Sulfated Progesterone Metabolites That Enhance Insulin Secretion via TRPM3 Are Reduced in Serum From Women With Gestational Diabetes Mellitus

Serum progesterone sulfates were evaluated in the etiology of gestational diabetes mellitus (GDM). Serum progesterone sulfates were measured using ultra-performance liquid chromatography–tandem mass spectrometry in four patient cohorts: 1) the Hyperglycemia and Adverse Pregnancy Outcomes study; 2) London-based women of mixed ancestry and 3) U.K.-based women of European ancestry with or without GDM; and 4) 11–13 weeks pregnant women with BMI ≤25 or BMI ≥35 kg/m² with subsequent uncomplicated pregnancies or GDM. Glucose-stimulated insulin secretion (GSIS) was evaluated in response to progesterone sulfates in mouse islets and human islets. Calcium fluorescence was measured in HEK293 cells expressing transient receptor potential cation channel subfamily M member 3 (TRPM3). Computer modeling using Molecular Operating Environment generated three-dimensional structures of TRPM3. Epiallopregnanolone sulfate (PM5S) concentrations were reduced in GDM (P < 0.05), in women with higher fasting plasma glucose (P < 0.010), and in early pregnancy samples from women who subsequently developed GDM with BMI ≥35 kg/m² (P < 0.05). In islets, 50 µmol/L PM5S increased GSIS by at least twofold (P < 0.001); isosakuranetin (TRPM3 inhibitor) abolished this effect. PM5S increased calcium influx in TRPM3-expressing HEK293 cells. Computer modeling and docking showed identical positioning of PM5S to the natural ligand in TRPM3. PM5S increases GSIS and is reduced in GDM serum. The activation of GSIS by PM5S is mediated by TRPM3 in both mouse and human islets.     

Lactoferrin Induces Erythropoietin Synthesis and Rescues Cognitive Functions in the Offspring of Rats Subjected to Prenatal Hypoxia

The protective effects of recombinant human lactoferrin rhLF (branded “CAPRABEL™”) on the cognitive functions of rat offspring subjected to prenatal hypoxia (7% O₂, 3 h, 14th day of gestation) have been analyzed. About 90% of rhLF in CAPRABEL was iron-free (apo-LF). Rat dams received several injections of 10 mg of CAPRABEL during either gestation (before and after the hypoxic attack) or lactation. Western blotting revealed the appearance of erythropoietin (EPO) alongside the hypoxia-inducible factors (HIFs) in organ homogenates of apo-rhLF-treated pregnant females, their embryos (but not placentas), and in suckling pups from the dams treated with apo-rhLF during lactation. Apo-rhLF injected to rat dams either during pregnancy or nurturing the pups was able to rescue cognitive deficits caused by prenatal hypoxia and improve various types of memory both in young and adult offspring when tested in the radial maze and by the Novel Object Recognition (NOR) test. The data obtained suggested that the apo-form of human LF injected to female rats during gestation or lactation protects the cognitive functions of their offspring impaired by prenatal hypoxia.     

mGluR5 and GABAA receptor‐specific parametric PET atlas construction—PET/MR data processing pipeline,validation, and application

The glutamate and γ‐aminobutyric acid neuroreceptor subtypes mGluR₅ and GABA_A are hypothesized to be involved in the development of a variety of psychiatric diseases. However, detailed information relating to their in vivo distribution is generally unavailable. Maps of such distributions could potentially aid clinical studies by providing a reference for the normal distribution of neuroreceptors and may also be useful as covariates in advanced functional magnetic resonance imaging (MR) studies. In this study, we propose a comprehensive processing pipeline for the construction of standard space, in vivo distributions of non‐displaceable binding potential (BP _ND), and total distribution volume (V _T) based on simultaneously acquired bolus‐infusion positron emission tomography (PET) and MR data. The pipeline was applied to [¹¹C]ABP688‐PET/MR (13 healthy male non‐smokers, 26.6 ± 7.0 years) and [¹¹C]Flumazenil‐PET/MR (10 healthy males, 25.8 ± 3.0 years) data. Activity concentration templates, as well as V _T and BP _ND atlases of mGluR₅ and GABA_A, were generated from these data. The maps were validated by assessing the percent error δ from warped space to native space in a selection of brain regions. We verified that the average δ_ABP = 3.0 ± 1.0% and δ_FMZ = 3.8 ± 1.4% were lower than the expected variabilities σ of the tracers (σ_ABP = 4.0%–16.0%, σ_FMZ = 3.9%–9.5%). An evaluation of PET‐to‐PET registrations based on the new maps showed higher registration accuracy compared to registrations based on the commonly used [¹⁵O]H₂O‐template distributed with SPM12. Thus, we conclude that the resulting maps can be used for further research and the proposed pipeline is a viable tool for the construction of standardized PET data distributions.     

