Potential of acetaminophen on the sublingual microcirculation and peripheral tissue perfusion of febrile septic patients: prospective observational study.

BACKGROUND: Acetaminophen (ACT) has been studied in septic patients with detectable plasmatic levels of cell-free hemoglobin (Hb), where it demonstrated to inhibit the hemoprotein-mediated lipid peroxidation and oxidative injury, with a potential of beneficial effect on the endothelium. On the basis of this background, the aim of this study was to evaluate the sublingual microcirculation and the peripheral tissue perfusion before-and-after administration of ACT on clinical judgment in a cohort of febrile septic and septic shock patients. METHODS: Prospective observational study. 50 adult septic and septic shocks treated with ACT for pyrexia, where the sublingual microcirculation and the peripheral tissue perfusion with Near Infrared Spectroscopy (NIRS) and vascular occlusion test (VOT) were evaluated before ACT (t0), after 30 min (t1) and after 2 h (t2). Cell-free Hb and the markers of oxidative stress and endothelial damage were measured at t0 and t2. RESULTS: The study showed a significant increase of the density of the perfused small and total vessels of the sublingual microcirculation 30 min after the infusion of ACT; it also showed an increase of the Microvascular Flow Index (MFI) and a decrease in the heterogeneity of the flow. At a peripheral muscular level, we found an acceleration in the reperfusion curve after VOT at t1, expression of a higher reactivity of the microvasculature. CONCLUSIONS: ACT infusion did not show a clear correlation with cell-free Hb; however, it exhibited protective effect toward the microcirculation that was evident in particular in septic patients. This correlation merits further exploration.

Arthur Conan Doyle, Sherlock Holmes, and gout.

Arthur Conan Doyle, the creator of Sherlock Holmes, was an experienced physician who treated gouty patients. A gouty character appears in The Adventure of the Missing Three-Quarter, a Sherlock Holmes novel. This offers the possibility of discussing gout from the peculiar perspective of a medical writer in light of the historical-medical context of the time. This study was conducted using Conan Doyle's autobiographical, scientific, and literary primary sources, as well as past and current medical literature. The Adventure of the Missing Three-Quarter was autobiographical. Conan Doyle himself was a rugby player and his wife died of tuberculosis. Furthermore, in 1884, in The Lancet, he described the hereditary case of a female gouty patient, presenting with ocular manifestations. In agreement with the concept of rich man's gout, the gouty patient of Sherlock Holmes' story, Lord Mount James, was a rich irascible noble but he was not addicted to the pleasures of food and sex. Following the usual funny representation of gouty patients, Conan Doyle made fun of Lord Mount James, but he misquoted a true case of gout cited in the literature. In his scientific and literary production on gout, Conan Doyle stuck to the most updated medical concepts of the time, demonstrating an uncommon knowledge of scientific literature.

Pharmacogenetics in critical care: association between CYP3A5 rs776746 A/G genotype and acetaminophen response in sepsis and septic shock.

BACKGROUND: Pharmacogenetics could represent a further resource to understand the interindividual heterogeneity of response of the host to sepsis and to provide a personalized approach to the critical care patient. METHODS: Secondary analysis of data from the prospective observational study NCT02750163, in 50 adult septic and septic shock patients treated with Acetaminophen (ACT) for pyrexia. We investigated the presence of two polymorphisms, located respectively in the genes UGT1A1 and CYP3A5, that encode for proteins related to the hepatic metabolism of ACT. The main dependent variables explored were plasmatic concentration of ACT, body temperature and hepatic parameters. RESULTS: 8% of the patients carried CYP3A5 rs776746 A/G genotypes and showed significantly higher plasma levels of ACT than GG wild type patients, and than patients with UGT1A1 rs8330 C/G genotypes. CONCLUSIONS: Identifying specific genotypes of response to ACT may be helpful to guide a more personalized titration of therapy in sepsis and septic shock. CYP3A5 might be a good biomarker for ACT metabolism; however further studies are needed to confirm this result. TRIAL REGISTRATION: NCT02750163.

Microvascular dysfunction in pediatric patients with SARS-COV-2 pneumonia: report of three severe cases.

