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Ethnopharmacological Relevance: Stemona is a medicinal plant that has been used in China for thousands of years to treat respiratory diseases such as cough and tuberculosis. The tuberostemonine is the component of the Stemona tuberosa Lour., Stemona sessilifolia (Miq.) Miq. or Stemona japonica (Blume) Miq. (The plant name has been checked with http://www.theplantlist.org), of which multiple biological activities has been verified. However, whether it may alleviate pulmonary fibrosis via regulating ferroptosis mechanism has not been confirmed., Aim of the Study: The aim of this study is to observe whether tuberostemonine alleviates pulmonary fibrosis by enhancing the function of the SLC7A11/glutamate antiporter to restrain the ferroptosis., Materials and Methods: We validated the effects of tuberostemonine and ferroptosis on TGF-β1-induced proliferation of human lung fibroblast and bleomycin-induced pulmonary fibrosis in mice. In vitro, the ferroptosis effect of TGF-β1 on human lung fibroblast were examined and the activity of ɑ-SMA, collagen, hydroxyproline and ferrous ions in cells were also examined. In vivo, ferroptosis impacts respiratory function. Inflammatory manifestations, hydroxyproline, collagen activity and ferrous ions in the lung or blood were subject to evaluation., Results: Tuberostemonine significantly improved respiratory function in mice with bleomycin-induced pulmonary fibrosis, decreased cellular and lung hydroxyproline content, reduced inflammation and collagen deposition in cells and lung, and promoted an increase in the SLC7A11 and GPX4 proteins. Tuberostemonine inhibits the ferroptosis phenomenon, up-regulates SLC7A11, GPX4 and GSH, and down-regulates the accumulation of iron and ROS., Conclusions: Tuberostemonine significantly inhibited ferroptosis and improved pulmonary fibrosis both in vivo and vitro., Competing Interests: Declaration of competing interest There was no commercial or financial conduct associated with any potential conflict of interest in this study., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Unlike conventional antimicrobials, the study of bacterial resistance to silver nanoparticles (AgNPs) remains in its infancy and the mechanism(s) through which it evolves are limited and inconclusive. The central question remains whether bacterial resistance is driven by the AgNPs, released Ag(I) ions or a combination of these and other factors. Here, we show a specific resistance in an Escherichia coli K-12 MG1655 strain to subinhibitory concentrations of AgNPs, and not Ag(I) ions, as indicated by a statistically significant greater-than-twofold increase in the minimum inhibitory concentration occurring after eight repeated passages that was maintained after the AgNPs were removed and reintroduced. Whole-population genome sequencing identified a cusS mutation associated with the heritable resistance that possibly increased silver ion efflux. Finally, we rule out the effect of particle aggregation on resistance and suggest that the mechanism of resistance may be enhanced or mediated by flagellum-based motility., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Radioprotectors with few side effects are useful for carbon-ion therapy, which directly induces clustering damage in DNA. With the aim of finding the most effective radioprotector, we investigated the effects of selected amino acids which might have chemical DNA-repair functions against therapeutic carbon ions. In the current study, we employed five amino acids: tryptophan (Trp), cysteine (Cys), methionine (Met), valine (Val) and alanine (Ala). Samples of supercoiled pBR322 plasmid DNA with a 17 mM amino acid were prepared in TE buffer (10 mM Tris, 1 mM ethylenediaminetetraacetic acid, pH 7.5). Phosphate buffered saline (PBS) was also used in assays of the 0.17 mM amino acid. The samples were irradiated with carbon-ion beams (290 MeV/u) on 6 cm spread-out Bragg peak at the National Institute of Radiological Sciences and Heavy Ion Medical Accelerator in Chiba, Japan. Breaks in the DNA were detected as changes in the plasmids and quantified by subsequent electrophoresis on agarose gels. DNA damage yields and protection factors for each amino acid were calculated as ratios relative to reagent-free controls. Trp and Cys showed radioprotective effects against plasmid DNA damage induced by carbon-ion beam, both in PBS and TE buffer, comparable to those of Met. The double-strand break (DSB) yields and protective effects of Trp were comparable to those of Cys. The yields of both single-strand breaks and DSBs correlated with the scavenging capacity of hydroxyl radicals (rate constant for scavenging hydroxyl radicals multiplied by the amino acid concentration) in bulk solution. These data indicate that the radioprotective effects of amino acids against plasmid DNA damage induced by carbon ions could be explained primarily by the scavenging capacity of hydroxyl radicals. These findings suggest that some amino acids, such as Trp, Cys and Met, have good potential as radioprotectors for preventing DNA damage in normal tissues in carbon-ion therapy., (©2021 by Radiation Research Society. All rights of reproduction in any form reserved.)

The oral cavity is a complex environment that is constantly undergoing remodeling. This provides a favorable electrolytic aqueous condition, which causes the corrosion of titanium implants and the release of titanium (Ti) ions. The accumulation of Ti ions in the peri‑implant tissues may affect the osteogenesis process. Therefore, the present study aimed to investigate the possible effects of Ti ions on osteoblast physiology and its underlying mechanism, specifically the MAPK/JNK signaling pathway. In the present study, MC3T3‑E1 osteoblasts were cultured the medium containing 10 ppm Ti ions. Confocal laser scanning microscopy was used to analyze cell morphology and adhesion. Alkaline phosphatase (ALP) activity assay and western blotting were performed to evaluate the expression of proteins associated with osteogenesis such as Runx2 and Osterix. Nuclear translocation of JNK, a key factor of the MAPK signaling pathway, was visualized and analyzed using immunofluorescence staining. The results showed that 10 ppm Ti ions exerted negative effects on the biological behaviors of MC3T3‑E1 cells, which exhibited reduced adhesion, ALP activity and osteogenic differentiation. It was also found that 10 ppm Ti ions activated the MAPK/JNK signaling pathway by promoting the nuclear translocation of JNK via phosphorylation. In addition, the inhibitory effects of 10 ppm Ti ions on MC3T3‑E1 cells was found to be reversed by the JNK inhibitor SP600125. In conclusion, the preset study suggests that the MAPK/JNK signaling pathway serves a key role in the molecular mechanism underlying the changes in osteoblast behavior following Ti ion exposure. These findings may serve as a valuable reference point for the further in‑depth exploration of peri‑implant bone loss.