Investigation of the Initial Corrosion Destruction of a Metal Matrix around Different Non-Metallic Inclusions on Surfaces of Pipeline Steels

Typical non-metallic inclusions in two industrial low-carbon steels for oil pipelines were investigated as three-dimensional objects on film filters after electrolytic extraction and filtration of metal samples. A method of soft chemical extraction using a 10%AA electrolyte was used to study the initial corrosion process in the steel matrix surrounding various non-metallic inclusions. To determine and compare “corrosive” inclusions and their influence on the initial stages of corrosion of the adjacent layer of the steel matrix, quantitative parameters (such as the diameter of the corrosion crater (D_cr) and pit (D_pit), and the relative dissolution coefficient of the metal matrix (KD) around various inclusions) were determined after chemical extraction. It was found that CaO-Al₂O₃-MgO oxides and TiN inclusions did not cause an initial corrosion of the steel matrix surrounding these inclusions. However, tensile stresses in the steel matrix occurred around CaS inclusions (or complex inclusions containing a CaS phase), which contributed to the initiation of corrosion around these inclusions.     

Risk Factors of Venous Thromboembolism in Noncritically Ill Patients Hospitalized for Acute COVID-19 Pneumonia Receiving Prophylactic-Dose Anticoagulation

Background: Therapeutic/intermediate-dose heparin reduces the risk of thromboembolic events but increases the risk of major bleeding in patients hospitalized for acute COVID-19 pneumonia. Objectives: To prospectively assess the incidence of objectively proven venous thromboembolism (VTE) and identify predisposing risk factors in a cohort of hospitalized patients with acute COVID-19 pneumonia undergoing prophylactic-dose heparin. Patients and methods: All consecutive patients admitted for acute COVID-19 pneumonia to the General Internal Medicine Unit of Padova University Hospital, Italy between November 2020 and April 2021, and undergoing prophylactic-dose heparin, were enrolled. Demographic and clinical characteristics and laboratory and radiological findings were recorded on admission. Cases were patients who developed VTE during their hospital stay. Univariable and multivariable logistic regression analyses were used to ascertain the risk factors associated with developing in-hospital VTE. Results: 208 patients (median age: 77 years; M/F 98/110) were included; 37 (18%) developed in-hospital VTE during a median follow-up of 10 days (IQR, 4–18). VTE patients were significantly younger (p = 0.004), more obese (p = 0.002), and had a lower Padua prediction score (p < 0.03) and reduced PaO2/FIO2 ratio (p < 0.03) vs. controls. Radiological findings of bilateral pulmonary infiltrates were significantly more frequent in VTE patients than controls (p = 0.003). Multivariable regression showed that obesity (1.75, 95% CI 1.02–3.36; p = 0.04) and bilateral pulmonary infiltrates on X-rays (2.39, 95% CI 1.22–5.69; p = 0.04) were correlated with increased risk of in-hospital VTE. Conclusions: Obesity and bilateral pulmonary infiltrates on imaging may help clinicians to identify patients admitted to medical wards for acute COVID-19 pneumonia at risk of developing VTE despite prophylactic-dose heparin. Further studies are needed to evaluate whether the administration of therapeutic/intermediate-dose heparin may help prevent VTE episodes without further increasing the bleeding risk.     

