The risk of QTc-interval prolongation in COVID-19 patients treated with chloroquine.

BACKGROUND: Chloroquine, a quinolone antimalarial drug, is known to potentially inhibit pH-dependent viral replication of the SARS-CoV­2 infection. Therefore, chloroquine is considered as a treatment option for coronavirus disease 2019 (COVID-19). Chloroquine is known for prolonging the QT interval, but limited data are available on the extent of this QT-prolonging effect. OBJECTIVE: To assess the QTc-prolonging potential of chloroquine in COVID-19 patients and to evaluate whether this prolongation increases with the cumulative dose of chloroquine and is associated with the peak plasma concentration of chloroquine. Furthermore, the number of patients who prematurely discontinued treatment or had an adjustment in dose due to QTc-interval prolongation was established. METHODS: A retrospective, observational study was performed in patients aged over 18 years, hospitalised for a suspected or proven infection with COVID-19, and therefore treated with chloroquine, with a baseline electrocardiogram (ECG) performed prior to the start of treatment and at least one ECG after starting the treatment. RESULTS: In total, 397 patients were included. The mean increase in QTc interval throughout the treatment with chloroquine was 33 ms. Nineteen out of 344 patients unnecessarily had their treatment prematurely discontinued or adjusted due to a prolonged QTc interval based on the computerised interpretation of the ECG. CONCLUSION: Chloroquine treatment in COVID-19 patients gradually increased the QTc interval. Due to a significant number of overestimated QTc intervals by computer analysis, it is advisable to measure the QTc interval manually before adjusting the dose or withdrawing this potentially beneficial medication.

Feasibility of a low concentration test bolus in CT angiography.

AIM: To investigate the feasibility of using a low-concentration test bolus in abdominal aorta computed tomography (CT) angiography (CTA). MATERIALS AND METHODS: In 10 patients referred for CTA of the abdominal aorta with a body mass index (BMI) ≤28 kg/m2, a standard test bolus of 10 ml contrast medium (CM; 350 mg iodine/ml) was compared with a low-concentration test bolus (5 ml CM; 350 mg iodine/ml; 1:1 diluted with saline) in terms of time to peak enhancement (tPE) and peak enhancement (PE). RESULTS: No significant differences were found between the standard and low-concentration test bolus in terms of tPE and PE. CONCLUSIONS: A low-concentration test bolus (5 ml, 1:1 diluted with saline) is feasible in patients with a BMI ≤28 kg/m2.

On the nature of dense CO adlayers on fcc(100) surfaces: a kinetic Monte Carlo study.

We present a kinetic Monte Carlo lattice gas model including top and bridge sites on a square lattice, with pairwise lateral interactions between the adsorbates. In addition to the pairwise lateral interactions we include an additional interaction: an adsorbate is forbidden to adsorb on a bridge site formed by two surface atoms when both surface atoms are already forming a bond with an adsorbate. This model is used to reproduce the low and high coverage adsorption behaviour of CO on Pt(100) and Rh(100). The parameter set used to simulate CO on Pt(100) produces the c(2 x 2)-2t ordered structure at 0.50 ML coverage, a one-dimensionally ordered structure similar to the experimentally observed (3 square root(2) x square root(2)) - 2t + 2b structure at 0.67 ML coverage, the c(4 x 2)-4t + 2b ordered structure at 0.75 ML coverage, and the recently reported c(6 x 2)-6t + 4b ordered structure at 0.83 ML coverage. The (5 square root(2) x square root(2)) ordered structure at 0.60 ML coverage is not reproduced by our model. The parameter set used to simulate CO on Rh(100) produces the c(2 x 2)-2t ordered structure at 0.50 ML coverage, a one-dimensionally ordered structure similar to the experimentally observed (4 square root(2) x square root(2)) - 2t + 4b structure at 0.75 ML coverage, and the c(6 x 2)-6t + 4b ordered structure at 0.83 ML coverage. Additionally, the simulated change of top and bridge site occupation as a function of coverage matches the trend in experimental vibrational peak intensities.

Pain-relieving properties of topically applied morphine on arterial leg ulcers: a pilot study.