Purpose: Studies are required to determine whether exposures to radiation encountered during manned missions in deep space may have adverse effects on the cardiovascular system. Most of the prior studies on effects of simulated space radiation on the heart and vasculature have been performed in mouse models. To provide data from a second animal species, two studies were performed to assess effects of high-energy charged particle radiation on the heart and abdominal aorta in a rat model., Materials and Methods: In study A, male Long Evans rats were exposed to whole-body protons (250 MeV, 0.5 Gy) or oxygen ions ( 16 O, 600 MeV/n, 0.5 Gy), and ultrasonography was used to measure in vivo cardiac function and blood flow parameters at 3, 5, 9 and 12 months after radiation, followed by tissue collection at 12 months. In study B, male Long Evans rats were exposed to 16 O (1 GeV/n, 0.01-0.25 Gy), and hearts collected at 6 to 7 and 12 months for histology and western-blots., Results: Both protons (250 MeV) and 16 O (600 MeV/n) caused a decrease in left ventricular posterior wall thickness at 3-5 months, but did not change echocardiographic measures of cardiac function. In Pulsed-wave Doppler assessment of the abdominal aorta, an increase was seen in mean velocity, peak velocity, and velocity time integral at 12 months after 16 O (600 MeV/n), suggesting a change in vascular function. There were no significant changes in histopathology or histological quantification of total collagens in heart or aorta. On the other hand, an increase was seen in a 75 kDa peptide of collagen type III in the left ventricle of rats exposed to protons (250 MeV) and 16 O (600 MeV/n and 1 GeV/n), suggesting that radiation caused remodeling of existing collagens in the heart. 16 O (600 MeV/n and 1 GeV/n) caused increases in left ventricular protein levels of immune cell markers CD2, CD4, CD8, and CD68., Conclusion: A single low dose of whole body protons or 16 O in male Long Evans rats did not change cardiac function or induce gross pathological changes in the heart or aorta, but induced mild changes in vascular function and remodeling of existing collagens in the heart. Altogether, studies in prior mouse models and the current work in rats indicate minor changes in cardiac function and structure after a low dose of single-ion radiation., Competing Interests: Declaration of Competing Interests. The authors report no conflicts of interest., (Copyright © 2020 The Committee on Space Research (COSPAR). Published by Elsevier Ltd. All rights reserved.)

Objective: To evaluate the effect of titanium (Ti) particles and ions on oral biofilm growth and composition., Background: Particles and ions of Ti released from dental implants can trigger unfavorable biological responses in human cells. However, their effect on oral biofilms composition has not been tested., Methods: In this blind in situ study, volunteers wore a palatal appliance containing Ti disks for 7 days to allow biofilm formation. Disks were then collected and biofilms were treated, in vitro, with Ti particles (0.75% and 1%), ions (10 and 20 ppm), or a combination of both (1% particles + 20 ppm ions). Biofilms exposed only to medium was used as control group. After 24 hours, biofilms were collected and analyzed by checkerboard DNA-DNA hybridization. Direct effects of Ti particles and ions on biofilm/cellular morphology were evaluated by transmission electron microscopy (TEM)., Results: Ti particles affected biofilm composition, increasing population of four bacterial species (P < .05), while Ti ions showed higher levels of putative pathogens from the orange complex with reduction in species from the yellow complex (P < .05), compared with control. The combination of particles + ions increased green complex and reduced yellow complex proportions (P < .05). TEM showed clusters of particles agglomerated in extracellular environment, while Ti ions were precipitated in both extracellular and intracellular sites., Conclusions: Ti products, especially Ti ions, have the potential to change the microbiological composition of biofilms formed on Ti surfaces. Therefore, the presence of Ti products around dental implants may contribute to microbial dysbiosis and peri-implantitis., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Because of their biocide properties, silver nanoparticles (AgNPs) are present in numerous consumer products. The biocidal properties of AgNPs are due to both the interactions between AgNP and cell membranes and the release of dissolved silver (Ag + ). Recent studies emphasized the role of different nanoparticle coatings in complexing and storing Ag + . In this study, the availability of dissolved silver in the presence of algae was assessed for three AgNPs with different silver contents (59%, 34% and 7% of total Ag), silver core sizes and casein shell thicknesses. The impact of ionic silver on the photosynthetic yield of Chlamydomonas reinhardtii was used as a proxy to estimate the amount of ionic silver toxically active during in vivo assays. The results showed that cysteine, a strong silver ligand, mitigated the toxicity of AgNPs in all cases, demonstrating the key role of Ag + in this toxicity. The results showed that the AgNPs presenting an intermediate level of silver (34%) were 10 times more effective in terms of total mass (EC 50 ten times smaller) than those presenting more (59%) or less (7%) silver. The higher toxicity was due to the higher release of Ag + under biotic conditions due to the high surface/mass ratio of the nanoparticle silver core. Protein shells played a minor role in altering the availability of Ag + , probably acting as intermediate reservoirs. This study highlighted the utility of a very sensitive biological endpoint (i.e., algal photosynthesis) for the optimization of ionic silver delivery by nanomaterials., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: To review recent studies to better understand the risk of second cancer after ion beam radiotherapy and to clarify the importance of animal radiobiology therein. Results: Risk of developing second cancer after radiotherapy is a concern, particularly for survivors of childhood tumors. Ion beam radiotherapy is expected to reduce the risk of second cancer by reducing exposure of normal tissues to radiation. Large uncertainty lies, however, in the choice of relative biological effectiveness (RBE) of high linear energy transfer (LET) radiation (e.g. carbon ions and neutrons) in cancer induction, especially for children. Studies have attempted to predict the risk of second cancer after ion beam radiotherapy based on an assessment of radiation dose, the risk of low LET radiation, and assumptions about RBE. Animal experiments have yielded RBE values for selected tissues, radiation types, and age at the time of irradiation; the results indicate potentially variable RBE which depends on tissues, ages, and dose levels. Animal studies have also attempted to identify genetic alterations in tumors induced by high LET radiation. Conclusions: Estimating the RBE value for cancer induction is important for understanding the risk of second cancer after ion beam radiotherapy. More comprehensive animal radiobiology studies are needed.

Ions released from metal implants have been associated with adverse tissue reactions and are therefore a major concern. Studies with macrophages have shown that cobalt, chromium, and nickel ions can activate the NLRP3 inflammasome, a multiprotein complex responsible for the activation of caspase-1 (a proteolytic enzyme converting pro-interleukin [IL]-1β to mature IL-1β). However, the mechanism(s) of inflammasome activation by metal ions remain largely unknown. The objectives of the present study were to determine if, in macrophages: 1. caspase-1 activation and IL-1β release induced by metal ions are oxidative stress-dependent; and 2. IL-1β release induced by metal ions is NF-κB signaling pathway-dependent. Lipopolysaccharide (LPS)-primed murine bone marrow-derived macrophages (BMDM) were exposed to Co2+ (6-48 ppm), Cr3+ (100-500 ppm), or Ni2+ (12-96 ppm), in the presence or absence of a caspase-1 inhibitor (Z-WEHD-FMK), an antioxidant (L-ascorbic acid [L-AA]), or an NF-κB inhibitor (JSH-23). Culture supernatants were analyzed for caspase-1 by western blotting and/or IL-1β release by ELISA. Immunoblotting revealed the presence of caspase-1 (p20 subunit) in supernatants of BMDM incubated with Cr3+, but not with Ni2+ or Co2+. When L-AA (2 mM) was present with Cr3+, the caspase-1 p20 subunit was undetectable and IL-1β release decreased down to the level of the negative control, thereby demonstrating that caspase-1 activation and IL-1β release induced by Cr3+ was oxidative stress-dependent. ELISA demonstrated that Cr3+ induced the highest release of IL-1β, while Co2+ had no or limited effects. In the presence of Ni2+, the addition of L-AA (2 mM) also decreased IL-1β release, below the level of the negative control, suggesting that IL-1β release induced by Ni2+ was also oxidative stress-dependent. Finally, when present during both priming with LPS and activation with Cr3+, JSH-23 blocked IL-1β release, demonstrating NF-κB involvement. Overall, this study showed that while both Cr3+ and Ni2+ may be inducing inflammasome activation, Cr3+ is likely a more potent activator, acting through oxidative stress and the NF-κB signaling pathway., Competing Interests: The authors have declared that no competing interests exist.

