Aggression expression among League of Legends and Fortnite players - a brief report.

BACKGROUND AND AIMS: Our primary goal was to determine and compare the anger expression strategies used by players of the two most popular online games, League of Legends and Fortnite Battle Royale, as well as those used by non-gamers. METHODS: The study sample was comprised of 450 subjects, of whom 338 were males and 112 females. The sample was further divided into four groups: 1. Non-gamers; 2. League of Legends gamers; 3. Fortnite gamers; and 4. League of Legends and Fortnite gamers. Anger attributes were measured using the validated Hungarian version of the 20-item Anger Expression Scale (Oláh 1987; Spielberger, 1985). Multinomial Logistic Regression was used to analyze the role of age and gender of the subjects to predict whether subjects were non-gamers or gamers. Subjects were further assessed by employing the Anger Expression Scale, which determines Anger-In (turning anger inwards or suppressing anger) and Anger-Out (expressing anger outwardly) profiles of individuals. The Anger-In and Anger-Out variables were added to the model. RESULTS: Compared to League of Legends gamers, Fortnite gamers had a more passive (Anger-In) anger expression strategy. Fortnite and League of Legends gamers possessed a more passive anger expression strategy relative to nongamers. DISCUSSION AND CONCLUSION: Further research is needed to determine whether the games themselves have a determining influence on the gamers anger expression strategy, or whether the gamers personality and anger expression strategy predisposed them to choose one game over the other.

Gallium maltolate has in vitro antiviral activity against SARS-CoV-2 and is a potential treatment for COVID-19.

BACKGROUND: Gallium has demonstrated strong anti-inflammatory activity in numerous animal studies, and has also demonstrated direct antiviral activity against the influenza A H1N1 virus and the human immunodeficiency virus (HIV). Gallium maltolate (GaM), a small metal-organic coordination complex, has been tested in several Phase 1 clinical trials, in which no dose-limiting or other serious toxicity was reported, even at high daily oral doses for several months at a time. For these reasons, GaM may be considered a potential candidate to treat coronavirus disease 2019 (COVID-19), which is caused by the SARS-CoV-2 virus and can result in severe, sometimes lethal, inflammatory reactions. In this study, we assessed the ability of GaM to inhibit the replication of SARS-CoV-2 in a culture of Vero E6 cells. METHODS: The efficacy of GaM in inhibiting the replication of SARS-CoV-2 was determined in a screening assay using cultured Vero E6 cells. The cytotoxicity of GaM in uninfected cells was determined using the Cell Counting Kit-8 (CCK-8) colorimetric assay. RESULTS: The results showed that GaM inhibits viral replication in a dose-dependent manner, with the concentration that inhibits replication by 50% (EC50) being about 14 µM. No cytotoxicity was observed at concentrations up to at least 200 µM. CONCLUSION: The in vitro activity of GaM against SARS-CoV-2, together with GaM's known anti-inflammatory activity, provide justification for testing GaM in COVID-19 patients.

Topical treatment with gallium maltolate reduces Treponema pallidum subsp. pertenue burden in primary experimental lesions in a rabbit model of yaws.

BACKGROUND: Gallium is a semi-metallic element known since the 1930s to have antimicrobial activity. This activity stems primarily from gallium's ability to mimic trivalent iron and disrupt specific Fe(III)-dependent pathways, particularly DNA synthesis (due to inhibition of ribonucleotide reductase). Because of its novel mechanism of action, gallium is currently being investigated as a new antibacterial agent, particularly in light of the increasing resistance of many pathogenic bacteria to existing antibiotics. Gallium maltolate (GaM) is being developed as an orally and topically administrable form of gallium. Yaws is a neglected tropical disease affecting mainly the skin and skeletal system of children in underprivileged settings. It is currently the object of a WHO-promoted eradication campaign using mass administration of the macrolide azithromycin, an antibiotic to which the yaws agent Treponema pallidum subsp. pertenue has slowly begun to develop genetic resistance. METHODS: Because yaws transmission is mainly due to direct skin contact with an infectious skin lesion, we evaluated the treponemicidal activity of GaM applied topically to skin lesions in a rabbit model of yaws. Treatment efficacy was evaluated by measuring lesion diameter, treponemal burden in lesion aspirates as determined by dark field microscopy and amplification of treponemal RNA, serology, and immunohistochemistry of biopsied tissue samples. RESULTS: Our results show that topical GaM was effective in reducing treponemal burden in yaws experimental lesions, particularly when applied at the first sign of lesion appearance but, as expected, did not prevent pathogen dissemination. CONCLUSION: Early administration of GaM to yaws lesions could reduce the infectivity of the lesions and thus yaws transmission, potentially contributing to current and future yaws control campaigns.