Platelet Activation Favours NOX2-Mediated Muscle Damage in Elite Athletes: The Role of Cocoa-Derived Polyphenols

Mechanisms of exercise-induced muscle injury with etiopathogenesis and its consequences have been described; however, the impact of different intensities of exercise on the mechanisms of muscular injury development is not well understood. The aim of this study was to exploit the relationship between platelet activation, oxidative stress and muscular injuries induced by physical exercise in elite football players compared to amateur athletes. Oxidant/antioxidant status, platelet activation and markers of muscle damage were evaluated in 23 elite football players and 23 amateur athletes. Compared to amateurs, elite football players showed lower antioxidant capacity and higher oxidative stress paralleled by increased platelet activation and muscle damage markers. Simple linear regression analysis showed that sNOX2-dp and H₂O₂, sCD40L and PDGF-bb were associated with a significant increase in muscle damage biomarkers. In vitro studies also showed that plasma obtained from elite athletes increased oxidative stress and muscle damage in human skeletal muscle myoblasts cell line compared to amateurs’ plasma, an effect blunted by the NOX2 inhibitor or by the cell treatment with cocoa-derived polyphenols. These results indicate that platelet activation increased muscular injuries induced by oxidative stress. Moreover, NOX2 inhibition and polyphenol extracts treatment positively modulates redox status and reduce exercise-induced muscular injury.     

Wettability and Surface Roughness Analysis of Laser Surface Texturing of AISI 430 Stainless Steel

Due to its wide applicability in industry, devising microstructures on the surface of materials can be easily implemented and automated in technological processes. Laser Surface Texturing (LST) is applied to modify the chemical composition, morphology, and roughness of surfaces (wettability), cleaning (remove contaminants), reducing internal stresses of metals (hardening, tempering), surface energy (polymers, metals), increasing the adhesion (hybrid joining, bioengineering) and decreasing the growth of pathogenic bacteria (bioengineering). This paper is a continuation and extension of our previous studies in laser-assisted texturing of surfaces. Three different patterns (crater array-type C, two ellipses at 90° overlapping with its mirror-type B and 3 concentric octagons-type A) were applied with a nanosecond pulsed laser (active medium Nd: Fiber Diode-pumped) on the surface of a ferritic stainless steel (AISI 430). Micro texturing the surface of a material can modify its wettability behavior. A hydrophobic surface (contact angle greater than 90°) was obtained with different variations depending on the parameters. The analysis performed in this research (surface roughness, wettability) is critical for assessing the surface functionality, characteristics and properties of the stainless steel surface after the LST process. The values of the surface roughness and the contact angle are directly proportional to the number of repetitions and inversely proportional to the speed. Recommendations for the use of different texturing pattern designs are also made.     

The judgements that evidence‐based medicine adopts

In “The evidence that evidence‐based medicine omits”, Brendan Clarke and colleagues argue that when establishing causal facts in medicine, evidence of mechanisms ought to be included alongside evidence of correlations. One of the reasons they provide is that correlations can be spurious and generated by unknown confounding variables. A causal mechanism can provide a plausible explanation for the correlation, and the absence of such an explanation is an indication that the correlation is not causal. Evidence‐based medicine (EBM) proponents remain sceptical about this argument, one problem being that the formulation of a mechanism requires judgements that are external to the evaluation of data and experimental designs—for instance judgements of plausibility against, or derivability from, background knowledge. Because background knowledge is always incomplete and therefore unreliable, EBM proponents maintain that the plausibility of a hypothesis should be evaluated mainly by the quality of population data that yielded it. Here, I use the example of oestrogen replacement therapy's effect on coronary heart disease, an example that is often quoted in defence of the epistemic advantage of randomized controlled trials, to show that the evaluation of the most reliable study design necessarily implies the adoption of judgements that are external to the specific evidence of correlation. The exclusion of evidence of mechanism, therefore, is not effective in bypassing paradigm‐dependent judgements, which are external to specific evidence. Because such judgements cannot be excluded by evidence evaluation, they can only be kept under scrutiny, or adopted uncritically. I propose that the latter option can hinder the maintenance of an active critical inquiry, as well as the analysis of experts' disagreement.