Peri-implantitis is a destructive inflammatory process affecting tissues surrounding dental implants and it is considered a new global health concern. Human studies have suggested that the frequencies of Langerhans cells (LCs), the main antigen-presenting cells (APCs) of the oral epithelium, are dysregulated around the implants. Since LCs play a role in regulating oral mucosal homeostasis, we studied the impact of dental titanium implants on LC differentiation using a novel murine model. We demonstrate that whereas the percentage of LC precursors (CD11c + MHCII + ) increased in the peri-implant epithelium, the frequencies of LCs (CD11c + MHCII + EpCAM + langerin + ) were significantly reduced. Instead, a population of partially developed LCs expressing CD11c + MHCII + EpCAM + but not langerin evolved in the peri-implant mucosa, which was also accompanied by a considerable leukocyte infiltrate. In line with the increased levels of LC precursors, expression of CCL2 and CCL20, chemokines mediating their translocation to the epithelium, was elevated in the peri-implant epithelium. However, expression of TGF-β1, the major cytokine driving final differentiation of LCs, was reduced in the epithelium. Further analysis revealed that while the expression of the TGF-β1 canonical receptor activing-like kinase (ALK)5 was upregulated, expression of its non-canonical receptor ALK3 was decreased. Since titanium ions releasing from implants were proposed to alter APC function, we next analyzed the impact of such ions on TGF-β1-induced LC differentiation cultures. Concurring with the in vivo studies, the presence of titanium ions resulted in the generation of partially developed LCs that express CD11c + MHCII + EpCAM + but failed to upregulate langerin expression. Collectively, these findings suggest that titanium dental implants have the capacity to impair the development of oral LCs and might subsequently dysregulate immunity in the peri-implant mucosa.

Iron acquisition by bacteria is well studied, but iron export from bacteria is less understood. Herein, we identified dr1440 with a P-type ATPase motif as a potential exporter of iron from Deinococcus radiodurans, a bacterium known for its extreme resistance to radiation and oxidants. The DR1440 was located in cell membrane as demonstrated by fluorescence labelling analysis. Mutation of dr1440 resulted in cellular accumulation of iron ions, and expression level of dr1440 was up-regulated significantly under iron ion or hydrogen peroxide stress in the wild-type strain, implicating DR1440 as a potential iron efflux protein. The dr1440 mutant displayed higher sensitivity to iron ions and oxidative stresses including hydrogen peroxide, hypochlorous acid, and gamma-ray irradiation compared with the wild-type strain. The high amount of iron in the mutant strain resulted in severe protein carbonylation, suggesting that DR1440 might contribute to intracellular protein protection against reactive oxygen species (ROS) generated from ferrous ion-mediated Fenton-reaction. Mutations of S297A and C299A led to intracellular accumulation of iron, indicating that S297 and C299 might be important functional residues of DR1440. Thus, DR1440 is a potential iron efflux protein involved in iron homeostasis and oxidative stress-resistance of D. radiodurans., Competing Interests: The authors have declared that no competing interests exist.

Significance: Essential metals such as copper, iron, manganese, and zinc play a role as cofactors in the activity of a wide range of processes involved in cellular homeostasis and survival, as well as during organ and tissue development. Throughout our life span, humans are also exposed to xenobiotic metals from natural and anthropogenic sources, including aluminum, arsenic, cadmium, lead, and mercury. It is well recognized that alterations in the homeostasis of essential metals and an increased environmental/occupational exposure to xenobiotic metals are linked to several neurological disorders, including neurodegeneration and neurodevelopmental alterations. Recent Advances: The redox activity of essential metals is key for neuronal homeostasis and brain function. Alterations in redox homeostasis and signaling are central to the pathological consequences of dysfunctional metal ion homeostasis and increased exposure to xenobiotic metals. Both redox-active and redox-inactive metals trigger oxidative stress and damage in the central nervous system, and the exact mechanisms involved are starting to become delineated., Critical Issues: In this review, we aim to appraise the role of essential metals in determining the redox balance in the brain and the mechanisms by which alterations in the homeostasis of essential metals and exposure to xenobiotic metals disturb the cellular redox balance and signaling. We focus on recent literature regarding their transport, metabolism, and mechanisms of toxicity in neural systems., Future Directions: Delineating the specific mechanisms by which metals alter redox homeostasis is key to understand the pathological processes that convey chronic neuronal dysfunction in neurodegenerative and neurodevelopmental disorders. Antioxid. Redox Signal. 28, 1669-1703.

Objectives: The etiology of the reduced marginal bone loss observed around platform-switched implant-abutment connections is not clear but could be related to the release of variable amounts of corrosion products. The present study evaluated the effect of different concentrations of metal ions released from different implant abutment couples on osteoblastic cell viability, apoptosis and expression of genes related to bone resorption., Methods: Osteoblastic cells were exposed to five conditions of culture media prepared containing metal ions (titanium, aluminum, vanadium, cobalt, chromium and molybdenum) in different concentrations representing the amounts released from platform-matched and platform-switched implant-abutment couples as a result of an earlier accelerated corrosion experiment. Cell viability was evaluated over 21days using the Alamar Blue assay. Induction of apoptosis was measured after 24h of exposure using flow cytometry. Expression of interleukin-6, interleukin-8, cyclooxygenase-2, caspase-8, osteoprotegerin and receptor activator of nuclear factor kappa-B ligand (RANKL) by osteoblastic cells were analysed after exposure for 1, 3 and 21days using real-time quantitative polymerase chain reaction assay RESULTS: Metal ions in concentrations representing the platform-matched groups led to a reduction in cell viability (P<0.01) up to 7days of exposure. Stimulated cells showed higher rates of early apoptosis (P<0.01) compared to non-treated cells. Metal ions up-regulated the expression of interleukin-6, interleukin-8, cyclooxygenase-2 and RANKL in a dose dependent manner after 1day of exposure (P<0.05). The up-regulation was more pronounced in the groups containing the corrosion products of platform-matched implant-abutment couples., Conclusion: Osteoblastic cell viability, apoptosis, and regulation of bone resorbing mediators were significantly altered in the presence of metal ions. The change in cytokine levels expressed was directly proportional to the metal ion concentration., Clinical Significance: The observed biological responses to decreased amounts of metal ions released from platform-switched implant-abutment couples compared to platform-matched couples may partly explain the positive radiographic findings in respect to crestal bone level when utilising the "platform-switching" concept, which highlights the possible role of corrosion products in the mediation of crestal bone loss around dental implants., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: We aimed to assess the early outcome following revision arthroplasty for failed metal-on-metal (MoM) total hip replacements (THR) due to adverse reaction to metal debris (ARMD)., Methods: We reviewed 106 consecutive revision arthroplasties. Case notes and radiological investigations were reviewed to assess the complications. Oxford Hip Score (OHS) and Euroqol (EQ-5D-3L) scores were used to assess the functional outcome and improvement of quality of life., Results: At a mean follow-up of 20 months (12-48 months), the mean OHS was 28.7. Pain improved in 61% patients. A majority of patients were in level 2 for all the EQ-5D-3L dimensions. The overall complication rate was 16%. Survivorship free from further revision for any cause was 94.3% at 48 months. There was no correlation between pre-revision blood metal ions and the final outcome., Conclusions: Revision surgery for failed MoM hip replacement due to ARMD is associated with a relatively higher rate of complications and risk of chronic pain. There is poor correlation between serum metal ions and development of ARMD and outcome following revision surgery.