Serum and tissue concentrations of gallium after oral administration of gallium nitrate and gallium maltolate to neonatal calves.

OBJECTIVE: To determine serum and tissue concentrations of gallium (Ga) after oral administration of gallium nitrate (GaN) and gallium maltolate (GaM) to neonatal calves. ANIMALS: 8 healthy neonatal calves. PROCEDURES: Calves were assigned to 1 of 2 groups (4 calves/group). Gallium (50 mg/kg) was administered as GaN or GaM (equivalent to 13.15 mg of Ga/kg for GaN and 7.85 mg of Ga/kg for GaM) by oral gavage once daily for 5 days. Blood samples were collected 0, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after Ga administration on day 1; 4 and 24 hours after Ga administration on days 2, 3, and 4; and 4, 12, and 24 hours after Ga administration on day 5. On day 6, calves were euthanized and tissue samples were obtained. Serum and tissue Ga concentrations were measured by use of mass spectrometry. RESULTS: Data were adjusted for total Ga dose, and comparisons were made between the 2 groups. Calves receiving GaM had a significantly higher dose-adjusted area under the curve and dose-adjusted maximum serum Ga concentration than did calves receiving GaN. Despite receiving less Ga per dose, calves receiving GaM had tissue Ga concentrations similar to those for calves receiving GaN. CONCLUSIONS AND CLINICAL RELEVANCE: In this study, calves receiving GaM had significantly higher Ga absorption than did calves receiving GaN. These findings suggested that GaM might be useful as a prophylactic agent against Mycobacterium avium subsp paratuberculosis infection in neonatal calves.

Drug repurposing as an alternative for the treatment of recalcitrant bacterial infections.

Bacterial infection remains one of the leading causes of death worldwide, and the options for treating such infections are decreasing, due the rise of antibiotic-resistant bacteria. The pharmaceutical industry has produced few new types of antibiotics in more than a decade. Researchers are taking several approaches toward developing new classes of antibiotics, including (1) focusing on new targets and processes, such as bacterial cell-cell communication that upregulates virulence; (2) designing inhibitors of bacterial resistance, such as blockers of multidrug efflux pumps; and (3) using alternative antimicrobials such as bacteriophages. In addition, the strategy of finding new uses for existing drugs is beginning to produce results: antibacterial properties have been discovered for existing anticancer, antifungal, anthelmintic, and anti-inflammatory drugs. In this review, we discuss the antimicrobial properties of gallium compounds, 5-fluorouracil, ciclopirox, diflunisal, and some other FDA-approved drugs and argue that their repurposing for the treatment of bacterial infections, including those that are multidrug resistant, is a feasible strategy.

Gallium maltolate as an alternative to macrolides for treatment of presumed Rhodococcus equi pneumonia in foals.

BACKGROUND: Macrolide-resistant isolates of Rhodococcus equi are emerging, prompting the search for clinically effective alternative antimicrobials. HYPOTHESIS: The proportion of foals with ultrasonographic evidence of pneumonia presumed to be caused by R. equi that had a successful outcome when administered gallium maltolate (GaM) PO would not be more than 10% inferior (ie, lower) than that of foals receiving standard treatment. ANIMALS: Fifty-four foals with subclinical pulmonary abscesses among 509 foals at 6 breeding farms in Kentucky. METHODS: Controlled, randomized, prospective noninferiority study. Foals with ultrasonographic lesions >1 cm in diameter (n = 54) were randomly allocated to receive per os either clarithromycin combined with rifampin (CLR+R) or GaM, and followed up for 28 days by daily physical inspections and weekly (n = 1 farm) or biweekly (n = 4 farms) thoracic ultrasound examinations by individuals unaware of treatment-group assignments. Treatment success was defined as resolution of ultrasonographically identified pulmonary abscesses within 28 days of initiating treatment. Noninferiority was defined as a 90% confidence interval for the observed difference in CLR+R minus GaM that was ≤10%. RESULTS: The proportion of GaM-treated foals that resolved (70%; 14/20) was similar to that of foals treated with CLR+R (74%; 25/34), but we failed to demonstrate noninferiority for GaM relative to CLR+R; however, GaM was noninferior to CLR+R treatment when results from a noncompliant farm were excluded. CONCLUSIONS AND CLINICAL IMPORTANCE: Gallium maltolate is not inferior to macrolides for treating foals with subclinical pneumonia. Use of GaM might reduce pressure for macrolide-resistance in R. equi.

Comparison of the antimicrobial activities of gallium nitrate and gallium maltolate against Mycobacterium avium subsp. paratuberculosis in vitro.

