Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus,Respiratory Syncytial Virus and Influenza A Virus

The long-term control strategy of SARS-CoV-2 and other major respiratory viruses needs to include antivirals to treat acute infections, in addition to the judicious use of effective vaccines. Whilst COVID-19 vaccines are being rolled out for mass vaccination, the modest number of antivirals in use or development for any disease bears testament to the challenges of antiviral development. We recently showed that non-cytotoxic levels of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca²⁺ ATPase pump, induces a potent host innate immune antiviral response that blocks influenza A virus replication. Here we show that TG is also highly effective in blocking the replication of respiratory syncytial virus (RSV), common cold coronavirus OC43, SARS-CoV-2 and influenza A virus in immortalized or primary human cells. TG’s antiviral performance was significantly better than remdesivir and ribavirin in their respective inhibition of OC43 and RSV. Notably, TG was just as inhibitory to coronaviruses (OC43 and SARS-CoV-2) and influenza viruses (USSR H1N1 and pdm 2009 H1N1) in separate infections as in co-infections. Post-infection oral gavage of acid-stable TG protected mice against a lethal influenza virus challenge. Together with its ability to inhibit the different viruses before or during active infection, and with an antiviral duration of at least 48 h post-TG exposure, we propose that TG (or its derivatives) is a promising broad-spectrum inhibitor against SARS-CoV-2, OC43, RSV and influenza virus.     

Improvement in renal function following cryoballoon ablation for atrial fibrillation

Purpose

Patients with chronic kidney disease are predisposed to heart rhythm disorders including atrial fibrillation (AF). Several studies have suggested that radiofrequency catheter ablation of AF improves renal function. However, little data exists for pulmonary vein isolation with cryoballoon ablation (CBA). The purpose of this study is to assess change in renal function following CBA for AF.

Method

This is a single-center retrospective study that included patients who underwent CBA for AF between 2011 and 2016. Patients were grouped by baseline-estimated glomerular filtration rate (eGFR): ≥?90 (Stage G1), 60–89.9 (Stage G2), and 30–59.9 mL/min/1.73 m² (Stage G3). Change in eGFR was assessed >?3 months post-ablation.

Results

A total of 306 patients with both pre- and post-ablation serum creatinine measurements available were included. Baseline eGFRs for Stages G1, G2, and G3 patients were 103.5?±?12.9 (n?=?82), 74.7?±?8.2 (n?=?184), and 52.6?±?6.6 mL/min/1.73 m² (n?=?40), respectively. Renal function was assessed 310.8?±?104.2 days post-ablation. Average intra-procedural contrast use was 58.4?±?23.8 mL. There was no significant change in eGFR following CBA in Stage G1 patients (p?=?0.10). For those with Stages G2 and G3 renal function, eGFR improved by 6.1% (4.2 mL/min/1.73 m², p?<?0.01) and 13.8% (7.2 mL/min/1.73 m², p?<?0.01), respectively. This improvement was seen regardless of the presence or absence of recurrent atrial arrhythmias.

Conclusions

CBA for AF may be associated with an improvement in renal function, particularly among those with a reduced baseline eGFR despite recurrence of atrial arrhythmias and intra-procedural contrast use.

     

Recombinant antibodies to an oxidized low-density lipoprotein epitope induce rapid regression of atherosclerosis in apobec-1(-/-)/low-density lipoprotein receptor(-/-) mice.

OBJECTIVES: The present study tested the hypothesis that treatment with human recombinant immunoglobulin G1 (IgG1) antibodies against a specific oxidized low-density lipoprotein (oxLDL) epitope will induce regression of existing atherosclerotic lesions in LDL receptor-deficient mice expressing apolipoprotein B-100 (apoB-100) (Apobec-1(-/-)/LDLR(-/-)). BACKGROUND: Oxidized LDL plays an essential role in the pathogenesis of atherosclerosis. We previously showed that an antibody against oxLDL reduces progression of atherosclerosis in mice. METHODS: Apobec-1(-/-)/LDLR(-/-) mice were fed a high-fat diet until they were 24 weeks and were subsequently transferred to chow. Starting at 25 weeks, mice were given 3 weekly injections of either of 2 recombinant human IgG1 antibodies (IEI-E3 or 2D03) against a malondialdehyde-modified apoB-100 peptide sequence. RESULTS: At 25 weeks, atherosclerotic lesions covered 10.3 +/- 3.7% of the descending aorta. Transfer to chow diet resulted in a modest regression of atherosclerosis over a 5-week period (8.28 +/- 4.36%; p = NS). Antibody treatment induced additional regression of atherosclerosis by 50% (2D03; p = 0.001) and 36% (IEI-E3; p = 0.004) compared with control IgG1. The 2D03 treatment also reduced plaque inflammation, enhanced plaque expression of the adenosine triphosphate-binding cassette transporter A1, and inhibited expression of monocyte chemoattractant protein-1 in cultured monocytes. CONCLUSIONS: Human IgG1 against a specific oxLDL epitope can induce rapid and substantial regression of atherosclerotic lesions, possibly by stimulating lipid efflux and inhibiting macrophage recruitment. These recombinant human antibodies could represent a novel strategy for rapid regression/stabilization of atherosclerotic lesions.     