Background . Increased metal ion levels following total hip arthroplasty (THA) with metal-on-metal bearings are a highly debated topic. Local soft tissue reactions with chronic pain and systemic side effects such as neuropathy are described. The aim of the current study was to determine the serum metal ion concentrations of Cobalt (Co) and Chrome (Cr) after THA with a ceramic-on-metal (CoM) bearing. Patients and Methods . Between 2008 and 2010, 20 patients underwent THA using a CoM bearing. Clinical function was evaluated by standardized scores systems (Harris Hip Score and WOMAC Score) and radiological examination included X-rays. Patient's blood samples were obtained for metal ion analysis and correlation analysis was done between these results and implant position. Results . Overall, 13 patients with 14 CoM devices were available for the current series. The mean age at time of surgery was 61 years (range, 41 to 85). The postoperative follow-up ranged from 49 to 68 months (mean, 58). Metal ion determination showed mean concentrations of 3,1  µ g/L (range, 0,3-15,2  µ g/L) for Co and 1,6  µ g/L (range, 0,1-5,5  µ g/L) for Cr, respectively. A correlation between cup anteversion and Co and Cr concentrations was shown. Conclusion . The current series showed increments for Co and Cr following CoM THA. However, these levels are lower compared to metal ion concentrations in patients with metal-on-metal bearings and the international accepted threshold for revision of MoM devices. We recommend routine follow-up including at least one obligatory evaluation of serum metal ion concentrations and an MRI once to exclude local soft tissue reactions.

Aims: Proteomic analysis of serum biomarkers to determine liver toxicity after exposure to cosmic radiation has not been performed previously. This study was to identify serum biomarkers associated with hepatotoxicity following exposure to iron ion radiation., Main Methods: Male mice were whole-body irradiated with a 2grayunit (Gy) iron ion beam, and after 3months, serum and liver samples were collected. Two-dimensional electrophoresis (2-DE) was used to separate the identified serum proteins, and matrix-assisted laser desorption/ionization tandem mass spectrometry (MALDI-TOF-TOF) was performed to identify differentially expressed proteins. Enzyme-linked immunosorbent assays and immunoblotting were applied to evaluate protein expression, and immunohistochemistry and immunofluorescence were used to investigate protein localization. Real-time polymerase chain reaction (PCR) was performed to confirm altered gene expression., Key Findings: A total of 11 spots that showed differential expression were screened and identified as seven proteins. Of these, six proteins were in the same bioinformatics network and included complement component 3, serum amyloid P-component, apolipoprotein E, alpha-2-macroglobulin, fibrinogen alpha chain, and fibrinogen gamma chain. All of these proteins are synthesized by the liver, and may play an important role in liver toxicity. We also confirmed the mRNA transcription, and found that mRNA expression of the six identified proteins increased in the liver in irradiated mice., Significance: These results suggest that these proteins may be potential biomarkers of hepatotoxicity in astronauts enduring long space missions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

This study aims to synthesize, characterize and investigate the water solubility and cytotoxicity of branched anionic/cationic β-cyclodextrins (bβCDs) obtained by reaction with epichlorohydrin and chloroacetic acid or choline chloride, respectively, by a single step polycondensation reaction. Obtained ionic bβCDs were investigated as an attempt to comparatively study anionic and cationic bβCDs. Water solubility of both ionic derivatives was similar (400 mg/mL) at neutral and basic pHs and remarkably higher than that of their neutral homologues. Additionally, a pH-dependent solubility of anionic bβCDs was observed. Cytotoxicity of ionic bβCDs was evaluated on Human colon carcinoma Caco-2 cells and high cell viability (>99%) was observed in the range of 0-100 mg/mL for anionic and cationic samples, in the same range of that of neutral and parent β-CDs. Additionally, complexes formation capacity with triclosan, a poor water soluble antimicrobial agent, was confirmed by several techniques observing a complexation limit around 4 mg/mL for both systems and higher stability constant for anionic bβCDs than cationic derivatives., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Unlabelled: As adverse events related to metal on metal hip arthroplasty have been better understood, there has been increased interest in toxicity related to the high circulating levels of cobalt ions. However, distinguishing true toxicity from benign elevations in cobalt levels can be challenging. The purpose of this review is to examine the use of cobalt alloys in total hip arthroplasty, to review the methods of measuring circulating cobalt levels, to define a level of cobalt which is considered pathological and to review the pathophysiology, risk factors and treatment of cobalt toxicity. To the best of our knowledge, there are 18 published cases where cobalt metal ion toxicity has been attributed to the use of cobalt-chromium alloys in hip arthroplasty. Of these cases, the great majority reported systemic toxic reactions at serum cobalt levels more than 100 μg/L. This review highlights some of the clinical features of cobalt toxicity, with the goal that early awareness may decrease the risk factors for the development of cobalt toxicity and/or reduce its severity., Take Home Message: Severe adverse events can arise from the release of cobalt from metal-on-metal arthroplasties, and as such, orthopaedic surgeons should not only be aware of the presenting problems, but also have the knowledge to treat appropriately., (©2016 The British Editorial Society of Bone & Joint Surgery.)