OBJECTIVE: To assess whether topical morphine is pharmacologically effective in relieving pain from ulcers caused by arterial insufficiency and identify whether this effect is centrally or peripherally mediated. METHOD: The analgesic effect of a topically applied hydrogel containing 0.5% of morphine was evaluated in a double-blind, placebo-controlled, three-way crossover pilot study involving nine patients with painful arterial leg ulcers. All patients had a baseline pain intensity of at least 5 on a 10-point numeric rating scale. They received the following three treatments in random order: morphine hydrogel plus a subcutaneous (SC) placebo infusion; placebo gel plus a SC infusion of 5mg morphine over six hours and a placebo gel plus a SC placebo infusion. Each treatment lasted one day. Pain was assessed during the first 24 hours after application of the hydrogel and the start of the subcutaneous infusion. RESULTS: There was a statistically significant difference between average baseline pain scores and those reported during treatment, but this difference was not clinically relevant. The three treatments did not differ in terms of the pain relief provided. CONCLUSION: Topical morphine does not have a clinically relevant analgesic effect in patients with painful arterial leg ulcers. Further research should focus on ulcers of other aetiology.

The influence of carbon on the adsorption of CO on a Rh(100) single crystal.

The influence of carbon on the adsorption of CO from a Rh(100) single crystal has been studied by a combination of experimental techniques: Temperature Programmed Desorption (TPD), Low Energy Electron Diffraction (LEED), and High Resolution Electron Energy Loss Spectroscopy (HREELS). These experimental techniques were combined with a computational approach using Density Functional Theory (DFT). Using this combination of techniques, we have shown that surface carbon greatly influences adsorbed CO and we have determined the exact magnitude of this interaction. Furthermore, we have demonstrated that carbon does not remain fully on the surface; at higher coverage it diffuses partially to subsurface positions. The presence of these subsurface species significantly influences the adsorbates on the surface.

Expression of macrophage p120 depends on early protein synthesis.

We have previously identified a group of early proteins preceding the expression of a 120-kDa protein (p120) which coincides with tumoricidal activation in peritoneal macrophages. In the present report, we have asked whether the in vitro induction of new or enhanced expression of p120 depends on early protein synthesis and RNA synthesis during the treatment period. Expression of p120 was sensitive to pretreatment of the macrophages with either actinomycin D or cycloheximide, indicating that both active protein synthesis and RNA synthesis were required. When poly-adenylated RNA isolated from various macrophage populations was translated in a rabbit reticulocyte in vitro translation system, only mRNA isolated from cells which express p120 was able to direct synthesis of a 120-kDa polypeptide. This product showed identical mobility to p120 induced in intact activated macrophages radiolabeled with [35S]methionine. The presence of translatable p120 mRNA was dependent upon treatment of thioglycollate-elicited macrophages with both IFN-gamma plus LPS at low doses, as is expression of p120 in intact cells. Accumulation of translatable p120 mRNA was blocked by treatment with cycloheximide, indicating that active protein synthesis was required during the induction period. These results suggest that the presence of specific translatable mRNA encoding the p120 polypeptide is dependent upon the expression of early macrophage gene products.

Characterization of lipopolysaccharide-induced macrophage gene expression.

A cDNA library from LPS-treated murine peritoneal macrophages has been screened by differential hybridization with radiolabeled cDNA from untreated and LPS-treated macrophages. Six clones hybridizing with mRNA sequences present in LPS-treated cells but not in controls were selected for further characterization. When the recombinant bacteriophage DNA from each clone was used as a probe in Northern analysis of total RNA from LPS-treated macrophages, inducible mRNA ranging from 1.45 to 6.4 kb were seen. In five of six cases, the mRNA expression was undetectable in untreated macrophage cultures. All but one clone identified mRNA that were inducible even in the presence of cycloheximide, indicating the independence of such gene expression from protein synthesis; none of the genes were superinduced by this treatment. The time course of expression differed among the individual genes. Four were induced transiently, whereas two showed stable increasing accumulation through an 8-h period after stimulation. In addition, four of the genes were seen within 30 min of stimulation, whereas two were seen only after 2 to 4 h. Two genes were induced only by treatment with LPS, whereas four were also induced in response to other agents, including IFN-gamma, macrophage CSF, and PMA. The insert sequences from these recombinant clones did not hybridize with a set of cDNA encoding other inducible gene products, including TNF, IL-1, ornithine decarboxylase, c-myc, c-fos, JE, or KC. Thus, these six cDNA appear to encode inducible macrophage genes that are distinct from one another as well as from a selection of previously described early genes. Although their functional identity remains indeterminate, they may encode previously described early proteins induced in macrophages treated with LPS.

