not with T cell, B cell, platelet, or erythroid markers. Clonogenic cells (CFU-GEMM, BFUe, and CFU-GM) were selectively recovered from aIL2r positive CML cells and thus were IL2 receptor positive. The addition of recombinant IL2 (rIL2) to CFU-GM and BFUe cultures, in concentrations from 50 to 500 U/mL, did not influence the efficiency of colony formation. Binding of a radiolabeled IL2 preparation to the in vitro activated CML cells indicated the presence of low affinity receptors for IL2. In contrast to CML, normal human marrow cells were consistently aIL2r nonreactive. Thus, IL2 receptor inducibility is a characteristic feature of CML clonogenic cells, which they share with AML, but not with normal marrow progenitors. The role of IL2 receptors in the regulation of proliferation of CML cells requires further investigation.