Unlabelled: Recently, the use of metal-on-metal articulations in total hip arthroplasty (THA) has led to an increase in adverse events owing to local soft-tissue reactions from metal ions and wear debris. While the majority of these implants perform well, it has been increasingly recognised that a small proportion of patients may develop complications secondary to systemic cobalt toxicity when these implants fail. However, distinguishing true toxicity from benign elevations in cobalt ion levels can be challenging. The purpose of this two part series is to review the use of cobalt alloys in THA and to highlight the following related topics of interest: mechanisms of cobalt ion release and their measurement, definitions of pathological cobalt ion levels, and the pathophysiology, risk factors and treatment of cobalt toxicity. Historically, these metal-on-metal arthroplasties are composed of a chromium-cobalt articulation. The release of cobalt is due to the mechanical and oxidative stresses placed on the prosthetic joint. It exerts its pathological effects through direct cellular toxicity. This manuscript will highlight the pathophysiology of cobalt toxicity in patients with metal-on-metal hip arthroplasties., Take Home Message: Patients with new or evolving hip symptoms with a prior history of THA warrant orthopaedic surgical evaluation. Increased awareness of the range of systemic symptoms associated with cobalt toxicity, coupled with prompt orthopaedic intervention, may forestall the development of further complications., (©2016 The British Editorial Society of Bone & Joint Surgery.)

Since the beginning of the 20th century there has been a scientific debate about the potential effects of air ions on biological tissues, wellbeing and health. Effects on the cardiovascular and respiratory system as well as on mental health have been described. In recent years, there has been a renewed interest in this topic. In an experimental indoor setting we conducted a double-blind cross-over trial to determine if higher levels of air ions, generated by a special wall paint, affect cognitive performance, wellbeing, lung function, and cardiovascular function. Twenty healthy non-smoking volunteers (10 female, 10 male) participated in the study. Levels of air ions, volatile organic compounds and indoor climate factors were determined by standardized measurement procedures. Air ions affected the autonomous nervous system (in terms of an increase of sympathetic activity accompanied by a small decrease of vagal efferent activity): In the test room with higher levels of air ions (2194/cm³ vs. 1038/cm³) a significantly higher low to high frequency ratio of the electrocardiography (ECG) beat-to-beat interval spectrogram was found. Furthermore, six of nine subtests of a cognitive performance test were solved better, three of them statistically significant (verbal factor, reasoning, and perceptual speed), in the room with higher ion concentration. There was no influence of air ions on lung function and on wellbeing. Our results indicate slightly activating and cognitive performance enhancing effects of a short-term exposure to higher indoor air ion concentrations.

Although myeloid leukemia (ML) is one of the major health concerns from exposure to space radiation, the risk prediction for developing ML is unsatisfactory. To increase the reliability of predicting ML risk, a much improved understanding of space radiation-induced changes in the target cells, i.e. hematopoietic stem/progenitor cells (HSPCs), is important. We focused on the in vivo induction of late-occurring damage in HSPCs of mice exposed to (28)Si ions since such damage is associated with radiation-induced genomic instability (a key event of carcinogenesis). We gave adult male CBA/CaJ mice, known to be sensitive to radiation-induced ML, a whole-body exposure (2 fractionated exposures, 15 days apart, that totaled each selected dose, delivered at the dose-rate of 1 cGy/min) to various doses of 300 MeV/n (28)Si ions, i.e. 0 (sham controls), 0.1, 0.25, or 0.5 Gy. At 6 months post-irradiation, we collected bone marrow cells from each mouse (five mice per treatment-group) for obtaining the myeloid-lineage of HSPC-derived clones for analyses. We measured the frequencies of late-occurring chromosome aberrations (CAs), using the genome-wide multicolor fluorescence in situ hybridization method. The measurement of CAs was coupled with the characterization of the global DNA methylation patterns, i.e. 5-methylcytosine (5 mC) and 5-hydroxymethylcytosine (5 hmC). A dose-dependent increase in the frequencies of CAs was detected (Analysis of Variance or ANOVA, p<0.01), indicating the induction of genomic instability after exposure of mice to 300 MeV/n (28)Si ions. Slight increases in the levels of 5 mC were observed in all treatment groups, as compared to the sham-control level. In contrast, there was a significant reduction in levels of 5 hmC (ANOVA, p<0.01). Since these endpoints were evaluated in the same mouse, our data suggested for the first time a link between a reduction in 5 hmC and genomic instability in HSPC-derived myeloid colonies of CBA/CaJ mice exposed to 300 MeV/n (28)Si ions., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Autoimmune nephritis triggered by metallic ions was assessed in a Long-Evans rat model. The parameters evaluated included antinuclear autoantibody production, kidney damage mediated by immune complexes detected by immunofluorescence, and renal function tested by retention of nitrogen waste products and proteinuria. To accomplish our goal, the animals were treated with the following ionic metals: HgCl2, CuSO4, AgNO3, and Pb(NO3)2. A group without ionic metals was used as the control. The results of the present investigation demonstrated that metallic ions triggered antinuclear antibody production in 60% of animals, some of them with anti-DNA specificity. Furthermore, all animals treated with heavy metals developed toxic glomerulonephritis with immune complex deposition along the mesangium and membranes. These phenomena were accompanied by proteinuria and increased concentrations of urea. Based on these results, we conclude that metallic ions may induce experimental autoimmune nephritis.

Background: The vast majority of studies investigating gene delivery have utilized cationic delivery vehicles, but anionic nanoparticles can also possess high transfection activity, and offer significant benefits in terms of ease of preparation and reduced toxicity., Results: Our study on lipoplexes possessing cholesterol nanodomains demonstrates that in vitro transfection after exposure to serum can be high at anionic charge ratios, and that this effect is also evident in studies assessing delivery to tumors in vivo, despite reduced circulation times. In addition, accumulation in the liver and lungs is reduced as compared with lipoplexes formulated at cationic charge ratios., Conclusion: Lipoplexes prepared at anionic charge ratios offer comparable tumor delivery and reduced liver toxicity despite shorter circulation times.

Increased wear leads to elevated systemic and local metal ion concentrations for patients treated with metal-on-metal bearings. The local metal ion content in the close environment of the joint replacement (e.g. joint aspirate or tissue) is several times higher compared to the systemic metal content (e.g. in blood or serum). As a result of increased metal ion levels, local and systemic effects, such as osteolysis, pseudotumors, sensitization or in rare cases toxicity may occur. Although the definition of a specific threshold to define clinical problems is difficult due to a lack of sensitivity, the systemic metal concentration is frequently measured clinically. Currently a threshold for cobalt and chromium between 4 µg/l and 7 µg/l is under debate. Very high levels (≥ 20 µg/l) or a steady increase over time should be a warning sign; however, metal ion levels should not be interpreted as a single diagnostic tool but rather in the entire context of the clinical, radiological and cross-sectional imaging, metal artefact reduction sequence (MARS) magnetic resonance imaging (MRI), ultrasound and computed tomography (CT) findings.

