Key elements of preparedness for pandemic coronavirus disease 2019 (COVID-19) in nuclear medicine units

European Journal of Nuclear Medicine and Molecular Imaging -     

Identification of undeclared active pharmaceutical ingredients in counterfeit herbal medicines used as opioid substitution therapy

Adulteration of traditional herbal drugs with undeclared active pharmaceutical ingredients is a global problem with the increase in popularity of herbal-based medications. Many unprofessional herbal stores introduce herbal medicines as traditional formulations, but there are poor regulations for traditional herbal products’ consistency and safety in Iran. The current study aimed to identify undeclared active pharmaceutical ingredients in traditional herbal medicines used as opioid substitution therapy. In this research study, systematic toxicological analysis was performed for the analysis of 80 traditional herbal medicine samples. Samples were prepared and analysed by gas chromatography/mass spectrometry (GC/MS) instrumentation. More than 96% of samples contained at least one pharmaceutical active ingredient. Diphenoxylate and tramadol were detected in 90% and 67% of samples respectively. Moreover, some other pharmaceutical ingredients such as acetaminophen, codeine, sertraline, and fluoxetine were found in the samples. Quantitative analysis of samples showed that capsules contained diphenoxylate and tramadol at concentrations of 1.4–4 mg/capsule and 67–150 mg/capsule respectively. Traditional herbal preparations are not regulated as medicines in Iran. Herbal drugs with undeclared active ingredients are potentially dangerous for consumers; therefore, serious safety concerns must be associated with their production, distribution and use.     

Significance of abnormal myocardial perfusion scintigraphy in young adult patients with SLE

Objectives  

Detection of subclinical coronary artery disease (CAD) is a potential challenge in patients with systemic lupus erythematosus (SLE) and it is suggested that myocardial perfusion single photon emission computerized tomography (SPECT) is more sensitive than exercise test in this setting. However, the significance of perfusion abnormalities in SLE patients is not well known. In this study, we evaluated the prognostic significance of myocardial perfusion defects in patients with SLE.     

Clinical characteristics of Staphylococcus epidermidis: a systematic review

Staphylococci are known as clustering Gram-positive cocci, nonmotile, non-spore forming facultatively anaerobic that classified in two main groups, coagulase-positive and coagulase-negative. Staphylococcus epidermidis with the highest percentage has the prominent role among coagulase-negative Staphylococci that is the most important reason of clinical infections. Due to various virulence factors and unique features, this microorganism is respected as a common cause of nosocomial infections. Because of potential ability in biofilm formation and colonization in different surfaces, also using of medical implant devices in immunocompromised and hospitalized patients the related infections have been increased. In recent decades the clinical importance and the emergence of methicillin-resistant Staphylococcus epidermidis strains have created many challenges in the treatment process.     

Carcinogenic metal induced sites of reactive oxygen species formation in hepatocytes

Severe chronic liver disease results from the hepatic accumulation of copper nickel, cobalt or iron in humans and on the other hand cadmium, dichromate and arsenic may induce lung or kidney cancer. Acute or chronic CdCl₂, HgCl₂ or dichromate administration induces hepatic and nephrotoxicity in rodents. Oxidative stress is often cited as a possible cause but has not yet been measured. For the first time we have measured the reactive oxygen species (ROS) formation induced when cells are incubated with metals and determined its source. Hepatocytes incubated with 2′,7′-dichlorofluorescin diacetate resulted in its rapid uptake and deacetylation by intracellular esterases to form 2′,7′-dichlorofluorescin. A marked increase in ROS formation occurred with LD₅₀ concentrations of cadmium [Cd(II)], Hg(II) or arsenite [As(III)] which was released by proton ionophores that uncouple oxidative phosphorylation. Uncouplers or oxidative phosphorylation also inhibited ROS formation induced by these metals, which suggests that mitochondria are major contributors to endogenous ROS formation. Glycolytic substrates also inhibited Cd(II)/Hg(II)/As(III)-induced ROS formation and confirms that mitochondria are the site of ROS formation. By contrast ROS formation by LD₅₀ concentrations of Cu(II), Ni(II), Co(II) or dichromate [Cr(VI)] were not affected by uncouplers or glycolytic substrates. However they were inhibited by lysosomotropic agents or endogenous inhibitors [in contrast to Hg(II), Cd(II) or As(III)]. Furthermore Cu(II), Ni(II), Co(II) or Cr(VI) accumulated in the lysosomes and the ROS formed caused a loss of lysosomal membrane integrity. The release of lysosomal proteases and phospholipases also contributed to hepatocyte cytotoxicity. ROS formation and cytotoxicity induced by added H₂O₂ or generated by the intracellular redox cycling of nitrofurantoin was also inhibited by lysosomotropic agents and ferric chelators suggesting that lysosomal Fe(II) contributes to H₂O₂-induced cytotoxicity. In conclusion, lysosomes are sites of cytotoxic ROS formation with redox transition metals (CuII, CrVI, NiII, CoII) whereas mitochondria are the ROS sites for non-redox or poor redox cycling transition metals (CdII, HgII, AsIII).     