Intraoperative blood loss during decompressive craniectomy for intractable intracranial hypertension after severe traumatic brain injury in children

Purpose

There are no data available on the risk of intraoperative bleeding during decompressive craniectomy (DC) after traumatic brain injury (TBI) in children. The objectives of this study were to assess the risk of intraoperative bleeding during DC for intractable intracranial hypertension after TBI, to identify potential factors associated with the risk of bleeding during DC, and to assess the impact of DC on systemic and cerebral hemodynamics and on coagulation.

Methods

Twelve children were identified as having undergone DC after TBI from April 2009 to June 2013 in our center. Subjects were allocated into two groups according to the percentage of blood loss (IBL) during the intraoperative period (<or ≥50 % of the estimated blood volume (EBV)).

Results

The median IBL during DC was 49 [17–349] % of the EBV. Children with an IBL?≥?50 % of EBV had higher preoperative intracranial pressure (ICP) (p?=?0.03) and international normalized ratio (INR) (p?=?0.02) than those with an IBL?<?50 % of EBV. DC induced significant decreases in ICP (p?=?0.0005), mean arterial pressure (p?=?0.01), and a significant increase in norepinephrine flow rate (p?=?0.04) between the immediate pre- and postoperative periods.

Conclusions

DC allows a significant decrease in ICP after severe pediatric TBI but is a surgical procedure at a high risk of bleeding. High ICP and INR during the immediate preoperative period are the main factors associated with increased IBL during DC. Further studies are needed to confirm our results and to assess the impact of the amount of IBL on the postoperative survival and functional outcome.     

Clinical oxygen enhancement ratio of tumors in carbon ion radiotherapy: the influence of local oxygenation changes

The effect of carbon ion radiotherapy on hypoxic tumors has recently been questioned because of low linear energy transfer (LET) values in the spread-out Bragg peak (SOBP). The aim of this study was to investigate the role of hypoxia and local oxygenation changes (LOCs) in fractionated carbon ion radiotherapy. Three-dimensional tumors with hypoxic subvolumes were simulated assuming interfraction LOCs. Different fractionations were applied using a clinically relevant treatment plan with a known LET distribution. The surviving fraction was calculated, taking oxygen tension, dose and LET into account, using the repairable–conditionally repairable (RCR) damage model with parameters for human salivary gland tumor cells. The clinical oxygen enhancement ratio (OER) was defined as the ratio of doses required for a tumor control probability of 50% for hypoxic and well-oxygenated tumors. The resulting OER was well above unity for all fractionations. For the hypoxic tumor, the tumor control probability was considerably higher if LOCs were assumed, rather than static oxygenation. The beneficial effect of LOCs increased with the number of fractions. However, for very low fraction doses, the improvement related to LOCs did not compensate for the increase in total dose required for tumor control. In conclusion, our results suggest that hypoxia can influence the outcome of carbon ion radiotherapy because of the non-negligible oxygen effect at the low LETs in the SOBP. However, if LOCs occur, a relatively high level of tumor control probability is achievable with a large range of fractionation schedules for tumors with hypoxic subvolumes, but both hyperfractionation and hypofractionation should be pursued with caution.     