The effects of salvianolic acid B (Sal B) decoction on antioxidative activities were evaluated. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity, Fe(2+)-chelating activity, reducing power, and total phenolic content of the Sal B-decocted solutions did not change significantly after decoction in an aqueous solution. However, the formation of cholesteryl ester hydroperoxide (CE-OOH) in rat blood plasma containing the Sal B-decocted solutions was more effectively inhibited than that of plasma containing the Sal B solution, regardless of the decoction time. In addition, the accumulation of CE-OOH in rat plasma after oral administration of the Sal B-decocted solutions was more effectively suppressed than when the Sal B solution was administered, considering the lag time. It is likely that the decoction was partly responsible for the increased antioxidant activity in blood plasma. Therefore, the Sal B-decocted solution may contribute more to antioxidant defense in blood than a Sal B solution that is not decocted.

Introduction: Over half of all active pharmaceutical ingredients currently approved for use in the USA are pharmaceutical salts. The safety assessment of a pharmaceutical salt provides additional challenges in addition to those encountered when assessing the safety of the free acid or base form of a new chemical entity (NCE). The addition of a counter ion may have an impact on pharmacokinetics, toxicity, impurity profile and potential route of administration., Areas Covered: In this review, the toxicologic profiles of commonly used counter ions and strategies for supporting the development of novel or alternate pharmaceutical salt forms are summarized. Furthermore, the article highlights the major concerns that may be encountered by the non-clinical toxicologist when considering a novel pharmaceutical salt., Expert Opinion: Given the large numbers of pharmaceutical salts approved for use in the USA, relatively little non-clinical toxicologic data are available for commonly used counter ions. This information gap leaves the non-clinical toxicologist with limited resources to assess the impact of a counter ion on the toxicologic program for an NCE. The data summarized in this review provide a starting point toward a more detailed understanding of counter ion-related effects on the toxicity of pharmaceutical salts.

Background: To report on establishment of workflow and clinical results of particle therapy at the Heidelberg Ion Therapy Center., Materials and Methods: We treated 36 pediatric patients (aged 21 or younger) with particle therapy at HIT. Median age was 12 years (range 2-21 years), five patients (14%) were younger than 5 years of age. Indications included pilocytic astrocytoma, parameningeal and orbital rhabdomyosarcoma, skull base and cervical chordoma, osteosarcoma and adenoid-cystic carcinoma (ACC), as well as one patient with an angiofibroma of the nasopharynx. For the treatment of small children, an anesthesia unit at HIT was established in cooperation with the Department of Anesthesiology., Results: Treatment concepts depended on tumor type, staging, age of the patient, as well as availability of specific study protocols. In all patients, particle radiotherapy was well tolerated and no interruptions due to toxicity had to be undertaken. During follow-up, only mild toxicites were observed. Only one patient died of tumor progression: Carbon ion radiotherapy was performed as an individual treatment approach in a child with a skull base recurrence of the previously irradiated rhabdomyosarcoma. Besides this patient, tumor recurrence was observed in two additional patients., Conclusion: Clinical protocols have been generated to evaluate the real potential of particle therapy, also with respect to carbon ions in distinct pediatric patient populations. The strong cooperation between the pediatric department and the department of radiation oncology enable an interdisciplinary treatment and stream-lined workflow and acceptance of the treatment for the patients and their parents.

The importance of nuclear interactions for ion therapy arises from the influence of the particle spectrum on, first, radiobiology and therefore also on treatment planning, second, the accuracy of measuring dose and, third, the delivered dose distribution. This study tries to determine the qualitative as well as the quantitative influence of the modeling of inelastic nuclear interactions on ion therapy. Thereby, three key disciplines are investigated, namely dose delivery, dose assessment and radiobiology. In order to perform a quantitative analysis, a relative comparison between six different descriptions of nuclear interactions is carried out for carbon ions. The particle transport is simulated with the Monte Carlo code SHIELD-HIT10A while dose planning and radiobiology are covered by the analytic treatment planning program for particles TRiP, which determines the relative biological effectiveness (RBE) with the local effect model. The obtained results show that the physical dose distribution can in principle be significantly influenced by the modeling of fragmentation (about 10% for a 20% change in all inelastic nuclear cross sections for a target volume ranging from 15 to 25 cm). While the impact of nuclear fragmentation on stopping power ratios can be neglected, the fluence correction factor may be influenced by the applied nuclear models. In contrast to the results for the physical dose, the variation of the RBE is only small (about 1% for a 20% change in all inelastic nuclear cross sections) suggesting a relatively weak dependence of radiobiology on the detailed composition of the particle energy spectrum of the mixed radiation field. Also, no significant change (about 0.2 mm) of the lateral penumbra of the RBE-weighted dose is observed.

This paper is devoted to the analysis of the complex damage of DNA irradiated by ions. The assessment of complex damage is important because cells in which it occurs are less likely to survive because the DNA repair mechanisms may not be sufficiently effective. We study the flux of secondary electrons through the surface of nucleosomes and calculate the radial dose and the distribution of clustered damage around the ion's path. The calculated radial dose distribution is compared to simulations. The radial distribution of the complex damage is found to be different from that of the dose. A comparison with experiments may solve the question of what is more lethal for the cell, damage complexity or absorbed energy. We suggest a way to calculate the probability of cell death based on the complexity of the damage. This work is done within the framework of the phenomenon-based multiscale approach to radiation damage by ions.

Cobalt-chromium (Co-Cr) alloy metal-on-metal hip resurfacing is increasingly common among younger more active patients suffering from osteoarthritis. Recent reports have increased awareness of metal ions leaching from metallic articulations; this ion exposure may have adverse effects on the immune system. As previous studies reported alterations in lymphocyte number and function in patients with Co-Cr implants, we investigated effects of clinically relevant concentrations of Cr(6+) and Co(2+) on primary human lymphocytes in vitro. Here, both resting and activated (anti-CD3 ± anti-CD28 antibodies) primary human lymphocytes were exposed to Cr(6+) or Co(2+) (0.1-100 µM). Following 24 or 48 h of exposure, cell viability, proliferation, cytokine [interferon-γ (IFNγ and interleukin-2 (IL-2)] release, and apoptosis (with and without pre-treatment of cells with a caspase-3 inhibitor) were assessed. Exposure to 10 and 100 µM Cr(6+) significantly decreased cell viability and increased apoptosis in both resting and activated lymphocytes. Cell proliferation and cytokine release were also significantly reduced in activated lymphocytes following exposure. The exposure of resting lymphocytes to 100 µM Co(2+) resulted in significant decreases in cell viability accompanied by a significant increase in apoptosis. Activated lymphocytes also showed this response after exposure to 100 µM Co(2+); in fact, activated cells were significantly more sensitive to Co(2+) toxicity. Exposure to 10 µM Co(2+) led to significant decreases in cell proliferation and cytokine release, but no significant increase in apoptosis, in activated cells. The results indicate that exposure to high concentrations of metal ions initiate apoptosis that results in decreased lymphocyte proliferation. IL-2 release is inhibited by both metal ions at concentrations that are not overtly toxic. However, metal ion concentrations not directly cytotoxic to lymphocytes may affect events at a molecular level, thereby impeding lymphocyte proliferation. Hence, this may contribute to altered immune system function in patients with Co-Cr implants.