A comparison of hepatocyte cytotoxic mechanisms for chromate and arsenite

In the following, we have compared the cytotoxic mechanisms of the chromate CrO(4)(2-) and arsenite AsO(2)(-). Chromate (Cr (VI)) cytotoxicity was associated with reactive oxygen species (ROS) formation, lipid peroxidation and loss of mitochondrial membrane potential, which were prevented by catalase, antioxidants and ROS scavengers. Hepatocyte glutathione was also rapidly oxidized. Chromate reduction was inhibited in glutathione depleted hepatocytes, and glutathione depleted hepatocytes were also much more resistant to chromate induced cytotoxicity, ROS formation and lipid peroxidation. This suggests that chromate is reductively activated by glutathione. Chromate cytotoxicity also involved lysosomal injury and protease activation, which were prevented by lysosomotropic agents, endocytosis inhibitors, protease inhibitors and ROS scavengers. On the other hand, arsenite cytotoxicity was associated with much less oxidative stress, and lysosomal damage did not occur. However, arsenite cytotoxicity was also associated with loss of mitochondrial membrane potential, which in contrast to chromate cytotoxicity was inhibited by the ATP generators fructose, xylitol and glutamine. Arsenite induced cytotoxicity, mitochondrial membrane potential decline and also ROS formation were significantly increased by inactivating hepatocyte methionine synthase or hepatocyte methyl transferase. However, methyl donors such as betaine, methionine or folic acid prevented arsenite but not chromate cytotoxicity, and this suggests that arsenite is detoxified by reductive methylation. In conclusion, chromate induced cytotoxicity could be attributed to oxidative stress and lysosomal damage, whereas arsenite induced cytotoxicity could be attributed to mitochondrial toxicity and ATP depletion.     

Loss of one <Emphasis Type="Italic">Tgfbr2</Emphasis> allele in fibroblasts promotes metastasis in MMTV: polyoma middle T transgenic and transplant mouse models of mammary tumor progression

Accumulation of fibroblasts is a phenomenon that significantly correlates with formation of aggressive cancers. While studies have shown that the TGF-β signaling pathway is an important regulator of fibroblast activation, the functional contribution of TGF-β signaling in fibroblasts during multi-step tumor progression remains largely unclear. In previous studies, we used a sub-renal capsule transplantation model to demonstrate that homozygous knockout of the Tgfbr2 gene (Tgbr2^FspKO) enhanced mammary tumor growth and metastasis. Here, we show for the first time a significant role for loss of one Tgfbr2 allele during multi-step mammary tumor progression. Heterozygous deletion of Tgfbr2 in stromal cells in MMTV–PyVmT transgenic mice (PyVmT/Tgfbr2^hetFspKO mice) resulted in earlier tumor formation and increased stromal cell accumulation. In contrast to previous studies of Tgbr2^FspKO fibroblasts, Tgfbr2^hetFspKO fibroblasts did not significantly increase tumor growth, but enhanced lung metastasis in PyVmT transgenic mice and in co-transplantation studies with PyVmT mammary carcinoma cells. Furthermore, Tgfbr2^hetFspKO fibroblasts enhanced mammary carcinoma cell invasiveness associated with expression of inflammatory cytokines including CXCL12 and CCL2. Analyses of Tgbr2^FspKO and Tgfbr2^hetFspKO fibroblasts revealed differences in the expression of factors associated with metastatic spread, indicating potential differences in the mechanism of action between homozygous and heterozygous deletion of Tgfbr2 in stromal cells. In summary, these studies demonstrate for the first time that loss of one Tgfbr2 allele in fibroblasts enhances mammary metastases in a multi-step model of tumor progression, and demonstrate the importance of clarifying the functional contribution of genetic alterations in stromal cells in breast cancer progression.