Maleyl-BSA and fucoidan induce expression of a set of early proteins in murine mononuclear phagocytes.

We examined the effect of maleyl-BSA on specific protein expression in murine peritoneal macrophages by radiolabeling treated macrophages with [35S]methionine followed by SDS-polyacrylamide gel electrophoresis. Such treatment induces the expression of a set of at least seven proteins (38, 42, 57, 65, 75, 80, and 85 kD). A similar set of proteins is also induced by treatment of macrophages with the algal polysaccharide fucoidan. The proteins resemble those induced in response to treatment of this same cell population with bacterial lipopolysaccharide (LPS), as judged by co-migration in both one- and two-dimensional electrophoresis. Two proteins induced by either LPS or maleyl-BSA (e.g., p57 and p85) show similar primary structure, as assessed by partial proteolytic peptide mapping confirming their identity. The induction of these proteins by maleyl-BSA is a transient phenomenon, being expressed as early as 1 hr after treatment and declining after 8 hr even in the continuous presence of the stimulus. The dose of maleyl-BSA required to induce the response varies to some extent with the protein in question, but agrees with the Kd for ligand-receptor binding. Chloroquine, which blocks the degradation of ligand, does not inhibit the induction of early protein synthesis. Whereas the induction of these proteins is blocked by inhibition of RNA synthesis with actinomycin D, the reversible inhibition of protein synthesis with cycloheximide during the induction phase does not prevent their expression. LPS, maleyl-BSA, and fucoidan previously have been shown to stimulate protease secretion and tumoricidal function in appropriately primed macrophages. The present findings now demonstrate that all three agents can also mediate the expression of early genes which may participate in the acquisition of functional competence.

Effects of bacterial lipopolysaccharide on protein synthesis in murine peritoneal macrophages: relationship to activation for macrophage tumoricidal function.

Early biochemical events in the response of murine peritoneal macrophages to bacterial lipopolysaccharide (LPS) have been examined (i.e., 0-4 hr after initiation of treatment). At concentrations of 10 ng/ml or less, LPS stimulated the new or enhanced synthesis of a series of at least six polypeptides of 85, 80, 75, 65, 57, and 38 kD. This effect was dependent upon the lipid A moiety of LPS as lipid A itself could induce the changes and the effect of LPS could be blocked by inclusion of polymixin B sulfate in the culture medium. The effect was specific for LPS in that other endotoxin-free agents known to alter macrophage physiology could not produce the same changes. The time course of LPS stimulation of macrophage protein synthesis was remarkable in that the synthesis of all six proteins was transient even in the continued presence of LPS, being first detected approximately 1 hr after exposure and no longer apparent by 8-10 hr after treatment was initiated. Furthermore, both pulse-chase and cumulative radiolabeling studies indicated that at least two of the proteins (85 and 38 kD) were short-lived and did not accumulate in LPS-treated cells, suggesting the possibility that they participate in a regulatory rather than a functional role. Macrophage tumoricidal activation involves cooperation in response to two independent signals; interferon gamma and LPS. Pretreatment of macrophages with interferon gamma increased the sensitivity of macrophages to LPS-stimulated protein synthesis by one to two orders of magnitude documenting such cooperativity in molecular terms. The LPS-induced stimulation of specific protein synthesis could be reproduced by treatment of macrophages with heat killed Listeria monocytogenes, a gram-positive, endotoxin-negative bacterial stain which has been shown to substitute effectively for LPS in macrophage tumoricidal activation. Furthermore, reversible inhibition (i.e., treatment with cycloheximide) of protein synthesis during LPS treatment abrogated the acquisition of tumoricidal function. These results identify an early biochemical response to LPS which may be a necessary component of the intracellular transduction of signals which regulate macrophage functional development.