Background: There is mounting evidence to suggest the involvement of the immune system by means of activation by metal ions released via biocorrosion, in the pathophysiologic mechanisms of aseptic loosening of orthopedic implants. However, the detailed mechanisms of how metal ions become antigenic and are presented to T-lymphocytes, in addition to how the local inflammatory response is driven, remain to be investigated., Methods: Human T-lymphocytes were cultured in the presence of a variety of metal ions before investigating functional and phenotypic changes using flow cytometric analysis. Additionally, human monocyte-derived dendritic cells (mDC) loaded with metal ions were used as antigen-presenting cells and incubated with naive T-lymphocytes with the aim of generating titanium-specific T-lymphocytes., Results: Using an autologous in vitro model, with mDC treated with Titanium (IV), we were able to induce Titanium (IV)-specific T-lymphocytes. These T-lymphocytes responded in a dose-related manner to Titanium (IV), while they did not cross-react with Titanium (III) or other metal ions, indicating that the new antigenic peptide complexes formed by Titanium (IV) are highly specific., Conclusion: This study showed that mDC exposed to Titanium (IV) are able to induce the generation of Titanium (IV)-specific T-lymphocytes, demonstrating the strong and specific antigenicity of Titanium (IV) ions released by biocorrosion.

In recent years there has been a resurgence of interest in the concept of hip resurfacing. Much of this interest has stemmed from the work of McMinn in the West Midlands. Hip resurfacing is now emerging as a viable alternative to conventional hip replacement. In this article, we discuss the conceptual advantages offered by hip resurfacing and review the early clinical results and the ongoing clinical concerns regarding this technology.

It was hypothesized that relative mass relationships among select constituent metals and iron (Fe3+) govern the pulmonary immunotoxic potential of any PM(2.5) sample, as these determine the extent to which Fe3+ binding by transferrin is affected (resulting in altered alveolar macrophage [AM] Fe status and subsequent antibacterial function). Iron response protein (IRP) binding activity is a useful indirect measurement of changes in Fe status, as reductions in cell Fe levels lead to increases in IRP binding. However, AM IRP activity can be affected by an increased presence of nitric oxide generated by inducible nitric oxide synthase (iNOS). This study sought to determine if any changes in AM IRP activity induced by PM(2.5) constituents V, Mn, or Al were independent from effects of the metals on cell NO formation. NR8383 rat AM were exposed to Fe3+ alone or combined with V, Mn, or Al at metal:Fe ratios representative of those in PM(2.5) collected in New York City, Los Angeles, and Seattle during fall 2001. Cells were then assessed for changes in IRP activity and iNOS expression. Phosphorylated extracellular signal-regulated kinase (ERK) 1 and 2 levels were also measured since activated ERKs are involved in signaling pathways that lead to increased iNOS expression. The results indicate that V and Al, and to a lesser extent Mn, altered IRP activity, though the effects were not consistently concentration dependent. Furthermore, while V and Mn treatments did not induce iNOS expression, Al did. These results confirmed our hypothesis that certain metals associated with PM(2.5) might alter the pulmonary immunocompetence of exposed hosts by affecting the Fe status of AM, a major class of deep lung defense cells.

Metal-on-metal (MOM) bearings offer extremely low wear and the avoidance of polyethylene but generate metallic wear particles. Although their total volume is dramatically smaller than polyethylene debris, these particles are in the nanometre size range and are many times more numerous. Metallic particles are ingested by macrophages or may be disseminated via lymphatics to the reticuloendothelial system. They corrode, and metal ions are present in the circulation and concentrated in erythrocytes. Excretion of metal ions via the kidneys seems to balance their generation in patients with MOM implants. However, highly sensitive detection methods can be used to show that levels of circulating cobalt and chromium ions are several times the normal level. These concentrations are well within the limits identified as dangerous to health in workers exposed to industrial chemicals, and also considerably lower than the levels found to cause cell toxicity in vitro. The local concentrations of particles and metal ions in the synovial tissue may occasionally exceed these limits and cause tissue necrosis. Clinical experience of lysis is rare in association with MOM bearings, as are hypersensitivity reactions and MOM bearings have had an excellent record over four decades and have a favourable benefit to risk ratio. Further reduction in risk will be achieved by improvement of materials, engineering, and accuracy of insertion.

The classical cytogenetic assay to estimate the dose to which an individual has been exposed relies on the measurement of chromosome aberrations in lymphocytes at the first post-irradiation mitosis 48 h after in vitro stimulation. However, evidence is accumulating that this protocol results in an underestimation of the cytogenetic effects of high LET radiation due to a selective delay of damaged cells. To address this issue, human lymphocytes were irradiated with C-ions (25-mm extended Bragg peak, LET: 60-85 keV/ micro m) and aberrations were measured in cells reaching the first mitosis after 48, 60, 72 and 84 h and in G2-phase cells collected after 48 h by calyculin A induced premature chromosome condensation (PCC). The results were compared with recently published data on the effects of X-rays and 200 MeV/u Fe-ions (LET: 440 keV/ micro m) on lymphocytes of the same donor (Ritter et al., 2002a). The experiments show clearly that the aberration yield rises in first-generation metaphase (M1) with culture time and that this effect increases with LET. Obviously, severely damaged cells suffer a prolonged arrest in G2. The mitotic delay has a profound effect on the RBE: RBE values estimated from the PCC data were about two times higher than those obtained by conventional metaphase analysis at 48 h. Altogether, these observations argue against the use of single sampling times to quantify high LET induced chromosomal damage in metaphase cells., (Copyright 2003 S. Karger AG, Basel)

Chromosome aberration formation was analysed in two human tumour cell lines displaying different radiosensitivity. Aberrations involving chromosomes 2, 4, and 5 were studied in one radioresistant cell line (WiDr) and in one radiosensitive cell line (MCF-7). Chromosome aberrations were studied by application of single-colour FISH. We studied the effects of monoenergetic 100 MeV/u carbon ions and carbon ions from extended Bragg peak. Chromosome aberrations induced by carbon ions were compared with aberrations induced by standard 200 kV X-rays. In both tumour cell lines, carbon ions induced aberrations more effectively than X-rays. The radioresistance and radiosensitivity of the corresponding cell lines, as observed for X-rays, were also found after carbon ion irradiation. In both cell lines, the typical effects of ion irradiation were an increased proportion of cells containing complex aberrations, and an increased complexity of these complex exchanges. However, comparable effects were induced in MCF-7 cells by a much lower dose than in WiDr cells. Insertions were also induced more efficiently in MCF-7 cells than in WiDr cells., (Copyright 2003 S. Karger AG, Basel)