Johne's disease (JD) is an enteric infection of cattle and other ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP). This study compared the antimicrobial activities of gallium nitrate (GaN) and gallium maltolate (GaM) against two field MAP isolates by use of broth culture. The concentrations that resulted in 99% growth inhibition of isolates 1 and 2 were, respectively, 636 µM and 183 µM for GaN, and 251 µM and 142 µM for GaM. For both isolates, time to detection was significantly higher for GaM than GaN. These results suggest that GaM is more efficient than GaN in inhibiting MAP growth in vitro.

Successful treatment of refractory postherpetic neuralgia with topical gallium maltolate: case report.

INTRODUCTION: Postherpetic neuralgia is a common sequela of herpes zoster (shingles), in which chronic pain may last for weeks to years. Currently, available treatments include systemic opioid analgesics, tricyclic antidepressants, corticosteroids, and anticonvulsants, as well as topical capsaicin and lidocaine. These treatments are commonly unsatisfactory, with fewer than half of treated patients experiencing more than a 50% reduction in pain. CASE: A 99-year-old woman had a 4-year history of severe postherpetic (trigeminal) neuralgia on the left side of her face. During those 4 years, numerous treatments were tried, including systemic opioid analgesics and anticonvulsants, and topical lidocaine and capsaicin, all with unsatisfactory results. The topical application of gallium maltolate, at a concentration of 0.5% in an emulsion of water and hydrophilic petrolatum, was found to relieve the severe pain within about 10 minutes, with the relief lasting for about 6-8 hours. The patient has been using this treatment for more than 5 years, with no adverse effects and a highly significant improvement in her quality of life. DISCUSSION: Gallium has significant anti-inflammatory activity, inhibiting the activation and proliferation of pro-inflammatory T cells. Because gallium is chemically similar to zinc, it can interfere with the activity of matrix metalloproteinases (zinc-bearing proteases), which have been implicated in the etiology of neuropathic pain, and it may suppress the secretion of substance P. Gallium may also inhibit viral replication and the inflammatory activity of viral proteins. This case provides rationale to study topical gallium maltolate in patients with refractory peripheral neuropathic pain.

Antimicrobial activity of gallium maltolate against Staphylococcus aureus and methicillin-resistant S. aureus and Staphylococcus pseudintermedius: An in vitro study.

Gallium is a trivalent semi-metallic element that has shown antimicrobial activity against several important human pathogens. This antimicrobial activity is likely related to its substitution in important iron-dependent pathways of bacteria. The genus Staphylococcus, which includes human and animal pathogens that cause significant morbidity and mortality, requires iron for growth and colonization. In this study, gallium maltolate, at various concentrations between 50 and 200µM, inhibited the in vitro growth of Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) at time-points between 8 and 36h after inoculation. The inhibitory activity of gallium maltolate against clinical isolates of MRSA and methicillin-resistant Staphylococcus pseudintermedius (MRSP) from a veterinary teaching hospital was determined.

Evaluation of the efficacy of gallium maltolate for chemoprophylaxis against pneumonia caused by Rhodococcus equi infection in foals.

OBJECTIVE: To determine the chemoprophylactic effect of gallium maltolate on the cumulative incidence of pneumonia caused by Rhodococcus equi infection in foals. ANIMALS: 483 foals born and raised on 12 equine breeding farms with a history of endemic R equi infections. PROCEDURES: Group 1 foals were treated with a placebo and group 2 foals were treated with gallium maltolate (approx 30 mg/kg, PO, q 24 h) during the first 2 weeks after birth. Foals were monitored for development of pneumonia attributable to R equi infection and for adverse effects of gallium maltolate. RESULTS: There were no significant differences in the cumulative incidence of R equi pneumonia among the 2 groups. CONCLUSIONS AND CLINICAL RELEVANCE: Chemoprophylaxis via gallium maltolate administered orally at approximately 30 mg/kg daily for the first 2 weeks after birth failed to reduce the cumulative incidence of pneumonia attributable to R equi infection among foals on breeding farms with endemic R equi infections. Further investigation is needed to identify strategies for control of R equi infections.

Hepatocellular carcinoma detection by gallium scan and subsequent treatment by gallium maltolate: rationale and case study.

Gallium is antiproliferative to many types of cancer, due primarily to its ability to act as a non-functional mimic of ferric iron (Fe(3+)). Because Fe(3+) is needed for ribonucleotide reductase activity--and thus DNA synthesis--gallium can inhibit DNA production and cell division. Diagnostic gallium scans have shown that hepatocellular carcinoma (HCC) is commonly avid for gallium. Furthermore, in vitro studies have found that gallium nitrate, and particularly gallium maltolate (GaM), have dose-dependent antiproliferative activity against HCC cell lines. Rationale thus exists to use GaM, an orally active compound that has been well tolerated in Phase I clinical trials, to treat patients whose HCC is gallium-avid in a gallium scan. Because gallium absorbed from orally administered GaM is bound predominately to serum transferrin, which travels to all tissues in the body, GaM has the potential to treat even distant metastases. A patient with advanced HCC (20 × 10 cm primary tumor, ascites around liver and spleen, resistant to Nexavar(®) (sorafenib)), whose cancer was highly gallium-avid in a (67)Ga-scan, was treated with oral gallium maltolate at 1500 mg/day q.d. After four weeks of treatment, the patient had a large reduction in pain, with greatly increased mobility and quality of life, and significantly lowered serum bilirubin and inflammation-related liver enzymes. At eight weeks, CT scans showed apparent necrosis of the tumor.