The coronavirus 19 (COVID-19) pandemic has affected hundreds of millions of people worldwide: in most of cases children and young people developed asymptomatic or pauci-symptomatic clinical pictures. However authors have showed that there are some categories of childhood more vulnerable to COVID-19 infection such as newborns or children with comorbidities. We report for the first time to the best of our knowledge about microvascular dysfunction in three pediatric clinical cases who developed COVID-19 infections with need of pediatric critical care. We found that sublingual microcirculation is altered in children with severe COVID-19 infection. Our findings confirmed most of data already observed by other authors in adult population affected by severe COVID-19 infection, but with distinct characteristics than microcirculation alterations previous observed in a clinical case of MIS-C. However we cannot establish direct correlation between microcirculation analysis and clinical or laboratory parameters in our series, by our experience we have found that sublingual microcirculation analysis allow clinicians to report directly about microcirculation dysfunction in COVID-19 patients and it could be a valuable bedside technique to monitor thrombosis complication in this population.

Platelet-activating factor induces cell cycle arrest and disrupts the DNA damage response in mast cells.

Platelet-activating factor (PAF) is a potent phospholipid modulator of inflammation that has diverse physiological and pathological functions. Previously, we demonstrated that PAF has an essential role in ultraviolet (UV)-induced immunosuppression and reduces the repair of damaged DNA, suggesting that UV-induced PAF is contributing to skin cancer initiation by inducing immune suppression and also affecting a proper DNA damage response. The exact role of PAF in modulating cell proliferation, differentiation or transformation is unclear. Here, we investigated the mechanism(s) by which PAF affects the cell cycle and impairs early DNA damage response. PAF arrests proliferation in transformed and nontransformed human mast cells by reducing the expression of cyclin-B1 and promoting the expression of p21. PAF-treated cells show a dose-dependent cell cycle arrest mainly at G2-M, and a decrease in the DNA damage response elements MCPH1/BRIT-1 and ataxia telangiectasia and rad related (ATR). In addition, PAF disrupts the localization of p-ataxia telangiectasia mutated (p-ATM), and phosphorylated-ataxia telangiectasia and rad related (p-ATR) at the site of DNA damage. Whereas the potent effect on cell cycle arrest may imply a tumor suppressor activity for PAF, the impairment of proper DNA damage response might implicate PAF as a tumor promoter. The outcome of these diverse effects may be dependent on specific cues in the microenvironment.

IgE-mediated reaction induced by arugula (Eruca sativa) ingestion compared with a spectrum of Brassicaceae proteins

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Overexpression of histidine-rich calcium binding protein in equine ventricular myocardium.

Histidine-rich calcium binding protein (HRC) is a high capacity, low affinity Ca(2+) binding protein, specifically expressed in striated muscles of mammals. In rabbit skeletal and cardiac muscles, HRC binds to sarcoplasmic reticulum (SR) membranes via triadin, a junctional SR protein. Recently, a potential role in heart failure and arrhythmogenesis has been assigned to HRC due to its activity as regulator of SR Ca(2+) uptake and Ca(2+) release. HRC might play a particularly relevant role in the equine heart, given its slower resting heart rate (20-35 beats/min) and longer action potential duration (APD) (0.6-1.0 s) than are found in other mammals. The results from this study showed for the first time direct evidence that HRC protein in equine cardiac muscle was expressed in association with the SR membranes and that HRC transcriptional activity was three times higher in the ventricles compared to the atria. The predominance of HRC mRNA up-regulation in ventricular myocardium was specific to the horse heart, since a more even distribution between atria and ventricles was found in animals of similar body size or species, such as cattle or domestic donkeys.

Reference gene validation for qPCR on normoxia- and hypoxia-cultured human dermal fibroblasts exposed to UVA: is ß-actin a reliable normalizer for photoaging studies?

Data normalization of gene expression on human dermal fibroblasts (HDF) exposed to UVA has commonly been done using either GAPDH or ß-actin as reference genes without any validation of their expression stability. Since this aspect, important for accurate normalization, has been overlooked, we aimed to establish a suitable set of reference genes for studies on UVA-treated HDF cultured under both standard atmospheric oxygen tension (normoxia, 21%) and under a physiological, low oxygen tension for these cells (hypoxia, 5%). The stability of six commonly used reference genes was assessed using the geNorm and NormFinder softwares subsequent to reverse-transcription quantitative real-time PCR (RT-qPCR). GAPDH/SDHA were found to be the most stable genes under normoxia, while SDHA/TBP or HPRT1/ß2M were the most stable ones under hypoxia in HDF exposed to 18 J/cm(2) UVA. ß-Actin was always the most unstable reference gene. To emphasize the importance of selecting the most stably expressed reference genes for obtaining reliable results, mRNA expression levels of MMP-1 and COL1A1 were analyzed vs the best reference genes and the worst one. These reference genes are hence recommended for future qPCR analyses in studies concerning photo-damage on UVA-treated HDF.