Study of Wear Phenomenon of a Dental Milling Cutter by Statistical–Mathematical Modeling Based on the Experimental Results

The wear phenomenon of a dental milling cutter is studied based on experimental results and data and validated by statistical–mathematical modeling. The results of the statistical–mathematical modeling by the interpolation of the experimental results (data) regarding the wear of the dental milling cutter analyzed and obtained in the work process are presented in this paper. These results (data) are important because they lead to polynomial functions which by interpolation approximate very well the dependent parameter, specifically the wear process (mass lost due to dental milling cutter wear, m_w), considered in the experimental program. The polynomial interpolation functions are valid, only during the experimental testing range of the dental milling cutter, to describe the wear phenomenon; the extrapolations do not lead to satisfactory results. However, by using a controlled interpolation function with an exponential component, the extrapolation of the results is possible. Therefore, the purpose of this paper is the statistical–mathematical modeling by the interpolation of the experimental results of the mass lost due to dental milling cutter wear, m_w, using the deterministic differential model for the work process of it. Thus, interesting conclusions can be drawn relating to the phenomenon. In support of these statements come the results of the statistical–mathematical modeling by the interpolation of the experimental data obtained in the work process of the dental milling cutters, leading to practical applications, such as the extension of the life of dental milling cutter, useful even for its operation optimization; determination of possible criteria for replacing the worn dental milling cutters; the extension of the life of the materials from which dental milling cutters are built; or the provision of ideas for constructive solutions. Based on the modeling results by interpolation, it was found that the dental milling cutter during the milling operation works with high efficiency (mass loss due to wear is very reduced) in the first 11 h of operation, i.e., about a 10% increase in lifetime. After 11 h of operation, mass loss due to wear of the dental milling cutter increases relatively exponentially; thus, it is recommended that, in the normal way, the dental milling cutter be replaced with a new one to ensure high standards of materials processing.     

Poly(vinyl alcohol)/Plant Extracts Films: Preparation,Surface Characterization and Antibacterial Studies against Gram Positive and Gram Negative Bacteria

In this study, we aim to obtain biomaterials with antibacterial properties by combining poly(vinyl alcohol) with the extracts obtained from various selected plants from Romania. Natural herbal extracts of freshly picked flowers of the lavender plant (Lavandula angustifolia) and leaves of the peppermint plant (Mentha piperita), hemp plant (Cannabis sativa L.), verbena plant (Verbena officinalis) and sage plant (Salvia officinalis folium) were selected after an intensive analyzing of diverse medicinal plants often used as antibacterial and healing agents from the country flora. The plant extracts were characterized by different methods such as totals of phenols and flavonoids content and UV-is spectroscopy. The highest amounts of the total phenolic and flavonoid contents, respectively, were recorded for Salvia officinalis. Moreover, the obtained films of poly(vinyl alcohol) (PVA) loaded with plant extracts were studied concerning the surface properties and their antibacterial or cytotoxicity activity. The Attenuated Total Reflection Fourier Transform Infrared analysis described the successfully incorporation of each plant extract in the poly(vinyl alcohol) matrix, while the profilometry demonstrated the enhanced surface properties. The results showed that the plant extracts conferred significant antibacterial effects to films toward Staphylococcus aureus and Escherichia coli and are not toxic against fibroblastic cells from the rabbit.     

The Influence of Abrasive and Acidic Aggressions on the Surface Condition of Flowable Composite Resin

The aim of this in vitro study was to evaluate the effect of hydrochloric acid associated with the abrasive effect of toothbrushing on the surface condition of three flowable composite resins used for direct restoration. Seventy samples of each composite resin: Grandio Flow (VOCO, Germany)—group A, Filtek Ultimate Flow (3M-ESPE, MN, USA)—group B, G-aenial Flo X (GC Europe)—group C were prepared, submersed in hydrochloric acid 30% for 60 min and then submitted to simulated toothbrushing procedure using 5000 cycles with toothbrushes with medium and hard bristles, immediately after the chemical attack, after 30 min or without any chemical attack. The sample’s surface roughness was analyzed using a noncontact profilometer (Dektak XT, Bruker, USA). ANOVA and post hoc Bonferroni tests, with a p < 0.05, were used to analyze the values. Hydrochloric acid action for 60 min and six months of toothbrushing using toothbrushes having medium hardness or firm bristles affects the surface roughness of tested flowable composite resins. Toothbrushing with firm bristles immediately after acidic challenge determines increased surface roughness for two of the three flowable composite resins (Grandio Flow and Filtek Ultimate Flow). Toothbrushing with medium or firm bristles thirty minutes after the acidic aggression determine no effect on surface condition of flowable composite resins.