Pharmacokinetics of gallium maltolate after intragastric administration in adult horses.

OBJECTIVE: To determine the pharmacokinetics of gallium maltolate (GaM) after intragastric administration in adult horses. ANIMALS: 6 adult horses. PROCEDURES: Feed was withheld for 12 hours prior to intragastric administration of GaM (20 mg/kg). A single dose of GaM was administered to each horse via a nasogastric tube (time 0). Blood samples were collected at various time points from 0 to 120 hours. Serum was used to determine gallium concentrations by use of inductively coupled plasma-mass spectroscopy. Noncompartmental and compartmental analyses of serum gallium concentrations were performed. Pharmacokinetic models were selected on the basis of the Akaike information criterion and visual analysis of plots of residuals. RESULTS: Serum concentration data for 1 horse were such that this horse was considered an outlier and excluded from noncompartmental and compartmental analyses. Noncompartmental analysis was used to determine individual pharmacokinetic parameters. A 1-compartment model with first-order input and output and lag time was selected as the best-fit model for the data and used to determine mean ± SD values for maximum observed serum concentration (0.28 ± 0.09 µg/mL), time of maximum concentration (3.09 ± 0.43 hours), time to the first measurable concentration (0.26 ± 0.11 hours), apparent elimination half-life (48.82 ± 5.63 hours), area under the time-concentration curve (20.68 ± 757 h•µg/mL), and apparent volume of distribution (73,493 ± 18,899 mL/kg). CONCLUSION AND CLINICAL RELEVANCE: Further studies are necessary to determine the bioavailability of GaM after intragastric administration in adult horses.

Pharmacokinetics of gallium maltolate after intragastric administration in neonatal foals.

OBJECTIVE: To determine the pharmacokinetics of gallium maltolate (GaM) after intragastric administration in healthy foals. ANIMALS: 6 healthy neonatal foals. PROCEDURES: Each foal received GaM (20 mg/kg) by intragastric administration. Blood samples were obtained before (time 0) and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36, and 48 hours after GaM administration for determination of serum gallium concentrations by use of inductively coupled plasma mass spectroscopy. RESULTS: Mean +/- SD pharmacokinetic variables were as follows: peak serum gallium concentration, 1,079 +/- 311 ng/mL; time to peak serum concentration, 4.3 +/- 2.0 hours; area under the serum concentration versus time curve, 40,215 +/- 8,420 ng/mL/h; mean residence time, 39.5 +/- 17.2 hours; area under the moment curve, 1,636,554 +/- 931,458 ng([h](2)/mL); and terminal half-life, 26.6 +/- 11.6 hours. The mean serum concentration of gallium at 12 hours was 756 +/- 195 ng/mL. CONCLUSIONS AND CLINICAL RELEVANCE: Gallium maltolate administered via nasogastric tube at a dose of 20 mg/kg to neonatal foals resulted in gallium serum concentrations considered sufficient to suppress growth or kill Rhodococcus equi in macrophages and other infected tissues.

Gallium maltolate is a promising chemotherapeutic agent for the treatment of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a particularly lethal cancer with few treatment options. Since gallium is known to accumulate specifically in HCC tumors but not in non-tumor liver, we investigated two gallium compounds, gallium nitrate (GaN) and gallium maltolate (GaM), as potential new agents for treating HCC. MATERIALS AND METHODS: The anti-proliferative and apoptotic activities of GaN and GaM were assessed in vitro using four HCC cell lines. HCC gene expression data was analyzed to provide a mechanistic rationale for using gallium in the treatment of HCC. RESULTS: Both compounds showed dose-dependent antiproliferative activity in all four HCC cell lines after 6-day drug exposure (IC50 values range from 60-250 microM for gallium nitrate and 25-35 microM for gallium maltolate). Gallium maltolate at 30 microM additionally induced apoptosis after 6 days. HCC gene expression data showed significantly elevated expression of the M2 subunit of ribonucleotide reductase, which is a target for the antiproliferative activity of gallium. CONCLUSION: These data support clinical testing of gallium maltolate, an orally active compound, in the treatment of HCC.