Thymoquinone, a potential therapeutic agent of Nigella sativa, binds to site I of human serum albumin.

Thymoquinone (TQ) is the main constituent of Nigella sativa essential oil which shows promising in vitro and in vivo antineoplastic growth inhibition against various tumor cell lines. Because of the increasing interest to test it in pre-clinical and clinical researches for assessing its health benefits, we here evaluate the interactions between TQ and human serum albumin (HSA), a possible carrier of this drug in vivo. Binding to HSA was studied using different spectroscopic techniques. Fourier transform infrared (FT-IR) and circular dichroism (CD) spectroscopies suggest that the association between TQ and HSA does not affect the secondary structure of HSA. Using fluorescence spectroscopy, one mole of TQ was found to bind one mole of HSA with a binding constant of 2.39 +/- 0.2 10(4)M(-1). At 25 degrees C (pH 7.4), van't Hoff's enthalpy and entropy that accompany the binding were found to be -10.24 kJ/mol(-1) and 45 J/mol(-1)K(-1) respectively. The thermodynamic analysis of the TQ-HSA complex formation shows that the binding process is enthalpy driven and spontaneous, and that hydrophobic interactions are the predominant intermolecular forces stabilizing the complex. Furthermore, displacement experiments using warfarin and ibuprofen indicate that TQ could bind to site I of HSA, which is also in agreement with the results of the molecular modeling study.

In vitro photostability and photoprotection studies of a novel 'multi-active' UV-absorber.

This paper reports on the synthesis and properties of a new UV-absorber (OC-NO) based on the most popular UV filter worldwide, ethylhexyl methoxycinnamate (OMC) in which the methoxy group has been replaced with a pyrrolidine nitroxide bearing antioxidant activity. This sunscreen active has therefore both UV-absorbing and antioxidant properties which could ideally address both the UV-B and UV-A skin photo-damage. For broad-spectrum coverage, the combinations of OC-NO with two commonly used UV-A absorbers (BMDBM and DHHB) were also studied. The results obtained reveal that OC-NO: (a) is as photostable as OMC after UV-A exposure; (b) acts as free radical scavenger as demonstrated by EPR and chemical studies; (c) reduces UV-A and UV-A+BMDBM induced lipid peroxidation in liposomes and cells, measured as reduced TBARS levels and increased C11-BODIPY red fluorescence, respectively; (d) has comparable antioxidant activity to that of vitamin E and BHT commonly used in skin care formulations; (e) is non-cytotoxic to human skin fibroblasts as assessed with the MTT assay when exposed to increasing doses of UV-A; and (f) OC-NO+DHHB is a promising, photostable broad spectrum UV-filter combination that concomitantly reduces UV-induced free radical damage. These results suggest that nitroxide/antioxidant-based UV-absorbers may pave the way for the utilization of 'multi-active' ingredients in sunscreens thereby reducing the number of ingredients in these formulations.

Treatment of mountain refuge wastewater by fixed and moving bed biofilm systems.

Tourists visiting mountain refuges in the Alps have increased significantly in the last decade and the number of refuges and huts at high altitude too. In this research the results of an intensive monitoring of a wastewater treatment plant (WWTP) for a tourist mountain refuge located at 2,981 m a.s.l. are described. Two biofilm reactors were adopted: (a) a Moving Bed Biofilm Reactor (MBBR); (b) a submerged Fixed Bed Biofilm Reactor (FBBR). The aims of this research were: (i) the evaluation of the main parameters characterising the processes and involved in the design of the wastewater plants, in order to compare advantages and disadvantages of the two tested alternatives; (ii) the acquisition of an adequate knowledge of the problems connected with the wastewater treatment in alpine refuges. The main results have been: (i) a quick start-up of the biological reactors obtainable thanks to a pre-colonization before the transportation of the plastic carriers to the refuge at the beginning of the tourist season; (ii) low volume and area requirement; (iii) significantly higher removal efficiency compared to other fixed biomass systems, such as trickling filters, but the energy consumption is higher.