Dense ionization tracks from high linear energy transfer (LET) radiations form multiple damaged sites (MDS), which involve several types of DNA lesions in close vicinity. The primary DNA damage triggers sensor proteins that activate repair processes, cell cycle control or eventually apoptosis in subsequent cellular responses. The question how homologous recombination (HR) and non-homologous end joining (NHEJ) interact in the repair of radiation-induced DNA damage of MDS type has been addressed in different model systems but several questions remain to be answered. We have therefore challenged cells with treatments of ionizing radiation of different qualities to investigate whether primary DNA damages of different complexity are reflected in the processes of repair by HR as well as cell survival. We used the V79 derived SPD8 cell line to determine the induction of HR in the hprt exon 7 and clonogenic assay for survival in response to radiation. SPD8 cells were irradiated with gamma-rays (137Cs 0.5 keV/microm), boron ions (40 and 80 keV/microm) and nitrogen ions (140 keV/microm), with doses up to 5 Gy. Analysis of clonogenic survival showed that B-ions (80 keV/microm) and N-ions were more toxic than gamma-rays, 4.1 and 5.0 times respectively, while B-ions at 40 keV/microm were 2.0 times as toxic as gamma-rays. Homologous recombination in the cells exposed to B-ions (80 keV/microm) increased 2.9 times, a significant response as compared to cells exposed to gamma-rays, while for B-ions (40 keV/microm) and N-ions a nonsignificant increase in HR of 1.2 and 1.4, respectively, was observed. We hypothesize that the high-LET generated formation of MDS is responsible for the enhanced cytotoxicity as well as for the mobilization of the HR machinery., (Copyright 2003 S. Karger AG, Basel)

We describe a peculiar and relatively rare type of chromosomal rearrangement induced in human peripheral lymphocytes that were ostensibly irradiated in G(0) phase of the cell cycle by accelerated heavy ions, and which, to the best of our knowledge, have not been previously described. The novel rearrangements which were detected using mFISH following exposure to 500 MeV/nucleon and 5 GeV/n 56Fe particles, but were not induced by either 137Cs gamma rays or 238Pu alpha particles, can alternatively be described as either complex chromatid-isochromatid or complex chromatid-chromosome exchanges. Different mechanisms potentially responsible for their formation are discussed., (Copyright 2003 S. Karger AG, Basel)

It has been suggested that the ratio complex/simple exchanges can be used as a biomarker of exposure to high-LET radiation. We tested this hypothesis in vivo, by considering data from several studies that measured complex exchanges in peripheral blood from humans exposed to mixed fields of low- and high-LET radiation. In particular, we studied data from astronauts involved in long-term missions in low-Earth-orbit, and uterus cancer patients treated with accelerated carbon ions. Data from two studies of chromosomal aberrations in astronauts used blood samples obtained before and after space flight, and a third study used blood samples from patients before and after radiotherapy course. Similar methods were used in each study, where lymphocytes were stimulated to grow in vitro, and collected after incubation in either colcemid or calyculin A. Slides were painted with whole-chromosome DNA fluorescent probes (FISH), and complex and simple chromosome exchanges in the painted genome were classified separately. Complex-type exchanges were observed at low frequencies in control subjects, and in our test subjects before the treatment. No statistically significant increase in the yield of complex-type exchanges was induced by the space flight. Radiation therapy induced a high fraction of complex exchanges, but no significant differences could be detected between patients treated with accelerated carbon ions or X-rays. Complex chromosomal rearrangements do not represent a practical biomarker of radiation quality in our test subjects., (Copyright 2003 S. Karger AG, Basel)

Background: Changes in weather and season have been linked to stroke occurrence. However, the association has been inconsistent across stroke types. Calgary is a city in the Chinook belt and is subject to high variability in weather conditions., Methods: We obtained hourly weather data over a 5-year period from 1996 to 2000; Chinook events were identified according to the accepted definition. We reviewed administrative data to determine stroke occurrence and defined stroke types to maximize specificity of diagnosis. To examine the hypothesis that weather affected the number of strokes occurring in a given day, we compared average daily stroke occurrence on Chinook days and non-Chinook days; we compared mean daily temperature, relative humidity, barometric pressure, and wind speed by the number of strokes occurring on any given day., Results: Annual variation in stroke frequency was observed. No seasonal, monthly, or weekly variation in overall stroke occurrence or occurrence by type was evident. No relationship with changes in weather parameters was observed., Conclusions: We found no association between weather changes and stroke occurrence. A cause-and-effect relationship between weather and stroke occurrence is dubious because of a lack of consistency across studies.

Homage to the scientific work of Franz Halberg is inevitably connected with the development and importance of chronobiology and its applications in chronomedicine. We show that nonlinear reaction-diffusion systems with feedsideward coupling give rise to oscillations between different limit cycles favoring either inhibition or stimulation of the growth or decay of a component. The inclusion of the diffusion part of each concentration distribution offers the possibility of also taking into account the interaction of charged constituents with external magnetic fields. Concentration oscillations between different limit cycles of the constituents can thus be stabilized. It is assumed that the z-component of the external magnetic field is related to the rather weak solar magnetic field (ca. 10(-9) Tesla). Periods of about one week result for some positive (Mg2+, Ca2+, K+) and negative (e.g. Cl-) ions and some organic acids containing phosphates. The resonance time of a free proton H+ determining the oscillations of the pH-value is about 1 day and that of OH1 is about 3.5 days (half a week). The influence of the geomagnetic field (x- or y-component) in the same range is of a few to ca. 20-30 minutes in the case of charged proteins. An essential condition for this separation is that in general the geomagnetic field does not coincide with the z-component of the solar magnetic field. As an example, the role of the timedependence of the growth and ATP-concentration of the irradiation of the tumor spheroid C3H-MA (mammary adenocarcinoma of mice) is presented.

A novel poly(vinyl chloride) membrane electrode with dibutyl phthalate as plasticizer based on the pethidine-tetraphenylborate ion-association complex as ion-exchange site for the determination of pethidine hydrochloride in injections and tablets was developed. A linear response for 1 x 10(-5) to 1 x 10(-2) mol/L drug with a slope of 51.77 mV/decade was established. The optimum pH range was 2-8. The lower detection limit was 2.18 x 10(-6) mol/L. There were negligible interferences from a number of inorganic and organic cations and some common drug excipients. The electrode proposed had been successfully applied to determine pethidine hydrochloride in tablets and injections. The results correlated well with those obtained by the United States Pharmacopoeia standard procedure.

In this study 67 workmen exposed to ions of heavy metals have been investigated because of their fertility. Concentrations of the noxious substances and their metabolites in blood and urine have been estimated and spermiograms were performed. The investigations demonstrated that a correlation exists between the concentrations of noxious substances in the place of employment, in the blood, and in the ejaculate, besides of zinc. An increased number of pathological spermiograms could be established especially in cases with an exceed of maximum permitted concentrations in the place of employment.